Language：Japanese   Publisher：耳鼻と臨床会  

Language：Japanese   Publisher：耳鼻と臨床会  

頭頸部領域には発生学的に病因の異なる嚢胞が生じることがあり、正中頸嚢胞、側頸嚢胞、リンパ管腫/奇形などの先天性嚢胞や、ガマ腫などの後天性嚢胞が挙げられる。これら嚢胞の治療法としては、手術摘出とOK-432(ピシバニール)に代表される硬化療法の2つに大別される。手術摘出や複数回の穿刺排液を繰り返すも難治性であった、咽頭に発生した嚢胞に対し、OK-432(ピシバニール)を投与し、効果を認めた2例を経験したので報告する。症例1は30代の女性で、舌根の嚢胞を2回切除するも数ヵ月で再増大した症例である。症例2は60代の女性で、30年以上にわたり舌根の嚢胞に手術処置を繰り返した症例である。2例ともOK-432(ピシバニール)投与で、縮小した状態が維持できるようになった。頭頸部領域に発生する嚢胞の中には、まれではあるが複数回再発し難治性のものもあり、この場合治療に難渋することとなる。外科的治療法で対応が困難な症例において、OK-432(ピシバニール)による硬化療法は、外来で対応可能な、かつ効果的な治療選択肢の一つとなり得ると思われた。(著者抄録)

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Language：English   Publisher：Journal of Craniofacial Surgery  

Orbital reconstruction after total maxillectomy is essential to maintain ocular function and facial contour. Free flap transfer with simultaneous orbital bone reconstruction is a straightforward approach; however, it is challenging in medically unstable patients with multimorbidity. The authors developed an easily harvested temporoparietal fascial flap combined with vascularized outer table calvarial bone and entire temporalis muscle. The authors applied this technique in an 81-year-old patient with multiple comorbidities who required orbital floor reconstruction following total maxillectomy. Intraoperative indocyanine green fluorescence imaging confirmed excellent perfusion of the temporoparietal fascia, entire temporalis muscle, and calvarial bone. Although the patient developed postoperative local wound infection, the vascularized bone graft resisted infection and preserved the orbital structure without bone exposure. Our technique is minimally invasive and results in a well-vascularized flap for orbital reconstruction after total maxillectomy involving the orbital bone, and particularly beneficial in patients with multimorbidity or at high risk of local infection.

DOI： 10.1097/SCS.0000000000010571

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Squamous cell carcinoma of the external auditory canal (EACSCC) is an extraordinarily rare and aggressive malignant disease. Establishment of EACSCC cell line with robust molecular characteristics is essential for the basic and translational research of EACSCC. Here, we show the newly established EACSCC cell line SCEACono2, derived from a patient with well-to-moderately differentiated EACSCC. We analyzed histologic and genetic features of SCEACono2 hiring multiple experiments, including next-generation sequencing (NGS). Immunocytochemical staining of SCEACono2 showed positivity of p53 and SCC1/2. Furthermore, SCEACono2 exhibited a unique characteristic that cytokeratin, vimentin as well as cancer stem cell markers (CD44, CD133, ALP and Oct3/4) were positive. SCEACono2 had an ability to form tumors at the temporal lesion xenograft nude mice model. NGS revealed that SCEACono2 harbored the somatic mutations of TP53 (p.G245S) and NOTCH1 (p.A465T). RNA-seq and downstream bioinformatics analysis revealed significant enrichment of genes involved in inflammation and cell adhesion in SCEACono2 compared to SCC-9 and HSC-4. STR profiling indicated no evidence of cross-contamination. In conclusion, SCEACono2 could serves as a promising and robust research resource of EACSCC in vitro and in vivo.

