Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage.

Language：English   Publishing type：Research paper (scientific journal)  

Mutated gene-specific phenotypes of dinucletide repeat instability in human colorectal carcinoma cell lines defiecient in DNA mismatch repair

DOI： 10.1038/sj.onc.1202583

Language：English   Publishing type：Research paper (scientific journal)  

Precise assessment of microsatellite instability using high resolution fluorescent microsatellite analysis

DOI： 10.1093/nar/25.17.3415

Language：English   Publisher：International Journal of Surgery Case Reports  

Introduction and importance: Brunner's gland hamartoma is a rare benign duodenal tumor. Resection is recommended for large or symptomatic lesions, but conventional pancreaticoduodenectomy and other procedures can be overly invasive for the lesion. We report a case of Brunner's gland hamartoma resected using laparoscopic and endoscopic cooperative surgery (LECS). Case presentation: A 51-year-old woman was referred to our hospital with an asymptomatic duodenal tumor that had increased in size. A submucosal tumor was found on the anterior wall of the duodenal bulb during a detailed examination, and surgery was performed because the tumor was large (2 cm). In order to optimally resect the tumor, duodenal LECS (D-LECS) was selected. The resection line was determined while checking the base of the lesion with an intraoperative endoscope, and after the lesion was resected, the mucosal defect was closed using laparoscopic manipulation. Histopathological evaluation revealed Brunner's gland hyperplasia and mixed smooth muscle bundles, and the lesion was diagnosed as a Brunner's gland hamartoma. The surgery was completed without any problems, and the patient made a full recovery after the surgery with no complications such as stenosis, and no recurrence was observed. Clinical discussion: With D-LECS, the lesion can be resected without excess or deficiency, and the incision can be sutured with minimal invasiveness. D-LECS is an effective method as a treatment option for Brunner's gland hamartoma. Conclusion: We herein report a case of Brunner's gland hamartoma treated safely with a minimally invasive surgical technique: D-LECS.

DOI： 10.1016/j.ijscr.2024.110617

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Publisher：Discover Artificial Intelligence  

Generalizability of AI colonoscopy algorithms is important for wider adoption in clinical practice. However, current techniques for evaluating performance on unseen data require expensive and time-intensive labels. We show that a "Masked Siamese Network" (MSN), trained to predict masked out regions of polyp images without labels, can predict the performance of Computer Aided Detection (CADe) of polyps on colonoscopies, without labels. This holds on Japanese colonoscopies even when MSN is only trained on Israeli colonoscopies, which differ in scoping hardware, endoscope software, screening guidelines, bowel preparation, patient demographics, and the use of techniques such as narrow-band imaging (NBI) and chromoendoscopy (CE). Since our technique uses neither colonoscopy-specific information nor labels, it has the potential to apply to more medical imaging domains.

DOI： 10.1007/s44163-024-00187-4

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Language：English  

DOI： 10.1007/s10147-024-02666-1

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Language：English  

DOI： 10.1158/1078-0432.CCR-24-2396

PubMed

Language：English  

DOI： 10.1186/s40792-024-02033-2

PubMed

Language：English   Publisher：Asian Journal of Endoscopic Surgery  

Introduction: This study aimed to clarify the validity of laparoscopic surgery for lower gastrointestinal perforation by comparing the clinical outcomes of laparoscopic and open emergency surgery. Methods: We reviewed the data of patients who underwent surgery for lower gastrointestinal perforation. Patients were categorized into two groups: the laparoscopic group who underwent laparoscopic surgery, and the open group who underwent laparotomy. Clinical and operative outcomes between the two groups were evaluated. Results: A total of 219 patients were included in the study. There were 66 and 153 patients with small bowel and colorectal perforations, respectively. The median operative time in the laparoscopic group was shorter than that in the open group (126 min vs. 146 min, p =.049). The mean amount of intraoperative blood loss was significantly lower in the laparoscopic group (50.4 mL vs. 400.1 mL, p <.001). The incidence of postoperative complication was higher in the open group (20.0% vs. 66.5%, p <.001), especially wound infection (0% vs. 26.3%, p =.002). Median hospital stays were 14 days and 24 days in the laparoscopic and open groups, respectively (p <.001). In the laparoscopic group, hospital mortality was 0%. Conclusions: The laparoscopic approach for small bowel and colorectal perforation in an emergency setting is a safe procedure in carefully selected patients and may contribute to decreased intraoperative blood loss, shortened hospital stay, and decreased incidence of postoperative complications, especially wound infection.

DOI： 10.1111/ases.13373

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Language：Japanese  

PubMed

Language：English   Publisher：Annals of Oncology  

Background: The prognostic role of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection and its utility for postsurgical risk stratification has been reported in colorectal cancer. In this study, we explored the use of ctDNA-based MRD detection in patients with colorectal liver metastases (CLM), for whom the survival benefit of adjuvant chemotherapy (ACT) after surgical resection remains unclear. Methods: Patients with CLM without extrahepatic disease from the GALAXY study (UMIN000039205) were included. The disease-free survival (DFS) benefit of ACT was evaluated in MRD-positive and -negative groups after adjusting for age, gender, number, and size of liver metastases, RAS status, and previous history of oxaliplatin for primary cancer. ctDNA was detected using a personalized, tumor-informed 16-plex polymerase chain reaction-next-generation sequencing (mPCR-NGS) assay. ctDNA-based MRD status was evaluated 2-10 weeks after curative surgery, before the start of ACT. Results: Among 6061 patients registered in GALAXY, 190 surgically resected CLM patients without any preoperative chemotherapy were included with a median follow-up of 24 months (1-48 months). ctDNA positivity in the MRD window was 32.1% (61/190). ACT was administered to 25.1% (48/190) of patients. In the MRD-positive group, 24-month DFS was higher for patients treated with ACT [33.3% versus not reached, adjusted hazard ratio (HR): 0.07, P < 0.0001]; whereas no benefit of ACT was seen in the MRD-negative group (24-month DFS: 72.3% versus 62.2%, adjusted HR: 0.68, P = 0.371). Multivariate analysis showed that the size of liver metastases (HR: 3.94, P = 0.031) was prognostic of DFS in the MRD-positive group. In the MRD-negative group, however, none of the clinicopathological factors were prognostic of DFS. Conclusions: Our data suggest that ACT may offer notable clinical benefits in MRD-positive patients with CLM. MRD status-based risk stratification could be potentially incorporated in future clinical trials for CLM.

DOI： 10.1016/j.annonc.2024.08.2240

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Language：English   Publisher：Surgery Today  

Purpose: We aimed to define borderline resectable colorectal liver metastases (CRLM) based on the analysis of risk factors for early surgical failure and investigate the efficacy of neoadjuvant chemotherapy in these patients. Methods: This was a retrospective analysis of a multi-institutional cohort of patients diagnosed with technically resectable CRLM. Early surgical failure within 6 months of liver surgery was defined as ESF6. We classified CRLM into three grades (A, B, and C) according to the definition of the Japanese Society for Cancer of the Colon and Rectum. Results: Among the 249 patients with technically resectable CRLM, 46 (18.5%) developed ESF6. The survival rate of these patients was significantly lower than that of the patients without ESF6. In the multivariate analysis of synchronous CRLM patients, no neoadjuvant chemotherapy, Grade B/C, and Charlson comorbidity index ≥ 3 were independent predictors of ESF6. Among patients with synchronous and Grade B/C CRLM, ESF6 rates, surgical failure-free survival, and overall survival in the neoadjuvant chemotherapy group were significantly better relative to the upfront surgery group. Conclusions: Patients with synchronous and Grade B/C CRLM are at a high risk of early surgical failure, have a poor long-term prognosis, and can be defined as borderline resectable and good candidates for neoadjuvant chemotherapy.

DOI： 10.1007/s00595-024-02920-z

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Publisher：日本メディカルセンター  

DOI： 10.19020/cg.0000003178

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Language：English   Publisher：Clinical Cancer Research  

Purpose: Posttreatment detection of ctDNA is strongly predictive of recurrence. Most minimal/molecular residual disease assays require prior tissue testing to guide ctDNA analysis, resulting in lengthy time to initial results and unevaluable patients. Experimental Design: We assessed a tissue-free assay (Guardant Reveal) that bioinformatically evaluates >20,000 epigenomic regions for ctDNA detection in 1,977 longitudinally collected postoperative plasma samples from 342 patients with resected colorectal cancer. Results: We observed sensitive and specific detection of minimal/ molecular residual disease associated with clinically meaningful differences in recurrence-free intervals at each time point evaluated with a median lead time of 5.3 months. The longitudinal sensitivity in stage II or higher colon cancer was 81%. Sensitivity increased with serial measurement and varied by recurrence site: higher for liver (100%) versus lung (53%) and peritoneal (40%). Sensitivity among patients with rectal cancer was 60% owing to a high proportion of lung metastases. Specificity was 98.2% among 1,461 posttreatment samples (99.1% among those with follow-up longer than the upper IQR of the lead time observed in this study). Conclusions: Our data demonstrate the potential clinical utility of ctDNA as a tool to improve the management of stage II and higher colorectal cancer with a methodology that is noninvasive, accessible, and allows for rapid evaluation to inform clinical decisions.

DOI： 10.1158/1078-0432.CCR-24-1651

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Language：English   Publisher：Annals of Gastroenterological Surgery  

Aim: To evaluate the feasibility and safety of total neoadjuvant therapy with long-course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer. Methods: This prospective, multicenter, single-arm, phase II trial was conducted at 10 centers. The eligibility criteria included age ≥20 y, locally advanced rectal cancer within 12 cm of the anal verge, and cT3-4N0M or TanyN+M0 at diagnosis, enabling curative resection. The protocol treatment was capecitabine (1650 mg/m2/day)-based long-course chemoradiotherapy (50.4 Gy/28 fractions) and consolidation chemotherapy (CAPOX, four courses) followed by total mesorectal excision. Nonoperative management was allowed if a clinical complete response was achieved. The primary endpoint was the pathologic complete response rate. Results: Among 28 enrolled patients (19 men, 9 women; median age, 69.5 [41–79] y), the long-course chemoradiotherapy and consolidation chemotherapy completion rates were 100% and 96.4%, respectively. The clinical responses included clinical complete response, (35.7%, 10/28), near-complete response (28.6%, 8/28), and incomplete response (32.1%, 9/28). Total mesorectal excision and nonoperative management were performed in 21 and six patients, respectively. The final analysis included 21 patients. Five patients (23.8% [90% confidence interval 11.8%–41.8%]) achieved pathologic complete response, while 10 of 28 patients (35.7%) achieved a pathological complete response or a sustained clinical complete response. No treatment-related deaths occurred. Grade ≥3 adverse events included diarrhea (7.1%) and leukopenia (7.1%). Conclusion: ENSEMBLE-2 demonstrated comparable pathologic complete response rates and well-tolerated safety of total neoadjuvant therapy with long-course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer.

DOI： 10.1002/ags3.12848

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Language：English   Publisher：Surgery Today  

Telesurgery is expected to improve medical access in areas with limited resources, facilitate the rapid dissemination of new surgical procedures, and advance surgical education. While previously hindered by communication delays and costs, recent advancements in information technology and the emergence of new surgical robots have created an environment conducive to societal implementation. In Japan, the legal framework established in 2019 allows for remote surgical support under the supervision of an actual surgeon. The Japan Surgical Society led a collaborative effort, involving various stakeholders, to conduct social verification experiments using telesurgery, resulting in the development of a Japanese version of the “Telesurgery Guidelines” in June 2022. These guidelines outline requirements for medical teams, communication environments, robotic systems, and security measures for communication lines, as well as responsibility allocation, cost burden, and the handling of adverse events during telesurgery. In addition, they address telementoring and full telesurgery. The guidelines are expected to be revised as needed, based on the utilization of telesurgery, advancements in surgical robots, and improvements in information technology.

DOI： 10.1007/s00595-024-02863-5

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Language：English  

DOI： 10.1038/s44276-024-00073-7

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1407214592

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Language：English   Publisher：Gastric Cancer  

Background: The significance of reinforcement of the duodenal stump with seromuscular sutures and the effectiveness of reinforced staplers in preventing duodenal stump leakage remain unclear. We aimed to explore the importance of duodenal stump reinforcement and determine the optimal reinforcement method for preventing duodenal stump leakage. Methods: This retrospective cohort study was conducted between January 1, 2012 and December 31, 2021, with data analyzed between December 1, 2022 and September 30, 2023. This multicenter study across 57 institutes in Japan included 16,475 patients with gastric cancer who underwent radical gastrectomies. Elective open or minimally invasive (laparoscopic or robotic) gastrectomy was performed in patients with gastric cancer. Results: Duodenal stump leakage occurred in 153 (0.93%) of 16,475 patients. The proportions of males, patients aged ≥ 75 years, and ≥ pN1 were higher in patients with duodenal stump leakage than in those without duodenal stump leakage. The incidence of duodenal stump leakage was significantly lower in the group treated with reinforcement by seromuscular sutures or using reinforced stapler than in the group without reinforcement (0.72% vs. 1.19%, p = 0.002). Duodenal stump leakage incidence was also significantly lower in high-volume institutions than in low-volume institutions (0.70% vs. 1.65%, p = 0.047). The rate of duodenal stump leakage-related mortality was 7.8% (12/153). In the multivariate analysis, preoperative asthma and duodenal invasion were identified as independent preoperative risk factors for duodenal stump leakage-related mortality. Conclusions: The duodenal stump should be reinforced to prevent duodenal stump leakage after radical gastrectomy in patients with gastric cancer.

DOI： 10.1007/s10120-024-01538-x

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Language：English   Publisher：Cancer Discovery  

The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence–driven multiomics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease–based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% have participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% CI, 13.4–16.3) for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71–0.83). Significance: Our nationwide molecular profiling initiative played pivotal roles in facilitating the enrollment of patients with advanced solid tumors into matched clinical trials and highlighted the substantial survival benefits of patients treated with matched therapy. We aim to facilitate an industry–academia data-sharing infrastructure ecosystem, fostering new drug discovery paradigms and precision medicine.

DOI： 10.1158/2159-8290.CD-24-0206

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Language：English   Publisher：Cell Death Discovery  

The fluorinated thymidine analog trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD-induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD-induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage responses during the G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of the p53 function.

DOI： 10.1038/s41420-024-02083-3

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Language：English   Publisher：Oxford University Press  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Open Science  

BACKGROUND: Evidence regarding the application of the multispectral camera for blood flow measurement is insufficient, and its performance has not been compared with the conventional indocyanine green (ICG) method. Therefore, we retrospectively compared the effectiveness of a new multispectral camera for non-invasive, real-time, quantitative imaging of tissue oxygen (O2) saturation and hemoglobin (Hb) levels and commercially available ICG fluorescence imaging in hemodynamic assessment of gastric tubes in esophagectomy. METHODS: Thirty patients who underwent thoracoscopic esophagectomy and gastric tube reconstruction for esophageal cancer were included in this study. The multispectral camera was used to measure tissue O2 saturation and Hb levels. The ICG fluorescence imaging, with the analysis software tool Lumi view, was employed to record ICG luminance changes, with values measured at the anastomotic site. Furthermore, the usefulness of each assessment device was examined using the arterial and venous blood flow indices as cutoff lines for cases with anastomotic failure. RESULTS: In the evaluation of arterial perfusion, anastomotic leak occurred in three of the five (60 %) patients with arterial insufficiency as assessed by the ICG imaging, while anastomotic leakage occurred in all three patients (100 %) who were assessed as having arterial insufficiency by the multispectral camera. In the evaluation of venous perfusion, anastomotic leakage occurred in three of the nine (33.3 %) patients diagnosed with venous stasis by the IC imaging and in three of the five (60 %) patients assessed by the multispectral camera. CONCLUSION: The multispectral camera assessed gastric tube blood flow more accurately than the ICG fluorescence method.

DOI： 10.1016/j.sopen.2024.03.005

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Language：Japanese   Publisher：日本大腸検査学会  

隆起型早期大腸癌は内視鏡での深達度診断が難しい場合がある。本研究ではCT colonography(CTC)の側面像に着目し、粘膜内癌(M癌)と粘膜下層癌(SM癌)の鑑別が可能かを検証した。2名の放射線科医による読影で、SM癌の診断の感度は63.6%、100.0%、特異度は77.8%、66.7%であった。本法は、早期大腸癌の深達度診断における補助的な診断法として有用であると考えられる。(著者抄録)

Language：English   Publisher：Anticancer Research  

Background/Aim: Osteopenia, the loss of bone mineral density (BMD), was recently reported as a prognostic factor in various cancers. However, the prognostic significance of preoperative osteopenia in breast cancer remains unclear. This study aimed to clarify the clinical significance of preoperative osteopenia in breast cancer. Patients and Methods: We retrospectively analyzed the relationship between osteopenia and clinical factors and prognosis in 532 patients with pathological Stage I-III primary breast cancer between 2009 and 2017. Osteopenia was assessed by measuring the average pixel density (Hounsfield unit) in the midvertebral core of the 11th thoracic vertebra on enhanced preoperative computed tomography. Results: Osteopenia was diagnosed in 186 (35.0%) patients. The recurrence-free survival (RFS) rate was significantly worse in the osteopenia group than in the non-osteopenia group (p=0.0275), but there was no significant difference in overall survival (OS) between the two groups. When evaluated by menopausal status, RFS and OS were significantly worse in the osteopenia group than in the non-osteopenia group (p=0.0094 and p=0.0264, respectively) in premenopausal patients. However, there were no significant differences in RFS and OS between the two groups among postmenopausal patients. In premenopausal patients, osteopenia was an independent prognostic factor for RFS in a multivariate analysis (p=0.0266). Conclusion: Preoperative osteopenia was independently associated with recurrence of breast cancer.

DOI： 10.21873/anticanres.17074

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

Circulating tumor DNA (ctDNA) is the fraction of cell-free DNA in patient blood that originates from a tumor. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumors have increased interest in exploiting ctDNA to facilitate detection of molecular residual disease (MRD). Analysis of ctDNA as a promising MRD biomarker of solid malignancies has a central role in precision medicine initiatives exemplified by our CIRCULATE-Japan project involving patients with resectable colorectal cancer. Notably, the project underscores the prognostic significance of the ctDNA status at 4 weeks post-surgery and its correlation to adjuvant therapy efficacy at interim analysis. This substantiates the hypothesis that MRD is a critical prognostic indicator of relapse in patients with colorectal cancer. Despite remarkable advancements, challenges endure, primarily attributable to the exceedingly low ctDNA concentration in peripheral blood, particularly in scenarios involving low tumor shedding and the intrinsic error rates of current sequencing technologies. These complications necessitate more sensitive and sophisticated assays to verify the clinical utility of MRD across all solid tumors. Whole genome sequencing (WGS)-based tumor-informed MRD assays have recently demonstrated the ability to detect ctDNA in the parts-per-million range. This review delineates the current landscape of MRD assays, highlighting WGS-based approaches as the forefront technique in ctDNA analysis. Additionally, it introduces our upcoming endeavor, WGS-based pan-cancer MRD detection via ctDNA, in our forthcoming project, SCRUM-Japan MONSTAR-SCREEN-3.

DOI： 10.1007/s10147-024-02493-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Gastric Cancer  

BACKGROUND: In gastric solid-type poorly differentiated adenocarcinoma (PDA), the role of microsatellite instability and immune escape mechanism remains unclear. The current study aimed to elucidate the clinical significance of mismatch repair (MMR) status, genome profile, C-X-C motif chemokine receptor 2 (CXCR2) expression, and myeloid-derived suppressor cell (MDSC) infiltration in solid-type PDA. METHODS: In total, 102 primary solid-type PDA cases were retrieved, and classified into 46 deficient-MMR (dMMR) and 56 proficient-MMR (pMMR) cases based on immunohistochemistry (IHC) and polymerase chain reaction-based molecular testing results. The mRNA expression profiles (NanoString nCounter Assay) of stage-matched dMMR (n = 6) and pMMR (n = 6) cases were examined. The CXCR2 expression and MDSC infiltration (CD11b- and CD33-positive cells) were investigated via IHC in all solid-type PDA cases. RESULTS: mRNA analysis revealed several differentially expressed genes and differences in biological behavior between the dMMR (n = 46) and pMMR (n = 56) groups. In the multivariate analysis, the dMMR status was significantly associated with a longer disease-free survival (hazard ratio = 5.152, p = 0.002) and overall survival (OS) (hazard ratio = 5.050, p = 0.005). CXCR2-high expression was significantly correlated with a shorter OS in the dMMR group (p = 0.018). A high infiltration of CD11b- and CD33-positive cells was significantly correlated with a shorter OS in the pMMR group (p = 0.022, 0.016, respectively). CONCLUSIONS: dMMR status can be a useful prognostic predictor, and CXCR2 and MDSCs can be novel therapeutic targets in patients with solid-type PDA.

DOI： 10.1007/s10120-024-01474-w

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

PURPOSE: To evaluate the impact of dual cockpit telesurgery on proctors and operators, and acceptable levels of processing delay for video compression and restoration. METHODS: Eight medical advisors and eight trainee surgeons, one highly skilled per group, performed gastrectomy, rectal resection, cholecystectomy, and bleeding tasks on pigs. Using the Medicaroid surgical robot hinotori™, simulated delay times (0 ms, 50 ms, 100 ms, 150 ms, and 200 ms) were inserted mid-surgery to evaluate the tolerance level. Operative times and dual cockpit switching times were measured subjectively using 5-point scale questionnaires (mSUS [modified System Usability Scale], and Robot Usability Score). RESULTS: No significant difference was observed in operative times between proctors and operators (proctor: p = 0.247, operator: p = 0.608) nor in switching times to the dual cockpit mode (p = 0.248). For each survey setting, proctors tended to give lower ratings to delays of ≥ 150 ms. No marked difference was observed in the operator evaluations. On the postoperative questionnaires, there were no marked differences in the mSUS or Robot Usability Score between the proctors and operators (mSUS: p = 0.779, Robot Usability Score: p = 0.261). CONCLUSION: Telesurgery using a dual cockpit with hinotori™ is practical and has little impact on surgical procedures.

DOI： 10.1007/s00595-023-02784-9

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

Language：English   Publisher：シュプリンガー・ジャパン(株)  

Language：Japanese   Publisher：The Japan Broncho-esophagological Society  

DOI： 10.2468/jbes.75.144

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

PURPOSE: To verify the usefulness of haptic feedback in telesurgery and improve the safety of telerobotic surgery. METHODS: The surgeon's console was installed at two sites (Fukuoka and Beppu; 140 km apart), and the patient cart was installed in Fukuoka. During the experiment, the surgeon was blinded to the haptic feedback levels and asked to grasp the intestinal tract in an animal model. The surgeon then performed the tasks at each location. RESULTS: No marked differences in task accuracy or average grasping force were observed between the surgeon locations. However, the average task completion time was significantly longer, and the system usability scale (SUS) was significantly lower rating for remote operations than for local ones. No marked differences in task accuracy or task completion time were observed between the haptic feedback levels. However, with haptic feedback, the organ was grasped with a significantly weaker force than that without it. Furthermore, with haptic feedback, experienced surgeons in robotic surgery tended to perform an equivalent task with weaker grasping forces than inexperienced surgeons. CONCLUSION: The haptic feedback function is a tool that allows the surgeon to perform surgery with an appropriate grasping force, both on site and remotely. Improved safety is necessary in telesurgery; haptic feedback will thus be an essential technology in robotic telesurgery going forward.

DOI： 10.1007/s00595-023-02732-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

PURPOSE: Few studies have investigated the impact of the surgical proximal and distal margins on colon cancer recurrence. We conducted this study to investigate the effect of resection margins on the prognosis of resectable colon cancer. METHODS: We analyzed data on 1458 patients who underwent colorectal resection in our institute between January, 2004 and March, 2020, including 579 patients with resectable colon cancer. The association between the resection margin and recurrence for each oncological status was assessed and the value of the resection length that influenced recurrence was analyzed. RESULTS: Patients who had pT4 colon cancer with margins of more than 7 cm had a trend of fewer recurrences and longer relapse-free survival (RFS) than those with colon cancer of other stages (P = 0.033; hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.20-0.89). Multivariate analysis identified a margin of < 7 cm as an independent risk factor for RFS in patients with pT4 colon cancer (P = 0.023; HR, 2.65; 95% CI 1.013-6.17). No correlation was found between resection margins and recurrence, depending on the extent of lymph node metastasis and tumor location. CONCLUSION: A resection margin of at least 7 cm should be maintained for patients with pT4 colon cancer.

DOI： 10.1007/s00595-024-02836-8

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Adrenocortical carcinoma (ACC) patients with glucocorticoid excess have been reported to be associated with decreased tumor-infiltrating immune cells, but the effects of in situ glucocorticoid production on tumor immunity have remained unknown. In addition, ACC was also known to harbor marked intra-tumoral heterogeneity of steroidogenesis or disorganized steroidogenesis. Therefore, in this study, we immune-profiled tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) and pivotal steroidogenic enzymes of glucocorticoid biosynthesis (CYP17A and CYP11B1) to explore the potential effects of in situ glucocorticoid production and intra-tumoral heterogeneity/disorganized steroidogenesis on tumor immunity of ACC. We also studied the correlations of the status of tumor immunity with that of angiogenesis and tumor grade to further explore the tumor tissue microenvironment of ACC. TILs (CD3, CD4, CD8, and FOXP3), TAMs (CD68 and CD163), key steroidogenic enzymes of glucocorticoid (CYP17A and CYP11B1), angiogenesis (CD31 and vasohibin-1 (VASH-1)), tumor grade (Ki-67 and Weiss score) were immunohistochemically evaluated in 34 ACCs. Increased CYP17A immunoreactivity in the whole tumor area was significantly positively correlated with FOXP3-positive TILs (p = 0.021) and negatively with CD4/CD3 ratio (p = 0.001). Increased CYP11B1 immunoreactivity in the whole tumor area was significantly positively correlated with CD8/CD3 (p = 0.039) and CD163/CD68 ratios (p = 0.006) and negatively with CD4-positive TILs (p = 0.036) and CD4/CD3 ratio (p = 0.001). There were also significant positive correlations between CYP17A and CD8 (r = 0.334, p < 0.001) and FOXP3-positive TILs (r = 0.414, p < 0.001), CD8/CD3 ratio (r = 0.421, p < 0.001), and CD68-positive TAMs (r = 0.298, p < 0.001) in randomly selected areas. Significant positive correlations were also detected between CYP11B1 and CD8/CD3 ratio (r = 0.276, p = 0.001) and negative ones detected between CYP11B1 and CD3- (r = -0.259, p = 0.002) and CD4-positive TILs (r = -0.312, p < 0.001) in those areas above. Increased micro-vessel density (MVD) -VASH-1 was significantly positively correlated with CD68- (p = 0.015) and CD163-positive TAMs (p = 0.009) and CD163/CD68 ratio and the high VASH-1 with CD163-positive TAMs (p = 0.042). Ki-67 labeling index was significantly positively correlated with MAD-VASH-1 (p = 0.006) and VASH-1 (p = 0.006) status. Results of our present study indicated that in situ glucocorticoid production did influence the status of tumor immunity in ACC. In particular, increased levels of CYP17A and CYP11B1, both involved in glucocorticoid producing immunoreactivity played different effects on tumor immunity, i.e., reflecting the involvement of intra-tumoral heterogeneity and disorganized steroidogenesis of ACC, which also did indicate the importance of in situ approaches when analyzing tumor immunity of ACC.

DOI： 10.1016/j.jsbmb.2024.106462

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Gastroenterological Surgery  

AIM: Immune checkpoint inhibitors (ICIs) are less effective in mismatch repair (MMR)-proficient (pMMR) colorectal cancers (CRCs) than in MMR-deficient CRCs. Here, we investigated changes in the tumor microenvironment after neoadjuvant chemotherapy (NAC) without radiotherapy in locally advanced rectal cancer (LARC) and the potential of ICIs as therapeutic agents for pMMR CRCs. METHODS: This was an ad hoc analysis of a KSCC1301 randomized phase II trial in which patients with untreated resectable LARC were randomly assigned to receive S-1 and oxaliplatin or folinic acid, 5-fluorouracil, and oxaliplatin as NAC. Forty-nine patients were studied in this ad hoc analysis. As a reference cohort, we assessed 25 rectal cancer patients who underwent surgery without NAC outside the randomized trial. Immune checkpoint molecules (ICMs; PD-1, PD-L1, CTLA-4, LAG3), tumor-infiltrating lymphocytes (TILs; CD8, FOXP3), and other related proteins were evaluated by immunohistochemistry. Next-generation sequencing (NGS) using Oncomine™ Comprehensive Assay version 3 was conducted in 23 patients. RESULTS: The expression levels of PD-1, CTLA-4, and LAG3 in the NAC group were significantly higher than in reference patients (p < 0.001). Additionally, the infiltration of CD8+ and FOXP3+ T cells, and the CD8/FOXP3 ratio were significantly higher in the NAC group than in reference patients (p < 0.0001). NGS analysis revealed no specific gene alteration related to TILs or ICMs. CONCLUSION: We demonstrated changes in the tumor immune microenvironment after NAC in pMMR rectal cancer. NAC was associated with increased expression of ICMs and TILs. Rectal cancer could be susceptible to combined immunotherapy with chemotherapy.

DOI： 10.1002/ags3.12730

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Clinical Oncology  

OBJECTIVE: large-scale multicentre clinical trials conducted by cooperative groups have generated a lot of evidence to establish better standard treatments. The Clinical Trials Act was enforced on 1 April 2018, in Japan, and it has remarkably increased the operational burden on investigators, but its long-term impact on cancer cooperative groups is unknown. METHODS: a survey was conducted across the nine major cooperative groups that constitute the Japan Cancer Trials Network to assess the impact of Clinical Trials Act on the number of newly initiated trials from fiscal year (from 1 April to 31 March) 2017 to 2022 and that of ongoing trials on 1 April in each year from 2018 to 2023. RESULTS: the number of newly initiated trials dropped from 38 trials in fiscal year 2017 to 26 trials in fiscal year 2018, surged to 50 trials in fiscal year 2019, but then gradually decreased to 25 trials by fiscal year 2022. Specified clinical trials decreased from 32 trials in fiscal year 2019 to 12 trials in fiscal year 2022. The number of ongoing trials was 220 trials in 2018, peaked at 245 trials in 2020, but then gradually decreased to 219 trials by 2023. The number of specified clinical trials has been in consistent decline. By April 2023, of the 20 ongoing non-specified clinical trials, nine adhered to Clinical Trials Act and 11 followed the Ethical Guidelines for Medical and Health Research Involving Human Subjects. CONCLUSION: the number of multicentre clinical trials in oncology gradually decreased after the Clinical Trials Act's enforcement, which underscores the need for comprehensive amendment of the Clinical Trials Act to streamline the operational process.

DOI： 10.1093/jjco/hyae034

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Gastroenterological Surgery  

AIM: The aim of this study was to verify the clinical feasibility of tele-proctoring using our ultra-low latency communication system with shared internet access. METHODS: Connections between two multiple remote locations at various distances were established through the TELEPRO® tele-proctoring system. The server records the latency between the two locations for tele-proctoring using the annotations. Questionnaires were administered to the surgeons, assistants, and medical staff. Respondents rated the quickness and quality of communication in terms of latency and disturbances in the audio, video, and usefulness of the live telestrations with annotation. RESULTS: Seven hospitals tele-proctored with Sapporo Medical University between January 2021 and September 2022. The median latency of annotation between the two locations ranged from 24.5 to 48.5 ms. No major technological problems occurred, such as streaming interruption, loss of video or audio, poor resolution. The video encoding time was 10 ms, and its decoding time was 0.8 ms. The total latency positively correlated with the distance between two locations (R = 0.55, p < 0.01). The quality of communication regarding latency, disturbance, and surgical education with intraoperative annotative instructions showed similar trends, with perfectly fine being the most common response. No significant differences in surgical quality, educational effect, or social impact were observed between the latency ≥30 and <30 ms groups for whether the size of latency affects surgical education. CONCLUSION: The feasibility of the tele-proctoring system is expected to be a sustainable approach to help education for young surgeons and surgical supports in rural areas, thereby reducing disparities in health care.