DOI： 10.1038/s41598-023-46926-y

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Other Link： https://www.nature.com/articles/s41598-023-46926-y

Language：Japanese   Publisher：JIBI TO RINSHO KAI  

<p>Intracranial complications of rhinosinusitis are conditions in which inflammation of the paranasal sinuses spills over into the cranium, and even today it can be fatal. We herein report a case of intracranial complication arising from frontal sinusitis that resulted in extensive cerebral venous sinus thrombosis. The patient was an 82-year-old woman who was referred to our department because of left periorbital erythema. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed left frontal sinusitis and associated left superior ophthalmic vein thrombosis and cerebral venous sinus thrombosis. In addition to receiving systemic antibiotic therapy, the patient consulted the neurosurgery department and started continuous heparin administration, but there was no improvement. Endoscopic sinus surgery (ESS) was performed for drainage of the frontal sinus, and the patient responded well and was discharged from the hospital without sequelae. The patient had been treated with glucocorticoids for rheumatoid arthritis for a long time, which may have increased the risk of intracranial thrombosis. In cases of severe infection in patients receiving long-term steroid therapy, it is important to keep in mind the risk of thrombosis and to promptly collaborate with other departments for nasal intracranial complications so as not to miss the opportunity to perform surgical treatment of sinus drainage.</p>

DOI： 10.11334/jibi.69.5_357

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

Background/Aim: In recent years, individual patient cancer genomic profiling (CGP) has become more accessible, allowing determination of therapeutic strategies using driver gene mutations in cancer therapy. However, this precision oncology approach, tailored to specific patients, remains experimental. In this study, we verified the feasibility and benefit of using CGP to guide treatment of malignant head and neck tumors. We aimed to evaluate the profiling and clinical courses of patients with head and neck malignancies who underwent CGP and determine the extent to which CGP for head and neck malignancies has resulted in beneficial drug administration. Patients and Methods: We analyzed CGP results, prognosis, and drug administration status in 27 patients. These patients had completed (or were expected to complete) standard therapy or had rare cancers without standard therapy. Results: At least one somatic actionable gene alteration was seen in 25 (92.6%) patients, with a median number of actionable alterations per patient of 4 (range=0-11). Drugs in clinical trials were recommended to 22 (81.5%) patients, but none could participate. However, 3 patients (11.1%) could use approved drugs off-label based on CGP results. The most common genetic abnormality was TP53 (66.7%), with TP53 mutations leading to poor prognosis. Conclusion: CGP is clinically useful and serves as a bridge to increase the number of therapeutic options. However, candidate drugs confirmed using CGP may be ineffective when administered. Therefore, oncologists should not blindly accept CGP therapeutic recommendations but should make recommendations that lead to optimal therapies after proper verification.

DOI： 10.21873/invivo.13312

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

BACKGROUND/AIM: Pembrolizumab monotherapy and pembrolizumab with chemotherapy (combination therapy) are standard treatments for recurrent and metastatic head and neck squamous cell carcinoma (R/M-HNSCC). This study aimed to explore which of the two, pembrolizumab monotherapy or combination therapy is superior for long-term use. PATIENTS AND METHODS: Participants of the study were 139 patients with histologically confirmed squamous cell carcinoma who had been treated with pembrolizumab monotherapy or combination therapy at the Kyushu University and related facilities. We analysed differences regarding long-term survival rate and adverse events (AEs) between the pembrolizumab monotherapy and combination therapy groups. RESULTS: The overall 2-year progression-free survival and 2-year overall survival were 28.6% and 41.8%, respectively; these results were not significantly different between the two groups. Patients in the monotherapy group with AEs had a significantly better prognosis than those without AEs (in both the monotherapy and combination therapy groups). In the combination therapy group, there was no difference in prognosis between those with AEs and those without AEs (p=0.636). CONCLUSION: Considering the treatment of R/M-HNSCC from a long-term perspective, we identified that it is better to use pembrolizumab as monotherapy than to use it in combination with chemotherapy. Combination therapy did not improve prognosis; moreover, it can also cause additional adverse effects.

DOI： 10.21873/invivo.13318

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：JIBI TO RINSHO KAI  

<p>In 2018, the new TNM classification (AJCC 8th edition) was introduced. We investigated the prognosis of nasopharyngeal cancer in 45 nasopharyngeal cancer patients who underwent first-line therapy at the Department of Otolaryngology, Head and Neck Surgery, Kyushu University between January 2010 and January 2020. There were 31 male and 14 female patients, ranging in age from 12 to 88 years old, with a median age of 59 years old. Of these, 40 patients with nasopharyngeal squamous cell carcinoma were evaluated for their five-year overall survival (OS) and progression-free survival (PFS) as well as prognostic factors. The 5-year OS rate was 75.5%, and the 5-year PFS rate was 64.3%. As prognostic factors, there were no significant differences in outcome by stage, histological type, and Epstein-Barr virus positivity. In addition, it was considered necessary to further investigate the optimal dose of cisplatin for chemoradiotherapy combined with cisplatin, which is the main treatment for nasopharyngeal cancer.</p>