DOI： 10.1002/ags3.12750

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research  

BACKGROUND/AIM: The efficacy of neoadjuvant chemotherapy (NAC) for colon cancer remains unestablished. This study aimed to investigate the outcomes of NAC in patients with locally advanced T4b or obstructive T4a colon cancers (LACC). PATIENTS AND METHODS: Data of patients with LACC who underwent colon surgery between 2010 and 2022 after NAC at our institution were retrospectively reviewed. Patient characteristics, surgical outcomes, tumor features, and prognosis were analyzed. RESULTS: Among 800 patients with LACC who underwent radical resection, 11 received NAC because of cT4b or cT4a with mechanical obstruction. NAC, administered as a doublet regimen, had a median duration of three months, without grade ≥3 adverse events. R0 resection was achieved in all patients and downstaging was observed in eight patients. One patient developed a postoperative abdominal abscess, and adjuvant chemotherapy was administered to eight patients. Four patients experienced recurrence: liver metastasis in two, and local recurrence in two. Among these, three patients underwent resection of recurrent tumors. Median follow-up was 30 months. CONCLUSION: NAC is feasible for T4b or obstructive T4a colon cancer and may be a treatment option for LACC. Further large-scale studies are required to confirm the efficacy of NAC in these patients.

DOI： 10.21873/anticanres.16923

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

共有型インターネットアクセス(SIA)を備えた超低遅延通信システムを使用した遠隔監視の臨床的実施可能性を検証した。遠隔監視システムを通じて、種々の距離にある二つの遠隔地医療施設間の接続を確立し、低遅延と低障害の観点から臨床的実施可能性を評価した。客観的データは、2地点間の遅延を測定することで取得した他、質問票を外科医、アシスタント、医療スタッフに行い、画像と音声の遅延と乱れの観点から通信速度と品質、有用性を評価した。2施設間のアノテーション平均遅延は24.5～48.5ミリ秒で、ストリーミング中断、ビデオやオーディオの損失、解像度低下等大きな技術的問題は発生しなかった。ビデオのエンコード時間は10ms、デコード時間は0.8msで、合計遅延は2施設間の距離と正の相関関係があった。遅延、障害、術中アノテーション指示による手術教育に関するコミュニケーションの質は同様の傾向を示し、「全く問題ない」の回答が最多であった。手術教育に及ぼす遅延長の影響調査では、遅延が30ms以上の群とそれ未満の群で手術の質、教育効果、社会的影響に有意差はなかった。SIAを使用した1対1の遠隔監視は臨床的に実施可能で、地方の若手外科医教育や外科支援に役立つ持続可能なアプローチになり得ると考えられた。

Language：English   Publisher：The Japanese Society of Balneology, Climatology and Physical Medicine  

DOI： 10.11390/onki.87_1.3

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Publisher：金原出版  

DOI： 10.18888/op.0000003717

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of the American College of Surgeons  

BACKGROUND: Laparoscopic gastrectomy is widely used as a curative treatment for gastric cancer. Although delta-shaped anastomosis is commonly used for Billroth I anastomosis after totally laparoscopic distal gastrectomy (TLDG), it has some drawbacks. The book-binding technique (BBT) was developed as an alternative, and this study aimed to examine its short-term results in 188 consecutive cases. STUDY DESIGN: This retrospective study included patients who underwent BBT reconstruction after TLDG for gastric malignancy between 2011 and 2020. BBT is a technique for intracorporeal gastroduodenostomy, which is a triangular anastomosis with a linear stapler that does not require additional dissection or rotation of the duodenum. The short-term outcomes of BBT reconstruction and postoperative endoscopic findings were analyzed. RESULTS: This study evaluated 188 patients who underwent TLDG and BBT reconstruction. Anastomotic stenosis and leakage occurred in 1.1% and 0.5% of the patients, respectively. The median time to the first diet was 3.1 days, and the median postoperative hospital stay was 11.9 days. BBT anastomoses were performed by 19 surgeons and took an average of 32.8 minutes to complete, with completion times decreasing as the surgical team became more proficient. On endoscopy performed 1 year postoperatively, 5.2% had reflux esophagitis (grade A or higher), 67.8% had gastritis (grade 1 or higher), 37.4% had residual food (grade 1 or higher), and 37.4% had bile reflux (grade 1). CONCLUSIONS: BBT is a safe and feasible method for intracorporeal gastroduodenostomy in TLDG for patients with gastric malignancy and demonstrates good surgical outcomes.

DOI： 10.1097/XCS.0000000000000891

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research  

BACKGROUND/AIM: This study examined the clinical significance of very high preoperative carbohydrate antigen 19-9 (CA19-9) levels in patients with early-stage colorectal cancer (CRC). PATIENTS AND METHODS: We retrospectively analyzed the clinicopathological data of patients who underwent curative resection for primary CRC (c-Stage I-III) between 2004 and 2022 in our facility. The patients were classified into three groups according to the preoperative CA19-9 level: normal (≤37.0 U/ml), high (>37.0 to ≤100.0 U/ml), and very high (>100.0 U/ml). RESULTS: Of 971 patients, 885 (91.1%), 67 (6.9%), and 19 (2.0%) had normal, high, and very high CA19-9 levels, respectively. Overall survival (very high vs. normal: p<0.0001, very high vs. high: p=0.01) and recurrence-free survival (very high vs. normal: p<0.0001, very high vs. high: p=0.18) were significantly worse in the very high group. On multivariate analysis including TNM stage, very high preoperative CA19-9 levels were independently associated with worse overall (odds ratio=4.54; 95% confidence interval=2.03-10.16; p=0.0002) and recurrence-free survival (odds ratio=3.49; 95% confidence interval=1.82-6.69; p=0.0002). CONCLUSION: High preoperative CA19-9 levels were associated with poor survival in early-stage CRC. Careful intraoperative observation and close follow-up might be necessary.

DOI： 10.21873/anticanres.16871

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Language：Japanese   Publisher：Japan Association on Odor Environment  

<p>We verified a screening method using canine scent detection of cancer and reported that it was possible to identify colorectal cancer with a sensitivity of 91% and a specificity of 99%, and that a distinctive odor appears when cancer develops. We identified the odorants produced by breast cancer cells and found that several moderate-volatile medium-chain fatty acids were present at high concentrations in the culture fluid derived from breast cancer cell lines. We reported that this may be related to the exhaled breath odor characteristic of cancer patients, which has been reported so far. Furthermore, breast cancer patients excrete more medium-chain fatty acids in their urine than normal subjects. We have confirmed that this is the case and are currently investigating the matter.</p>

DOI： 10.2171/jao.55.3

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DOI： 10.1200/JCO.2024.42.3_suppl.123

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DOI： 10.1200/JCO.2024.42.3_suppl.93

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DOI： 10.1200/JCO.2024.42.3_suppl.103

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DOI： 10.1200/JCO.2024.42.3_suppl.115

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DOI： 10.1200/JCO.2024.42.3_suppl.180

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DOI： 10.1200/JCO.2024.42.3_suppl.23

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Publisher：医歯薬出版  

DOI： 10.32118/ayu28802137

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Robotic Surgery  

Assuring communication redundancy during the interruption and establishing appropriate teaching environments for local surgeons are essential to making robotic telesurgery mainstream. This study analyzes robotic telesurgery with telementoring using standard domestic telecommunication carriers. Can multiple carriers guarantee redundancy with interruptions? Three commercial optical fiber lines connected Hirosaki University and Mutsu General Hospitals, 150 km apart. Using Riverfield, Inc. equipment, Hirosaki had a cockpit, while both Mutsu used both a cockpit and a surgeon's console. Experts provided telementoring evaluating 14 trainees, using objective indices for operation time and errors. Subjective questionnaires addressed image quality and surgical operability. Eighteen participants performed telesurgery using combined lines from two/three telecommunication carriers. Manipulation: over 30 min, lines were cut and restored every three minutes per task. Subjects were to press a switch when noticing image quality or operability changes. Mean time to task completion was 1510 (1186-1960) seconds: local surgeons alone and 1600 (1152-2296) seconds for those under remote instructor supervision, including expert intervention time. There was no significant difference (p = 0.86). The mean error count was 0.92 (0-3) for local surgeons and 0.42 (0-2) with remote instructors. Image quality and operability questionnaires found no significant differences. Results communication companies A, B, and C: the A/B combination incurred 0.17 (0-1) presses of the environment change switch, B/C had 0, and C/A received 0.67 (0-3), showing no significant difference among provider combinations. Combining multiple communication lines guarantees communication redundancy and enables robotic telementoring with enhanced communication security.

DOI： 10.1007/s11701-023-01792-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Asian Journal of Endoscopic Surgery  

The purpose of this study is to evaluate the performance of tele-robotic distal gastrectomy (tele-RDG) with lymph node dissection (LND) using a novel Japanese-made surgical robot hinotori™ (Medicaroid, Kobe, Japan) in a cadaver with a presumptive gastric cancer. The Cadaveric Anatomy and Surgical Training Laboratory (CAST-Lab.) at Hokkaido University and Kushiro City General Hospital (KCGH) are connected by a guaranteed type line (1 Gbps), and the distance between the two facilities is 250 km. A patient cart was installed at CAST-Lab, and a surgeon cockpit was installed at KCGH. Tele-RDG with D2 LND was performed on an adult human cadaver. In all surgical processes, the communication environment was stable without image degradation, and the mean round trip time was 40 milliseconds (36.5-55 milliseconds). For tele-RDG with D2 LND, the operation time was 199 minutes without any technical problems. Tele-RDG using hinotori™ was feasible and similar to local robotic RDG.

DOI： 10.1111/ases.13246

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Targeted Oncology  

BACKGROUND: The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC). OBJECTIVE: This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC. PATIENTS AND METHODS: The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed. RESULTS: Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS. CONCLUSION: Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: jRCTs031180122.

DOI： 10.1007/s11523-023-01027-8

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publisher：Med  

Background: The QUATTRO-II trial examined the efficacy and safety of capecitabine+oxaliplatin+irinotecan (CAPOXIRI)+bevacizumab (BEV) vs. 5-fluorouracil+folinic acid+oxaliplatin+irinotecan (FOLFOXIRI)+BEV in metastatic colorectal cancer (mCRC). Methods: In this phase II study (ClinicalTrials.gov: NCT04097444; jRCTs041190072), patients were randomized (1:1) to FOLFOXIRI+BEV or CAPOXIRI+BEV. The induction treatment in the FOLFOXIRI+BEV/CAPOXIRI+BEV arms was continued for 8/6 cycles (maximum 12/8 cycles if feasible), and the maintenance treatment was 5-fluorouracil/leucovorin+BEV or capecitabine+BEV at the investigators’ discretion. The primary endpoint was progression-free survival (PFS), with the two arms deemed equivalent if the hazard ratio (HR) of the point estimate was 0.80 < HR < 1.25. Secondary endpoints were overall response rate (ORR), overall survival (OS), incidence of adverse events (AEs), and patient-reported outcomes. Findings: Overall, 51 and 52 patients were randomized to FOLFOXIRI+BEV and CAPOXIRI+BEV, respectively. The study met its primary endpoint; PFS at median follow-up of 23.7 months was 10.6 months (95% confidence interval [CI], 7.7–13.3) in the FOLFOXIRI+BEV arm vs. 10.9 months (95% CI, 9.3–14.3) in the CAPOXIRI+BEV arm (HR 1.114 [0.80 < HR < 1.25], p = 0.654). In the FOLFOXIRI+BEV vs. CAPOXIRI+BEV arms, the 2-year OS rate (95% CI) was 65.5% (49.5%–77.6%) vs. 74.3% (59.8%–84.2%), and the ORR (95% CI) was 76.5% (62.5%–87.2%) vs. 84.6% (71.9%–93.1%). Major (grade ≥3) AEs in the FOLFOXIRI+BEV vs. CAPOXIRI+BEV arms were neutropenia (68.6% vs. 40.4%), febrile neutropenia (9.8% vs. 11.5%), diarrhea (7.8% vs. 17.3%), and appetite loss (7.8% vs. 17.3%). Conclusion: CAPOXIRI+BEV was well tolerated with reduced hematological toxicity and efficacy comparable to those of FOLFOXIRI+BEV, providing a potentially convenient first-line treatment alternative to FOLFOXIRI+BEV in patients with mCRC. Funding: Chugai Pharmaceutical Co., Ltd.

DOI： 10.1016/j.medj.2024.05.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Diagnosis and Prognosis  

BACKGROUND/AIM: Recent research has demonstrated that laparoscopic multivisceral resection (MVR) for advanced colorectal cancer is safe, practicable, and yields satisfactory oncological results, which is in line with the growing usage of laparoscopic surgery. The effectiveness of laparoscopic MVR is still debatable, though. The goal of this study was to compare the short- and long-term results of patients with advanced colorectal cancer treated with open MVR with laparoscopic procedures. PATIENTS AND METHODS: Data on 3,571 consecutive patients hospitalized at the Kyushu University National Kyushu Cancer Center for colorectal cancer surgery between 2004 and 2020 were gathered retrospectively. In the end, 84 individuals with advanced colorectal cancer who had a colectomy with MVR were examined. We evaluated invasiveness in terms of complications, blood loss, and operating time. Recurrence-free survival rates and overall 5-year survival were among the oncological outcomes. RESULTS: Of the 84 patients examined, 29 underwent laparoscopic treatment, and 55 underwent open treatment. The laparoscopic surgery group experienced shorter hospital stays (15 vs. 18 days, p<0.05) and much less blood loss (median volume: 167 vs. 1,058 g, p<0.005) than the open surgery group. Following the exclusion of patients with stage IV colorectal cancer from the study (groups undergoing laparoscopic surgery, n=25; open surgery, n=38), the groups displayed comparable pathologic results and no discernible variations in either the 5-year overall survival (p=0.87) or recurrence-free survival (p=0.86). CONCLUSION: In certain individuals with advanced colorectal cancer, a laparoscopic method of manipulation with MVR may be less invasive than an open method without compromising the prognosis.

DOI： 10.21873/cdp.10302

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Language：English   Publisher：Nature Medicine  

Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.

DOI： 10.1038/s41591-024-03244-8

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Language：English   Publisher：Nature Medicine  

The interim analysis of the CIRCULATE-Japan GALAXY observational study demonstrated the association of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection with recurrence risk and benefit from adjuvant chemotherapy (ACT) in resectable colorectal cancer (CRC). This updated analysis with a 23-month median follow-up, including 2,240 patients with stage II–III colon cancer or stage IV CRC, reinforces the prognostic value of ctDNA positivity during the MRD window with significantly inferior disease-free survival (DFS; hazard ratio (HR): 11.99, P < 0.0001) and overall survival (OS; HR: 9.68, P < 0.0001). In patients who experienced recurrence, ctDNA positivity correlated with shorter OS (HR: 2.71, P < 0.0001). The significantly shorter DFS in MRD-positive patients was consistent across actionable biomarker subsets. Sustained ctDNA clearance in response to ACT was an indicator of favorable DFS and OS compared to transient clearance (24-month DFS: 89.0% versus 3.3%; 24-month OS: 100.0% versus 82.3%). True spontaneous clearance rate with no clinical recurrence was 1.9% (2/105). Overall, our findings provide evidence for the utility of ctDNA monitoring for post-resection recurrence and mortality risk stratification that could be used for guiding adjuvant therapy.

DOI： 10.1038/s41591-024-03254-6

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Language：English   Publisher：Oncology (Switzerland)  

Introduction: This study aimed to evaluate the clinical impact of skeletal muscle mass and nutritional status in gastric cancer patients treated with nivolumab monotherapy as late-line treatment. Methods: We conducted a multi-institutional retrospective study of 90 gastric cancer patients who previously received anti-PD-1 therapy (nivolumab). On computed tomography images captured before nivolumab induction, the skeletal muscle index (SMI, cm2/m2) wasdefined as the erectormuscle area (cm2) divided by the height (m) squared. Patientswere divided into two groups: Those with SMI-high (n = 45) and those with SMI-low (n = 45). Prognostic nutritional index (PNI) was also calculated before nivolumab induction. The associations of SMI and PNI with response rate (RR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety were analyzed. Results: The cutoff values for SMIwere determined as 13.45 formales and 10.41 for females. SMI-high was significantly associated with a higher RR (odds ratio = 12.36, p = 0.02) andDCR (odds ratio = 2.97, p = 0.02). Although not significant, PNI-high also tended to be associated with a higher RR. Multivariate analysis showed that SMI-high was independently associated with a higher RR and higher DCR in gastric cancer. Moreover, prognostic analyses revealed that SMI-high (log-rank test p = 0.008) and PNI-high (logrank test p = 0.0008) were significantly associated with longer OS since nivolumab induction. SMI-high was also associated with longer PFS (log-rank test p = 0.03). There were no significant differences in immune-related adverse event between SMI-low and SMI-high. Conclusion: SMI and PNI were associated with nivolumab efficacy in gastric cancer patients. Management of skeletal muscle loss and nutritional status in gastric cancer patients whowill receive nivolumabwould be beneficial to enhance survival outcomes.

DOI： 10.1159/000540840

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Language：English   Publisher：Cancer Science  

The tumor immune microenvironment is increasingly becoming a key consideration in developing treatment regimens for aggressive cancers, with evidence that regulatory T cells (Tregs) attenuate the antitumor response by interrupting cytotoxic T cells (CD8+). Here, we hypothesized the prognostic relevance of the proportions of Tregs (marked by forkhead box protein 3 [FOXP3]) and CD8+ cells in diffuse, non-Epstein–Barr virus (EBV)/non-microsatellite instability (MSI)-high gastroesophageal adenocarcinomas (GEAs), which are clinically characterized as more aggressive, immunologically inactive tumors as compared with their intestinal counterparts. Cell-count ratios of FOXP3+/CD8+ expression were calculated at the intratumoral region and invasive margin discretely on digital images from 303 chemo-naive non-EBV/non-MSI-high esophagogastric junction (EGJ) adenocarcinomas. A significant modifying prognostic effect of tumor histology was observed between 5-year EGJ cancer-specific survival and the FOXP3+/CD8+ ratio at the invasive margin in pStage I–III tumors (p for interaction = 0.022; hazard ratio [HR] = 8.47 and 95% confidence interval [CI], 2.04–35.19 for high ratio [vs. low] for diffuse; HR = 1.57 and 95% CI, 0.88–2.83 for high ratio [vs. low] for intestinal). A high FOXP3+/CD8+ ratio at the invasive margin was associated with RUNX3 methylation (p = 0.035) and poor prognosis in RUNX3-methylated diffuse histological subtype (5-year EGJ cancer-specific survival, 52.3% for high and 100% for low, p = 0.015). Multiomics data from The Cancer Genome Atlas linked CCL28 with RUNX3-suppressed diffuse histological subtypes of non-EBV/non-MSI-high GEA. Our data suggest that a high FOXP3+/CD8+ ratio at the invasive margin might indicate tumor immune escape via CCL28, particularly in the RUNX3-methylated diffuse histological subtype.

DOI： 10.1111/cas.16373

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Future Oncology  

Aims: Physicians determine the treatment regimen for metastatic colorectal cancer on a case-by-case bases, according to the individual disease characteristics. We retrospectively compared the baseline characteristics and efficacies of first-line treatment among patients with metastatic colorectal cancer who received intensive therapy involving fluoropyrimidine plus oxaliplatin and/or irinotecan, potentially with molecularly targeted agents as well, versus less intensive fluoropyrimidine and/or bevacizumab therapy. Materials & methods: Data were collected from a medical claims database. The efficacy outcomes were: time to treatment failure, time to first subsequent therapy and overall survival. Results: The less intensive therapy group (n = 633) had higher median age, lower daily activity levels and shorter time to treatment failure, time to first subsequent therapy and overall survival than the intensive therapy group (n = 3829). Combination therapy with molecularly targeted agents and bevacizumab improved treatment efficacy outcomes in the intensive and less intensive groups, respectively. Conclusion: Patient age and daily activity levels were important factors for determining treatment intensity.

DOI： 10.2217/fon-2022-1284

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgical Endoscopy  

BACKGROUND: In telementoring, differences in teaching methods affect local surgeons' comprehension. Because the object to be operated on is a three-dimensional (3D) structure, voice or 2D annotation may not be sufficient to convey the instructor's intention. In this study, we examined the usefulness of telementoring using 3D drawing annotations in robotic surgery. METHODS: Kyushu University and Beppu Hospital are located 140 km apart, and the study was conducted using a Saroa™ surgical robot by RIVERFIELD Inc. using a commercial guarantee network on optical fiber. Twenty medical students performed vertical mattress suturing using a swine intestinal tract under surgical guidance at the Center for Advanced Medical Innovation Kyushu University. Surgical guidance was provided by Beppu Hospital using voice, 2D, and 3D drawing annotations. All robot operations were performed using 3D images, and only the annotations were independently switched between voice and 2D and 3D images. The operation time, needle movement, and performance were also evaluated. RESULTS: The 3D annotation group tended to have a shorter working time than the control group (25.6 ± 63.2 vs. - 36.7 ± 65.4 min, P = 0.06). The 3D annotation group had fewer retries than the control group (1.3 ± 1.7 vs. - 1.1 ± 0.7, P = 0.006), and there was a tendency for fewer needle drops (0.4 ± 0.7 vs. - 0.5 ± 0.9, P = 0.06). The 3D annotation group scored significantly higher than the control group on the Global Evaluate Assessment of Robot Skills (16.8 ± 2.0 vs. 22.8 ± 2.4, P = 0.04). The 3D annotation group also scored higher than the voice (13.4 ± 1.2) and 2D annotation (16.2 ± 1.8) groups (3D vs. voice: P = 0.03, 3D vs. 2D: P = 0.03). CONCLUSION: Telementoring using 3D drawing annotation was shown to provide good comprehension and a smooth operation for local surgeons.

DOI： 10.1007/s00464-023-10521-z

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OBJECTIVE: To clarify the surgical outcomes of esophagectomy in Japan and comprehensively evaluate trends over time. It is important to analyze data from a large number of consecutive patients from a single institution. METHODS: We evaluated the treatment outcomes, complications, and prognosis of 1500 consecutive patients who underwent esophagectomy during 5 periods: group A (n = 284), 1964-1984; group B (n = 345), 1985-1993; group C (n = 253), 1994-2002; group D (n = 297), 2003-2012; and group E (n = 321), 2013-March 2020. RESULTS: The incidences of squamous cell carcinoma and adenocarcinoma were 93.8% and 3.3%, respectively. The proportion of adenocarcinoma cases has gradually increased over time. The in-hospital mortality rates for groups A, B, C, D, and E were 12%, 4.6%, 1.2%, 2.9%, and 1.5%, respectively. Group A had a significantly higher mortality rate than the other groups (P < 0.0001). Three-year survival rates were 22.2%, 47.8%, 53.4%, 69.9%, and 72.6% in groups A-E, respectively, 5-year survival rates were 17.2%, 41.3%, 49.2%, 63.9%, and 68.4%, respectively (P < 0.0001, group A vs groups D and E). The prognosis improved over time. Multivariate analysis revealed that depth of invasion, lymph node metastasis, the extent of lymph node resection, curative resection, pulmonary complications, and anastomotic leakage were significant independent prognostic factors. However, for recent surgeries (groups D and E), only the depth of invasion, lymph node metastasis, and curative resection were significant independent prognostic factors. CONCLUSIONS: Valuable changes in background and prognostic factors occurred over time. These findings will help optimize esophageal cancer management and improve patient outcomes.

DOI： 10.1097/AS9.0000000000000347

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Radiology  

PURPOSE: Small gastrointestinal stromal tumors (GISTs) can generally have nonspecific CT findings similar to those with benign submucosal tumors of the stomach. The purpose of this study was to explore the potential dual-layer dual-energy CT (dlDECT) parameters to differentiate small-sized (≤ 4 cm) GISTs from leiomyomas of the stomach. MATERIALS AND METHODS: This retrospective study included 26 SMTs ≤ 4 cm in diameter with pathological confirmation of either GIST (n = 17) or leiomyoma (n = 9) from May 2018 to January 2022. All patients received contrast-enhanced CT. The normalized iodine concentration (NIC) and spectral slope (λHU) were compared between GIST and leiomyoma. Receiver-operating characteristic (ROC) curves were plotted and the areas under the curve (AUCs) were calculated to estimate the diagnostic performance of these markers for differentiating GISTs from leiomyomas. RESULTS: NIC was significantly higher in GIST than in leiomyoma in the portal (P = 0.0019) and delayed phases (P = 0.0011). λHU was significantly higher in GIST than in leiomyoma in the portal (P = 0.0006) and delayed phases (P = 0.0009). AUC of the ROC curves using NIC to differentiate between GIST and leiomyoma were 0.875 and 0.895 in the portal and delayed phase; using λHU, they were 0.918 and 0.902 in the portal and delayed phase. CONCLUSION: dlDECT parameters including NIC and λHU show promise as indicators for differentiating small-sized GISTs from leiomyomas.

DOI： 10.1007/s11604-023-01473-4

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Language：English   Publisher：(公社)日本医学放射線学会  

胃の小型の消化管間質腫瘍(GIST)と平滑筋腫の鑑別におけるdual-energy dual-layer CT(dlDECT)パラメータの有用性について後方視的に検討した。2018年5月～2022年1月に病理学的に確認された直径4cm以下のGIST患者17人(男性11人、女性6人、40～81歳)と平滑筋腫患者9人(男性5人、女性4人、27～72歳)を対象とした。GISTと平滑筋腫におけるdlDECTパラメータの標準化ヨウ素濃度及びスペクトル傾斜を比較した。その結果、dlDECTパラメータは小型のGSTと平滑筋腫の鑑別に有用な指標であることが示された。

Publisher：メディカルレビュー社  

DOI： 10.34449/j0001.40.03_0050-0051

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by frequent esophageal involvement. However, there are few reports on esophagectomy for esophageal strictures associated with SSc. Herein, we present a case of successful treatment of an esophageal stricture associated with SSc through subtotal esophagectomy. CASE PRESENTATION: A 53-year-old female patient was diagnosed with SSc, interstitial pneumonia, and gastroesophageal reflux disease (GERD). The patient developed an esophageal ulcer and benign stricture that required a subtotal esophagectomy 10 years after the diagnosis. Histopathological findings revealed thinning of the muscle layer, a characteristic feature of SSc. The patient was free of dysphagia or regurgitation. CONCLUSIONS: An esophagectomy is a valuable option for treating esophageal strictures in SSc. Therefore, surgical approaches should be established for patients with SSc.

DOI： 10.1186/s40792-023-01727-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Gastroenterological Surgery  

AIM: To evaluate the feasibility and safety of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC) in Japan. METHODS: This prospective, multicenter, open-label, single-arm phase II trial was conducted at five institutions. The key eligibility criteria were age ≥ 20 years, LARC within 12 cm from the anal verge, and cT3-4N0M0 or TanyN+M0 at the time of diagnosis that enabled curative resection. Preoperative short-course radiation therapy (SCRT) 5 Gy × 5 days (total 25 Gy) + CAPOX (six courses) followed by total mesorectum excision (TME) was the treatment protocol. Non-operative management (NOM) was allowed if clinical complete response (cCR) was obtained in the preoperative evaluation. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty patients (male, n = 26; female, n = 4; median age, 62.5 [44-74] years; cT [T2, n = 1; T3, n = 25; T4, n = 4]; cN [N0, n = 13; N1, n = 13; N2, n = 4]) were enrolled. The final analysis included 30 patients in total. The completion rates were 100% for SCRT and 83% for CAPOX. TME and NOM were performed in 20 and seven patients, respectively. pCR was observed in six patients (30% [95% CI 14.0%-50.8%]). The primary endpoint was met. pCR+cCR was observed in 13 (43.3%) patients. There were no treatment-related deaths. Grade ≥3 (CTCAE ver. 5.0) adverse events (≥20%), including diarrhea (23.3%) and neutropenia (23.3%). The median follow-up period was 15.6 (10.5-22.8) months, with no recurrence or regrowth in NOM. CONCLUSIONS: ENSEMBLE-1 demonstrated satisfactory pCR and cCR, and well-tolerated safety of TNT for patients with LARC in Japan.

DOI： 10.1002/ags3.12715

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

本研究の目的は、日本における、局所進行直腸癌(LARC)に対するtotal neoadjuvant therapy(TNT)の妥当性と安全性を評価することである。本研究は、5施設で施行された前向き多施設オープンラベル、シングルアーム第2相試験である。主たる適格基準は、年齢20歳以上、肛門縁から12cm以内のLARC、診断時にcT3-4N0M0またはTanyN+M0で、治癒切除可能であることとした。術前短期間放射線照射(SRCT)5Gy×5日(合計25Gy)+CAPOX(6コース)施行後に、全直腸間膜切除(TME)を施行するプロトコールとした。手術前の評価で臨床的に完全緩解(cCR)と診断された場合、非手術療法(NOM)を許容した。主要観察項目は病理学的完全緩解(pCR)率とした。30症例が登録された(男性、n=26、女性、n=4、年齢中央値、62.5(44～74)歳、cT(T2、n=1、T3、n=25、T4、n=4)、cN(N0、n=13、N1、n=13、N2、n=4))。30例全例が最終解析対象となった。SCRT完遂率は100%、CAPOX完遂率は83%であった。TME施行例が20例、NOMとなった症例が7例であった。pCRが得られた症例は6例(30%、95%CI 14.0%-50.8%)で、主要観察項目に合致した。pCR+cCRは13例(43.3%)で認められた。治療関連死はなかった。グレード3以上(CTCAE第5版)の有害事象が20%以上で認められ、下痢が23.3%、好中球減少症が23.3%であった。経過観察期間の中央値は15.6(10.5～22.8)ヵ月で、NOM症例に再発、再増殖は認められなかった。

Language：English   Publisher：Springer Berlin Heidelberg  

症例は53歳女性。全身性硬化症(SSc)に罹患しており、食道狭窄の精査加療目的に当科紹介となった。15年前に胃食道逆流症(GERD)および間質性肺炎と診断され、プロトンポンプ阻害剤(PPI)、ミコフェノール酸モフェチル、タクロリムス、プレドニゾロンを処方されていた。5年前、逆流症状と咳嗽を呈して入院となり、内視鏡検査で軽度逆流性食道炎と食道裂孔ヘルニアを認め、食道内圧検査にて平均積算弛緩圧は14.3mmHgを示し蠕動の全欠損がみられた。さらに3年前、嚥下障害の増悪をきたし、食道造影で食道無蠕動ならびに液体通過に障害がみられ、内視鏡検査で中等度の逆流性食道炎を検出、PPIを増量して退院となった。しかし、1年前にGERD症状の悪化を呈し、内視鏡検査で重度逆流性食道炎と潰瘍形成を認め、radical incision and cuttingを行うも拘縮再発がみられたため手術目的に当科へ紹介された。受診時、重度嚥下障害、食道逆流、皮膚硬化、顔面と手指の拘縮が認められ、内視鏡検査で重度逆流性食道炎と食道狭窄、食道造影にて食道拘縮が検出された。胸腔鏡下食道亜全摘術と腹腔鏡下胃管再建術を施行し、術後の組織病理所見では筋層の菲薄化および断裂、筋組織への線維性組織への置換がみられた。タクロリムスの用量調整目的に1ヵ月の入院を要し、状態の安定を得た後に退院となった。術後6ヵ月、GERDや食道拘縮の所見は認めていない。

DOI： 10.1016/j.annonc.2023.10.225

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DOI： 10.1016/j.annonc.2023.09.025

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DOI： 10.1016/j.annonc.2023.10.762

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DOI： 10.1016/j.annonc.2023.09.3096

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DOI： 10.1016/j.annonc.2023.09.123

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Primary adenocarcinoma of the duodenum is a rare neoplasm that is often microsatellite instability-high (MSI-H). Pembrolizumab, a monoclonal antibody, has been recently approved in Japan for treatment of MSI-H solid tumors. Lynch syndrome is a frequent hereditary cancer predisposition syndrome. It is linked to an increased risk of various types of cancer, including colorectal and endometrial cancer, and is closely related to MSI-H. We present the case of a 55-year-old woman who was diagnosed with duodenal cancer. Biopsy findings revealed MSI-H, and pembrolizumab therapy was initiated because the tumor was in contact with the left renal vein and had metastasized to the mesenteric lymph nodes of the small intestine. Subsequently, after completing two courses of pembrolizumab therapy, the patient developed duodenal stenosis and underwent surgery. Pathological analysis of the resected specimen revealed no evidence of malignancy. Given the patient's previous cancer history and the occurrence of cancer in close relatives, genetic testing of peripheral blood was performed, which revealed the diagnosis of Lynch syndrome. Furthermore, the variant responsible for Lynch syndrome was found to be a mutation of NM_000251.3:c.211 + 1G > C in MSH2.

DOI： 10.1007/s13691-023-00622-w

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：British Journal of Cancer  

BACKGROUND: Although nivolumab has a high efficacy, reliable biomarkers are needed to predict the efficacy. We evaluated the nivolumab efficacy according to the TP53 mutation in advanced gastric cancer patients enrolled in the GI-SCREEN project. METHODS: Sequence data of tumour specimens and clinicopathological information of 913 patients with advanced gastric cancer who were enrolled between April 2015 and March 2017 were obtained from the GI-SCREEN database. The follow-up information of 266 patients treated with nivolumab was also provided. RESULTS: Among 266 patients treated with nivolumab, the objective response rate (ORR) of TP53 wild type (wt) patients (24.6%) was higher than that of TP53 mutant patients (14.8%). Among TP53 mutant patients, the ORR of the frameshift type tended to be higher than the transition and transversion type (23.1%, 13.6%, and 13.0%, respectively). The median progression-free survival (PFS) was statistically longer in TP53 wt patients than in mutant patients (3.3 vs 2.1 months, HR 1.4, 95% CI 1.1-1.9). Among TP53 mutant patients, PFS was statistically longer in the frameshift type than in the transversion type. CONCLUSION: Nivolumab showed better efficacy in TP53 wt patients than in mutant patients. Among TP53 mutant patients, the frameshift type may have efficacy from nivolumab treatment.

DOI： 10.1038/s41416-023-02378-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

BACKGROUND: Clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. The accumulated evidence of tumor agnostic agent has been made since PD-1 inhibitor was approved and used in clinical practice. Therefore, we have revised the guideline "Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition". METHODS: Clinical questions regarding medical care were formulated for patients with dMMR advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO and the public comments among all societies' members were done. RESULTS: The current guideline describes two clinical questions and eight recommendations for whom, when, and how MMR status should be tested. CONCLUSION: In this guideline, the committee proposed eight recommendations for performing MMR testing properly to select patients who are likely to benefit from immunotherapy.

DOI： 10.1007/s10147-023-02397-9

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DOI： 10.1016/j.annonc.2023.09.1806

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DOI： 10.1016/j.annonc.2023.09.1782

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

症例は55歳女性。腹痛を主訴に受診し、上部消化管内視鏡検査で十二指腸第3部にBorrmann 2型腫瘍が認められ、生検により高頻度マイクロサテライト不安定性(MSI-H)と高分化型から中分化型の腺癌が明らかになった。上部消化管造影とCTでも十二指腸に腫瘍が認められ、ステージIV十二指腸腺癌と診断した。腫瘍は左腎静脈に近接しており、小腸の腸間膜リンパ節転移も認められたため、ペムブロリズマブによる術前治療を開始した。2コース終了後に十二指腸狭窄のため緊急入院となり、上部消化管内視鏡検査で十二指腸内腔に微小な穴が認められた。CTでは、腫瘍の著しい退縮と十二指腸狭窄が認められた。リンパ節も著明に縮小していたことから、根治切除が可能であると判断し、腹腔鏡下十二指腸部分切除術とリンパ節郭清を行った。術後経過は順調で、病理学的完全奏効を達成した。生検でMSI-Hが検出されたこと、子宮癌の既往があること、近親者に癌の既往があることから、Lynch症候群(LS)が疑われた。患者の末梢血を用いて遺伝子検査を行ったところ、MSH2遺伝子のNM_000251.3:c.211+1G>Cに変異が認められ、LSと診断した。

DOI： 10.1016/j.annonc.2023.09.1749

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

BACKGROUND: Gastrectomy with D2 dissection and adjuvant chemotherapy is the standard treatment for locally advanced gastric cancer (LAGC) in Asia. However, administering chemotherapy with sufficient intensity after gastrectomy is challenging. Several trials demonstrated the efficacy of neoadjuvant chemotherapy (NAC). However, limited studies explored the feasibility of NAC-SOX for older patients with LAGC. This phase II study (KSCC1801) evaluated the safety and efficacy of NAC-SOX in patients with LAGC aged ≥ 70 years. METHODS: Patients received three cycles of SOX130 (oxaliplatin 130 mg/m2 on day 1, oral S-1 40-60 mg twice daily for two weeks every three weeks) as NAC, followed by gastrectomy with lymph node dissection. The primary endpoint was the dose intensity (DI). The secondary endpoints were safety, R0 resection rate, pathological response rate (pRR), overall survival, and relapse-free survival. RESULTS: The median age of 26 enrolled patients was 74.5 years. The median DI in NAC-SOX130 was 97.2% for S-1 and 98.3% for oxaliplatin. Three cycles of NAC were administered in 25 patients (96.2%), of whom 24 (92.3%) underwent gastrectomy with lymphadenectomy. The R0 resection rate was 92.3% and the pRR (≥ grade 1b) was 62.5%. The major adverse events (≥ grade 3) were neutropenia (20.0%), thrombocytopenia (11.5%), anorexia (11.5%), nausea (7.7%), and hyponatremia (7.7%). Postoperative complications of abdominal infection, elevated blood amylase, and bacteremia occurred in one patient each. Severe diarrhea and dehydration caused one treatment-related death. CONCLUSIONS: NAC-SOX130 is a feasible therapy for older patients, although systemic management and careful monitoring of adverse events are necessary.

DOI： 10.1007/s10147-023-02373-3

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

70歳以上の局所進行胃癌(LAGC)患者に対する術前補助化学療法(NAC)としてのS-1+オキサリプラチン(SOX)の安全性と有効性を評価するため、第II相試験(KSCC1801)を行った。オキサリプラチン(130mg/m2、1日目に静脈内投与)とS-1(40～60mg、1日2回、14日間経口投与)(SOX130)を用いる3コースのNACを3週毎に実施した後、胃切除とリンパ節郭清を行った。対象患者は26例(男性73.1%、年齢中央値74.5歳)で、主要評価項目の用量強度中央値はS-1で97.2%、オキサリプラチンで98.3%であった。24例が胃切除を受けた。R0切除率は92.3%、病理学的奏効率は62.5%であった。全例が少なくとも1件の有害事象を経験した。主なグレード3以上の有害事象は好中球減少症(20.0%)と血小板減少症(11.5%)であった。1件の治療関連死が発生した。2年全生存率は89.7%、2年無再発生存率は58.6%であった。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Surgical Oncology  

BACKGROUND: A molecular budding signature (MBS), which consists of seven tumor budding-related genes, was recently presented as a prominent prognostic indicator in colon cancer (CC) using microarray data acquired from frozen specimens. This study aimed to confirm the predictive power of MBS for recurrence risk based on formalin-fixed, paraffin-embedded (FFPE) materials. METHODS: This research utilized the same microarray data from a prior multicenter study using FFPE whole tissue sections, which retrospectively reviewed 232 stage II CC patients without adjuvant chemotherapy and 302 stage III CC patients with adjuvant chemotherapy. All patients underwent upfront curative surgery without neoadjuvant therapy between 2009 and 2012. An MBS score was calculated using the mean of log2 [each signal] of seven genes (MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3, and FOXC1) as described before. RESULTS: The MBS-low group exhibited a better relapse-free survival (RFS) than the MBS-high group in stage II (P = 0.0077) and in stage III CC patients (P = 0.0003). Multivariate analyses revealed that the MBS score was an independent prognostic factor in both stage II (P = 0.0257) and stage III patients (P = 0.0022). Especially among T4, N2, or both (high-risk) stage III patients, the MBS-low group demonstrated markedly better RFS compared with the MBS-high group (P = 0.0013). CONCLUSIONS: This study confirmed the predictive power of the MBS for recurrence risk by employing FFPE materials in stage II/III CC patients.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgical Endoscopy  

BACKGROUND: Although several studies on telesurgery have been reported globally, a clinically applicable technique has not yet been developed. As part of a telesurgical study series conducted by the Japan Surgical Society, this study describes the first application of a double-surgeon cockpit system to telesurgery. METHODS: Surgeon cockpits were installed at a local site and a remote site 140 km away. Three healthy pigs weighing between 26 and 29 kg were selected for surgery. Non-specialized surgeons performed emergency hemostasis, cholecystectomy, and renal vein ligation with remote assistance using the double-surgeon cockpits and specialized surgeons performed actual telesurgery. Additionally, the impact of adding internet protocol security (IPsec) encryption to the internet protocol-virtual private network (IP-VPN) line on communication was evaluated to address clinical security concerns. RESULTS: The average time required for remote emergency hemostasis with the double-surgeon cockpit system was 10.64 s. A non-specialized surgeon could safely perform cholecystectomy or renal vein ligation with remote assistance. Global Evaluative Assessment of Robotic Skills and System Usability Scale scores were higher for telesurgical support-assisted surgery by a non-specialized surgeon using the double-surgeon cockpits than for telesurgery performed by a specialized surgeon without the double-cockpit system. Adding IPsec encryption to the IP-VPN did not have a significant impact on communication. CONCLUSION: Telesurgical support through our double-surgeon cockpit system is feasible as first step toward clinical telesurgery.

DOI： 10.1007/s00464-023-10061-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC Cancer  

BACKGROUND: The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS: The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION: The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION: jRCT2031220025, April. 16, 2022.

DOI： 10.1186/s12885-023-11311-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we developed recommendations for tumor-agnostic treatments in patients with solid tumors with DNA mismatch repair deficient or neurotrophic receptor tyrosine kinase fusions. Recently, immune checkpoint inhibitors have shown efficacy in patient with tumor mutation burden-high (TMB-H) solid tumors and have been established as a third tumor-agnostic agent, making it necessary to develop the guideline prioritized for these patients. Clinical questions regarding medical care were formulated for patients with TMB-H advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. The current guideline describes three clinical questions and seven recommendations for whom, when, and how TMB should be tested, and what is recommended for patients with TMB-H advanced solid tumors. In this guideline, the committee proposed seven recommendations for performing TMB testing properly to select patients who are likely to benefit from immunotherapy.

DOI： 10.1007/s10147-023-02360-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Medicine  

BACKGROUND: We aimed to clarify the genomic characteristics of HER2-positive and negative gastric cancer cases that potentially affect tumor progression and treatment response in a prospective trial. METHODS: We collected 80 formalin-fixed paraffin-embedded (FFPE) samples (49 HER2+ and 31 HER2-) from gastric cancer patients who participated in the TROX-A1 trial (UMIN000036865). We queried a 435-gene panel (CANCERPLEX-JP) to generate comprehensive genomic profiling data, including the tumor mutation burden, somatic mutations, and copy number variations. In addition, the genomic differences between HER2+ and HER2- gastric cancer patients were analyzed. RESULTS: Mutational analyses showed that TP53 was the most frequently mutated gene regardless of HER2 status. ARID1A mutation was significantly enriched in HER2-negative patients. The number of total mutations in HER2-negative patients with ARID1A mutation was remarkably higher than that in HER2-positive patients. Next, copy number variation analyses showed that the number of amplified genes (such as CCNE1, PGAP3, and CDK12) in HER2-positive cases was significantly higher than that in HER2-negative cases. Moreover, PTEN deletion was more common in HER2-positive cases. Finally, we found that, compared with HER2-positive patients, HER2-negative patients tended to have a higher tumor mutation burden, particularly in patients with ARID1A mutation. Pathway analyses of the gene alterations showed an enrichment of several immune-related pathways in HER2-negative patients. CONCLUSIONS: According to the genomic profiling of HER2-positive and negative gastric cancer, several gene alterations in the HER2 pathway may be the potential mechanism underlying trastuzumab resistance. Relative to HER2-positive gastric cancer, HER2-negative gastric tumors with ARID1A mutation may be sensitive to immune checkpoint inhibitors.

DOI： 10.1002/cam4.6269

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

It is important to ensure the redundancy of communication during remote surgery. The purpose of this study is to construct a communication system that does not affect the operation in the event of a communication failure during telesurgery. The hospitals were connected by two commercial lines, a main line and a backup line, with redundant encoder interfaces. The fiber optic network was constructed using both guaranteed and best-effort lines. The surgical robot used was from Riverfield Inc. During the observation, a random shutdown and restoration process of either line was conducted repeatedly. First, the effects of communication interruption were investigated. Next, we performed a surgical task using an artificial organ model. Finally, 12 experienced surgeons performed operations on actual pigs. Most of the surgeons did not feel the effects of the line interruption and restoration on still and moving images, in artificial organ tasks, and in pig surgery. During all 16 surgeries, a total of 175-line switches were performed, and 15 abnormalities were detected by the surgeons. However, there were no abnormalities that coincided with the line switching. It was possible to construct a system in which communication interruptions would not affect the surgery.

DOI： 10.1038/s41598-023-37730-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Cancer Research and Clinical Oncology  

PURPOSE: This study evaluated the reliability, validity, and responsiveness of the Japanese version of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-ELD14 and measured the health-related quality of life (HRQOL) of elderly Japanese patients with cancer aged ≥ 60 and ≥ 70 years. METHODS: The study recruited elderly Japanese patients with cancer aged ≥ 60 (≥ 70) years (n = 1803 [n = 1236]). The EORTC QLQ-ELD14 was evaluated for reliability, validity, responsiveness, and correlations of changes in score between the EORTC QLQ-ELD14 and the EORTC QLQ-C30 before and after the commencement of the COVID-19 pandemic. RESULTS: In both age groups, the proportion of missing items was low (< 3%). Cronbach's α was good at ≥ 0.70, except for two of the seven items. All the intraclass coefficient constants were good at ≥ 0.70. The concurrent validity was good but correlation with the EORTC QLQ-C30 was not strong, except for the hypothesis items. Regarding the assessment of responsiveness, only one item ("maintaining purpose") of the EORTC QLQ-ELD14 worsened (- 6.14 ± 29.20, standard response of mean > 0.2) after the commencement of the COVID-19 pandemic. The changes in score between the EORTC QLQ-ELD14 and the "global health status/QOL" and "summary score" of the EORTC QLQ-C30 had moderate-to-high negative correlations for all items, except two. Hypotheses to evaluate construct validity were accepted at 90%, while responsiveness was accepted at 80%. CONCLUSION: The Japanese version of the EORTC QLQ-ELD14 questionnaire appears to have acceptable reliability, validity, and responsiveness to evaluate HRQOL in elderly Japanese people with cancer.

DOI： 10.1007/s00432-022-04414-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：World Journal of Surgical Oncology  

BACKGROUND: Because the robotic arm is located on the dorsal side of the patient, when the esophagus is pulled dorsally for the left recurrent nerve lymph node (LRLN) dissection, the robotic arm interferes with the surgical field. This made it difficult to prepare for the left recurrent lymph node dissection. We developed LRLN dissection in robotic surgery with natural space creation by physiological organ movement and evaluated the short-term results. METHODS: In this retrospective study, we analyzed 102 cases of robot-assisted thoracoscopic subtotal esophagectomy (RATE) among radical subtotal esophagectomies performed between December 2018 and December 2022 using medical records. LRLN dissection is preceded by a dissection of the esophagus from the trachea. Leaving the esophagus on the vertebral side and away from the trachea resulted in a physiological elevation of the esophagus, providing space between the trachea and esophagus. RESULTS: The thoracic surgery time in RATE was 181 (115-394) min. The number of LRLNs dissected was 4 (1-14). Six patients (6%) had a postoperative recurrence in the mediastinal lymph nodes. Seven patients (7%) had grade ≥ 1 left recurrent nerve palsy. CONCLUSIONS: LRLN dissection with RATE using natural space creation was performed safely with a sufficient number of dissected lymph nodes and little left recurrent nerve palsy.

DOI： 10.1186/s12957-023-03117-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

BACKGROUND: Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the 'Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)'. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.

DOI： 10.1007/s10147-023-02345-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Radiology  

PURPOSE: To assess the relationship between histopathological features of gastric cancer and the extracellular volume fraction (ECV) measured by preoperative equilibrium contrast-enhanced computed tomography (CECT). MATERIALS AND METHODS: The study group consisted of 66 patients with surgically resected gastric adenocarcinoma who underwent preoperative multiphasic CECT. Tumor ECVs were calculated using region-of-interest measurements within the gastric cancer and aorta of each case on unenhanced and equilibrium-phase images. The relationship between the mean ECV values and clinicopathological parameters was examined by univariate analysis. Parameters showing a significant difference in the former test were further tested by linear regression and receiver operating characteristic (ROC) curve analyses. RESULTS: In the univariate analysis, the values of venous invasion (p = 0.0487) and tumor infiltration (INF) pattern (p < 0.0001) were significantly correlated with the tumor ECV. INF was significantly correlated (β = 0.57, p < 0.0001) in the linear regression analysis. The tumor ECV showed better diagnostic accuracy for predicting INF (INFa/b vs INFc), and the area under the ROC curve value was 0.89. CONCLUSION: Tumor ECV determined by equilibrium CECT is significantly correlated with the pathological INF of gastric cancer.

DOI： 10.1007/s11604-023-01393-3

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Language：English   Publisher：(公社)日本医学放射線学会  

胃癌の病理組織学的特徴と術前の平衡相造影CT(CECT)により測定した腫瘍の細胞外容積分画(ECV)の関連について検討した。術前に多時相CECTを受け、切除組織の病理学検査で胃腺癌が確認された患者66人(男性33人、女性33人)を対象とした。単変量解析により血管浸潤及び浸潤増殖様式(INF)は腫瘍ECVと有意に相関し、多変量線形回帰分析においてもINFと腫瘍ECVの有意な相関が認められた。また、腫瘍ECVはINFの予測において良好な診断正確度を示しROC曲線下面積は0.89であった。

DOI： 10.1245/s10434-023-13684-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

PURPOSE: Analyzing the gut microbiome is essential for planning treatment strategies to manage esophageal squamous cell carcinoma. This study aimed to characterize the gut microbiome of patients with esophageal squamous cell carcinoma and to identify alterations in its composition during treatment. METHODS: We observed alterations in the gut microbiome in 21 consecutive patients with esophageal squamous cell carcinoma at five different time points, from neoadjuvant treatment to postoperative surgery. Ten healthy individuals were used as a non-cancer control group. Fecal samples were collected and analyzed using 16S ribosomal ribonucleic acid sequencing. RESULTS: Before treatment, participants with esophageal squamous cell carcinoma had different alpha and beta diversity in comparison to healthy controls. The number of Streptococcus, a facultative anaerobic bacterium, was significantly higher, whereas that of Faecalibacterium, an obligate anaerobic bacterium, was significantly lower. Both alpha and beta diversity remained unchanged during neoadjuvant treatment, but the alterations were pronounced after surgery. The increase in the relative abundance of Streptococcus and the decrease in that of Faecalibacterium also tended to be more pronounced after surgery. CONCLUSIONS: The gut microbiome in patients with esophageal squamous cell carcinoma is altered with surgical intervention.

DOI： 10.1007/s00595-022-02607-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Robotic Surgery  

Although robotic telesurgery is growing in popularity, the benefits of telesurgery compared to local surgery are unclear. This study aimed to evaluate the performance of robotic tele-cholecystectomy with a commercial line using the Saroa™ (Riverfield, Inc., Tokyo, Japan) system. The operation rooms of the Hokkaido University Hospital and Kushiro City General Hospital were connected using a best effort-type line (1 Gbps), with a distance of 250 km between the two hospitals. In this experimental single-blind randomized crossover trial, eight expert robotic surgeons performed robotic cholecystectomy in an artificial organ model using the Saroa™ system and were randomized to begin with either local surgery or telesurgery. All surgeons were assessed on task completion time, total path length of the right- and left- hand forceps and camera, Global Evaluative Assessment of Robotic Skills (GEARS), Global Operative Assessment of Laparoscopic Skills (GOALS), and System and Piper Fatigue Scale-12 (PFS-12). In all experiments, the communication environment was stable and the mean communication delay was 8 ms (3-31 ms). All tele-cholecystectomies were performed safely. There was no significant difference in completion time (P = 0.495), score of GEARS (P = 0.258), GOALS (P = 0.180), or PFS-12 (P = 0.528) between local surgery and telesurgery. The total path of the forceps tended to be longer in tele-cholecystectomy, particularly with significantly longer left-hand forceps total path length (P = 0.041). Robotic tele-cholecystectomy using a commercial line can be performed safely as same as local robotic surgery, but the total path of the left-hand forceps was prolonged in robotic tele-cholecystectomy due to overshoot. Therefore, a solution for overshooting will be required in the future.

DOI： 10.1007/s11701-023-01522-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ESMO Open  

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer (mCRC), published in late 2022, were adapted in December 2022, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with mCRC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with mCRC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian countries. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with mCRC across the different countries of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation, coupled with a disparity in the drug approvals and reimbursement strategies, between the different countries.

DOI： 10.1016/j.esmoop.2023.101558

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Bone Reports  

INTRODUCTION: Sleeve gastrectomy is the most common surgical procedure to reduce weight and treat metabolic complications in patients with moderate-to-severe obesity; however, it affects the musculoskeletal system. Dual-energy X-ray absorptiometry (DXA), which is commonly used to measure bone mineral density (BMD), may be affected by excess fat tissue around the bones, interrupting BMD measurement. Due to the strong correlation between DXA and the Hounsfield units (HU) obtained from computed tomography (CT) scans, BMD assessment using clinical abdominal CT scans has been useful. To date, there has been no report of detailed CT evaluation in patients with severe obesity after sleeve gastrectomy. OBJECTIVE: This study investigated the effect of sleeve gastrectomy in severely obese patients on bone and psoas muscle density, and cross-sectional area using retrospective clinical CT scans. METHODS: This was a retrospective observational study that included 86 patients (35 males and 51 females) who underwent sleeve gastrectomy between March 2012 and May 2019. Patients' clinical data (age at the time of surgery, sex, body weight, body mass index (BMI), comorbidities, and preoperative and postoperative blood test results, HU of the lumbar spine and psoas muscle and psoas muscle mass index (PMI)) were evaluated. RESULTS: The mean age at the time of surgery was 43 years, and the body weight and BMI significantly reduced (p < 0.01) after surgery. The mean hemoglobin A1c level showed significant improvement in males and females. Serum calcium and phosphorus levels remained unchanged before and after surgery. In CT analysis, HU of the lumbar spine and psoas muscle showed no significant decrease, but PMI showed a significant decrease (p < 0.01). CONCLUSIONS: Sleeve gastrectomy could dramatically improve anthropometric measures without causing changes in serum calcium and phosphorus levels. Preoperative and postoperative abdominal CT revealed no significant difference in the bone and psoas muscle density, and the psoas muscle mass was significantly decreased after sleeve gastrectomy.

DOI： 10.1016/j.bonr.2023.101661

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BACKGROUND: Intramural metastasis (IM) of esophageal cancer is classified as distant metastasis according to the Japanese Classification of Esophageal Cancer, and it is well-known to be associated with a poor prognosis. We herein report a case of perforated gastric IM of esophageal cancer that was successfully controlled with nonradical surgery and subsequent immune checkpoint inhibitor (ICI) treatment. CASE PRESENTATION: A 72-year-old woman was referred to our department for the treatment of esophageal cancer and perforated gastric ulcer. A histological examination of the main tumor and gastric ulcer lesion revealed squamous cell carcinoma. Since the gastric wall tumor had invaded the celiac artery, complete resection was considered impossible. Chemotherapy was administered but led to severe adverse events, so palliative resection was performed. Two months after surgery, computed tomography revealed enlargement of the residual tumor around the celiac artery. However, after nivolumab monotherapy was started, the tumor diminished remarkably, and the quality of life of the patient dramatically improved. Nine months after nonradical surgery, she is surviving without any disease concern. CONCLUSIONS: With the increased availability of ICIs, multidisciplinary treatment with surgery and ICIs can potentially lead to long-term survival, even in cases expected to have a poor prognosis.

DOI： 10.1186/s40792-023-01703-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JCO Precision Oncology  

PURPOSE: Circulating tumor DNA (ctDNA) genotyping on the basis of next-generation sequencing (NGS) may guide targeted therapy for metastatic colorectal cancer (mCRC). However, the validity of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment and the efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA results remains unclear. PATIENTS AND METHODS: The performance of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment was compared with that of a validated polymerase chain reaction-based tissue testing in patients with mCRC enrolled in the GOZILA study, a nationwide plasma genotyping study. The primary end points were concordance rate, sensitivity, and specificity. The efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA were also evaluated. RESULTS: In 212 eligible patients, the concordance rate, sensitivity, and specificity were 92.9% (95% CI, 88.6 to 96.0), 88.7% (95% CI, 81.1 to 94.0), and 97.2% (95% CI, 92.0 to 99.4) for RAS and 96.2% (95% CI, 92.7 to 98.4), 88.0% (95% CI, 68.8 to 97.5), and 97.3% (95% CI, 93.9 to 99.1) for BRAF V600E, respectively. In patients with a ctDNA fraction of ≥1.0%, sensitivity rose to 97.5% (95% CI, 91.2 to 99.7) and 100% (95% CI, 80.5 to 100.0) for RAS and BRAF V600E mutations, respectively. In addition to a low ctDNA fraction, previous chemotherapy, lung and peritoneal metastases, and interval between dates of tissue and blood collection were associated with discordance. The progression-free survival of anti-EGFR therapy and BRAF-targeted treatment was 12.9 months (95% CI, 8.1 to 18.5) and 3.7 (95% CI, 1.3 to not evaluated) months, respectively, for matched patients with RAS/BRAF V600E results by ctDNA. CONCLUSION: ctDNA genotyping effectively detected RAS/BRAF mutations, especially with sufficient ctDNA shedding. Clinical outcomes support ctDNA genotyping for determining the use of anti-EGFR and BRAF-targeted therapies in patients with mCRC.

DOI： 10.1200/PO.22.00688

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Surgical Oncology  

BACKGROUND: To develop an artificial intelligence-based model to predict recurrence after curative resection for stage I-III colorectal cancer from digitized pathological slides. PATIENTS AND METHODS: In this retrospective study, 471 consecutive patients who underwent curative resection for stage I-III colorectal cancer at our institution from 2004 to 2015 were enrolled, and 512 randomly selected tiles from digitally scanned images of hematoxylin and eosin-stained tumor tissue sections were used to train a convolutional neural network. Five-fold cross-validation was used to validate the model. The association between recurrence and the model's output scores were analyzed in the test cohorts. RESULTS: The area under the receiver operating characteristic curve of the cross-validation was 0.7245 [95% confidence interval (CI) 0.6707-0.7783; P < 0.0001]. The score successfully classified patients into those with better and worse recurrence free survival (P < 0.0001). Multivariate analysis revealed that a high score was significantly associated with worse recurrence free survival [odds ratio (OR) 1.857; 95% CI 1.248-2.805; P = 0.0021], which was independent from other predictive factors: male sex (P = 0.0238), rectal cancer (P = 0.0396), preoperative abnormal carcinoembryonic antigen (CEA) level (P = 0.0216), pathological T3/T4 stage (P = 0.0162), and pathological positive lymph node metastasis (P < 0.0001). CONCLUSIONS: The artificial intelligence-based prediction model discriminated patients with a high risk of recurrence. This approach could help decision-makers consider the benefits of adjuvant chemotherapy.

DOI： 10.1245/s10434-022-12926-x

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

食道扁平上皮癌患者の腸内微生物叢の特徴と治療時における組成の変化について検討した。食道扁平上皮癌連続患者21例(患者群)と健常者10例(対照群)の便検体を採取し、16S rRNAシーケンシングにより腸内微生物叢の解析を行った。患者の便検体は、ネオアジュバント療法から食道切除術後までの期間中5時点で採取した。治療前の患者群と対照群では、腸内微生物叢のα多様性とβ多様性に違いがみられ、患者群では対照群に比べて通性嫌気性菌のStreptococcus属が有意に多く、偏性嫌気性菌のFaecalibacterium属が有意に少なかった。ネオアジュバント療法中、腸内微生物叢のα/β多様性には変化がみられなかった。食道切除術後、腸内微生物叢の多様性は変化し、Streptococcus属の相対存在量が有意に増加し、Faecalibacterium属の相対存在量は有意に減少した。

Language：English   Publisher：Springer Berlin Heidelberg  

症例は72歳女性。胸部食道癌と胃潰瘍穿孔の診断で加療を目的に当院へ紹介された。CTで腹水および小彎近くの胃壁に胃潰瘍穿孔による膿瘍の形成を認めた。PET/CTで同部位にFDGの集積亢進を認めた。生検で胃壁の潰瘍性病変と食道癌はいずれも腺癌と診断された。腫瘍は腹腔動脈を囲むように位置しており、浸潤が疑われた。根治手術は困難と診断し、食道癌と胃癌に対してドセタキセル、シスプラチン、5-FUの3剤を併用した化学療法を開始した。15日後に好中球減少症が出現し、ドセタキセルを中止した。1サイクル終了後に発熱性好中球減少症と下痢の有害事象により化学療法の中止を余儀なくされ、ロボット支援手術を施行した。Open laparotomy法によりカメラポートを作製し、ポート挿入後に食道切除術を施行した。膿瘍病変は腹腔動脈浸潤のため完全切除できず、ドレナージを施行した。病理組織学的検査で胃壁の潰瘍性病変は食道腺癌の胃壁内転移と診断した。2ヵ月後に残存腫瘍の増大を認め、2次治療としてニボルマブ療法を開始した。3サイクル終了後に腫瘍径は著明に縮小し、QOLは改善した。9ヵ月後現在、無病生存中である。

DOI： 10.1016/j.annonc.2023.04.502

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DOI： 10.1016/j.annonc.2023.04.255

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DOI： 10.1245/s10434-022-12974-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

Prof. Setsuro Fujii achieved significant results in the field of drug discovery research in Japan. He developed nine well-known drugs: FT, UFT, S-1 and FTD/TPI are anticancer drugs, while cetraxate hydrochloride, camostat mesilate, nafamostat mesilate, gabexate mesilate and pravastatin sodium are therapeutic drugs for various other diseases. He delivered hope to patients with various diseases across the world to improve their condition. Even now, drug discovery research based on Dr. Fujii's ideas is continuing.

DOI： 10.1007/s10147-023-02326-w

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：British Journal of Cancer  

BACKGROUND: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC). METHODS: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33. RESULTS: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; Pnoninferiority = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%). CONCLUSIONS: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC. CLINICAL TRIAL REGISTRATION: JapicCTI-173618, jRCTs031180122.

DOI： 10.1038/s41416-023-02212-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research  

BACKGROUND/AIM: Tumour lysis syndrome (TLS) is a life-threatening oncological emergency. TLS is rare and associated with a higher mortality rate in solid tumours than in haematological malignancies. Our case report and literature review aimed to identify the distinctive features and hazards of TLS in breast cancer. CASE REPORT: A 41-year-old woman complained of vomiting and epigastric pain and was diagnosed with HER2-positive, hormone-receptor-positive breast cancer with multiple liver and bone metastases and lymphangitis carcinomatosis. She had several risk factors for TLS: high tumour volume, high sensitivity to antineoplastic treatment, multiple liver metastases, high lactate dehydrogenase levels, and hyperuricaemia. To prevent TLS, she was treated with hydration and febuxostat. One day after the first course of trastuzumab and pertuzumab, she was diagnosed with disseminated intravascular coagulation (DIC). After 3 further days of observation, she was relieved of DIC and administered a reduced dose of paclitaxel without life-threatening complications. The patient achieved a partial response after four cycles of anti-HER2 therapy and chemotherapy. CONCLUSION: TLS in solid tumours is a lethal situation and can be complicated by DIC. Early recognition of patients who are at risk of TLS and initiation of therapy is essential to avoid fatal situations.