DOI： 10.11334/jibi.69.2_75

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Language：Japanese   Publisher：JIBI TO RINSHO KAI  

DOI： 10.11334/jibi.69.1_68

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

Background/Aim: Differentiated thyroid cancer (DTC) has a good prognosis, except in the case of patients with radioiodine therapy (RIT)-refractory cancer. However, since DTC is essentially a slowly progressing cancer, it is usually judged to be a DTC with a poor prognosis after multiple RITs and yearly follow-up with echo, computed tomography (CT), and serum thyroglobulin values. This study investigated whether fluorodeoxyglucose-positron emission tomography/CT (FDG PET/CT) combined with initial RIT could identify early-stage patients with poor prognosis. Patients and Methods: We evaluated 100 patients with high-risk DTC who underwent total thyroidectomy and received RIT at our institution. We analyzed the clinical outcomes of patients and 18F-FDG accumulation using univariate and multivariate Cox proportional hazards regression models. Results: The 10-year overall survival (OS) was 87.9%, with no significant difference in OS between 18F-FDG accumulation at pre-total or near-total thyroidectomy (NTT) (p=0.180) and 131I accumulation at initial RIT (p=0.577). However, 18F-FDG positive patients had a significantly worse prognosis than negative patients (p=0.005) at initial RIT. Conclusion: 18F-FDG PET/CT plays an important role in both the diagnosis and prognostic prediction of RIT refractory disease in DTC patients. 18F-FDG PET/CT can be a useful tool particularly at the time of initial RIT since the 18F-FDG accumulation enables the screening of high-risk DTC with poor prognosis at a very early time stage.

DOI： 10.21873/anticanres.16148

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DOI： 10.1002/ccr3.6157

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neurological Surgery, Part B: Skull Base  

Objective  En bloc and margin-negative surgical resection seems to offer the best prognosis for patients with temporal bone squamous cell carcinoma (TB-SCC). In this study, we summarize the outcomes of surgical cases of advanced TB-SCC (T3-T4) that were managed in two institutions, with an accompanying description of the surgical procedure that was utilized: modified subtotal temporal bone resection (STBR), which involves the en bloc removal of the temporal bone including or transecting the otic capsule. Design  This is a case series study with chart review. Setting  The study was conducted at two academic tertiary care medical centers. Participants  Chart information was collected for all patients who underwent surgical resection of advanced TB-SCC between July 1998 and February 2019. The resulting dataset contained 43 patients with advanced TB-SCC who underwent en bloc resection during the review period. Tumor staging followed the modified Pittsburgh classification. Disease-specific survival (DSS) rates were calculated according to the Kaplan-Meier method. Main Outcome Measure  This study shows disease-specific 5-year DSS rate. Results  The 5-year DSS rate of the cases who underwent en bloc resection was 79.7%. En bloc lateral temporal bone resection was employed in a total of 25 cases (DSS: 79.0%). En bloc modified STBR was utilized in 18 cases (DSS: 81.7%). Conclusion  En bloc margin-negative resection is a reliable treatment strategy for advanced TB-SCC. Modified STBR can be a treatment option for TB-SCC without marked posterior extension.