DOI： 10.21873/anticanres.16403

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Language：Japanese   Publisher：The Japan Broncho-esophagological Society  

DOI： 10.2468/jbes.74.118

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAMA  

IMPORTANCE: For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined. OBJECTIVE: To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022). INTERVENTIONS: Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days. MAIN OUTCOMES AND MEASURES: The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate. RESULTS: In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%). CONCLUSIONS AND RELEVANCE: Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02394795.

DOI： 10.1001/jama.2023.4428

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Asian Journal of Endoscopic Surgery  

INTRODUCTION: Telerobotic surgery relies on communication lines, causing delays, and video information requires pre-transmission compression. Such delays and video degradation will continue to be unavoidable making communication conditions verification essential. Understanding the network specification values required for telerobotic surgery entails determining acceptable levels of delay and degradation due to the video compression and restoration processes during surgery. METHODS: The hinotori™ surgical robot from Medicaroid was used. Eight surgeons, skilled in robotic surgery, performed gastrectomy or rectal resection on pigs. Image compression (bitrate: 120, 60, 30, 20, 10 Mbps) was random, changing encoder settings during surgery, and delay times (30, 50, 100, 150 milliseconds) were pseudo-randomly inserted, changing emulator settings. Acceptable video levels were evaluated. Subjective evaluations by surgeons and evaluators regarding image degradation and operability, and objective evaluations of image degradation and operability were given five-point ratings. RESULTS: Regarding delay time, 30 and 50 millisecond periods garnered average ratings of 3.6 and 4.0, respectively, signifying that surgery was feasible. However, at 100 and 150 millisecond, average ratings were 2.9 and 2.3, respectively, indicating surgery was not feasible for the most part in these cases. The average rating for image compression was 4.0 or higher for bitrates of 20, 30, 60, and 120 Mbps, suggesting that surgery is possible even at bitrates as low as 10 Mbps, with an average rating of 4.0. CONCLUSION: In remote robotic surgery using the hinotori™, image compression and delay time are largely acceptable, so surgery can be safely performed.

DOI： 10.1111/ases.13150

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

遠隔ロボット手術におけるビデオ動画の遅延時間と画像圧縮が手術の実行可能性に及ぼす影響について検討した。Hinotori外科用ロボットを用いて、ロボット手術に習熟した外科医8名がブタモデルに対して胃切除術または直腸切除術を行った。手術に際して画像圧縮度(ビットレート:120、60、30、20、10Mbps)をランダムに切り替え、さらに遅延時間(30、50、100、150ミリ秒)を疑似ランダムに変更し、受容可能な動画レベルを評価した。画像劣化と手術可能性について外科医と評価者が主観的評価を行い、5点法で客観的評価を下した。外科医8名による遅延時間の評価では30ミリ秒が3.6点、50ミリ秒が4.1点、100ミリ秒が2.8点、150ミリ秒が2.3点となり、30ミリ秒から150ミリ秒、50ミリ秒から100ミリ秒、50ミリ秒から150ミリ秒の間にそれぞれ有意差が認められた。画像圧縮度の評価では、120Mbpsが4.8点、60Mbpsが4.4点、30Mbpsが4.1点、20Mbpsが4.5点、10ミリ秒が4.0点であり有意差はみられなかった。遠隔ロボット手術時に生じる画像の遅延時間と圧縮度に対する受容性は高く、安全に手術を施行できる可能性が高いと考えられた。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JCO Precision Oncology  

PURPOSE: Genomic profiling programs have been implemented to apply next-generation sequencing (NGS) for facilitating trial enrollment. SCRUM-Japan GI-SCREEN is a large-scale genomic profiling program in advanced gastrointestinal cancers using a validated genomic assay with the goal of facilitating enrollment in targeted clinical trials, generating real-world data, and performing clinicogenomic analysis for biomarker discovery. PATIENTS AND METHODS: Genotyping of tumor tissue samples from 5,743 patients with advanced gastrointestinal cancers enrolled in GI-SCREEN was centrally performed with NGS. Patients were enrolled in matched trials of targeted agents affiliated with GI-SCREEN on the basis of genotyping results. RESULTS: A total of 11 gastrointestinal cancers were included, with colorectal cancer being the most common. The median age ranged from 59 to 70.5 years across cancer types. Patients enrolled after initiation of first-line treatment had significantly longer overall survival (OS) than that before treatment initiation with a median survival time difference of 8.9 months and a hazard ratio (HR) ranging from 0.25 to 0.73 across cancer types, demonstrating an immortal time bias. One hundred and forty-nine patients received matched therapies in clinical trials on the basis of their identified alterations. Among patients with colorectal cancer harboring actionable alterations, the median OS was significantly longer in patients who received matched therapies in trials than in those who did not (HR, 0.52; 95% CI, 0.26 to 1.01; P = .049). Cancer-specific pathway alterations were significantly associated with shorter survival and related to primary resistance to matched trial therapies. CONCLUSION: Our genomic profiling program led to patient enrollment in targeted clinical trials and improved survival of patients with colorectal cancer who received matched therapies in clinical trials. To avoid immortal time bias, precautions are needed when using data from patients who have undergone NGS testing after initiation of the evaluated treatment line.

DOI： 10.1200/PO.22.00653

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Colorectal Cancer  

The body of evidence supporting the utility of the detection of molecular residual disease (MRD) in resected colorectal cancer (CRC) using circulating tumor DNA (ctDNA) analysis is rapidly growing. Furthermore, this evidence provides the rationale for escalation and de-escalation adjuvant chemotherapy (ACT) strategies using ctDNA MRD analysis. This has led to various randomized clinical trials, and CIRCULATE-Japan is one of the largest of these trial platforms. In this review, we provide an overview of the potential utility of ctDNA-based MRD detection for escalation and de-escalation ACT approaches. Furthermore, we highlight the feasibility using ctDNA clearance as a surrogate endpoint for ACT trials in patients with resected CRC, based on findings of the CIRCULATE-Japan project.

DOI： 10.1016/j.clcc.2022.12.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Oncology  

PURPOSE: Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. MATERIALS AND METHODS: We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. RESULTS: Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. CONCLUSION: In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

DOI： 10.1200/JCO.21.02726

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Language：English   Publisher：Cell Reports  

The cellular interactions in the tumor microenvironment of colorectal cancer (CRC) are poorly understood, hindering patient treatment. In the current study, we investigate whether events occurring at the invasion front are of particular importance for CRC treatment strategies. To this end, we analyze CRC tissues by combining spatial transcriptomics from patients with a public single-cell transcriptomic atlas to determine cell-cell interactions at the invasion front. We show that CRC cells are localized specifically at the invasion front. These cells induce human leukocyte antigen G (HLA-G) to produce secreted phosphoprotein 1 (SPP1)+ macrophages while conferring CRC cells with anti-tumor immunity, as well as proliferative and invasive properties. Taken together, these findings highlight the signaling between CRC cell populations and stromal cell populations at the cellular level.

DOI： 10.1016/j.celrep.2022.111929

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Gastroenterological Surgery  

AIM: Gastric mucosal changes associated with chronic gastritis are known to be precancerous lesions of gastric cancer. We aimed to identify individuals with a high risk of gastric cancer by detection of microRNAs (miRNA) in the blood as biomarkers. METHODS: Of 1206 individuals screened, 144 who were positive for Helicobacter pylori (H. pylori) by the serum antibody test and who underwent endoscopy were the subjects of this study. For the gross assessment of mucosal inflammation, we applied the Kimura-Takemoto classification, in which normal mucosa was defined as grade 0, and atrophy was categorized as grade 1 (C-1 and C-2), grade 2 (C-3 and O-1), and grade 3 (O-2 and O-3). Serum samples were divided into two phases and used for miRNA microarray profiling. We compared the expression of miRNAs in grade 3 mucosa and other grades. Expression in gastric cancer was confirmed with TCGA data. RESULTS: miR-196b-3p was significantly upregulated, and miR-92a-2-5p was downregulated (P < .05 and q < 0.2). TCGA data showed a high expression of miR-196b-3p in gastric cancer cases (P < .001). Comparing grade 3 and the others, the area under the receiver operating characteristic curve using the detected miRNAs was as high as about 0.7. Furthermore, the combination of miRNAs resulted in higher accuracy. In terms of the significance of the combinatory mRNAs, the combination of three miRNAs (miR-196b-3p, miR-92a-2-5p, and miR-6791-3p) revealed high sensitivity and specificity, with the area under the curve exceeding 0.8. CONCLUSION: The identified combinatory miRNAs may represent promising biomarkers of precancerous lesions in gastric cancer.

DOI： 10.1002/ags3.12610

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Gastroenterological Surgery  

AIM: Communication and video transmission delays negatively affect telerobotic surgery. Since latency varies by communication environment and robot, to realize remote surgery, both must perform well. This study aims to examine the feasibility of telerobotic surgery by validating the communication environment and local/remote robot operation, using secure commercial lines and newly developed robots. METHODS: Hirosaki University and Mutsu General Hospital, 150 km apart, were connected via a Medicaroid surgical robot. Ten surgeons performed a simple task remotely using information encoding and decoding. The required bandwidth, delay time, task completion time, number of errors, and image quality were evaluated. Next, 11 surgeons performed a complex task using gallbladder and intestinal models in local/remote environments; round trip time (RTT), packet loss, time to completion, operator fatigue, operability, and image were observed locally and remotely. RESULTS: Image quality was not so degraded as to affect remote robot operation. Median RTT was 4 msec (2-12), and added delay was 29 msec. There was no significant difference in accuracy or number of errors for cholecystectomy, intestinal suturing, completion time, surgeon fatigue, or image evaluation. CONCLUSION: The fact that remote surgery succeeded equally to local surgery showed that this system has the necessary elemental technology for widespread social implementation.

DOI： 10.1002/ags3.12611

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgical Endoscopy  

BACKGROUND: Mucosal incision-assisted biopsy (MIAB) is a valuable alternative to endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNAB) for sampling gastric subepithelial lesions (SELs). This study aimed to evaluate the potential risk of dissemination and impact on postoperative prognosis associated with MIAB, which has not yet been investigated. METHODS: Study 1: A prospective observational study was conducted to examine the presence or absence and growth rate of tumor cells in gastric juice before and after the procedure in patients with SELs who underwent MIAB (n = 25) or EUS-FNAB (n = 22) between September 2018 and August 2021. Study 2: A retrospective study was conducted to examine the impact of MIAB on postoperative prognosis in 107 patients with gastrointestinal stromal tumors diagnosed using MIAB (n = 39) or EUS-FNAB (n = 68) who underwent surgery between January 2001 and July 2020. RESULTS: In study 1, although no tumor cells were observed in gastric juice in MIAB before the procedure, they were observed in 64% of patients after obtaining samples (P < 0.001). In contrast, no tumor cells were observed in the gastric juice in EUS-FNAB before and after the procedure. In study 2, there was no significant difference in 5-year disease-free survival between MIAB (100%) and EUS-FNAB (97.1%) (P = 0.27). CONCLUSION: MIAB is safe, with little impact on postoperative prognosis, although the procedure releases some tumor cells after damaging the SEL's pseudocapsule.

DOI： 10.1007/s00464-022-09419-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Medicine  

Despite standard-of-care treatment, more than 30% of patients with resectable colorectal cancer (CRC) relapse. Circulating tumor DNA (ctDNA) analysis may enable postsurgical risk stratification and adjuvant chemotherapy (ACT) treatment decision-making. We report results from GALAXY, which is an observational arm of the ongoing CIRCULATE-Japan study (UMIN000039205) that analyzed presurgical and postsurgical ctDNA in patients with stage II-IV resectable CRC (n = 1,039). In this cohort, with a median follow-up of 16.74 months (range 0.49-24.83 months), postsurgical ctDNA positivity (at 4 weeks after surgery) was associated with higher recurrence risk (hazard ratio (HR) 10.0, P < 0.0001) and was the most significant prognostic factor associated with recurrence risk in patients with stage II or III CRC (HR 10.82, P < 0.001). Furthermore, postsurgical ctDNA positivity identified patients with stage II or III CRC who derived benefit from ACT (HR 6.59, P < 0.0001). The results of our study, a large and comprehensive prospective analysis of ctDNA in resectable CRC, support the use of ctDNA testing to identify patients who are at increased risk of recurrence and are likely to benefit from ACT.

DOI： 10.1038/s41591-022-02115-4

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

安全な民間回線と新規開発ロボットを用いて、通信環境とローカルおよびリモートのロボット動作を検証し、遠隔手術の実現可能性について検討した。150km離れた弘前大学とむつ総合病院を、手術用ロボットであるメディカロイドを介して接続した。10人の外科医が情報の符号化と復号化を用いて簡単な処置を遠隔操作で行った。必要な帯域幅、遅延時間、処置完了時間、誤謬数、および画質を評価した。続いて、11人の外科医が、ローカルおよびリモート環境で胆嚢と腸のモデルを用いて複雑な処置を実行し、ラウンドトリップタイム(RTT)、パケットロス、完了までの時間、術者の疲労、操作性、画像をローカルおよびリモートで観察した。画質に関しては、遠隔ロボット操作に影響を与えるほどの劣化はなかった。RTTの中央値は4ミリ秒(2～12)、付加遅延は29ミリ秒であった。胆嚢摘出、腸管吻合、完了時間、術者疲労、画像評価の精度や誤謬数に有意差は認められなかった。遠隔手術が局所手術と同等に施行できたことは、このシステムが社会に広く普及するために必要な基本技術を備えていることを示した。

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

本研究の目的は、血中マイクロRNA(miRNA)をバイオマーカーとして検出することで、胃癌リスクの高い症例を同定することである。スクリーニングを行った1206名のうち、血清抗体検査でヘリコバクター・ピロリ(H.pylori)陽性で、内視鏡検査を受けた144名を本研究の対象とした。粘膜炎症の肉眼的評価には、正常粘膜をグレード0、萎縮をグレード1(C-1、C-2)、グレード2(C-3、O-1)、グレード3(O-2、O-3)に分類する木村・竹本分類を適用した。血清サンプルは2相に分け、miRNAマイクロアレイプロファイリングに使用した。グレード3の粘膜とその他のグレードの粘膜におけるmiRNAの発現を比較した。胃癌における発現は、TCGAのデータで確認した。miR-196b-3pは有意に増加し、miR-92a-2-5pは減少していた(P<0.05、q<0.2)。TCGAのデータでは、胃癌症例においてmiR-196b-3pの発現が高いことが示された(P<0.001)。グレード3とそれ以外を比較すると、検出されたmiRNAを用いた受信者動作特性曲線下面積は0.7であった。さらに、miRNAを組み合わせることで、より高い精度が得られた。miRNAを組み合わせる場合、3種類のmiRNA(miR-196b-3p、miR-92a-2-5p、miR-6791-3p)の組み合わせが高い感度と特異性を示し、曲線下面積は0.8を超えていた。ここに示されたmiRNAの組み合わせは、胃癌の前癌病変のバイオマーカーとして有望である可能性がある。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Genomics and Proteomics  

BACKGROUND/AIM: Peritoneal metastasis (PM) of gastric cancer (GC) leads to poor clinical outcomes. Tumor-derived exosomes promote metastasis via communication between tumor cells and host cells. In this study, we investigated the effect of Rab27, which is required for exosome secretion, on the PM of GC. MATERIALS AND METHODS: We established a stable knockdown of two Rab27 homologs, Rab27a and Rab27b, in human GC cells (58As9) with a high potential of PM. We examined the level of exosome secretion from Rab27-knockdown 58As9 cells by Western blotting and the ability of Rab27b knockdown to suppress PM in 58As9 cells using a mouse xenograft model. In vitro proliferation and invasion assays were performed in the Rab27b-knockdown cells. Next, Rab27b expression was evaluated in human GC tissues by immunohistochemistry. Finally, we assessed the clinicopathological and prognostic significance of Rab27b expression by RT-qPCR in both our and other TCGA datasets of GC. RESULTS: Rab27a and Rab27b knockdown in 58As9 cells decreased the secretion of exosomes, characterized by the endocytic marker CD63. Rab27b knockdown decreased PM in vivo without affecting the in vitro proliferation or invasion ability of 58As9 cells. In human GC tissues, Rab27b was overexpressed in tumor cells. The overall and recurrence-free survival rates were significantly lower in GC patients with high compared to low Rab27b mRNA expression in our and other TCGA datasets. CONCLUSION: Rab27b expression potentially serves as a poor prognostic biomarker, possibly affecting PM via exosome secretion from GC cells.

DOI： 10.21873/cgp.20362

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Publisher：Nature Medicine  

DOI： 10.1038/s41591-022-02119-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

PURPOSE: We investigated the communication bandwidth (CB) limitation for remote robotics surgery (RRS) using hinotori™ (Medicaroid, Kobe, Japan). METHODS: The operating rooms of the Hokkaido University Hospital and Kyushu University Hospital were connected using the Science Information NETwork (SINET). The minimum required CB for the RRS was verified by decreasing the CB from 500 to 100 Mbps. Ten surgeons were tested on a task (intracorporeal suturing) at different levels of video compression (VC) (VC1: 120 Mbps, VC2: 40 Mbps, VC3: 20 Mbps) with the minimum required CB, and assessed based on the task completion time, Global Evaluative Assessment of Robotic Skills (GEARS), and System and Piper Fatigue Scale-12 (PFS-12). RESULTS: Packet loss was observed at 3-7% and image degradation was observed at 145 Mbps CB. The task performance with VC1 was significantly worse than that with VC2 and VC3 according to the task completion time (VC1 vs VC2, P = 0.032; VC1 vs. VC3, P = 0.032), GEARS (VC1 vs VC2; P = 0.029, VC1 vs VC3; P = 0.031), and PFS-12 (VC1 vs. VC2; P = 0.032, VC1 vs. VC3; P = 0.032) with 145 Mbps. CONCLUSION: Our findings provide evidence that RRS using hinotori™ requires a CB ≥ 150 Mbps. We also found that when there is insufficient CB, RRS can be continued by compressing the image.

DOI： 10.1007/s00595-022-02497-5

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

Hinotoriを用いた遠隔ロボット手術(RRS)における必要通信帯域(CB)を調査するため、北海道大学病院と九州大学病院の手術室を学術情報ネットワーク(SINET)で連携して実証研究を行った。CBを500～100Mbpsの範囲で漸減させ、必要最小限のCB下で外科医10名が体腔内縫合作業を異なるレベルの画像圧縮(120、40、20Mbps)で実施して作業完了時間、Global Evaluative Assessment of Robotic Skills、System and Piper Fatigue Scale-12を評価した。CBが145Mbpsの時に3～7%のパケットロスと画像の劣化を認めた。課題遂行性は、120Mbpsが40Mbpsや20Mbpsに比べて有意に悪い結果であった。hinotoriを用いたRRSに必要なCBは150Mbps以上と考えられた。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PLoS ONE  

AIM: To determine acceptable limits of communication delays in telesurgery, we investigated the impact of communication delays under a dynamic environment using a surgical assist robot. Previous studies have evaluated acceptable delays under static environments. Effects of delays may be enhanced in dynamic environments, but studies have not yet focused on this point. METHODS: Thirty-four subjects with different surgical experience (Group1: no surgical experience; Group2: only laparoscopic surgical experience; Group3: robotic surgery experience) performed 4 tasks under different delays (0, 70, 100, 150, 200, or 300 ms) using a surgical assist robot. Task accomplishment time and total movement distance of forceps were recorded and compared under different communication delays of 0-300 ms. In addition, surgical performance was compared between Group1or Group2 without delay and Group3 with communication delays. RESULTS: Significant differences in task accomplishment time were found between delays of 0 and 70 ms, but not between delays of 70 and 100 ms. Thereafter, the greater the communication delay, the longer the task accomplishment time. Similar results were obtained in total movement distance of forceps. Comparisons between Group3 with delay and Group1 or Group2 without delay demonstrated that surgical performance in Group3 with delay was superior or equal to that of Group1 or Group2 without delay as long as the delay was 100 ms or less. CONCLUSIONS: Communication delays in telesurgery may be acceptable if 100 ms or less. Experienced surgeons with more than 100 ms of delay could outperform less-experienced surgeons without delay.

DOI： 10.1371/journal.pone.0274328

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

Gastrointestinal stromal tumors (GISTs) are common subepithelial lesions (SELs) and require treatment considering their malignant potential. We recently developed an endoscopic ultrasound-based artificial intelligence (EUS-AI) system to differentiate GISTs from non-GISTs in gastric SELs, which were used to train the system. We assessed whether the EUS-AI system designed for diagnosing gastric GISTs could be applied to non-gastric GISTs. Between January 2015 and January 2021, 52 patients with non-gastric SELs (esophagus, n = 15; duodenum, n = 26; colon, n = 11) were enrolled. The ability of EUS-AI to differentiate GISTs from non-GISTs in non-gastric SELs was examined. The accuracy, sensitivity, and specificity of EUS-AI for discriminating GISTs from non-GISTs in non-gastric SELs were 94.4%, 100%, and 86.1%, respectively, with an area under the curve of 0.98 based on the cutoff value set using the Youden index. In the subanalysis, the accuracy, sensitivity, and specificity of EUS-AI were highest in the esophagus (100%, 100%, 100%; duodenum, 96.2%, 100%, 0%; colon, 90.9%, 100%, 0%); the cutoff values were determined using the Youden index or the value determined using stomach cases. The diagnostic accuracy of EUS-AI increased as lesion size increased, regardless of lesion location. EUS-AI based on gastric SELs had good diagnostic ability for non-gastric GISTs.

DOI： 10.1038/s41598-022-20863-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pathology Research and Practice  

Solid-type poorly differentiated adenocarcinoma (solid-type-PDA) of the stomach is a unique histological subtype of "tubular adenocarcinoma", but little is known about its clinicopathological features, molecular pathological characteristics and immunoregulatory tumor microenvironment. Herein, we examined the immunohistochemical expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, MSH6) in 57 cases of solid-type-PDA and classified them as either MMR-deficient or -proficient (dMMR, N = 23; pMMR, N = 34), and additionally identified 18 dMMR-well-differentiated adenocarcinoma (WDA) and 34 pMMR-WDA as control groups. We analyzed and compared solid-type-PDA with WDA by evaluating the immunoexpressions of key immune pathway proteins (programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1)) and tumor-infiltrating lymphocytes (TILs) (CD8, Foxp3 and PD-1). The results reveled IDO1 was significantly more frequent in dMMR-solid-type-PDA than in dMMR-WDA (P = 0.0046). Moreover, dMMR-solid-type-PDA tended to have higher mean CD8+ and Foxp3+ TILs compared with dMMR-WDA [P = 0.0006 (CD8+) and P = 0.1061 (Foxp3+)], and IDO1-positive tended to be associated with a large number of CD8+, Foxp3+ or PD-1+ TILs in almost all tumor subtypes. PD-L1 was significantly observed in 44 % (15/34) of pMMR-solid-type-PDA compared with 18 % (6/34) of pMMR-WDA (P = 0.0344). Although they are molecularly and morphologically classified as the same chromosomal instability subtype, overall survival (OS) and disease-free-survival (DFS) in pMMR-solid-type-PDA were significantly worse than those in pMMR-WDA [P = 0.0216 (OS) and P = 0.0160 (DFS)]. Our study demonstrates that immunoexpressions of several immunoregulatory proteins and TILs are more prevalent in dMMR-solid-type-PDA, potentially a useful discovery for designing tumor treatments with immune checkpoint inhibitors or combination therapies with a PD-1/PD-L1-inhibitor and IDO1-inhibitor.

DOI： 10.1016/j.prp.2022.154124

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Oncology  

PURPOSE: The phase III ACHIEVE trial conducted in Japan was one of six prospective studies included in the International Duration Evaluation of Adjuvant Therapy collaboration, which explored whether 3 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) therapy would be noninferior to 6 months of treatment in patients with curatively resected stage III colon cancer. We report the final analyses of survival and long-term safety. PATIENTS AND METHODS: Eligible patients were randomly assigned (1:1) to either 3 or 6 months of adjuvant chemotherapy (modified [m]FOLFOX6 or CAPOX, as selected by the treating physician). Random assignment was stratified according to number of involved lymph nodes, center, regimen, primary site, and age. The primary end point was disease-free survival, assessed in the modified intention-to-treat population. Overall survival (OS) was a secondary end point. RESULTS: The modified intention-to-treat population comprised 1,291 patients: 641 in the 6-month treatment group and 650 in the 3-month treatment group. Median follow-up for this analysis was 74.7 months. Five-year OS rates were comparable: 87.0% in the 3-month treatment group and 86.4% in the 6-month treatment group (hazard ratio, 0.91; 95% CI, 0.69 to 1.20; P = .51). Subgroup analysis of OS did not reveal a significant interaction between baseline characteristics and treatment duration. Peripheral sensory neuropathy lasting longer than 5 years was more common in the 6- compared with 3-month treatment group (16% v 8%, respectively), and in those receiving mFOLFOX6 compared with CAPOX (14% v 11%, respectively). CONCLUSION: In Asian patients, shortening adjuvant therapy duration from 6 to 3 months did not compromise efficacy and reduced the rate of long-lasting peripheral sensory neuropathy. In this setting, 3 months of CAPOX therapy is an appropriate adjuvant treatment option.

DOI： 10.1200/JCO.21.02628

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancers  

We compared the preplanned histopathological responses of resected liver metastases from patients who received modified FOLFOX6 plus bevacizumab or modified FOLFOX6 plus cetuximab for liver-limited colorectal metastases in the ATOM trial. Fibrosis and viable tumor cells in tumor regression grade (TRG), infarct-like necrosis in modified TRG (mTRG), and dangerous halo (DH) were assessed. Fifty-five patients (28 and 27 patients in the bevacizumab and cetuximab arms, respectively) were divided into the low (viable tumor cells ≤ 50%) and high (>50%) TRG or mTRG groups. DH was characterized as absent/rare or focal/diffuse. Compared to the bevacizumab arm, the cetuximab arm was more effective, with respect to low TRG (13 vs. 23 patients) and absent/rare DH (14 vs. 19 patients), respectively. Low mTRG was similarly observed in both arms. Low TRG/mTRG and absent/rare DH showed better relapse-free survival (RFS) than high TRG/mTRG and focal/diffuse DH. In the bevacizumab arm, a significant difference in RFS existed between the low and high TRG groups, while in the cetuximab arm, for TRG, mTRG, and DH, the low and absent/rare groups demonstrated significantly longer RFS than the high and focal/diffuse groups, respectively. TRG could estimate RFS in patients who underwent liver metastasectomy after bevacizumab or cetuximab chemotherapy.

DOI： 10.3390/cancers14184392

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DOI： 10.1016/j.annonc.2022.07.461

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DOI： 10.1016/j.annonc.2022.07.526

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DOI： 10.1016/j.annonc.2022.07.487

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DOI： 10.1016/j.annonc.2022.07.1863

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Science  

CD44 is a widely expressed polymorphic adhesion molecule that has pleiotropic functions in development and tumor progression. Its mRNA undergoes alternative splicing to generate multiple variant (CD44v) isoforms, although the function of each CD44v isoform is not fully elucidated. Here, we show that CD44v plays an important role in the induction of vimentin expression upon transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT). Among multiple CD44v isoforms expressed in NUGC3 gastric cancer cells, CD44v8-10 and CD44v3,8-10 are involved in the acquisition of migratory and invasive properties associated with TGF-β1-induced EMT, and only CD44v3,8-10 induces the transcription of vimentin mediated by the EMT transcription factor Slug. In primary tumor specimens obtained from patients with gastric cancer, CD44-containing variant exon 9 (CD44v9) expression and EMT features [E-cadherin(-)vimentin(+)] were significantly correlated, and EMT features in the cells expressing CD44v9 were associated with tumor invasion depth, lymph node metastasis, and pStage, which indicate invasive and metastatic properties, and poor prognosis. These results indicate that certain CD44v isoforms promote tumor cell motility and metastasis in gastric cancer in association with EMT features, and CD44v3,8-10 may contribute to these clinical characteristics.

DOI： 10.1111/cas.15353

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgical Laparoscopy, Endoscopy and Percutaneous Techniques  

AIM: This study was performed to clarify the relationship between robotic rectal resection and postoperative ileus (POI) by comparing robotic surgery with laparoscopic surgery. MATERIALS AND METHODS: We retrospectively reviewed 238 patients who underwent robotic (n=41) or laparoscopic (n=197) rectal resection for rectal cancer in our institution from January 2013 to June 2020. First, we compared the background factors and short-term surgical outcomes between robotic and laparoscopic surgery. Next, we investigated the postoperative complications of robotic and laparoscopic rectal resection. Finally, we identified the risk factors for POI following rectal cancer resection. RESULTS: The percentages of patients with an Rb tumor location, treatment by abdominoperitoneal resection/intersphincteric resection/low anterior resection, a temporary diverting ileostomy, and a long operation time were significantly higher in robotic than laparoscopic surgery ( P <0.0001, P =0.0002, P =0.0078, and P =0.0001, respectively). There was no significant difference in any individual postoperative complication between robotic and laparoscopic surgery. Risk factors for POI were male sex ( P =0.0078), neoadjuvant chemoradiotherapy ( P =0.0007), an Rb tumor location ( P =0.0005), treatment by abdominoperitoneal resection/intersphincteric resection/low anterior resection ( P =0.0044), a temporary diverting ileostomy ( P <0.0001), and operation time of ≥240 minutes ( P =0.0024). Notably, robotic surgery was not a risk factor for POI following rectal resection relative to laparoscopic surgery. CONCLUSION: Although patients who underwent robotic surgery had more risk factors for POI, the risk of POI was similar between robotic and laparoscopic rectal resection.

DOI： 10.1097/SLE.0000000000001056

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

トランスフォーミング増殖因子β1(TGF-β1)誘導性上皮間葉転換(EMT)において、CD44バリアントアイソフォーム(CD44v)の関与を検討した。NUGC3胃癌細胞に発現する複数のCD44vアイソフォームのうち、CD44v8-10とCD44v3,8-10はTGF-β1誘発EMTに伴う遊走能や浸潤能の獲得に関与し、CD44v3,8-10のみがEMT転写因子Slugを介したビメンチンの転写を誘導した。胃癌患者から得られた原発性腫瘍標本では、CD44v9の発現とEMT特徴(E-カドヘリン(-)、ビメンチン(+))が有意に相関し、CD44v9発現細胞におけるEMT特徴は、浸潤性および転移性を示す腫瘍浸潤深達度、リンパ節転移、病理分類、予後不良と関連していた。以上より、CD44vがTGF-β1誘発EMTに伴うビメンチンの発現誘導に重要な役割を果たすことが示された。

Language：English   Publishing type：Research paper (scientific journal)  

Inhibitors of bromodomain and extraterminal domain (BET) proteins are possible anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prophylactics as they downregulate angiotensin-converting enzyme 2 (ACE2). Here we show that BET proteins should not be inactivated therapeutically because they are critical antiviral factors at the post-entry level. Depletion of BRD3 or BRD4 in cells overexpressing ACE2 exacerbates SARS-CoV-2 infection; the same is observed when cells with endogenous ACE2 expression are treated with BET inhibitors during infection and not before. Viral replication and mortality are also enhanced in BET inhibitor-treated mice overexpressing ACE2. BET inactivation suppresses interferon production induced by SARS-CoV-2, a process phenocopied by the envelope (E) protein previously identified as a possible "histone mimetic." E protein, in an acetylated form, directly binds the second bromodomain of BRD4. Our data support a model where SARS-CoV-2 E protein evolved to antagonize interferon responses via BET protein inhibition; this neutralization should not be further enhanced with BET inhibitor treatment.

DOI： 10.1016/j.celrep.2022.111088

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DOI： 10.1016/j.annonc.2022.05.475

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DOI： 10.1016/j.annonc.2022.05.067

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DOI： 10.1016/j.annonc.2022.05.191

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DOI： 10.1016/j.annonc.2022.05.370

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DOI： 10.1016/j.annonc.2022.04.454

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DOI： 10.1016/j.annonc.2022.04.418

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DOI： 10.1016/j.annonc.2022.04.170

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Cancer  

BACKGROUND: The mainstream first-line chemotherapy for advanced/recurrent gastric cancer (ARGC) is combination therapy including platinum-based agents. With the progressive aging of the society, the incidence of gastric cancer in elderly patients is increasing. However, elderly patients cannot tolerate these agents because of renal dysfunction or low quality of life. The KSCC1701 study explored the efficacy and safety of S-1 + ramucirumab in elderly patients with ARGC. PATIENTS AND METHODS: Chemotherapy-naive patients aged ≥70 years with ARGC were eligible. Patients received S-1 (40-60 mg twice daily for 4 weeks in 6-week cycles) and ramucirumab (8 mg/kg every 2 weeks) until disease progression. The primary end-point was the 1-year overall survival (OS) rate. The anticipated lower threshold of 1-year survival was set at 40% in light of previous S-1-based regimens. The secondary end-points included progression-free survival (PFS), OS, the overall response rate (ORR) and safety. RESULTS: Between September 2017 and November 2019, 48 patients (34 men and 14 women) were enrolled in this study. The median patient age was 77.5 years, and all patients had a performance status of 0 (n = 20) or 1 (n = 28). The 1-year OS rate was 65.2%, which met the primary end-point. The median survival time and median PFS were 16.4 and 5.8 months, respectively. The ORR was 41.9%. The most frequent grade 3/4 (≥15%) adverse events were neutropenia, anorexia and anaemia. CONCLUSION: Considering these findings, S-1 + ramucirumab appears to be an excellent treatment option for elderly patients with ARGC. (250 words). This trial has been registered with the Japan Registry of Clinical Trials Registry under the number jRCTs071180066.

DOI： 10.1016/j.ejca.2022.02.028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Virchows Archiv  

Solid-type poorly differentiated adenocarcinoma (PDA) of the stomach is frequently associated with microsatellite instability (MSI) and aberrations of the SWI/SNF chromatin remodeling complex. Previous studies showed that aberrant ARID1A and SMARCA4 expression induces mesenchymal transition. We analyzed 51 primary-site cases and 209 metastatic lymph nodes among solid-type PDA for the expression of SWI/SNF complex subunits (ARID1A, SMARCA4, SMARCB1, SMARCC2) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, β-catenin, Snail). We also analyzed 40 cases of non-solid-type PDA as a stage-matched control group. Aberrant expression of ARID1A (39%) and SMARCA4 (49%) was more common in solid-type PDA than in non-solid-type PDA (ARID1A, P = 0.0049; SMARCA4, P < 0.0001). The group of solid-type PDA with aberrant ARID1A showed significantly longer overall and progression-free survival than the corresponding ARID1A-retained group (P = 0.0405 and P = 0.0296, respectively). Aberrant expression of EMT factors inducing mesenchymal transition in the groups with solid-type PDA at the primary site or metastatic lymph nodes with aberrant ARID1A was less common than in the corresponding groups with retained ARID1A (E-cadherin, primary site P = 0.0341, lymph node P < 0.0001; β-catenin, primary site P = 0.0293, lymph node P = 0.0010; Snail, primary site P = 0.0169, lymph node P = 0.0828). Furthermore, N3 of the TNM classification was more frequently observed in the group with solid-type PDA with retained ARID1A than in the corresponding ARID1A-aberrant group (P = 0.0288). Mesenchymal transition was not induced in the ARID1A-aberrant group, in which patients had favorable prognosis, and preserved epithelial characteristics in EMT may play an important role in low tumor aggressiveness of solid-type PDA.

DOI： 10.1007/s00428-021-03261-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pathology International  

Perineural invasion (PNI) at Auerbach's plexus in colorectal cancer (CRC), known as intramural PNI, is associated with adverse prognostic outcomes. This study aimed to characterize the three-dimensional (3D) architecture of CRC with intramural PNI and to evaluate the morphological features of tumor invasion around nerve tissue. Serial tissue sections from two cases of CRC were stained with cytokeratin AE1/AE3 and an anti-S-100 protein antibody. 3D models were reconstructed by scanning the virtual slides. In one case, intramural PNI was observed at the horizontal invasive front. The 3D reconstruction model showed tumor cells that appeared to infiltrate along the nervous meshwork, the structure of which was preserved. In the other case, intramural PNI was observed both at and behind the horizontal invasive front, and the 3D reconstruction model showed that the tumor cells appeared to be involved with nerve cells at the focal part of the horizontal invasive front. However, the nervous meshwork structure was not well identified in cancer-involved areas. This is the first study to characterize the 3D structure of tumor invasion around nerve tissue in CRC, demonstrating the morphological features of intramural PNI in CRC.

DOI： 10.1111/pin.13222

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Targeted Oncology  

BACKGROUND: Primary tumor site and genomic status are utilized for regimen selection in metastatic colorectal cancer; however, the impact on clinical practice is not well known. OBJECTIVE: We aimed to clarify the impact of primary tumor site and genomic status on clinical practice in metastatic colorectal cancer. METHODS: The relationship between primary tumor site, genomic alterations, and clinical outcomes was evaluated in patients with untreated metastatic colorectal cancer using real-world data of a prospective observational study, SCRUM-Japan GI-SCREEN with clinical and genomic data set in 1011 patients enrolled from February 2015 to March 2017. RESULTS: Five hundred and sixty-one patients were eligible for this study. Patients with right-sided tumors had a significantly worse survival, left-sided tumors with wild-type RAS had favorable outcomes when treated with anti-epidermal growth factor receptor monoclonal antibodies, and cecum tumors had poor prognosis when treated with bevacizumab. The rate of gene alterations varied considerably depending on the primary site. In addition, gene alterations of KRAS, BRAF, SMAD4, or TP53 had individually different contributions to survival from site to site. KRAS, BRAF, PTEN, or SMAD4 mutations were associated with efficacy of bevacizumab or anti-epidermal growth factor receptor monoclonal antibodies. CONCLUSIONS: Primary tumor site is a clinically useful biomarker to predict survival in patients with metastatic colorectal cancer treated with first-line chemotherapy. Moreover, the prognostic or predictive value of several gene alterations by primary tumor site should be considered in clinical practice.

DOI： 10.1007/s11523-022-00880-3

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Language：English   Publisher：Oxford University Press  

腫瘍微小環境へのエフェクターT細胞の浸潤を排除するメカニズムの解明を試みた。硫酸基転移酵素SULT2B1bによって生成される癌由来のコレステロール硫酸(CS)がRac活性化因子DOCK2を阻害し、エフェクターT細胞の腫瘍浸潤を阻害することが明らかになった。臨床サンプルを用いて、CSが大腸癌などの特定の種類のヒト癌で豊富に産生されていることを見出した。機能的には、CSを産生する癌細胞は、癌特異的T細胞移植や免疫チェックポイント阻害に対して抵抗性を示した。SULT2B1bはオキシステロールを硫酸化し、その腫瘍促進活性を不活性化することが知られているが、SULT2B1bを発現する癌ではオキシステロール産生を媒介するコレステロール水酸化酵素の発現量が低かった。したがって、SULT2B1bの阻害は、オキシステロール非産生癌の腫瘍免疫回避を妨害する治療戦略となる可能性があった。以上より、新たな腫瘍の免疫回避のメカニズムを明らかになり、効果的な免疫療法の開発に新たな知見が得られた。

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

大腸癌の壁内神経周囲浸潤(壁内PNI)、すなわちAuerbach神経叢への浸潤が生じている状況の形態的特徴と大腸癌組織の構築を三次元的に捉えるため、連続切片からの再構築を行った。大腸癌の手術を受けた2症例の組織検体を再構築材料とした。症例1は49歳男性で、S状結腸癌(pT4b、腹壁に浸潤)で腫瘍サイズは50×45mmであった。症例2は72歳男性で、下行結腸癌(pT3)、70×45mmであった。検体から連続切片を作製し、サイトケラチンAE1/AE3またはS-100を標的とする免疫組織化学染色を施した。その画像をスライド標本スキャナ(Axio Scan Z1)で取り込んで三次元モデルを再構築した。症例1では腫瘍浸潤の水平先進部で壁内PNIが観察され、腫瘍細胞は神経の網目構造に沿って浸潤し神経自身の構造は保たれているように思われた。症例2では壁内PNIが水平先進部とその後方のどちらの場所でも観察され、水平先進部の局所では腫瘍細胞が神経細胞を巻き込んでいるように思われる所見が示された。そのように癌が侵襲している領域では神経の網目構造は判然としなかった。

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Language：Japanese   Publisher：The Japan Broncho-esophagological Society  

DOI： 10.2468/jbes.73.170

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Language：Japanese   Publisher：The Japan Broncho-esophagological Society  

DOI： 10.2468/jbes.73.185

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Immunology  

Effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T-cell transfer and immune checkpoint blockade. Although SULT2B1b is known to sulfate oxysterols and inactivate their tumor-promoting activity, the expression levels of cholesterol hydroxylases, which mediate oxysterol production, are low in SULT2B1b-expressing cancers. Therefore, SULT2B1b inhibition could be a therapeutic strategy to disrupt tumor immune evasion in oxysterol-non-producing cancers. Thus, our findings define a previously unknown mechanism for tumor immune evasion and provide a novel insight into the development of effective immunotherapies.

DOI： 10.1093/intimm/dxac002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

PURPOSE: In recent years, the expectations for telesurgery have grown with the development of robot-assisted surgical technology and advances in communication technology. To verify the feasibility of the social implementation of telesurgery, we evaluated the communication integrity, availability, and communication delay of robotic surgery by remote control under different communication conditions of commercial lines. METHODS: A commercial line was used to connect hospitals 150 km apart. We had prepared guaranteed-type lines (1Gbps, 10Mbps, 5Mbps) and best effort-type lines. Two types of robotic teleoperations were performed, and we evaluated the round-trip time (RTT) of communication, packet loss, and glass-to-glass time. RESULTS: The communication delay was 4 ms for the guaranteed-type line and 10 ms for the best effort-type line. Packet loss occurred on the 5 Mbps guaranteed-type line. The mean glass-to-glass time was 92 ms for the guaranteed-type line and 95 ms for the best effort-type line. There was no significant difference in the number of errors in the task according to the type of line or the bandwidth speed. CONCLUSIONS: The social implementation of telesurgery using the currently available commercial communication network is feasible.

DOI： 10.1007/s00595-021-02384-5

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OBJECTIVE: The aim of this study is to identify biomarkers that predict efficacy of preoperative therapy and survival for esophageal squamous cell carcinoma (ESCC). BACKGROUND: It is essential to improve the accuracy of preoperative molecular diagnostics to identify specific patients who will benefit from the treatment; thus, this issue should be resolved with a large-cohort, retrospective observational study. METHODS: A total of 656 patients with ESCC who received surgery after preoperative CDDP + 5-FU therapy, docetaxel + CDDP + 5-FU therapy or chemoradiotherapy (CRT) were enrolled. Immunohistochemical analysis of TP53, CDKN1A, RAD51, MutT-homolog 1, and programmed death-ligand 1 was performed with biopsy samples obtained before preoperative therapy, and expression was measured by immunohistochemistry. RESULTS: In all therapy groups, overall survival was statistically separated by pathological effect (grade 3 > grade 2 > grade 0, 1, P < 0.0001). There was no correlation between TP53, CDKN1A, MutT-homolog 1, programmed death-ligand 1 expression, and pathological effect, whereas the proportion of positive RAD51 expression (≥50%) in cases with grade 3 was lower than that with grade 0, 1, and 2 (P = 0.022). In the CRT group, the survival of patients with RAD51-positive tumor was significantly worse than RAD51-negative expressors (P = 0.0119). Subgroup analysis of overall survival with respect to positive RAD51 expression indicated preoperative chemotherapy (CDDP + 5-FU or docetaxel + CDDP + 5-FU) was superior to CRT. CONCLUSIONS: In ESCC, positive RAD51 expression was identified as a useful biomarker to predict resistance to preoperative therapy and poor prognosis in patients who received preoperative CRT. Administration of preoperative chemotherapy may be warranted for patients with positive RAD51 expression.

DOI： 10.1097/SLA.0000000000003975

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JCO Precision Oncology  

PURPOSE: Low concordance between plasma-based and tissue-based tests for determining the RAS mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology. MATERIALS AND METHODS: We investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315). RESULTS: Of 1,187 patients with mCRC enrolled in GOZILA, 138 were eligible (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only metastases). The concordance of RAS/BRAF status between Guaradant360 and tissue in vitro diagnostic tests was 95.9% in patients with liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only metastases. ctDNA fraction, as measured by the median maximum variant allelic fraction (max VAF), and median number of detected variants were 23.1% and five in liver-only, 6.0% and five in lymph node-only, 0.4% and three in peritoneum-only, and 0.4% and three in lung-only metastases, respectively (all P < .001, Kruskal-Wallis test). Few patients with liver-only (2.0%) and lymph node-only metastasis (13.3%) had a max VAF < 0.2%, which is required to ensure a detection limit of 95%, but max VAF was more frequently < 0.2% in patients with lung-only (27.7%) or peritoneum-only metastasis (29.6%). CONCLUSION: Patients with lung-only and peritoneum-only metastatic disease have significantly lower levels of ctDNA, suggesting decreased clinical sensitivity for subclonal variants. This observation suggests that such patients may benefit from concurrent tissue and plasma testing to provide optimal genotyping for subsequent therapy selection.

DOI： 10.1200/PO.21.00535

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Science  

According to the current international guidelines, high-risk patients diagnosed with pathological T1 (pT1) colorectal cancer (CRC) who underwent complete local resection but may have risk of developing lymph node metastasis (LNM) are recommended additional intestinal resection with lymph node dissection. However, around 90% of the patients without LNM are exposed to the risk of being overtreated due to the insufficient pathological criteria for risk stratification of LNM. Circulating tumor DNA (ctDNA) is a noninvasive biomarker for molecular residual disease and relapse detection after treatments including surgical and endoscopic resection of solid tumors. The CIRCULATE-Japan project includes a large-scale patient-screening registry of the GALAXY study to track ctDNA status of patients with stage II to IV or recurrent CRC that can be completely resected. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective study, within the GALAXY study for patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk stratification criteria for LNM. The aim of this study is to explore the ability of predicting LNM using ctDNA analysis compared with the standard pathological criteria. The ctDNA assay will build new evidence to establish a noninvasive personalized diagnosis in patients, which will facilitate tailored/optimal treatment strategies for CRC patients.

DOI： 10.1111/cas.15226

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

150km離れた病院間を保証型回線(1Gbps、10Mbps、5Mbps)およびベストエフォート型回線の商用通信ネットワークで接続し、2種類のロボット遠隔手術を行い、通信の往復時間、パケットロス、glass-to-glass時間を評価した。通信遅延は保証型回線では4ms、ベストエフォート型回線では10msであった。パケットロスは5Mbpsの保証型回線で発生した。平均glass-to-glass時間は、保証型回線では92ms、ベストエフォート型回線では95msであった。エラー数について回線の種類または帯域幅速度による有意差は認めなかった。現在利用可能である商用通信ネットワークを用いた遠隔手術は実行可能であることが示された。

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

リキッドバイオプシーによる癌個別化医療の実現を目指すプロジェクト「CIRCULATE-Japan」は、観察研究(GALAXY試験)と2つの無作為化第III相試験(VEGA試験およびALTAIR試験)で構成されている。GALAXY試験では完全切除が可能なステージIIからIVまたは再発大腸癌患者の血中循環腫瘍DNA(ctDNA)状態を追跡している。著者らは、CIRCULATE-Japanのプラットフォームに基づき、GALAXY試験内で、局所完全切除を受けたpT1大腸癌患者のうち、リンパ節転移に関する標準的な病理学的リスク層別化基準に基づいてリンパ節郭清を伴う腸管追加切除が予定されている患者を対象に、新しい前向き研究であるDENEBを開始した。本研究の目的は、標準的な病理学的基準と比較して、ctDNA分析を用いたリンパ節転移の予測能力を探ることである。ctDNAアッセイは、大腸癌患者における非侵襲的な個別化診断を確立するための新たなエビデンスを構築し、大腸癌患者の個別化医療や最適な治療戦略を促進することが期待される。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Gastroenterological Surgery  

AIM: To investigate the impact of the triple-layered circular stapler compared with the double-layered circular stapler on anastomotic leakage after rectal cancer surgery. METHODS: The bursting pressure was compared between porcine ileocolic anastomoses created using a double- or triple-layered stapler. We also retrospectively analyzed the incidence of severe anastomotic leakage in 194 patients who underwent colorectal anastomosis using a double- or triple-layered circular stapler during rectal cancer resection performed in two cancer centers between January 2015 and April 2021. RESULTS: In the porcine model, the bursting pressure was higher in anastomoses created using the triple-layered stapler than the double-layered stapler (end-to-end anastomosis: 26.4 ± 6.2 mm Hg vs 14.5 ± 4.3 mm Hg, P = .0031; side-to-side anastomosis: 27.7 ± 5.0 mm Hg vs 18.0 ± 2.9 mm Hg, P = .0275). Intersectional leakage occurred in 41% and 83% of anastomoses created using the triple- or double-layered stapler, respectively (P = .0821). In the clinical cohort, the double- and triple-layered stapler was used in 153 and 41 patients, respectively. The incidence of anastomotic leakage was lower for anastomoses created using the triple-layered stapler vs the double-layered stapler (0.0% vs 5.8%, P = .0362). In multivariate analysis, the factors independently associated with a lower incidence of anastomotic leakage were female sex (odds ratio: 0.16, 95% confidence interval: 0.01-0.90, P = .0354) and triple-layered stapler usage (odds ratio: 0.00, 95% confidence interval: 0.00-0.96, P = .0465). CONCLUSION: Anastomoses created using a triple-layered circular stapler had high bursting pressure, which might contribute to a lower incidence of anastomotic leakage after rectal cancer surgery.

DOI： 10.1002/ags3.12516

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直腸癌手術後に生じる吻合部漏に対する三層サーキュラーステープラーと二層サーキュラーステープラーの有効性を比較検討した。ブタ回結腸吻合部における三層サーキュラーステープラーと二層サーキュラーステープラーの破裂圧を比較した。さらに、直腸癌に対して大腸吻合術を施行された194例を対象とする多施設後ろ向きコホート研究を実施して重度吻合部漏の術後発症率を評価した。二層サーキュラーステープラー使用群(EEA群)が153例(男性84例、女性69例、中央値66歳)、三層サーキュラーステープラー使用群(tri-EEA群)が41例(男性23例、女性18例、中央値67歳)であった。ブタを用いた実験での破裂圧は三層サーキュラーステープラーが26.4±6.2mmHg、二層サーキュラーステープラーが14.5±4.3mmHgと三層の方が有意に高値を示していた。臨床研究ではtri-EEA群の方がEEA群と比較して手術時間は有意に長く、術後在院期間と術後合併症の発症率に関してtri-EEA群とEEA群との間に有意差はみられなかったが、グレード3以上の吻合部漏の発症率はtri-EEA群の方が有意に低かった(0.0% vs 5.8%)。多変量解析ではtri-EEAの施行が吻合部漏の非発症を示す独立関連因子として抽出された。

DOI： 10.1200/JCO.2022.40.4_suppl.TPS215

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DOI： 10.1200/JCO.2022.40.4_suppl.011

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DOI： 10.1200/JCO.2022.40.4_suppl.161

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DOI： 10.1200/JCO.2022.40.4_suppl.168

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DOI： 10.1200/JCO.2022.40.4_suppl.256

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DOI： 10.1200/JCO.2022.40.4_suppl.087

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DOI： 10.1200/JCO.2022.40.4_suppl.254

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JCO Precision Oncology  

PURPOSE: Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard. PATIENTS AND METHODS: The performance of plasma-based MSI assessment using Guardant360, a next-generation sequencing-based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction-based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study. The primary end points were overall percent agreement, positive percent agreement (PPA), and negative percent agreement. The efficacy of immune checkpoint inhibitor therapy was also evaluated. RESULTS: In 658 patients with advanced GI cancers who underwent both plasma and tissue testing for MSI, the overall percent agreement, PPA, and negative percent agreement were 98.2% (95% CI, 96.8 to 99.1), 71.4% (95% CI, 47.8 to 88.7), and 99.1% (95% CI, 98.0 to 99.7), respectively. In patients whose plasma samples had a ctDNA fraction ≥ 1.0%, the PPA was 100.0% (15/15; 95% CI, 78.2 to 100.0). Three patients with MSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti-programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months. One patient with an aggressive cancer of an unknown primary site benefited from pembrolizumab after rapid detection of MSI-H by ctDNA genotyping. CONCLUSION: ctDNA genotyping was able to detect MSI with high concordance to validated tissue-based MSI testing, especially in patients with tumors that have sufficient ctDNA shedding. Furthermore, ctDNA genotyping enabled identification of patients with MSI-H tumors who benefited from immune checkpoint inhibitor treatment.

DOI： 10.1200/PO.21.00383

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Gastrointestinal Oncology  

BACKGROUND: Individualized estimates of the risk of recurrence in colon cancer patients are needed that reflect current medical practice and available treatment options. METHODS: Three validation studies of the 12-gene colon recurrence score assay were used with pre-specified patient-specific meta-analysis (PSMA) methods to integrate the 12-gene Oncotype DX Colon Recurrence Score result (RS) with the clinical and pathology risk factors stage, T-stage, mis-match repair (MMR) status, and number of nodes examined to calculate individualized recurrence risk estimates. Baseline risk estimation used the most recent studies, so the risk estimates reflect current medical practice. The effect of fluorouracil (5FU) was estimated with a meta-analysis of two studies. The effect of oxaliplatin was estimated using one of the RS assay validation studies, in which patients were randomized to 5FU with or without oxaliplatin. RESULTS: The RS result and each of the clinical-pathologic factors provided independent prognostic information for recurrence. Among stage II, T3, MMR-proficient patients with ≥12 nodes examined (the most common scenario), patients with RS ≤30 (approximately 48%) have estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-deficient patients with ≥12 nodes examined, patients with RS ≤19 (approximately 14%) have an estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-proficient patients with ≥12 nodes examined, those with RS ≤14 (approximately 6%) have estimated 5-year recurrence risk ≤10% with 5FU alone. DISCUSSION: The PSMA integrates the 12-gene colon RS result with clinical and pathology factors to provide individualized recurrence risk estimates that reflect current medical practice. The risk estimates are in a range that may help inform treatment decisions for a substantial number of stage II and stage III patients.

DOI： 10.21037/jgo-21-620

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Esophagus  

BACKGROUND: Several studies have reported the efficacy of resection for recurrent lesions. However, they involved a limited number of subjects. This study aimed to identify a subset of patients who benefit from surgical resection of recurrent lesions after curative esophagectomy for esophageal squamous cell carcinoma. METHODS: Clinicopathological features of 186 patients with esophageal squamous cell carcinoma who underwent surgical treatment for postoperative recurrent lesions at 37 accredited institutions of the Japanese Esophageal Society were evaluated. RESULTS: The most common recurrence site was the lymph node (106 cases; 58.6%), followed by the lung (40 cases; 22.1%). Univariate analyses revealed that pN 0-1 at esophagectomy (P = 0.0348), recurrence-free interval of ≥ 550 days (P = 0.0306), R0 resection (P < 0.0001), and absence of severe complications after resection for recurrent lesions (Clavien-Dindo grade < IIIa) (P = 0.0472) were associated with better overall survival after surgical resection. According to multivariate analyses, pN 0-1 (P = 0.0146), lung metastasis (P = 0.0274), recurrence-free interval after curative esophagectomy of ≥ 550 days (P = 0.0266), R0 resection (P = 0.0009), and absence of severe complications after resection for recurrent lesions (Clavien-Dindo grade < IIIa) (P = 0.0420) were independent predictive factors for better overall survival. CONCLUSIONS: Surgical resection of recurrent esophageal squamous cell carcinoma lesions is a useful option, especially for cases involving lower pN stage, lung metastasis, long recurrence-free intervals after esophagectomy, and technically resectable lesions. Surgical risks should be minimized as much as possible.

DOI： 10.1007/s10388-021-00878-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Reports  

BACKGROUND: ARID1A is a component of the SWI/SNF complex, which controls the accessibility of proteins to DNA. ARID1A mutations are frequently observed in colorectal cancers (CRCs) and have been reported to be associated with high mutational burden and tumor PD-L1 expression in vitro. AIM: To clarify the role of ARID1A mutation in CRC. METHOD AND RESULTS: We used next generation sequencing (NGS) and immunohistochemistry on clinically obtained samples. A total of 201 CRC tissues from Niigata University and Niigata Center Hospital were processed by NGS using the CANCERPLEX panel. Immunohistochemistry for ARID1A, PD-L1, MLH1, and MSH2 was performed on 66 propensity-matched (33 microsatellite instability-high [MSI-H] and 33 microsatellite-stable [MSS]) cases among 499 cases from Kyushu University. TCGA data were downloaded from cBioPortal. NGS showed significantly more mutations in ARID1A mutated CRCs (p = 0.01), and the trend was stronger for right-sided CRCs than left-sided. TCGA data confirmed these findings (p < 0.01). BRAF V600E and ATM mutations were also found at higher frequencies. Immunohistochemistry showed that 30% of MSI-H CRCs had ARID1A loss, while this was true in only 6% of MSS CRCs. In both MSI-H and MSS, PD-L1 expression by stromal cells was enhanced in the ARID1A-mutant groups (90% vs 39% in MSI-H, 100% vs 26% in MSS). CONCLUSION: We found a higher mutational burden in ARID1A-mutant CRCs, and IHC study showed that ARID1A loss was correlated with high PD-L1 expression in stromal cells regardless of MSI status. These data support the idea that mutant ARID1A is a potential biomarker for CRCs.

DOI： 10.1002/cnr2.1420

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Gastroenterological Surgery  

Numerous clinical studies in an adjuvant setting have been conducted and the combination therapy of 5-fluorouracil and oxaliplatin has been established as the standard treatment for Stage III and as an option for high-risk Stage II patients. Biologics such as bevacizumab and antiepidermal growth factor receptor antibodies have failed to show additional survival benefits. The indication of adjuvant chemotherapy has been determined according to the pathological stage. Nevertheless, a pathological diagnosis does not necessarily result in selection of the optimal treatment. To improve treatment decisions, many trials have aimed to stratify patients into treatment groups using genomic testing. Recently, gene signature, Immunoscore, and circulating tumor DNA (ctDNA) assays have been reported and among them, ctDNA was shown to be a promising accurate predictive marker for recurrence. Treatment of ctDNA-positive patients with aggressive chemotherapy may reduce recurrence rates. The ultimate goal is to accurately predict the risk of recurrence and to prevent recurrence in colon cancer patients. In this review we focus on the clinical development of adjuvant chemotherapy and stratification of patients according to risk of recurrence and the future direction of adjuvant chemotherapy.

DOI： 10.1002/ags3.12503

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Gastric Cancer  

BACKGROUND: Perioperative chemotherapy is the standard of care for locally advanced gastric cancer (LAGC). This phase II study investigated the efficacy and safety of S-1 and oxaliplatin (SOX) as neoadjuvant chemotherapy (NAC) for LAGC and esophagogastric junction cancer (EGJC). METHODS: Patients completed up to three cycles of SOX130 (oxaliplatin 130 mg/m2 on day 1, oral S-1 40-60 mg twice daily for 2 weeks every 3 weeks), followed by gastrectomy and D2 lymphadenectomy. The primary endpoint was the pathological response rate (pRR). The anastomosis leakage rate was the secondary endpoint in patients with EGJC, and other secondary endpoints were the R0 resection, overall survival (OS), and relapse-free survival (RFS) rates. RESULTS: Between April 2016 and July 2017, 47 patients (24 EGJC, 23 LAGC) were enrolled in this study. Forty-two patients (89.4%, 95% confidence interval [CI] = 76.9-96.5) underwent surgery, and R0 resection was achieved in 41 patients. The pRR was 59.5% (90% CI = 45.7-72.3). The major grade 3 or 4 toxicities were appetite loss in six patients (12.8%), thrombocytopenia in five patients (10.6%), and neutropenia and diarrhea in three patients (6.4%) each. The rate of severe anastomotic leakage (Clavien-Dindo classification grade III or higher) in 20 EGJC was 25.0% (90% CI = 10.4-45.6). The 3-year OS and RFS rate were 62.9% (95% CI = 47.2-75.1) and 53.2% (95% CI = 38.1-66.2), respectively. CONCLUSION: SOX130 demonstrated substantial benefit for LAGC and EGJC. However, special attention should be paid to anastomotic leakage during surgery for EGJC.

DOI： 10.1007/s10120-021-01218-0

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

日本食道学会認定の37施設で施行された、食道扁平上皮癌に対する根治手術後の再発に対する外科的切除例186例を検討対象とした。再発部位として最も多かったのはリンパ節で(106例、58.6%)、ついで肺(40例、22.1%)が多かった。単変量解析の結果、食道切除時pN0-1(P=0.0348)、無再発期間≧550日(P=0.0306)、R0切除(P<0.0001)および再発巣切除後の重篤な合併症なし(Clavien-Dindoグレード<IIIa)(P=0.0472)が、外科的切除後の良好な全生存と相関した。多変量解析の結果、pN0-1(P=0.0146)、肺転移(P=0.0274)、無再発生存期間≧550日(P=0.0266)、再発巣切除後の重篤な合併症なし(Clavien-Dindoグレード<IIIa)(P=0.0420)が、良好な全生存と関連する独立した因子であった。

Language：English   Publisher：シュプリンガー・ジャパン(株)  

局所進行胃癌(LAGC)および局所進行食道胃接合部癌(EGJC)症例に対して、3サイクルのSOX_130(1サイクル3週間、第1日目オキサリプラチン130mg/m2、2週間経口S-1 40～60mgを1日2回投与)後に、D2リンパ節郭清を伴う胃切除を施行した。主要評価項目は病理学的奏効率(pRR)とした。副次評価項目は、R0切除、全生存率(OS)、無再発生存率(RFS)とし、EGJCの場合には縫合不全率を加えた。2016年4月から2017年7月の間に、47例(EGJC 24例、LAGC 23例)が登録された。42例(89.4%、95%信頼区間[CI]=76.9～96.5)に外科手術が施行され、41例がR0切除であった。pRR率は59.5%(90%CI=45.7～72.3)であった。主要なグレード3ないし4の有害事象としては、食思不振が6例(12.8%)、血小板減少が5例(10.6%)、白血球数減少および下痢がそれぞれ3例(6.4%)に認められた。重度縫合不全(Clavien-Dindo分類グレードIII以上)は、EGJC 20例中25.0%(90%CI=10.4～45.6)に認められた。3年OSおよびRFSは、62.9%(95%CI=47.2～75.1)および53.2%(95%CI=38.1～66.2)であった。術前補助化学療法としてのSOX_130は有用であるが、EGJC症例では縫合不全に関して留意する必要があることが示唆された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PLoS ONE  

BACKGROUND: Remote surgery social implementation necessitates achieving low latency and highly reliable video/operation signal transmission over economical commercial networks. However, with commercial lines, communication bandwidth often fluctuates with network congestion and interference from narrowband lines acting as bottlenecks. Therefore, verifying the effects on surgical performance and surgeon fatigue when communication lines dip below required bandwidths are important. OBJECTIVES: To clarify the communication bandwidth environment effects on image transmission and operability when bandwidth is lower than surgical robot requirements, and to determine surgeon fatigue levels in suboptimal environments. METHODS: Employing a newly developed surgical robot, a commercial IP-VPN line connected two hospitals 150 km apart. Thirteen surgical residents remotely performed a defined suturing procedure at 1-Gbps to 3-Mbps bandwidths. Communication delay, packet loss, time-to-task completion, forceps-movement distance, video degradation, and robot operability were evaluated before and after bandwidth changes. The Piper Fatigue Score-12 (PFS-12) was used to measure fatigue associated with surgeon performance. RESULTS: Roundtrip communication time for both 1-Gbps and 3-Mbps lines averaged 4 ms. Video transmission delay from camera to monitor was comparable, at 92 ms. Surgical robot signal transmission rate averaged 5.2 Mbps, so changing to 1-Gbps-3-Mbps lines resulted in significant packet loss. Surgeons perceived significant roughness, image distortion, diplopia, and degradation of 3D images (p = 0.009), but not changes in delay time or maneuverability. All surgeons could complete tasks, but objective measurement of task-completion time and forceps-travel distance were significantly prolonged (p = 0.013, p = 0,041). Additionally, PFS-12 showed post-procedure fatigue increase at both 1-Gbps and 3-Mbps. Fatigue increase was significant at 3-Mbps (p = 0.041). CONCLUSIONS: In remote surgery environments with less than the optimal bandwidth, even when delay time and operability are equivalent, reduced surgical performance occurs from video degradation from packet loss. This may cause increased surgeon fatigue.