DOI： 10.1055/s-0041-1722930

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

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

There is no useful biomarker to evaluate treatment response and early relapse in head and neck squamous cell carcinoma (HNSCC). Circulating tumor DNA (ctDNA) is a promising biomarker for detecting minimal residual diseases and monitoring treatment effect. We investigated whether individualized ctDNA analysis could help monitor treatment response and relapse in HNSCC. Mutation analysis of tumor and peripheral blood mononuclear cell (PBMC) DNAs of 26 patients with HNSCC was performed using a custom squamous cell carcinoma (SCC) panel. The identified individualized mutated genes were defined as ctDNA candidates. We investigated whether frequent ctDNA monitoring via digital PCR (dPCR) is clinically valid for HNSCC patients. TP53 was the most frequently mutated gene and was detected in 14 of 24 cases (58.2%), wherein two cases were excluded owing to the absence of tumor-specific mutations in the SCC panel. Six cases were excluded because of undesignable and unusable primer-probes for dPCR. Longitudinal ctDNA was monitored in a total of 18 cases. In seven cases, ctDNA tested positive again or did not test negative, and all seven cases relapsed after initial curative treatment. In 11 cases, after initial curative treatment, ctDNA remained negative and patients were alive without recurrence. Patients who remained negative for ctDNA during follow-up after initial curative treatment (n = 11) had a significantly better prognosis than those who reverted to ctDNA positivity (n = 7; p < 0.0001; log-rank test). Individualized ctDNA monitoring using SCC panel and dPCR might be a novel and promising biomarker for HNSCC.

DOI： 10.1002/cam4.4726

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cam4.4726

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OBJECTIVE/HYPOTHESIS: Squamous cell carcinoma (SCC) of the temporal bone is an extremely rare condition. This rarity has led to a delay in the establishment of a standard treatment protocol and adequate staging system. Identification of prognostic markers of this disease from a variety of fields is desirable in the establishment of treatment guidelines for temporal bone SCC. The aim of this study is to assess the prognostic role of inflammation-based prognostic scores in cases of temporal bone SCC. STUDY DESIGN: Case reries with chart review. METHODS: A total of 71 cases of primary malignancy eligible for curative treatment at a single tertiary medical institute were retrospectively analyzed. Univariate and multivariate regression analyzes were used to investigate the association between the inflammation-based scores and 5-year overall survival. RESULTS: Univariate Cox regression analyzes showed that a high neutrophil-to-lymphocyte ratio, high platelet-to-lymphocyte ratio, low lymphocyte-to-monocyte ratio, a Glasgow prognostic score of 2, and the systemic inflammation score of 2 were significantly associated with a poor prognosis, as well as a classification of T4 stage, presence of cervical lymph node metastasis, high white blood cell counts, and high C-reactive protein levels. The multivariate analysis showed that a clinical stage of T4 and a systemic inflammation score of 2 were independent prognostic markers. CONCLUSIONS: Inflammation-based prognostic markers are associated with the survival of patients with temporal bone SCC, as well as other head and neck SCCs. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1782-1789, 2021.

DOI： 10.1002/lary.29421

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OBJECTIVES/HYPOTHESIS: The tumor immune microenvironment in temporal bone squamous cell carcinoma (TBSCC), including the programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs), has not been established. STUDY DESIGN: Retrospective cohort study. METHODS: We performed immunohistochemistry analyses to retrospectively analyze 123 TBSCC cases for PD-L1 expression and TILs and their prognostic significance. We also evaluated the prognostic correlations between these immunomarkers and the therapeutic responses to chemoradiotherapy (CRT). RESULTS: PD-L1 expression (≥1&#37;) was detected in 62 (50.4&#37;) TBSCC cases and was significantly associated with worse prognosis: progression-free survival (PFS), P < .0001; overall survival (OS), P = .0009. A high density of CD8+ TILs was significantly associated with better prognosis (PFS, P = .0012; OS, P = .0120). In contrast, a high density of Foxp3+ TILs tended to be associated with an unfavorable prognosis (PFS, P = .0148; OS, P = .0850). With regard to the tumor microenvironment subtypes defined by CD8+ TILs and PD-L1 expression, the CD8low /PD-L1+ group showed significantly worse prognosis. Among the 36 neoadjuvant CRT-treated cases, PD-L1 expression was significantly associated with worse OS (P = .0132). Among the 32 CRT-treated cases without surgery, a high density of CD8+ TILs tended to be more highly associated with complete response to CRT compared to a low density of CD8+ TILs (P = .0702). CONCLUSIONS: These results indicate that the evaluation of the tumor immune microenvironment may contribute to the prediction of prognoses and the selection of an individualized therapeutic strategy for patients with TBSCC. LEVEL OF EVIDENCE: 4 Laryngoscope, 2021.