DOI： 10.1371/journal.pone.0270039

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Language：English   Publishing type：Research paper (scientific journal)  

Background FOLFOXIRI plus bevacizumab is the first-line treatment for metastatic colorectal cancer (mCRC) but demonstrates high neutropenia incidence among Asian patients. Hence, we conducted the randomized phase II QUATTRO-II study (ClinicalTrials.gov identifier: NCT04097444; Japan Registry of Clinical Trials identifier: jRTCs041190072) to evaluate the safety and efficacy of capecitabine, oxaliplatin, and irinotecan (CAPOXIRI) combination plus bevacizumab versus FOLFOXIRI plus bevacizumab, expecting a lower incidence of neutropenia without compromising the efficacy. Methods We investigated the recommended doses (RD) of oxaliplatin and irinotecan as a safety lead-in portion of Step 1 before initiating the randomized portion as Step 2. Four dose levels of CAPOXIRI (fixed dose of capecitabine, 1600 mg/m2; escalated/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5 mg/kg) were investigated in a 3 + 3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results In Step 1, we included nine patients (three and six in levels 0 and + 1, respectively). Level 0 (irinotecan, 200 mg/m2; oxaliplatin, 100 mg/m2) did not demonstrate DLTs. In level + 1 (irinotecan, 200 mg/m2; oxaliplatin, 130 mg/m2), although one patient experienced grade 4 febrile neutropenia, no further safety concerns were observed. As a preliminary efficacy result, the objective response rate in all nine patients was 89 % (100 and 83 % in levels 0 and + 1, respectively). Conclusions The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600 mg/m2 for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5 mg/kg for bevacizumab. The randomized portion is still ongoing.

DOI： 10.1007/s10637-021-01125-2

Language：English   Publishing type：Research paper (scientific journal)  

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of localised colon cancer was published in 2020. It was decided by both the ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special virtual guidelines meeting in March 2021 to adapt the ESMO 2020 guidelines to take into account the ethnic differences associated with the treatment of localised colon cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with localised colon cancer representing the oncological societies of Japan (JSMO), China (CSCO), India (ISMPO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug availability and reimbursement situations in the different Asian countries.

DOI： 10.1016/j.annonc.2021.08.1752

Language：English   Publishing type：Research paper (scientific journal)  

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of localised colon cancer was published in 2020. It was decided by both the ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special virtual guidelines meeting in March 2021 to adapt the ESMO 2020 guidelines to take into account the ethnic differences associated with the treatment of localised colon cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with localised colon cancer representing the oncological societies of Japan (JSMO), China (CSCO), India (ISMPO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug availability and reimbursement situations in the different Asian countries.

DOI： 10.1016/j.annonc.2021.08.1752

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Patients with liver metastasis of head-and-neck carcinoma and esophageal carcinoma are generally not treated with hepatic resection, but there are no established standard treatment methods. We report 11 cases of hepatic resection for liver metastasis of head-and-neck carcinoma or esophageal carcinoma performed at 5 Japanese institutions. METHODS: The subjects of this retrospective analysis were 11 patients who underwent hepatic resection for metastatic liver tumors, originating from head-and-neck carcinoma in 5 and from esophageal cancer in 6, between January, 2010 and March, 2020 RESULTS: There were nine men and two women (median age, 64 years; range 40-72 years). The primary disease was esophageal carcinoma in six patients and pharyngeal carcinoma in five patients. All cancers were squamous cell carcinoma. The time from the initial treatment to the diagnosis of liver metastasis was 15.3 months and the 1-year and 3-year overall survival rates after hepatic resection were 72% and 32%, respectively. The overall and disease-free survival rates after hepatic resection were significantly higher for patients who underwent hepatic resection more than 12 months after the initial treatment than for those who underwent hepatic resection within 12 months after the initial treatment (p = 0.0172 and p = 0.0120, respectively). CONCLUSIONS: Liver resection may prolong the survival of patients with liver metastases controlled for more than 12 months after the initial treatment of head and neck or esophageal carcinoma.

DOI： 10.1007/s00595-021-02305-6

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Adjuvant chemotherapy reduces the risk of recurrence of stage III colon cancer (CC). However, more effective prognostic and predictive biomarkers are needed for better treatment stratification of affected patients. Here, we constructed a 55-gene classifier (55GC) and investigated its utility for classifying patients with stage III CC. METHODS: We retrospectively identified patients aged 20-79 years, with stage III CC, who received adjuvant chemotherapy with or without oxaliplatin, between the years 2009 and 2012. RESULTS: Among 938 eligible patients, 203 and 201 patients who received adjuvant chemotherapy with and without oxaliplatin, respectively, were selected by propensity score matching. Of these, 95 patients from each group were analyzed, and their 5-year relapse-free survival (RFS) rates with and without oxaliplatin were 73.7 and 77.1%, respectively. The hazard ratios for 5-year RFS following adjuvant chemotherapy (fluoropyrimidine), with and without oxaliplatin, were 1.241 (95% CI, 0.465-3.308; P = 0.67) and 0.791 (95% CI, 0.329-1.901; P = 0.60), respectively. Stratification using the 55GC revealed that 52 (27.3%), 78 (41.1%), and 60 (31.6%) patients had microsatellite instability (MSI)-like, chromosomal instability (CIN)-like, and stromal subtypes, respectively. The 5-year RFS rates were 84.3 and 72.0% in patients treated with and without oxaliplatin, respectively, for the MSI-like subtype (HR, 0.495; 95% CI, 0.145-1.692; P = 0.25). No differences in RFS rates were noted in the CIN-like or stromal subtypes. Stratification by cancer sidedness for each subtype showed improved RFS only in patients with left-sided primary cancer treated with oxaliplatin for the MSI-like subtype (P = 0.007). The 5-year RFS rates of the MSI-like subtype in left-sided cancer patients were 100 and 53.9% with and without oxaliplatin, respectively. CONCLUSIONS: Subclassification using 55GC and tumor sidedness revealed increased RFS in patients within the MSI-like subtype with stage III left-sided CC treated with fluoropyrimidine and oxaliplatin compared to those treated without oxaliplatin. However, the predictive power of 55GC subtyping alone did not reach statistical significance in this cohort, warranting larger prospective studies. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Education Network (UMIN) clinical trial registry (UMIN study ID: 000023879 ).

DOI： 10.1186/s12885-021-09088-6

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Early-onset (EO) colorectal cancer (CRC, age < 50 years) incidence is increasing. Decisions on optimal adjuvant therapy should consider treatment adherence, adverse events, and expected outcomes in a population with life expectancy longer than later-onset (LO) CRC (age ≥ 50 years). MATERIALS AND METHODS: Individual patient data from six trials in the International Duration Evaluation of Adjuvant Chemotherapy database were analyzed. Characteristics, treatment adherence, and adverse events in stage II or III EO-CRC and LO-CRC were compared. To reduce confounders of non-cancer-related deaths because of age or comorbidities, time to recurrence (3-year relapse-free rate) and cancer-specific survival (5-year cancer-specific mortality rate) were considered. RESULTS: Out of 16,349 patients, 1,564 (9.6%) had EO-CRC. Compared with LO-CRC, EO-CRC had better performance status (86% v 80%, P < .01), similar T stage (% T1-3/T4: 76/24 v 77/23, P = .97), higher N2 disease rate (24% v 22%, P < .01), more likely to complete the planned treatment duration (83.2% v 78.2%, P < .01), and received a higher treatment dose intensity, especially with 6-month regimens. Gastrointestinal toxicity was more common in EO-CRC; hematologic toxicity was more frequent in LO-CRC. Compared with LO-CRC, significantly worse cancer-specific outcomes were demonstrated especially in high-risk stage III EO-CRC: lower 3-year relapse-free rate (54% v 65%; hazard ratio [HR] 1.33; 95% CI, 1.14 to 1.55; P value < .001) and higher 5-year cancer-specific mortality rate (24% v 20%; HR 1.21; 95% CI, 1.00 to 1.47; P value < .06). In this subgroup, no difference was observed with 3 or 6 months of therapy, with equally poor disease-free survival rates (57% v 56%; HR 0.97; 95% CI, 0.73 to 1.29; P value = .85). CONCLUSION: Young age is negatively prognostic in high-risk stage III CRC and associated with significantly higher relapse rate; this is despite better treatment adherence and higher administered treatment intensity, suggesting more aggressive disease biology.

DOI： 10.1200/JCO.21.02008

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Patients with liver metastasis of head-and-neck carcinoma and esophageal carcinoma are generally not treated with hepatic resection, but there are no established standard treatment methods. We report 11 cases of hepatic resection for liver metastasis of head-and-neck carcinoma or esophageal carcinoma performed at 5 Japanese institutions. METHODS: The subjects of this retrospective analysis were 11 patients who underwent hepatic resection for metastatic liver tumors, originating from head-and-neck carcinoma in 5 and from esophageal cancer in 6, between January, 2010 and March, 2020 RESULTS: There were nine men and two women (median age, 64 years; range 40-72 years). The primary disease was esophageal carcinoma in six patients and pharyngeal carcinoma in five patients. All cancers were squamous cell carcinoma. The time from the initial treatment to the diagnosis of liver metastasis was 15.3 months and the 1-year and 3-year overall survival rates after hepatic resection were 72% and 32%, respectively. The overall and disease-free survival rates after hepatic resection were significantly higher for patients who underwent hepatic resection more than 12 months after the initial treatment than for those who underwent hepatic resection within 12 months after the initial treatment (p = 0.0172 and p = 0.0120, respectively). CONCLUSIONS: Liver resection may prolong the survival of patients with liver metastases controlled for more than 12 months after the initial treatment of head and neck or esophageal carcinoma.

DOI： 10.1007/s00595-021-02305-6

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Adjuvant chemotherapy reduces the risk of recurrence of stage III colon cancer (CC). However, more effective prognostic and predictive biomarkers are needed for better treatment stratification of affected patients. Here, we constructed a 55-gene classifier (55GC) and investigated its utility for classifying patients with stage III CC. METHODS: We retrospectively identified patients aged 20-79 years, with stage III CC, who received adjuvant chemotherapy with or without oxaliplatin, between the years 2009 and 2012. RESULTS: Among 938 eligible patients, 203 and 201 patients who received adjuvant chemotherapy with and without oxaliplatin, respectively, were selected by propensity score matching. Of these, 95 patients from each group were analyzed, and their 5-year relapse-free survival (RFS) rates with and without oxaliplatin were 73.7 and 77.1%, respectively. The hazard ratios for 5-year RFS following adjuvant chemotherapy (fluoropyrimidine), with and without oxaliplatin, were 1.241 (95% CI, 0.465-3.308; P = 0.67) and 0.791 (95% CI, 0.329-1.901; P = 0.60), respectively. Stratification using the 55GC revealed that 52 (27.3%), 78 (41.1%), and 60 (31.6%) patients had microsatellite instability (MSI)-like, chromosomal instability (CIN)-like, and stromal subtypes, respectively. The 5-year RFS rates were 84.3 and 72.0% in patients treated with and without oxaliplatin, respectively, for the MSI-like subtype (HR, 0.495; 95% CI, 0.145-1.692; P = 0.25). No differences in RFS rates were noted in the CIN-like or stromal subtypes. Stratification by cancer sidedness for each subtype showed improved RFS only in patients with left-sided primary cancer treated with oxaliplatin for the MSI-like subtype (P = 0.007). The 5-year RFS rates of the MSI-like subtype in left-sided cancer patients were 100 and 53.9% with and without oxaliplatin, respectively. CONCLUSIONS: Subclassification using 55GC and tumor sidedness revealed increased RFS in patients within the MSI-like subtype with stage III left-sided CC treated with fluoropyrimidine and oxaliplatin compared to those treated without oxaliplatin. However, the predictive power of 55GC subtyping alone did not reach statistical significance in this cohort, warranting larger prospective studies. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Education Network (UMIN) clinical trial registry (UMIN study ID: 000023879 ).

DOI： 10.1186/s12885-021-09088-6

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Early-onset (EO) colorectal cancer (CRC, age < 50 years) incidence is increasing. Decisions on optimal adjuvant therapy should consider treatment adherence, adverse events, and expected outcomes in a population with life expectancy longer than later-onset (LO) CRC (age ≥ 50 years). MATERIALS AND METHODS: Individual patient data from six trials in the International Duration Evaluation of Adjuvant Chemotherapy database were analyzed. Characteristics, treatment adherence, and adverse events in stage II or III EO-CRC and LO-CRC were compared. To reduce confounders of non-cancer-related deaths because of age or comorbidities, time to recurrence (3-year relapse-free rate) and cancer-specific survival (5-year cancer-specific mortality rate) were considered. RESULTS: Out of 16,349 patients, 1,564 (9.6%) had EO-CRC. Compared with LO-CRC, EO-CRC had better performance status (86% v 80%, P < .01), similar T stage (% T1-3/T4: 76/24 v 77/23, P = .97), higher N2 disease rate (24% v 22%, P < .01), more likely to complete the planned treatment duration (83.2% v 78.2%, P < .01), and received a higher treatment dose intensity, especially with 6-month regimens. Gastrointestinal toxicity was more common in EO-CRC; hematologic toxicity was more frequent in LO-CRC. Compared with LO-CRC, significantly worse cancer-specific outcomes were demonstrated especially in high-risk stage III EO-CRC: lower 3-year relapse-free rate (54% v 65%; hazard ratio [HR] 1.33; 95% CI, 1.14 to 1.55; P value < .001) and higher 5-year cancer-specific mortality rate (24% v 20%; HR 1.21; 95% CI, 1.00 to 1.47; P value < .06). In this subgroup, no difference was observed with 3 or 6 months of therapy, with equally poor disease-free survival rates (57% v 56%; HR 0.97; 95% CI, 0.73 to 1.29; P value = .85). CONCLUSION: Young age is negatively prognostic in high-risk stage III CRC and associated with significantly higher relapse rate; this is despite better treatment adherence and higher administered treatment intensity, suggesting more aggressive disease biology.

DOI： 10.1200/JCO.21.02008

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: An infusion-related reaction (IRR) is a well-known adverse event related to monoclonal antibodies, and antihistamine premedication is recommended to prevent IRRs. Ramucirumab plus FOLFIRI therapy is the standard second-line treatment for metastatic colorectal cancer (CRC). Ramucirumab is a fully human antibody, suggesting that the incidence of IRRs is lower, however, the current recommendation for the proper use of ramucirumab is antihistamine premedication, but the incidence and severity of ramucirumab-induced IRR without antihistamine premedication have not been elucidated. METHODS: A retrospective study to evaluate the incidence of ramucirumab-induced IRRs in unresectable CRC patients treated by ramucirumab plus FOLFIRI therapy. If the incidence of IRR without antihistamine premedication was not higher than that of cetuximab in a previous report (5.7%), planning a prospective study was considered. RESULTS: A total of 147 patients with unresectable CRC who had been treated by ramucirumab plus FOLFIRI therapy were identified. Of them, 106 (72%) patients received intravenous antihistamine premedication. An IRR occurred in 2 patients (1.4%), 1 grade 2 and 1 grade 3. They received antihistamine and steroid premedication. On the other hand, IRRs were not observed in 41 patients without antihistamine premedication, and the incidence of IRRs was significantly lower compared with the previous report of cetuximab (p < 0.001). CONCLUSION: The incidence of ramucirumab-induced IRRs without antihistamine premedication is low. Not using antihistamine premedication can decrease medical costs. These findings warrant further investigation in large-scale cohorts to clarify the incidence and severity of ramucirumab-induced IRRs and further clarify the proper use of ramucirumab.

DOI： 10.1007/s10147-021-02004-9

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: An infusion-related reaction (IRR) is a well-known adverse event related to monoclonal antibodies, and antihistamine premedication is recommended to prevent IRRs. Ramucirumab plus FOLFIRI therapy is the standard second-line treatment for metastatic colorectal cancer (CRC). Ramucirumab is a fully human antibody, suggesting that the incidence of IRRs is lower, however, the current recommendation for the proper use of ramucirumab is antihistamine premedication, but the incidence and severity of ramucirumab-induced IRR without antihistamine premedication have not been elucidated. METHODS: A retrospective study to evaluate the incidence of ramucirumab-induced IRRs in unresectable CRC patients treated by ramucirumab plus FOLFIRI therapy. If the incidence of IRR without antihistamine premedication was not higher than that of cetuximab in a previous report (5.7%), planning a prospective study was considered. RESULTS: A total of 147 patients with unresectable CRC who had been treated by ramucirumab plus FOLFIRI therapy were identified. Of them, 106 (72%) patients received intravenous antihistamine premedication. An IRR occurred in 2 patients (1.4%), 1 grade 2 and 1 grade 3. They received antihistamine and steroid premedication. On the other hand, IRRs were not observed in 41 patients without antihistamine premedication, and the incidence of IRRs was significantly lower compared with the previous report of cetuximab (p < 0.001). CONCLUSION: The incidence of ramucirumab-induced IRRs without antihistamine premedication is low. Not using antihistamine premedication can decrease medical costs. These findings warrant further investigation in large-scale cohorts to clarify the incidence and severity of ramucirumab-induced IRRs and further clarify the proper use of ramucirumab.

DOI： 10.1007/s10147-021-02004-9

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Oral mucositis (OM) is an unpleasant adverse event in patients receiving chemotherapy. A prospective feasibility study showed that elemental diet (ED), an oral supplement that does not require digestion, may prevent OM. Based on this, we established a central review system for oral cavity assessment by dental oncology specialists blinded to background data. We used this system to elucidate the preventive effect of an ED against OM in patients with esophageal cancer receiving docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy. PATIENTS AND METHODS: In this phase III, multicenter, parallel-group, controlled trial, patients consuming a normal diet orally were randomly assigned (1 : 1) to receive two cycles of DCF with (group A) or without (group B) an ED (Elental® 160 g/day). We assessed the incidence of grade ≥2 OM evaluated by two reviewers, changes in body weight, prealbumin, C-reactive protein, and DCF completion rate based on ED compliance. RESULTS: Of the 117 patients randomly assigned to treatment, four failed to start treatment and were excluded from the primary analysis; thus, groups A and B comprised 55 and 58 patients, respectively. There were no significant differences in background characteristics. Grade ≥2 OM was observed in eight (15%) and 20 (34%) patients in groups A and B, respectively (P = 0.0141). Changes in body weight and prealbumin during the two DCF cycles were significantly higher in group A than B (P = 0.0022 and 0.0203, respectively). During the first cycle, changes in C-reactive protein were significantly lower in group A than B (P = 0.0338). In group A (receiving ED), the DCF completion rate was 100% in patients with 100% ED compliance and 70% in patients failing ED completion (P = 0.0046). CONCLUSIONS: The study findings demonstrate that an ED can prevent OM in patients with esophageal cancer receiving chemotherapy.

DOI： 10.1016/j.esmoop.2021.100277

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To examine the relationship between circumferential tumor extent of colorectal cancer (CRC) on CT colonography (CTC) and clinicopathological features including patient prognosis after surgery. MATERIALS AND METHODS: This retrospective study performed at our institution from January 2013 to December 2019 enrolled 195 consecutive patients (110 men, 85 women; mean age, 64.7 years) with CRC evaluated by contrast-enhanced CTC before surgery. The circumferential tumor extent rate (CER) was measured by CTC in virtual colon dissection (VCD) mode to examine the relation between the CER and clinicopathological features and patient prognosis. RESULTS: CER had association with tumor invasion depth (T), nodal involvement (N), distant metastasis (M), and stage. The Kruskal-Wallis tests showed significant difference for T, N and the stage (p < 0.0001, p = 0.0021 and p < 0.0001) and Wilcoxon rank sum test showed significant difference for M (p = 0.0015). According to the log-rank test, there were no significant differences in OS or DFS between patients with high and low CER. CONCLUSION: Circumferential tumor extent was significantly correlated with TNM categories and stage of CRC, but not with patient prognosis after surgery.

DOI： 10.1007/s11604-021-01141-5

Language：English   Publishing type：Research paper (scientific journal)  

Cholangiocarcinoma is a biliary malignant tumor which can arise at any point of biliary tree. Surgical resection is the only curative treatment and chemotherapy is used for unresectable cases, but its prognosis is poor compared with other types of cancer. Recently, pembrolizumab (PEM), an anti-programmed cell death protein 1 (PD-1) antibody, has become available for microsatellite instability (MSI)-high advanced cancers. Here, we report the use of PEM for MSI-high locally advanced cholangiocarcinoma. A 57-year-old man presented to our department with jaundice. Contrast-enhanced computed tomography showed a solitary 28-mm-diameter tumor deep in the anterior segment of the liver. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography showed narrowing of the common bile duct and absence of contrast in the right hepatic duct, and tumor invaded from hilar region of liver into left hepatic duct. We diagnosed this as double primary cancers, locally advanced intrahepatic and distal cholangiocarcinomas. The patient began gemcitabine in combination with cisplatin therapy as first-line treatment and gemcitabine in combination with S-1 therapy as second-line treatment. However, the tumor gradually grew (maximum 69 mm), intrahepatic metastasis appeared, and tumor marker increased. Because MSI-high was confirmed not only by biopsy specimens but also by liquid biopsy, the patient began PEM (200 mg per every 3 weeks). After 15 cycles of PEM were administered over about 10 months, size of tumor was reduced and tumor marker dramatically decreased. We experienced the rare case which PEM has been successfully used for MSI-high double primary cancers.

DOI： 10.1007/s12328-021-01458-8

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To examine the relationship between circumferential tumor extent of colorectal cancer (CRC) on CT colonography (CTC) and clinicopathological features including patient prognosis after surgery. MATERIALS AND METHODS: This retrospective study performed at our institution from January 2013 to December 2019 enrolled 195 consecutive patients (110 men, 85 women; mean age, 64.7 years) with CRC evaluated by contrast-enhanced CTC before surgery. The circumferential tumor extent rate (CER) was measured by CTC in virtual colon dissection (VCD) mode to examine the relation between the CER and clinicopathological features and patient prognosis. RESULTS: CER had association with tumor invasion depth (T), nodal involvement (N), distant metastasis (M), and stage. The Kruskal-Wallis tests showed significant difference for T, N and the stage (p < 0.0001, p = 0.0021 and p < 0.0001) and Wilcoxon rank sum test showed significant difference for M (p = 0.0015). According to the log-rank test, there were no significant differences in OS or DFS between patients with high and low CER. CONCLUSION: Circumferential tumor extent was significantly correlated with TNM categories and stage of CRC, but not with patient prognosis after surgery.

DOI： 10.1007/s11604-021-01141-5

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Oral mucositis (OM) is an unpleasant adverse event in patients receiving chemotherapy. A prospective feasibility study showed that elemental diet (ED), an oral supplement that does not require digestion, may prevent OM. Based on this, we established a central review system for oral cavity assessment by dental oncology specialists blinded to background data. We used this system to elucidate the preventive effect of an ED against OM in patients with esophageal cancer receiving docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy. PATIENTS AND METHODS: In this phase III, multicenter, parallel-group, controlled trial, patients consuming a normal diet orally were randomly assigned (1 : 1) to receive two cycles of DCF with (group A) or without (group B) an ED (Elental® 160 g/day). We assessed the incidence of grade ≥2 OM evaluated by two reviewers, changes in body weight, prealbumin, C-reactive protein, and DCF completion rate based on ED compliance. RESULTS: Of the 117 patients randomly assigned to treatment, four failed to start treatment and were excluded from the primary analysis; thus, groups A and B comprised 55 and 58 patients, respectively. There were no significant differences in background characteristics. Grade ≥2 OM was observed in eight (15%) and 20 (34%) patients in groups A and B, respectively (P = 0.0141). Changes in body weight and prealbumin during the two DCF cycles were significantly higher in group A than B (P = 0.0022 and 0.0203, respectively). During the first cycle, changes in C-reactive protein were significantly lower in group A than B (P = 0.0338). In group A (receiving ED), the DCF completion rate was 100% in patients with 100% ED compliance and 70% in patients failing ED completion (P = 0.0046). CONCLUSIONS: The study findings demonstrate that an ED can prevent OM in patients with esophageal cancer receiving chemotherapy.

DOI： 10.1016/j.esmoop.2021.100277

Language：English   Publishing type：Research paper (scientific journal)  

Cholangiocarcinoma is a biliary malignant tumor which can arise at any point of biliary tree. Surgical resection is the only curative treatment and chemotherapy is used for unresectable cases, but its prognosis is poor compared with other types of cancer. Recently, pembrolizumab (PEM), an anti-programmed cell death protein 1 (PD-1) antibody, has become available for microsatellite instability (MSI)-high advanced cancers. Here, we report the use of PEM for MSI-high locally advanced cholangiocarcinoma. A 57-year-old man presented to our department with jaundice. Contrast-enhanced computed tomography showed a solitary 28-mm-diameter tumor deep in the anterior segment of the liver. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography showed narrowing of the common bile duct and absence of contrast in the right hepatic duct, and tumor invaded from hilar region of liver into left hepatic duct. We diagnosed this as double primary cancers, locally advanced intrahepatic and distal cholangiocarcinomas. The patient began gemcitabine in combination with cisplatin therapy as first-line treatment and gemcitabine in combination with S-1 therapy as second-line treatment. However, the tumor gradually grew (maximum 69 mm), intrahepatic metastasis appeared, and tumor marker increased. Because MSI-high was confirmed not only by biopsy specimens but also by liquid biopsy, the patient began PEM (200 mg per every 3 weeks). After 15 cycles of PEM were administered over about 10 months, size of tumor was reduced and tumor marker dramatically decreased. We experienced the rare case which PEM has been successfully used for MSI-high double primary cancers.

DOI： 10.1007/s12328-021-01458-8

Language：English  

DOI： 10.1007/s10120-021-01205-5

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Combination therapy comprised of fluoropyrimidine plus irinotecan with an angiogenesis inhibitor is widely used as a second-line treatment for metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: This retrospective study evaluated the efficacy and safety of fluorouracil and irinotecan (FOLFIRI) plus ramucirumab (RAM); FOLFIRI plus aflibercept (AFL); irinotecan and S-1 (IRIS) plus bevacizumab (BEV); and capecitabine and irinotecan (CAPIRI) plus BEV, with FOLFIRI plus BEV serving as the control among mCRC patients who failed treatment with fluoropyrimidine and oxaliplatin plus BEV. Data were collected from a medical claim database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). The primary outcome was time to treatment failure (TTF). Secondary outcomes were time to first subsequent therapy (TFST), overall survival (OS), and safety. RESULTS: Among 3,136 patients assessed, TTF was significantly shorter with FOLFIRI plus RAM (adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.26-1.56; P < .001) and FOLFIRI plus AFL (HR, 1.34; 95% CI, 1.09-1.66; P = .002), and significantly longer with IRIS plus BEV (HR, 0.80; 95% CI, 0.70-0.92; P = .002). TFST was significantly shorter with FOLFIRI plus RAM (HR, 1.32; 95% CI, 1.17-1.49; P < .001); no significant difference in OS was observed. The incidences of neutropenia requiring granulocyte colony-stimulating factor were significantly lower with IRIS plus BEV and CAPIRI plus BEV. CONCLUSION: Regarding TTF, BEV seemed to be a favorable option compared with RAM and AFL when combined with FOLFIRI, and IRIS might be preferable compared to FOLFIRI when combined with BEV for patients who failed to respond to fluoropyrimidine, oxaliplatin, and BEV.

DOI： 10.1016/j.clcc.2021.03.001

Language：English   Publishing type：Research paper (scientific journal)  

Gastric cancer (GC) is one of the most lethal malignant tumors. To improve the prognosis of GC, the identification of novel driver genes as therapeutic targets is in urgent need. Here, we aimed to identify novel driver genes and clarify their roles in gastric cancer. OSBPL3 was identified as a candidate driver gene by in silico analysis of public genomic datasets. OSBPL3 expression was analyzed by RT-qPCR and immunohistochemistry in GC cells and tissues. The biological functions and mechanisms of OSBPL3 in GC were examined in vitro and in vivo using GC cells. The association between OSBPL3 expression and clinical outcome in GC patients was also evaluated. Overexpression of OSBPL3 was detected in GC cells with OSBPL3 DNA copy number gains and promoter hypomethylation. OSBPL3-knockdown reduced GC cell growth in vitro and in vivo by inhibiting cell cycle progression. Moreover, an active Ras pull-down assay and western blotting demonstrated that OSBPL3 activates the R-Ras/Akt signaling pathway in GC cells. In a clinical analysis of two GC datasets, high OSBPL3 expression was predictive of a poor prognosis. Our findings suggest that OSBPL3 is a novel driver gene stimulating the R-Ras/Akt signaling pathway and a potential therapeutic target in GC patients.

DOI： 10.1038/s41598-021-98485-9

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Combination therapy comprised of fluoropyrimidine plus irinotecan with an angiogenesis inhibitor is widely used as a second-line treatment for metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: This retrospective study evaluated the efficacy and safety of fluorouracil and irinotecan (FOLFIRI) plus ramucirumab (RAM); FOLFIRI plus aflibercept (AFL); irinotecan and S-1 (IRIS) plus bevacizumab (BEV); and capecitabine and irinotecan (CAPIRI) plus BEV, with FOLFIRI plus BEV serving as the control among mCRC patients who failed treatment with fluoropyrimidine and oxaliplatin plus BEV. Data were collected from a medical claim database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). The primary outcome was time to treatment failure (TTF). Secondary outcomes were time to first subsequent therapy (TFST), overall survival (OS), and safety. RESULTS: Among 3,136 patients assessed, TTF was significantly shorter with FOLFIRI plus RAM (adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.26-1.56; P < .001) and FOLFIRI plus AFL (HR, 1.34; 95% CI, 1.09-1.66; P = .002), and significantly longer with IRIS plus BEV (HR, 0.80; 95% CI, 0.70-0.92; P = .002). TFST was significantly shorter with FOLFIRI plus RAM (HR, 1.32; 95% CI, 1.17-1.49; P < .001); no significant difference in OS was observed. The incidences of neutropenia requiring granulocyte colony-stimulating factor were significantly lower with IRIS plus BEV and CAPIRI plus BEV. CONCLUSION: Regarding TTF, BEV seemed to be a favorable option compared with RAM and AFL when combined with FOLFIRI, and IRIS might be preferable compared to FOLFIRI when combined with BEV for patients who failed to respond to fluoropyrimidine, oxaliplatin, and BEV.

DOI： 10.1016/j.clcc.2021.03.001

Language：English   Publishing type：Research paper (scientific journal)  

Gastric cancer (GC) is one of the most lethal malignant tumors. To improve the prognosis of GC, the identification of novel driver genes as therapeutic targets is in urgent need. Here, we aimed to identify novel driver genes and clarify their roles in gastric cancer. OSBPL3 was identified as a candidate driver gene by in silico analysis of public genomic datasets. OSBPL3 expression was analyzed by RT-qPCR and immunohistochemistry in GC cells and tissues. The biological functions and mechanisms of OSBPL3 in GC were examined in vitro and in vivo using GC cells. The association between OSBPL3 expression and clinical outcome in GC patients was also evaluated. Overexpression of OSBPL3 was detected in GC cells with OSBPL3 DNA copy number gains and promoter hypomethylation. OSBPL3-knockdown reduced GC cell growth in vitro and in vivo by inhibiting cell cycle progression. Moreover, an active Ras pull-down assay and western blotting demonstrated that OSBPL3 activates the R-Ras/Akt signaling pathway in GC cells. In a clinical analysis of two GC datasets, high OSBPL3 expression was predictive of a poor prognosis. Our findings suggest that OSBPL3 is a novel driver gene stimulating the R-Ras/Akt signaling pathway and a potential therapeutic target in GC patients.

DOI： 10.1038/s41598-021-98485-9

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: CD44 variant 9 (CD44v9) has been reported to suppress reactive oxygen spices (ROS) in association with antioxidant factors such as glutathione (GSH) and glutathione peroxidase 2 (GPx2), resulting in promoted tumor growth. METHODS: CD44v9 and GPx2 expression were investigated by immunohistochemistry in resected specimens from 193 gastric cancer (GC) patients without preoperative chemotherapy and in pretreatment biopsy specimens from 29 GC patients with preoperative chemotherapy. We analyzed the relationship between CD44v9 expression and clinicopathological factors, prognosis, and pathological response to chemotherapy. In GC cell lines, we examined the relationship between CD44v9 expression and chemotherapeutic sensitivity. RESULTS: In patients without preoperative chemotherapy, CD44v9 expression was significantly associated with depth of invasion, lymphatic permeation, vascular invasion, distant metastasis and GPx2 expression. In multivariate analysis, CD44v9 expression was an independent poor prognosis factor for overall survival and recurrence-free survival. In patients with preoperative chemotherapy, CD44v9 expression was significantly associated with worse pathological response and GPx2 expression. In GC cell lines, downregulation of CD44v9 expression enhanced chemotherapeutic sensitivity to 5-fluorouracil with changing GSH and ROS levels. CONCLUSIONS: CD44v9-positive expression was associated with chemotherapeutic resistance by controlling intracellular accumulated ROS, suggesting that CD44v9 may be a predictive biomarker for chemotherapy in GC.

DOI： 10.1007/s10120-021-01194-5

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: CD44 variant 9 (CD44v9) has been reported to suppress reactive oxygen spices (ROS) in association with antioxidant factors such as glutathione (GSH) and glutathione peroxidase 2 (GPx2), resulting in promoted tumor growth. METHODS: CD44v9 and GPx2 expression were investigated by immunohistochemistry in resected specimens from 193 gastric cancer (GC) patients without preoperative chemotherapy and in pretreatment biopsy specimens from 29 GC patients with preoperative chemotherapy. We analyzed the relationship between CD44v9 expression and clinicopathological factors, prognosis, and pathological response to chemotherapy. In GC cell lines, we examined the relationship between CD44v9 expression and chemotherapeutic sensitivity. RESULTS: In patients without preoperative chemotherapy, CD44v9 expression was significantly associated with depth of invasion, lymphatic permeation, vascular invasion, distant metastasis and GPx2 expression. In multivariate analysis, CD44v9 expression was an independent poor prognosis factor for overall survival and recurrence-free survival. In patients with preoperative chemotherapy, CD44v9 expression was significantly associated with worse pathological response and GPx2 expression. In GC cell lines, downregulation of CD44v9 expression enhanced chemotherapeutic sensitivity to 5-fluorouracil with changing GSH and ROS levels. CONCLUSIONS: CD44v9-positive expression was associated with chemotherapeutic resistance by controlling intracellular accumulated ROS, suggesting that CD44v9 may be a predictive biomarker for chemotherapy in GC.

DOI： 10.1007/s10120-021-01194-5

Language：English   Publishing type：Research paper (scientific journal)  

Signal regulatory protein alpha (SIRPα) is a type I transmembrane protein that inhibits macrophage phagocytosis of tumor cells upon interaction with CD47, and the CD47-SIRPα pathway acts as an immune checkpoint factor in cancers. This study aims to clarify the clinical significance of SIRPα expression in esophageal squamous cell carcinoma (ESCC). First, we assessed SIRPα expression using RNA sequencing data of 95 ESCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical analytic data from our cohort of 131 patients with ESCC. Next, we investigated the correlation of SIRPα expression with clinicopathological factors, patient survival, infiltration of tumor immune cells, and expression of programmed cell death-ligand 1 (PD-L1). Overall survival was significantly poorer with high SIRPα expression than with low expression in both TCGA and our patient cohort (P < .001 and P = .027, respectively). High SIRPα expression was associated with greater depth of tumor invasion (P = .0017). Expression of SIRPα was also significantly correlated with the tumor infiltration of M1 macrophages, M2 macrophages, CD8+ T cells, and PD-L1 expression (P < .001, P < .001, P = .03, and P < .001, respectively). Moreover, patients with SIRPα/PD-L1 coexpression tended to have a worse prognosis than patients with expression of either protein alone or neither. Taken together, SIRPα indicates poor prognosis in ESCC, possibly through inhibiting macrophage phagocytosis of tumor cells and inducing suppression of antitumor immunity. Signal regulatory protein alpha should be considered as a potential therapeutic target in ESCC, especially if combined with PD-1-PD-L1 blockade.

DOI： 10.1111/cas.14971

Language：English   Publishing type：Research paper (scientific journal)  

AIMS: Histological categorisation of the desmoplastic reaction (DR) is an independent prognostic factor in colorectal cancer. However, it is unknown whether DR categorisation is predictive of oesophageal squamous cell carcinoma (OSCC) outcomes. This study aimed to evaluate the prognostic value of DR categorisation in OSCC patients. METHODS AND RESULTS: Data were collected from 118 patients with OSCC who underwent a curative oesophagectomy with T2 or deeper wall invasion. The DR in each tumour was classified as mature, intermediate or immature based on the presence or absence of keloid-like collagen and myxoid stroma. We identified 49 mature DR tumours, 41 intermediate DR tumours and 28 immature DR tumours. The 5-year overall survival (OS) rate was highest in the mature DR group (42.8%), followed by the intermediate DR group (25.0%) and the immature DR group (19.9%) (P = 0.022, log-rank test; P = 0.006, log-rank trend test). The 5-year disease-specific survival (DSS) rate was also highest in the mature DR group (48.5%), followed by the intermediate DR group (30.8%) and the immature DR group (26.8%) (P = 0.031, log-rank test; P = 0.010, log-rank trend test, respectively). Multivariate analysis revealed that an immature DR was an independent poor prognostic factor of OS and DSS (P = 0.002 and P = 0.004). CONCLUSIONS: DR categorisation of OSCC stroma following oesophagectomy is a useful diagnostic tool and an independent prognostic marker.

DOI： 10.1111/his.14357

Language：English   Publishing type：Research paper (scientific journal)  

AIMS: Histological categorisation of the desmoplastic reaction (DR) is an independent prognostic factor in colorectal cancer. However, it is unknown whether DR categorisation is predictive of oesophageal squamous cell carcinoma (OSCC) outcomes. This study aimed to evaluate the prognostic value of DR categorisation in OSCC patients. METHODS AND RESULTS: Data were collected from 118 patients with OSCC who underwent a curative oesophagectomy with T2 or deeper wall invasion. The DR in each tumour was classified as mature, intermediate or immature based on the presence or absence of keloid-like collagen and myxoid stroma. We identified 49 mature DR tumours, 41 intermediate DR tumours and 28 immature DR tumours. The 5-year overall survival (OS) rate was highest in the mature DR group (42.8%), followed by the intermediate DR group (25.0%) and the immature DR group (19.9%) (P = 0.022, log-rank test; P = 0.006, log-rank trend test). The 5-year disease-specific survival (DSS) rate was also highest in the mature DR group (48.5%), followed by the intermediate DR group (30.8%) and the immature DR group (26.8%) (P = 0.031, log-rank test; P = 0.010, log-rank trend test, respectively). Multivariate analysis revealed that an immature DR was an independent poor prognostic factor of OS and DSS (P = 0.002 and P = 0.004). CONCLUSIONS: DR categorisation of OSCC stroma following oesophagectomy is a useful diagnostic tool and an independent prognostic marker.

DOI： 10.1111/his.14357

Language：English   Publishing type：Research paper (scientific journal)  

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.

DOI： 10.1111/cas.14926

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. METHODS: APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. RESULTS: Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1-5 and 8-12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8-45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5-6.5), 14.1 months (95% CI 12.2-19.3), 37.0% (95% CI 24.3-51.3), 81.5% (95% CI 68.6-90.8), and 5.8 months (95% CI 4.29-6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. CONCLUSION: Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

DOI： 10.1007/s10147-021-01902-2

Language：English   Publishing type：Research paper (scientific journal)  

Cancer research has made remarkable progress and new discoveries are beginning to be made. For example, the discovery of immune checkpoint inhibition mechanisms in cancer cells has led to the development of immune checkpoint inhibitors that have benefited many cancer patients. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiome, immunotherapy. and organoids. Exosomes research will lead to further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods. Microbiome are important in understanding the disease. Immunotherapy is the fourth treatment in cancer therapy. Organoid biology will further develop with a goal of translating the research into personalized therapy. These research areas may result in the creation of new cancer treatments in the future.

DOI： 10.1002/ags3.12440

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. METHODS: APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. RESULTS: Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1-5 and 8-12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8-45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5-6.5), 14.1 months (95% CI 12.2-19.3), 37.0% (95% CI 24.3-51.3), 81.5% (95% CI 68.6-90.8), and 5.8 months (95% CI 4.29-6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. CONCLUSION: Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

DOI： 10.1007/s10147-021-01902-2

Language：English   Publishing type：Research paper (scientific journal)  

Cancer research has made remarkable progress and new discoveries are beginning to be made. For example, the discovery of immune checkpoint inhibition mechanisms in cancer cells has led to the development of immune checkpoint inhibitors that have benefited many cancer patients. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiome, immunotherapy. and organoids. Exosomes research will lead to further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods. Microbiome are important in understanding the disease. Immunotherapy is the fourth treatment in cancer therapy. Organoid biology will further develop with a goal of translating the research into personalized therapy. These research areas may result in the creation of new cancer treatments in the future.

DOI： 10.1002/ags3.12440

Language：English   Publishing type：Research paper (scientific journal)  

Approximately 12-15% of gastric cancers (GCs) are human epidermal growth factor receptor-2 (HER2)-positive (HER2 immunohistochemistry 3 + or 2 + /in situ hybridization + [ERBB2/CEP17 ≥ 2.0]). While the anti-HER2 monoclonal antibody trastuzumab, in combination with chemotherapy, is the standard treatment for HER2-positive GC, other HER2-targeted therapies have not demonstrated survival benefits in patients with GC, despite showing efficacy in patients with HER2-positive breast cancer. This indicates that there are unique challenges to the use of currently available HER2-targeted therapies for the treatment of HER2-positive GC. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 human monoclonal IgG1 antibody with the same amino acid sequence as trastuzumab, an enzymatically cleavable peptide-based linker, and DXd, a novel topoisomerase I inhibitor, as its released payload. T-DXd has a high drug-antibody ratio (approximately 8) and a demonstrated bystander antitumor effect. It has demonstrated significant efficacy when compared with standard therapies and is approved as third- or later-line treatment for HER2-positive GC in Japan and second- or later-line treatment in the US. T-DXd treatment is associated with gastrointestinal and hematological adverse events, and a risk of interstitial lung disease (ILD), with the ILD risk being higher in Japan than in countries other than Japan. However, most adverse events, including ILD, can be managed with proactive monitoring and T-DXd dose modification, and initiation of adequate treatment. In this review, we summarize the discovery and development of T-DXd and provide guidance for T-DXd safety management, including ILD monitoring, for patients with HER2-positive GC.

DOI： 10.1007/s10120-021-01196-3

Language：English   Publishing type：Research paper (scientific journal)  

Approximately 12-15% of gastric cancers (GCs) are human epidermal growth factor receptor-2 (HER2)-positive (HER2 immunohistochemistry 3 + or 2 + /in situ hybridization + [ERBB2/CEP17 ≥ 2.0]). While the anti-HER2 monoclonal antibody trastuzumab, in combination with chemotherapy, is the standard treatment for HER2-positive GC, other HER2-targeted therapies have not demonstrated survival benefits in patients with GC, despite showing efficacy in patients with HER2-positive breast cancer. This indicates that there are unique challenges to the use of currently available HER2-targeted therapies for the treatment of HER2-positive GC. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 human monoclonal IgG1 antibody with the same amino acid sequence as trastuzumab, an enzymatically cleavable peptide-based linker, and DXd, a novel topoisomerase I inhibitor, as its released payload. T-DXd has a high drug-antibody ratio (approximately 8) and a demonstrated bystander antitumor effect. It has demonstrated significant efficacy when compared with standard therapies and is approved as third- or later-line treatment for HER2-positive GC in Japan and second- or later-line treatment in the US. T-DXd treatment is associated with gastrointestinal and hematological adverse events, and a risk of interstitial lung disease (ILD), with the ILD risk being higher in Japan than in countries other than Japan. However, most adverse events, including ILD, can be managed with proactive monitoring and T-DXd dose modification, and initiation of adequate treatment. In this review, we summarize the discovery and development of T-DXd and provide guidance for T-DXd safety management, including ILD monitoring, for patients with HER2-positive GC.

DOI： 10.1007/s10120-021-01196-3

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-020-09584-2

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The aim of this study was to develop a radiomics-based prediction model for the response of colorectal liver metastases to oxaliplatin-based chemotherapy. METHODS: Forty-two consecutive patients treated with oxaliplatin-based first-line chemotherapy for colorectal liver metastasis at our institution from August 2013 to October 2019 were enrolled in this retrospective study. Overall, 126 liver metastases were chronologically divided into the training (n = 94) and validation (n = 32) cohorts. Regions of interest were manually segmented, and the best response to chemotherapy was decided based on Response Evaluation Criteria in Solid Tumors (RECIST). Patients who achieved clinical complete and partial response according to RECIST were defined as good responders. Radiomics features were extracted from the pretreatment enhanced computed tomography scans, and a radiomics score was calculated using the least absolute shrinkage and selection operator regression model in a trial cohort. RESULTS: The radiomics score significantly discriminated good responders in both the trial (area under the curve [AUC] 0.8512, 95% confidence interval [CI] 0.7719-0.9305; p < 0.0001) and validation (AUC 0.7792, 95% CI 0.6176-0.9407; p < 0.0001) cohorts. Multivariate analysis revealed that high radiomics scores greater than - 0.06 (odds ratio [OR] 23.803, 95% CI 8.432-80.432; p < 0.0001), clinical non-T4 (OR 6.054, 95% CI 2.164-18.394; p = 0.0005), and metachronous disease (OR 11.787, 95% CI 2.333-70.833; p = 0.0025) were independently associated with good response. CONCLUSIONS: Radiomics signatures may be a potential biomarker for the early prediction of chemosensitivity in colorectal liver metastases. This approach may support the treatment strategy for colorectal liver metastasis.

DOI： 10.1245/s10434-020-09581-5

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge. METHODS: This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360). DISCUSSION: Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative. TRIAL REGISTRATION: The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.

DOI： 10.1186/s12885-021-08395-2

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: The camptothecin (CPT) analogs topotecan and irinotecan specifically target topoisomerase I (topoI) and are used to treat colorectal, gastric, and pancreatic cancer. Response rate for this class of drug varies from 10% to 30%, and there is no predictive biomarker for patient stratification by response. On the basis of our understanding of CPT drug resistance mechanisms, we developed an immunohistochemistry-based predictive test, P-topoI-Dx, to stratify the patient population into those who did and did not experience a response. PATIENTS AND METHODS: The retrospective validation studies included a training set (n = 79) and a validation cohort (n = 27) of gastric cancer (GC) patients, and 8 cohorts of colorectal cancer (CRC) patient tissue (n = 176). Progression-free survival for 6 months was considered a positive response to CPT-based therapy. Formalin-fixed, paraffin-embedded slides were immunohistochemically stained with anti-phospho-specific topoI-Serine10 (topoI-pS10), quantitated, and analyzed statistically. RESULTS: We determined a threshold of 35% positive staining to offer optimal test characteristics in GC. The GC (n = 79) training set demonstrated 76.6% (95% confidence interval, 64-86) sensitivity; 68.8% (41-88) specificity; positive predictive value (PPV) 92.5% (81-98); and negative predictive value (NPV) 42.3% (24-62). The GC validation set (n = 27) demonstrated 82.4% (56-95) sensitivity and 70.0% (35-92) specificity. Estimated PPV and NPV were 82.4% (56-95) and 70.0% (35-92) respectively. In the CRC validation set (n = 176), the 40% threshold demonstrated 87.5% (78-94) sensitivity; 70.0% (59-79) specificity; PPV 70.7% (61-79); and NPV 87.0 % (77-93). CONCLUSION: The analysis of retrospective data from patients (n = 282) provides clinical validity to our P-topoI-Dx immunohistochemical test to identify patients with disease that is most likely to respond to topoI inhibitors.

DOI： 10.1016/j.clcc.2020.11.005

Language：English   Publishing type：Research paper (scientific journal)  

Trifluridine/tipiracil (FTD/TPI) is an orally administrated anticancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC) or gastric cancer. FTD, a key component of FTD/TPI, exerts antitumor effects via its incorporation into DNA. Using specific antibodies against bromodeoxyuridine, FTD incorporation into DNA is detected in tumors and peripheral blood mononuclear cells (PBMC) of patients with mCRC who are administered FTD/TPI. The proportion of FTD-positive PBMC fluctuates according to the schedule of treatment, although the association between the proportion of FTD-positive PBMC and the clinical outcomes of patients is unknown. To answer this question, here we monitored the FTD-positive PBMC of 39 elderly patients with mCRC enrolled in KSCC1602, a single-arm phase 2 trial of FTD/TPI plus bevacizumab as a first-line treatment, for 1 month, during the first cycle of treatment. The median values and interquartile ranges of the percentage of FTD-positive PBMC on days 8, 15, and 29 were 39.3% (30.7%-52.2%), 66.9% (40.0%-75.3%), and 13.5% (5.7%-26.0%), respectively. Receiver operating characteristic analysis revealed that the percentage of FTD-positive PBMC on day 8 (the end of the first week of treatment) had moderate ability to accurately diagnose the occurrence of severe neutropenia and leukopenia within 1 month (area under the curve = 0.778 [95% confidence interval, 0.554-0.993]). This result suggests that excess FTD incorporation into PBMC at the initial phase of FTD/TPI plus bevacizumab treatment is a risk factor for early onset of severe hematological adverse events.

DOI： 10.1111/cas.14904

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Recent advances in adjuvant chemotherapy for early colon cancer have widened physicians' recommendations on the regimen and duration (3 or 6 months) of the treatment. We conducted this prospective study to evaluate whether the 12-gene recurrence score (12-RS) assay affected physicians' recommendations on adjuvant treatment selection. PATIENTS AND METHODS: Patients with stage IIIA/IIIB or stage II colon cancer were enrolled. After the patients discussed adjuvant treatment with their treating physicians, the physicians filled in the questionnaire before assay indicating the treatment recommendation. When the 12-RS assay results were available, the physicians again filled in the questionnaire after assay. The primary endpoint was the rate of change in treatment recommendations from before to after the assay, with a threshold rate of change being 20%. Patients with stage IIIA/B to II were enrolled in a ratio of 2 : 1. RESULTS: Overall, the treatment recommendations changed in 40% of cases after obtaining 12-RS assay results. Recommendations were changed in 45% (80/178; 95% confidence interval, 37% to 53%; P < 0.001) and 30% (29/97; 95% confidence interval, 21% to 40%; P < 0.001) of patients with stage IIIA/B and II colon cancer, respectively. Patients with stage IIIA/B cancer had significantly more change than those with stage II cancer (P = 0.0148). From before to after the 12-RS assay, the percentage of patients whose physicians reported being confident in their treatment recommendations significantly increased from 54% to 81% in stage IIIA/B (P < 0.001) and from 65% to 83% in stage II (P < 0.001). CONCLUSION: Our study confirmed the usefulness of the 12-RS assay in aiding the physician-patient decision-making process for tailoring adjuvant chemotherapy for stage IIIA/B colon cancer.

DOI： 10.1016/j.esmoop.2021.100146

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The aim of this study was to develop a radiomics-based prediction model for the response of colorectal liver metastases to oxaliplatin-based chemotherapy. METHODS: Forty-two consecutive patients treated with oxaliplatin-based first-line chemotherapy for colorectal liver metastasis at our institution from August 2013 to October 2019 were enrolled in this retrospective study. Overall, 126 liver metastases were chronologically divided into the training (n = 94) and validation (n = 32) cohorts. Regions of interest were manually segmented, and the best response to chemotherapy was decided based on Response Evaluation Criteria in Solid Tumors (RECIST). Patients who achieved clinical complete and partial response according to RECIST were defined as good responders. Radiomics features were extracted from the pretreatment enhanced computed tomography scans, and a radiomics score was calculated using the least absolute shrinkage and selection operator regression model in a trial cohort. RESULTS: The radiomics score significantly discriminated good responders in both the trial (area under the curve [AUC] 0.8512, 95% confidence interval [CI] 0.7719-0.9305; p < 0.0001) and validation (AUC 0.7792, 95% CI 0.6176-0.9407; p < 0.0001) cohorts. Multivariate analysis revealed that high radiomics scores greater than - 0.06 (odds ratio [OR] 23.803, 95% CI 8.432-80.432; p < 0.0001), clinical non-T4 (OR 6.054, 95% CI 2.164-18.394; p = 0.0005), and metachronous disease (OR 11.787, 95% CI 2.333-70.833; p = 0.0025) were independently associated with good response. CONCLUSIONS: Radiomics signatures may be a potential biomarker for the early prediction of chemosensitivity in colorectal liver metastases. This approach may support the treatment strategy for colorectal liver metastasis.

DOI： 10.1245/s10434-020-09581-5

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge. METHODS: This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360). DISCUSSION: Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative. TRIAL REGISTRATION: The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.

DOI： 10.1186/s12885-021-08395-2

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Tumor mutational burden-high (TMB-H), which is detected with gene panel testing, is a promising biomarker for immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC). However, in clinical practice, not every patient is tested for TMB-H using gene panel testing. We aimed to identify the histopathological characteristics of TMB-H CRC for efficient selection of patients who should undergo gene panel testing. Moreover, we attempted to develop a convolutional neural network (CNN)-based algorithm to predict TMB-H CRC directly from hematoxylin and eosin (H&E) slides. METHODS: We used two CRC cohorts tested for TMB-H, and whole-slide H&E digital images were obtained from the cohorts. The Japanese CRC (JP-CRC) cohort (N = 201) was evaluated to detect the histopathological characteristics of TMB-H using H&E slides. The JP-CRC cohort and The Cancer Genome Atlas (TCGA) CRC cohort (N = 77) were used to develop a CNN-based TMB-H prediction model from the H&E digital images. RESULTS: Tumor-infiltrating lymphocytes (TILs) were significantly associated with TMB-H CRC (P < 0.001). The area under the curve (AUC) for predicting TMB-H CRC was 0.910. We developed a CNN-based TMB-H prediction model. Validation tests were conducted 10 times using randomly selected slides, and the average AUC for predicting TMB-H slides was 0.934. CONCLUSIONS: TILs, a histopathological characteristic detected with H&E slides, are associated with TMB-H CRC. Our CNN-based model has the potential to predict TMB-H CRC directly from H&E slides, thereby reducing the burden on pathologists. These approaches will provide clinicians with important information about the applications of ICIs at low cost.

DOI： 10.1007/s00535-021-01789-w

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: The camptothecin (CPT) analogs topotecan and irinotecan specifically target topoisomerase I (topoI) and are used to treat colorectal, gastric, and pancreatic cancer. Response rate for this class of drug varies from 10% to 30%, and there is no predictive biomarker for patient stratification by response. On the basis of our understanding of CPT drug resistance mechanisms, we developed an immunohistochemistry-based predictive test, P-topoI-Dx, to stratify the patient population into those who did and did not experience a response. PATIENTS AND METHODS: The retrospective validation studies included a training set (n = 79) and a validation cohort (n = 27) of gastric cancer (GC) patients, and 8 cohorts of colorectal cancer (CRC) patient tissue (n = 176). Progression-free survival for 6 months was considered a positive response to CPT-based therapy. Formalin-fixed, paraffin-embedded slides were immunohistochemically stained with anti-phospho-specific topoI-Serine10 (topoI-pS10), quantitated, and analyzed statistically. RESULTS: We determined a threshold of 35% positive staining to offer optimal test characteristics in GC. The GC (n = 79) training set demonstrated 76.6% (95% confidence interval, 64-86) sensitivity; 68.8% (41-88) specificity; positive predictive value (PPV) 92.5% (81-98); and negative predictive value (NPV) 42.3% (24-62). The GC validation set (n = 27) demonstrated 82.4% (56-95) sensitivity and 70.0% (35-92) specificity. Estimated PPV and NPV were 82.4% (56-95) and 70.0% (35-92) respectively. In the CRC validation set (n = 176), the 40% threshold demonstrated 87.5% (78-94) sensitivity; 70.0% (59-79) specificity; PPV 70.7% (61-79); and NPV 87.0 % (77-93). CONCLUSION: The analysis of retrospective data from patients (n = 282) provides clinical validity to our P-topoI-Dx immunohistochemical test to identify patients with disease that is most likely to respond to topoI inhibitors.

DOI： 10.1016/j.clcc.2020.11.005

Language：English   Publishing type：Research paper (scientific journal)  

Trifluridine/tipiracil (FTD/TPI) is an orally administrated anticancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC) or gastric cancer. FTD, a key component of FTD/TPI, exerts antitumor effects via its incorporation into DNA. Using specific antibodies against bromodeoxyuridine, FTD incorporation into DNA is detected in tumors and peripheral blood mononuclear cells (PBMC) of patients with mCRC who are administered FTD/TPI. The proportion of FTD-positive PBMC fluctuates according to the schedule of treatment, although the association between the proportion of FTD-positive PBMC and the clinical outcomes of patients is unknown. To answer this question, here we monitored the FTD-positive PBMC of 39 elderly patients with mCRC enrolled in KSCC1602, a single-arm phase 2 trial of FTD/TPI plus bevacizumab as a first-line treatment, for 1 month, during the first cycle of treatment. The median values and interquartile ranges of the percentage of FTD-positive PBMC on days 8, 15, and 29 were 39.3% (30.7%-52.2%), 66.9% (40.0%-75.3%), and 13.5% (5.7%-26.0%), respectively. Receiver operating characteristic analysis revealed that the percentage of FTD-positive PBMC on day 8 (the end of the first week of treatment) had moderate ability to accurately diagnose the occurrence of severe neutropenia and leukopenia within 1 month (area under the curve = 0.778 [95% confidence interval, 0.554-0.993]). This result suggests that excess FTD incorporation into PBMC at the initial phase of FTD/TPI plus bevacizumab treatment is a risk factor for early onset of severe hematological adverse events.

DOI： 10.1111/cas.14904

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Recent advances in adjuvant chemotherapy for early colon cancer have widened physicians' recommendations on the regimen and duration (3 or 6 months) of the treatment. We conducted this prospective study to evaluate whether the 12-gene recurrence score (12-RS) assay affected physicians' recommendations on adjuvant treatment selection. PATIENTS AND METHODS: Patients with stage IIIA/IIIB or stage II colon cancer were enrolled. After the patients discussed adjuvant treatment with their treating physicians, the physicians filled in the questionnaire before assay indicating the treatment recommendation. When the 12-RS assay results were available, the physicians again filled in the questionnaire after assay. The primary endpoint was the rate of change in treatment recommendations from before to after the assay, with a threshold rate of change being 20%. Patients with stage IIIA/B to II were enrolled in a ratio of 2 : 1. RESULTS: Overall, the treatment recommendations changed in 40% of cases after obtaining 12-RS assay results. Recommendations were changed in 45% (80/178; 95% confidence interval, 37% to 53%; P < 0.001) and 30% (29/97; 95% confidence interval, 21% to 40%; P < 0.001) of patients with stage IIIA/B and II colon cancer, respectively. Patients with stage IIIA/B cancer had significantly more change than those with stage II cancer (P = 0.0148). From before to after the 12-RS assay, the percentage of patients whose physicians reported being confident in their treatment recommendations significantly increased from 54% to 81% in stage IIIA/B (P < 0.001) and from 65% to 83% in stage II (P < 0.001). CONCLUSION: Our study confirmed the usefulness of the 12-RS assay in aiding the physician-patient decision-making process for tailoring adjuvant chemotherapy for stage IIIA/B colon cancer.

DOI： 10.1016/j.esmoop.2021.100146

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Tumor mutational burden-high (TMB-H), which is detected with gene panel testing, is a promising biomarker for immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC). However, in clinical practice, not every patient is tested for TMB-H using gene panel testing. We aimed to identify the histopathological characteristics of TMB-H CRC for efficient selection of patients who should undergo gene panel testing. Moreover, we attempted to develop a convolutional neural network (CNN)-based algorithm to predict TMB-H CRC directly from hematoxylin and eosin (H&E) slides. METHODS: We used two CRC cohorts tested for TMB-H, and whole-slide H&E digital images were obtained from the cohorts. The Japanese CRC (JP-CRC) cohort (N = 201) was evaluated to detect the histopathological characteristics of TMB-H using H&E slides. The JP-CRC cohort and The Cancer Genome Atlas (TCGA) CRC cohort (N = 77) were used to develop a CNN-based TMB-H prediction model from the H&E digital images. RESULTS: Tumor-infiltrating lymphocytes (TILs) were significantly associated with TMB-H CRC (P < 0.001). The area under the curve (AUC) for predicting TMB-H CRC was 0.910. We developed a CNN-based TMB-H prediction model. Validation tests were conducted 10 times using randomly selected slides, and the average AUC for predicting TMB-H slides was 0.934. CONCLUSIONS: TILs, a histopathological characteristic detected with H&E slides, are associated with TMB-H CRC. Our CNN-based model has the potential to predict TMB-H CRC directly from H&E slides, thereby reducing the burden on pathologists. These approaches will provide clinicians with important information about the applications of ICIs at low cost.

DOI： 10.1007/s00535-021-01789-w

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: OncoBEAM™ is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital PCR technology. We clarified the association between the baseline tumor burden and discordance in the RAS status by metastatic sites in patients with a single metastatic site. EXPERIMENTAL DESIGN: Data from previous Spanish and Japanese studies investigating the concordance of the RAS status between OncoBEAM™ and tissue biopsy in 221 patients with metastatic colorectal cancer (mCRC) were used. We collected data from patients with liver, peritoneal, or lung metastases and evaluated the concordance rates according to the metastatic site and the association between the concordance rate and tumor burden. RESULTS: Patients had metastases in the liver (n = 151), peritoneum (n = 25), or lung (n = 45) with concordance rates of 91% (95% confidence interval, 85%-95%), 88% (68%-97%), and 64% (49%-78%), respectively. Factors associated with concordance included the baseline longest diameter and lesion number (P = 0.004), and sample collection interval (P = 0.036). Concordance rates ≥90% were observed in the following groups: liver metastases alone, regardless of the baseline longest diameter and lesion number; peritoneal metastases alone in patients with a baseline longest diameter ≥20 mm; and lung metastases alone in patients with a baseline longest diameter ≥20 mm and/or number of lesions ≥10. CONCLUSIONS: Plasma ctDNA-based liquid biopsy in patients with mCRC may be useful depending on the metastatic site. The maximum diameter and lesion number should be carefully considered when determining patients' RAS status with only peritoneal or lung metastases.

DOI： 10.1158/1078-0432.CCR-20-3677

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Given the lack of safety studies concerning laparoscopic surgery for rectal cancer in patients ≥ 80 years old with comorbidities, we sought to investigate this in the current study. METHODS: Between 2012 and 2019, 24 patients ≥ 80 years old underwent laparoscopic surgery for rectal cancer without preoperative treatment. These patients were divided into those with [comorbidity(+) group, n = 13] and without [comorbidity(-) group, n = 11] comorbidities. The preoperative nutritional status and ASA classification, postoperative complications, time to oral diet, and length of hospital stay were evaluated in each group. RESULTS: In the comorbidity(+)/comorbidity(-) groups, the average age was 85.9/84.1 years old, respectively. The major comorbidities were heart disease including atrial fibrillation and valvular disorder. The average PNI and CONUT scores in the comorbidity(+)/comorbidity(-) groups were 44.7/44.2 an 3.1/2.2, respectively. Planned surgical procedures were completed in all patients. Postoperative complications occurred in 2/3 cases in the comorbidity(+)/comorbidity(-) groups, respectively, and the average time to oral diet was 3.8/3.7 days, while the average length of hospitalization after surgery was 15.2/16.5 days, respectively. In the comorbidity(+) group, there was no exacerbation of comorbidities in any cases. CONCLUSION: The safety of laparoscopic surgery is acceptable among older rectal cancer patients with comorbidities.

DOI： 10.1007/s00595-020-02140-1

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Given the lack of safety studies concerning laparoscopic surgery for rectal cancer in patients ≥ 80 years old with comorbidities, we sought to investigate this in the current study. METHODS: Between 2012 and 2019, 24 patients ≥ 80 years old underwent laparoscopic surgery for rectal cancer without preoperative treatment. These patients were divided into those with [comorbidity(+) group, n = 13] and without [comorbidity(-) group, n = 11] comorbidities. The preoperative nutritional status and ASA classification, postoperative complications, time to oral diet, and length of hospital stay were evaluated in each group. RESULTS: In the comorbidity(+)/comorbidity(-) groups, the average age was 85.9/84.1 years old, respectively. The major comorbidities were heart disease including atrial fibrillation and valvular disorder. The average PNI and CONUT scores in the comorbidity(+)/comorbidity(-) groups were 44.7/44.2 an 3.1/2.2, respectively. Planned surgical procedures were completed in all patients. Postoperative complications occurred in 2/3 cases in the comorbidity(+)/comorbidity(-) groups, respectively, and the average time to oral diet was 3.8/3.7 days, while the average length of hospitalization after surgery was 15.2/16.5 days, respectively. In the comorbidity(+) group, there was no exacerbation of comorbidities in any cases. CONCLUSION: The safety of laparoscopic surgery is acceptable among older rectal cancer patients with comorbidities.

DOI： 10.1007/s00595-020-02140-1

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: A simple measure of immune cytolytic activity (CYT) base on mRNA expression levels of two genes, GZMA and PRF1, was recently reported. Here, we aimed to evaluate the CYT score's potential as a measure of antitumor immunity and predictor of clinical outcome in gastric cancer (GC) patients. MATERIALS AND METHODS: We evaluated the correlations between tumor-infiltrating immune cells and the CYT score in 238 GC samples from The Cancer Genome Atlas (TCGA). Next, we investigated CYT score associations with molecular subtypes, somatic mutation load, and immune checkpoint molecules in GC samples from TCGA and Asian Cancer Research Group (ACRG). Moreover, we evaluated the clinical significance of the CYT score calculated by reverse transcription (RT)-quantitative PCR (qPCR) data in 123 GC samples and the association of the CYT score with the response to anti-PD-1 therapy in 7 GC samples from Kyushu University Hospital. RESULTS: The CYT score positively correlated with the proportions of tumor-infiltrating CD8+ T cells and macrophages and negatively correlated with the proportion of regulatory T cells in GC tissues. A high CYT score was associated with common immune checkpoint molecules, a high mutation, the Epstein-Barr virus subtype, and the microsatellite instability subtype in GC. Moreover, a low CYT score was a poor prognosis factor in patients with GC. Finally, the CYT score was higher in a responder to anti-PD-1 therapy compared to nonresponders. CONCLUSION: The CYT score reflects antitumor immunity and predicts clinical outcome in GC patients.

DOI： 10.1002/cam4.3828

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: A simple measure of immune cytolytic activity (CYT) base on mRNA expression levels of two genes, GZMA and PRF1, was recently reported. Here, we aimed to evaluate the CYT score's potential as a measure of antitumor immunity and predictor of clinical outcome in gastric cancer (GC) patients. MATERIALS AND METHODS: We evaluated the correlations between tumor-infiltrating immune cells and the CYT score in 238 GC samples from The Cancer Genome Atlas (TCGA). Next, we investigated CYT score associations with molecular subtypes, somatic mutation load, and immune checkpoint molecules in GC samples from TCGA and Asian Cancer Research Group (ACRG). Moreover, we evaluated the clinical significance of the CYT score calculated by reverse transcription (RT)-quantitative PCR (qPCR) data in 123 GC samples and the association of the CYT score with the response to anti-PD-1 therapy in 7 GC samples from Kyushu University Hospital. RESULTS: The CYT score positively correlated with the proportions of tumor-infiltrating CD8+ T cells and macrophages and negatively correlated with the proportion of regulatory T cells in GC tissues. A high CYT score was associated with common immune checkpoint molecules, a high mutation, the Epstein-Barr virus subtype, and the microsatellite instability subtype in GC. Moreover, a low CYT score was a poor prognosis factor in patients with GC. Finally, the CYT score was higher in a responder to anti-PD-1 therapy compared to nonresponders. CONCLUSION: The CYT score reflects antitumor immunity and predicts clinical outcome in GC patients.

DOI： 10.1002/cam4.3828

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Several inflammation-based prognostic scores have a prognostic value in patients with various cancers. This study investigated the prognostic value of various inflammation-based prognostic scores in patients who underwent a surgery for adenocarcinoma of the esophagogastric junction (AEG) and upper gastric cancer (UGC). METHODS: We reviewed data of 206 patients who underwent surgery for AEG and UGC. We calculated neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), Glasgow Prognostic Score (GPS), modified GPS (mGPS), C-reactive protein (CRP)/albumin (Alb) ratio, prognostic index (PI), and prognostic nutritional index (PNI) and analyzed the relationship between these biomarkers and postoperative prognosis. RESULTS: In multivariate analyses for overall survival, mGPS (P = 0.0337, hazard ratio [HR] = 5.211), PI (P = 0.0002, HR = 21.20), and PNI (P < 0.0001, HR = 6.907) were identified as independent predictive factors. A multivariate analysis for recurrence-free survival showed that only PI (P = 0.0006, HR = 11.89) and PNI (P = 0.0002, HR = 4.972) were independent predictive factors among the above-mentioned inflammation-based prognostic scores. CONCLUSIONS: In various inflammation-based prognostic scores, PI and PNI were more strongly associated with poor prognosis in patients who underwent surgery for AEG and UGC.

DOI： 10.1245/s10434-020-08821-y

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although the efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) against metastatic colorectal cancer (mCRC) has been demonstrated, little is known about its effectiveness upon disease stratification by RAS mutations. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to RAS mutation status. PATIENTS AND METHODS: Eligible patients were mCRC refractory or intolerant to all standard therapies other than FTD/TPI and regorafenib. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m2, twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). The primary endpoint was disease control rate (DCR). The null hypothesis of DCR in both RAS wild-type (WT) and mutant (MUT) cohorts was 44%, assuming a one-sided significance level of 5.0%. The necessary sample size was estimated to be 49 patients (target sample size: 50 patients) for each cohort. RESULTS: Between January and September 2018, 102 patients were enrolled, and 97 patients fulfilled the eligibility criteria (48 in the RAS WT cohort and 49 in the RAS MUT cohort). DCRs in the RAS WT and MUT cohort were 66.7% [90% confidence interval (CI), 53.9%-77.8%, P = 0.0013] and 55.1% (90% CI, 42.4%-67.3%, P = 0.0780), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.8 and 9.3 months, respectively, in the RAS WT cohort and 3.5 and 8.4 months, respectively, in the RAS MUT cohort. The most common grade 3 or higher adverse event in both cohorts was neutropenia (46% in the RAS WT cohort and 62% in the RAS MUT cohort), without unexpected safety signals. CONCLUSIONS: FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT.

DOI： 10.1016/j.esmoop.2021.100093

Language：English   Publishing type：Research paper (scientific journal)  

No cases of late recurrence of colorectal cancer liver metastasis (CRLM) over 10 years have been reported in the literature. A 72-year-old woman had a surgical history of sigmoid colectomy and partial hepatic resections for sigmoid colon cancer and multiple liver metastases 15 years previously. The patient had been postoperatively treated with chemotherapy for 6 months and was observed regularly with no recurrence. Computed tomography (CT) performed due to high carcinoembryonic antigen (CEA) revealed a tumor of 70 mm in diameter at the anterior segment of the liver and a 6-mm nodule at the left lateral segment. There was no other malignant finding. We performed central bisegmentectomy and partial resection of the liver. Pathological findings showed the tumors to be well to moderately differentiated adenocarcinoma, and positive cytokeratin 20 (CK20) and caudal-type homeobox transcription factor 2 (CDX2) expression with negative expression of cytokeratin 7 (CK7). In addition, the tumors showed cluster of differentiation 44 (CD44) and 133 (CD133) positive signified cancer stem cell immunohistochemically. The postoperative diagnosis was recurrence of hepatic metastasis of sigmoid colon cancer. We report a rare case of late recurrence of CRLM more than 15 years after the primary diagnosis.

DOI： 10.1007/s12328-020-01330-1

Language：English   Publishing type：Research paper (scientific journal)  

No cases of late recurrence of colorectal cancer liver metastasis (CRLM) over 10 years have been reported in the literature. A 72-year-old woman had a surgical history of sigmoid colectomy and partial hepatic resections for sigmoid colon cancer and multiple liver metastases 15 years previously. The patient had been postoperatively treated with chemotherapy for 6 months and was observed regularly with no recurrence. Computed tomography (CT) performed due to high carcinoembryonic antigen (CEA) revealed a tumor of 70 mm in diameter at the anterior segment of the liver and a 6-mm nodule at the left lateral segment. There was no other malignant finding. We performed central bisegmentectomy and partial resection of the liver. Pathological findings showed the tumors to be well to moderately differentiated adenocarcinoma, and positive cytokeratin 20 (CK20) and caudal-type homeobox transcription factor 2 (CDX2) expression with negative expression of cytokeratin 7 (CK7). In addition, the tumors showed cluster of differentiation 44 (CD44) and 133 (CD133) positive signified cancer stem cell immunohistochemically. The postoperative diagnosis was recurrence of hepatic metastasis of sigmoid colon cancer. We report a rare case of late recurrence of CRLM more than 15 years after the primary diagnosis.

DOI： 10.1007/s12328-020-01330-1

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Several inflammation-based prognostic scores have a prognostic value in patients with various cancers. This study investigated the prognostic value of various inflammation-based prognostic scores in patients who underwent a surgery for adenocarcinoma of the esophagogastric junction (AEG) and upper gastric cancer (UGC). METHODS: We reviewed data of 206 patients who underwent surgery for AEG and UGC. We calculated neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), Glasgow Prognostic Score (GPS), modified GPS (mGPS), C-reactive protein (CRP)/albumin (Alb) ratio, prognostic index (PI), and prognostic nutritional index (PNI) and analyzed the relationship between these biomarkers and postoperative prognosis. RESULTS: In multivariate analyses for overall survival, mGPS (P = 0.0337, hazard ratio [HR] = 5.211), PI (P = 0.0002, HR = 21.20), and PNI (P < 0.0001, HR = 6.907) were identified as independent predictive factors. A multivariate analysis for recurrence-free survival showed that only PI (P = 0.0006, HR = 11.89) and PNI (P = 0.0002, HR = 4.972) were independent predictive factors among the above-mentioned inflammation-based prognostic scores. CONCLUSIONS: In various inflammation-based prognostic scores, PI and PNI were more strongly associated with poor prognosis in patients who underwent surgery for AEG and UGC.

DOI： 10.1245/s10434-020-08821-y

Language：English   Publishing type：Research paper (scientific journal)  

Microsatellite instability (MSI) is categorized by mutation frequency: high MSI (MSI-H), low MSI (MSI-L) and microsatellite stable (MSS). MSI-H tumors have a distinct immunogenic phenotype, with immunotherapies using checkpoint inhibitors already approved for the treatment of MSI-H gastroesophageal adenocarcinoma (GEA); this is not observed for MSI-L or MSS. Here, we tested the hypothesis that MSI-L tumors are also a distinct phenotype and potentially immunogenic. MSI-PCR assays (BAT25, BAT26, BAT40, D2S123, D5S346 and D17S250) were performed on 363 Epstein-Barr virus-negative, surgically resected esophagogastric junction (EGJ) adenocarcinoma samples. Tumors were characterized as MSI-H (≥2 markers), MSI-L (1 marker) or MSS (0 markers). CD8+ cell counts, PD-L1 and HER2 expression levels, TP53 mutations, epigenetic alterations and prognostic significance were also examined. All pathological and molecular experiments were conducted using serial, whole-tumor sections of chemo-naïve surgical specimens. MSI-H and MSI-L were assigned to 28 (7.7%) and 24 (6.6%) cases, respectively. Compared to MSS cases, MSI-L cases had significantly higher intratumoral CD8+ cell infiltration (P = .048) and favorable EGJ cancer-specific survival (multivariate hazard ratio = 0.35, 95% CI, 0.12-0.82; P = .012). MSI-L tumors were also significantly associated with TP53-truncating mutations as compared to MSI-H (P = .009) and MSS (P = .012) cases, and this trend was also observed in GEA data from The Cancer Genome Atlas (TCGA). Indel mutational burden among TCGA MSI-L tumors was significantly higher than that of MSS tumors (P = .016). These results suggest that MSI-L tumors may have a distinct tumor phenotype and be potentially immunogenic in EGJ adenocarcinoma.

DOI： 10.1002/ijc.33322

Language：Japanese   Publishing type：Research paper (scientific journal)  

BACKGROUND: Though irinotecan is commonly used for treating advanced gastric cancer, there is no predictive biomarker to date. We have studied the resistant mechanism for irinotecan and found that phosphorylation of serine 10 residue of topoisomerase Ⅰ(topo Ⅰ)is an important step for irinotecan resistance. We have developed an immunohistochemical staining-based biomarker; topo Ⅰ-pS10, for predicting irinotecan efficacy. PURPOSE: The purpose of this study is to test the accuracy of topo Ⅰ-pS10 immunohistochemical staining in gastric cancer clinical samples. METHODS: In this study we performed 2 sets of tests. In the training set, we stained 79 gastric cancer clinical samples which efficacy of irinotecan was measured by succinate dehydrogenase inhibition(SDI)test. In the validation set, we used 27 gastric cancer clinical samples which irinotecan was used and the efficacy was known. RESULTS: Training set: From the ROC curve the cut-off point was set at 35% positive nuclei. Sixty three cases were positive with topo Ⅰ-pS10 in the nuclei. With the result of irinotecan SDI, the sensitivity was 76.6% and the positive predictive value was 92.5%. This result showed that topo Ⅰ-pS10 positive case does not respond to irinotecan. Validation set: In this set, the sensitivity was 82.4% and the positive predictive value was 82.4%. CONCLUSION: topo Ⅰ-pS10 staining can be used as a predictive biomarker for irinotecan for gastric cancer patients.

Language：English   Publishing type：Research paper (scientific journal)  

Microsatellite instability-high (MSI-H) is an important biomarker for predicting the effect of immune checkpoint inhibitors (ICIs) on advanced solid tumors. Microsatellite instability-high is detected in various cancers, but its frequency varies by cancer type and stage. Therefore, precise frequency is required to plan ICI therapy. In this study, the results of MSI tests actually carried out in clinical practice were investigated. In total, 26 469 samples of various cancers were examined between December 2018 and November 2019 to determine whether programmed cell death-1 blockade was indicated. The results of MSI tests were obtained for 26 237 (99.1%) of these samples. The male : female ratio was 51:49 and mean age was 64.3 years. In all samples, the overall frequency of MSI-H was 3.72%. By gender, the frequency of MSI-H was higher in female patients (4.75%) than in male patients (2.62%; P < .001). A comparison by age revealed that the frequency of MSI-H was significantly higher in patients younger than 40 years of age (6.12%) and 80 years or older (5.77%) than in patients aged between 60 and 79 years (3.09%; P < .001). Microsatellite instability-high was detected in 30 cancer types. Common cancer types were: endometrial cancer, 16.85%; small intestinal cancer, 8.63%; gastric cancer, 6.74%; duodenal cancer, 5.60%; and colorectal cancer, 3.78%. Microsatellite instability-high was detected in cancer derived from a wide variety of organs. The frequency of MSI-H varied by cancer type and onset age. These data should prove especially useful when considering ICI treatment.

DOI： 10.1111/cas.14798

Language：Japanese   Publishing type：Research paper (scientific journal)  

BACKGROUND: Though irinotecan is commonly used for treating advanced gastric cancer, there is no predictive biomarker to date. We have studied the resistant mechanism for irinotecan and found that phosphorylation of serine 10 residue of topoisomerase Ⅰ(topo Ⅰ)is an important step for irinotecan resistance. We have developed an immunohistochemical staining-based biomarker; topo Ⅰ-pS10, for predicting irinotecan efficacy. PURPOSE: The purpose of this study is to test the accuracy of topo Ⅰ-pS10 immunohistochemical staining in gastric cancer clinical samples. METHODS: In this study we performed 2 sets of tests. In the training set, we stained 79 gastric cancer clinical samples which efficacy of irinotecan was measured by succinate dehydrogenase inhibition(SDI)test. In the validation set, we used 27 gastric cancer clinical samples which irinotecan was used and the efficacy was known. RESULTS: Training set: From the ROC curve the cut-off point was set at 35% positive nuclei. Sixty three cases were positive with topo Ⅰ-pS10 in the nuclei. With the result of irinotecan SDI, the sensitivity was 76.6% and the positive predictive value was 92.5%. This result showed that topo Ⅰ-pS10 positive case does not respond to irinotecan. Validation set: In this set, the sensitivity was 82.4% and the positive predictive value was 82.4%. CONCLUSION: topo Ⅰ-pS10 staining can be used as a predictive biomarker for irinotecan for gastric cancer patients.

Language：English   Publishing type：Research paper (scientific journal)  

Microsatellite instability-high (MSI-H) is an important biomarker for predicting the effect of immune checkpoint inhibitors (ICIs) on advanced solid tumors. Microsatellite instability-high is detected in various cancers, but its frequency varies by cancer type and stage. Therefore, precise frequency is required to plan ICI therapy. In this study, the results of MSI tests actually carried out in clinical practice were investigated. In total, 26 469 samples of various cancers were examined between December 2018 and November 2019 to determine whether programmed cell death-1 blockade was indicated. The results of MSI tests were obtained for 26 237 (99.1%) of these samples. The male : female ratio was 51:49 and mean age was 64.3 years. In all samples, the overall frequency of MSI-H was 3.72%. By gender, the frequency of MSI-H was higher in female patients (4.75%) than in male patients (2.62%; P < .001). A comparison by age revealed that the frequency of MSI-H was significantly higher in patients younger than 40 years of age (6.12%) and 80 years or older (5.77%) than in patients aged between 60 and 79 years (3.09%; P < .001). Microsatellite instability-high was detected in 30 cancer types. Common cancer types were: endometrial cancer, 16.85%; small intestinal cancer, 8.63%; gastric cancer, 6.74%; duodenal cancer, 5.60%; and colorectal cancer, 3.78%. Microsatellite instability-high was detected in cancer derived from a wide variety of organs. The frequency of MSI-H varied by cancer type and onset age. These data should prove especially useful when considering ICI treatment.

DOI： 10.1111/cas.14798

Language：English   Publishing type：Research paper (scientific journal)  

Microsatellite instability (MSI) is categorized by mutation frequency: high MSI (MSI-H), low MSI (MSI-L) and microsatellite stable (MSS). MSI-H tumors have a distinct immunogenic phenotype, with immunotherapies using checkpoint inhibitors already approved for the treatment of MSI-H gastroesophageal adenocarcinoma (GEA); this is not observed for MSI-L or MSS. Here, we tested the hypothesis that MSI-L tumors are also a distinct phenotype and potentially immunogenic. MSI-PCR assays (BAT25, BAT26, BAT40, D2S123, D5S346 and D17S250) were performed on 363 Epstein-Barr virus-negative, surgically resected esophagogastric junction (EGJ) adenocarcinoma samples. Tumors were characterized as MSI-H (≥2 markers), MSI-L (1 marker) or MSS (0 markers). CD8+ cell counts, PD-L1 and HER2 expression levels, TP53 mutations, epigenetic alterations and prognostic significance were also examined. All pathological and molecular experiments were conducted using serial, whole-tumor sections of chemo-naïve surgical specimens. MSI-H and MSI-L were assigned to 28 (7.7%) and 24 (6.6%) cases, respectively. Compared to MSS cases, MSI-L cases had significantly higher intratumoral CD8+ cell infiltration (P = .048) and favorable EGJ cancer-specific survival (multivariate hazard ratio = 0.35, 95% CI, 0.12-0.82; P = .012). MSI-L tumors were also significantly associated with TP53-truncating mutations as compared to MSI-H (P = .009) and MSS (P = .012) cases, and this trend was also observed in GEA data from The Cancer Genome Atlas (TCGA). Indel mutational burden among TCGA MSI-L tumors was significantly higher than that of MSS tumors (P = .016). These results suggest that MSI-L tumors may have a distinct tumor phenotype and be potentially immunogenic in EGJ adenocarcinoma.

DOI： 10.1002/ijc.33322

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. PATIENTS AND METHODS: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. RESULTS: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). CONCLUSION: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.

DOI： 10.1200/JCO.20.01330

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: In a randomized pivotal global phase III study, S-1 and oxaliplatin 100 mg/m2 (SOX100) combination chemotherapy was as effective as S-1 and cisplatin for advanced gastric cancer (AGC) and showed a favorable safety profile. In this phase II study, we analyzed survival outcomes to assess the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) in AGC. METHODS: Patients with HER2-negative AGC received 80 mg/m2/day S-1 orally on days 1-14 and 130 mg/m2 oxaliplatin intravenously on day 1 of each 21-day cycle until the criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the null hypothesis of RR in the current trial was 45%. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were recorded according to CTCAE version 4.0. RESULTS: Seventy-one patients were enrolled from June 2015 to November 2016, but eight were excluded for ineligibility. Therefore, all final analyses were conducted with 63 patients. The confirmed RR was 46.0% (90% confidence interval [CI]: 36.1-56.3), and the disease control rate was 77.8% (90% CI: 68.1-85.1). The median PFS and OS were 4.9 (95% CI: 4.2-7.1) and 14.8 (95% CI: 11.1-18.9) months, respectively. Incidences of grade 3-4 AEs > 10% were anorexia (19.0%), peripheral neuropathy (12.7%), nausea (11.1%), and thrombocytopenia (11.1%). CONCLUSIONS: This study represents the first evaluation of SOX130 in patients with HER2-negative AGC. SOX130 showed an acceptable safety profile, but the prespecified statistical efficacy targets were not achieved.

DOI： 10.1007/s10147-020-01803-w

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Tumor mutational burden (TMB) has been identified as one of the predictors for the response to anti-programmed cell death-1 (anti-PD-1) antibody therapy and reported to correlate with smoking history in lung adenocarcinoma. However, in squamous cell carcinoma of the lung, the association between TMB and clinicopathological background factors, such as smoking history, has not been reported, including in our previous study. The mutational signature is a tool to identify the mutagens that are contributing to the mutational spectrum of a tumor by investigating the pattern of DNA changes. Here, we analyzed the mutational signature in lung squamous cell carcinoma to identify mutagens affecting the TMB. METHODS: Seven representative mutational signatures including signature 7 (SI7) [ultraviolet (UV)-related], SI4 (smoking), SI6/15 [mismatch repair (MMR)], SI2/13 [apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)], and SI5 (clock-like) were analyzed in Japanese patients with lung squamous cell carcinoma (n=67) using data generated by next-generation sequencing consisting of a 415-gene panel. The relationships between signatures and clinico-pathological data including TMB and programmed death-ligand 1 (PD-L1) expression were analyzed. RESULTS: Although the reconstructed mutational counts were small with targeted sequencing (median: 30.1, range: 13.3-98.7), the distributions of signatures were comparable among samples, with 56 cases containing more than four signatures. The smoking-related SI4 was found in 45 cases and was significantly related with pack-year index (PYI) (P=0.026). The reconstructed mutation counts were highly correlated with SI4 (r=0.51, P<0.0001), whereas the correlation was weak with SI6/15 (MMR-related) and SI2/13 (APOBEC-related). There was no mutational signature related with PD-L1 expression. Some patients exhibited unique signatures; the patient with the highest mutational counts had a MMR signature, and another patient with a prominent UV signature had occupational exposure to UV, as he was employed as a neon sign engineer. CONCLUSIONS: Mutational signatures can predict the cause of lung squamous cell carcinoma. Tobacco smoking is the mutagen most related with TMB.

DOI： 10.21037/jtd-20-2602

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: In a randomized pivotal global phase III study, S-1 and oxaliplatin 100 mg/m2 (SOX100) combination chemotherapy was as effective as S-1 and cisplatin for advanced gastric cancer (AGC) and showed a favorable safety profile. In this phase II study, we analyzed survival outcomes to assess the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) in AGC. METHODS: Patients with HER2-negative AGC received 80 mg/m2/day S-1 orally on days 1-14 and 130 mg/m2 oxaliplatin intravenously on day 1 of each 21-day cycle until the criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the null hypothesis of RR in the current trial was 45%. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were recorded according to CTCAE version 4.0. RESULTS: Seventy-one patients were enrolled from June 2015 to November 2016, but eight were excluded for ineligibility. Therefore, all final analyses were conducted with 63 patients. The confirmed RR was 46.0% (90% confidence interval [CI]: 36.1-56.3), and the disease control rate was 77.8% (90% CI: 68.1-85.1). The median PFS and OS were 4.9 (95% CI: 4.2-7.1) and 14.8 (95% CI: 11.1-18.9) months, respectively. Incidences of grade 3-4 AEs > 10% were anorexia (19.0%), peripheral neuropathy (12.7%), nausea (11.1%), and thrombocytopenia (11.1%). CONCLUSIONS: This study represents the first evaluation of SOX130 in patients with HER2-negative AGC. SOX130 showed an acceptable safety profile, but the prespecified statistical efficacy targets were not achieved.

DOI： 10.1007/s10147-020-01803-w

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Tumor mutational burden (TMB) has been identified as one of the predictors for the response to anti-programmed cell death-1 (anti-PD-1) antibody therapy and reported to correlate with smoking history in lung adenocarcinoma. However, in squamous cell carcinoma of the lung, the association between TMB and clinicopathological background factors, such as smoking history, has not been reported, including in our previous study. The mutational signature is a tool to identify the mutagens that are contributing to the mutational spectrum of a tumor by investigating the pattern of DNA changes. Here, we analyzed the mutational signature in lung squamous cell carcinoma to identify mutagens affecting the TMB. METHODS: Seven representative mutational signatures including signature 7 (SI7) [ultraviolet (UV)-related], SI4 (smoking), SI6/15 [mismatch repair (MMR)], SI2/13 [apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)], and SI5 (clock-like) were analyzed in Japanese patients with lung squamous cell carcinoma (n=67) using data generated by next-generation sequencing consisting of a 415-gene panel. The relationships between signatures and clinico-pathological data including TMB and programmed death-ligand 1 (PD-L1) expression were analyzed. RESULTS: Although the reconstructed mutational counts were small with targeted sequencing (median: 30.1, range: 13.3-98.7), the distributions of signatures were comparable among samples, with 56 cases containing more than four signatures. The smoking-related SI4 was found in 45 cases and was significantly related with pack-year index (PYI) (P=0.026). The reconstructed mutation counts were highly correlated with SI4 (r=0.51, P<0.0001), whereas the correlation was weak with SI6/15 (MMR-related) and SI2/13 (APOBEC-related). There was no mutational signature related with PD-L1 expression. Some patients exhibited unique signatures; the patient with the highest mutational counts had a MMR signature, and another patient with a prominent UV signature had occupational exposure to UV, as he was employed as a neon sign engineer. CONCLUSIONS: Mutational signatures can predict the cause of lung squamous cell carcinoma. Tobacco smoking is the mutagen most related with TMB.

DOI： 10.21037/jtd-20-2602

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. PATIENTS AND METHODS: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. RESULTS: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). CONCLUSION: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.

DOI： 10.1200/JCO.20.01330

Language：English   Publishing type：Research paper (scientific journal)  

Precision oncology with next generation sequencing (NGS) using tumor tissue with or without blood has begun in Japan. Tumor molecular profiling tests are available, including the OncoGuide™ NCC Oncopanel System and FoundationOne® CDx (F1CDx). Our purpose was to identify potentially actionable genetic alterations in breast cancer with this comprehensive tumor profiling test. We enrolled 115 patients with pathologically diagnosed advanced or metastatic breast cancer. Comprehensive tumor genomic profiling, microsatellite instability, and tumor mutational burden (TMB) were determined using F1CDx. Testing was successful in 109/115 cases (94.8%). Clinically actionable alterations were identified in 76% of advanced breast cancer patients. The most frequent short variants were in TP53 (48.6%), PIK3CA (38.5%), GATA3 (11.0%), PTEN (11.0%), and BRCA1 (10.1%), and structural variants were in ERBB2 (24.8%), MYC (21.1%), RAD21 (21.1%), CCND1 (11.9%), FGF19 (10.1%), and PTEN (10.1%). Regarding human epidermal growth factor receptor (HER)2 status, 106/109 samples (97.2%) were concordant between F1CDx and HER2 testing with immunohistochemistry/fluorescence in situ hybridization. However, ERBB2 amplification was newly detected in four samples and ERBB2 mutations were detected in five HER2-negative breast cancer samples. Oncogenic BRCA mutations were found in three samples with F1CDx among 27 germline testing-negative samples. The mean TMB in all samples was 6.28 mut/Mb and tended to be higher in luminal B and triple-negative breast cancer (mean = 8.1 and 5.9 mut/Mb, respectively) compared with other subtypes. In conclusion, we established a system for precision oncology and obtained preliminary data with NGS as the first step. The information in this clinical sequencing panel will help guide the development of new treatments for breast cancer patients.

DOI： 10.1002/cam4.3619

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: A previous Phase I/II study demonstrated that TAS-102 (trifluridine/tipiracil [FTD/TPI]) plus bevacizumab (Bev) has encouraging efficacy and controllable safety for patients with previously treated metastatic colorectal cancer. Therefore, we designed for assessing the efficacy and safety of FTD/TPI plus Bev in elderly patients with previously untreated metastatic colorectal cancer. METHODS: This is a multicenter, single-arm Phase II study included patients ≥70 years old with previously untreated, unresectable metastatic colorectal cancer. Treatment consisted of FTD/TPI plus Bev given every 4 weeks. The primary endpoint was progression-free survival (PFS), assuming a null hypothesis of a PFS of 5 months. The secondary endpoints were the overall survival (OS), overall response rate (ORR), and adverse events (AEs). RESULTS: Between 5 January 2017 and 13 March 2018, 39 patients were enrolled from 18 institutions. The median patient age was 76.0 years (range, 70-88); the ECOG-PS was 0 in 24 patients and 1 in 15 patients. The median PFS was 9.4 months as a primary endpoint, and the median OS was 22.4 months. The ORR was 40.5% and the disease control rate was 86.5%. Grade 3-4 AEs included neutropenia (71.8%), leukopenia (51.3%), anorexia (15.4%), febrile neutropenia (10.3%), and fatigue (10.3%). CONCLUSIONS: FTD/TPI plus Bev is an effective and well-tolerated regimen for elderly patients with previously untreated metastatic colorectal cancer. Capecitabine/bevacizumab can be selected as a subsequent maintenance therapy without irinotecan and oxaliplatin because FTD/TPI has no cross-resistance with 5-fluorouracil. CLINICAL TRIAL REGISTRATION: UMIN clinical trials registry (UMIN000025241).

DOI： 10.1002/cam4.3618