DOI： 10.1002/lary.29689

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BACKGROUND: There is no guideline for hearing compensation after temporal bone resection. This study aimed to retrospectively analyze surgical cases with reconstruction for hearing preservation after temporal bone malignancy resection and propose a new alternative to compensate for hearing loss. METHODS: We retrospectively reviewed the medical records of 30 patients who underwent lateral temporal bone surgery for temporal bone malignancy at our institution and examined their hearing abilities after surgery. RESULT: The hearing outcomes of patients with an external auditory meatus reconstruction varied widely. The mean postoperative air-bone gap at 0.5, 1, 2, and 4 kHz ranged from 22.5 dB to 71.25 dB. On the other hand, the average difference between the aided sound field thresholds with cartilage conduction hearing aid and bone conduction thresholds at 0.5, 1, 2, and 4 kHz ranged from -3.75 to 41.25. More closely located auricular cartilage and temporal bone resulted in smaller differences between the aided sound field and bone conduction thresholds. CONCLUSIONS: There is still room for improvement of surgical techniques for reconstruction of the auditory meatus to preserve hearing after temporal bone resection. The cartilage conduction hearing aid may provide non-invasive postoperative hearing compensation after lateral temporal bone resection.

DOI： 10.3390/audiolres11020024

Language：Japanese  

頸部リンパ漏は、頭頸部領域の手術後に発症し得る合併症の一つであるが、時に難治性となり対応に苦慮することがある。今回われわれの施設では、無脂肪消化態流動食(ペプチーノ)の経管投与にてリンパ漏を治療した8例を経験した。8例中5例で創処置や薬物療法との併用となったが、5-12日間のペプチーノの投与でいずれの症例もリンパ漏は停止した。無脂肪消化態流動食(ペプチーノ)は比較的安価で投与方法も簡便であるため、臨床的にリンパ漏を疑った場合、積極的に投与開始を検討すべきであると考えられた。(著者抄録)

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Two cases of synovial sarcoma of the neck
Synovial sarcoma is a malignant soft-tissue tumor that usually occurs in the extremities. However, less than 10％ of all synovial sarcomas originate in the head and neck, springing from mesenchyme rather than synovial tissues. We report two cases of synovial sarcoma. In the first case, a 20-year-old woman who had neck tumor resection for schwannoma was histopathologically diagnosed with synovial sarcoma. Postoperatively, the patient received radiotherapy. In the second case, a man received submandibular gland resection at 23 years of age. The mass was diagnosed as synovial sarcoma, and neck dissection was also performed at the previous hospital. Three years later, we identified local recurrence and it was resected. Both patients have remained disease-free for over 2 years since surgery. SS18-SSX fusion transcripts are a defining diagnostic marker of synovial sarcoma. The first choice of treatment is complete surgical excision; however, this may be difficult because of the anatomical features of the head and neck. Radiotherapy or chemotherapy are performed occasionally. Patients with synovial sarcoma should be followed up carefully in order to detect local recurrence and lung metastasis.

DOI： 10.11334/jibi.66.4_121

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External auditory canal squamous cell carcinoma (EACSCC) is an extremely rare and aggressive malignancy. Due to its rarity, the molecular and genetic characteristics of EACSCC have not yet been elucidated. To reveal the genetic alterations of EACSCC, we performed whole exome sequencing (WES) on 11 primary tumors, 1 relapsed tumor and 10 noncancerous tissues from 10 patients with EACSCC, including 1 with a rare case of synchronous bilateral EACSCC of both ears. WES of the primary tumor samples showed that the most frequently mutated gene is TP53 (63.6&#37;). In addition, recurrent mutations in CDKN2A, NOTCH1, NOTCH2, FAT1 and FAT3 were detected in multiple samples. The mutational signature analysis of primary tumors indicated that the mutational processes associated with the activation of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) deaminases are the most common in EACSCC, suggesting its similarity to SCC from other primary sites. Analysis of arm-level copy number alterations detected notable amplification of chromosomes 3q, 5p and 8q as well as deletion of 3p across multiple samples. Focal chromosomal aberrations included amplifications of 5p15.33 (ZDHHC11B) and 7p14.1 (TARP) as well as deletion of 9p21.3 (CDKN2A/B). The protein expression levels of ZDHHC11B and TARP in EACSCC tissues were validated by immunohistochemistry. Moreover, WES of the primary and relapsed tumors from a case of synchronous bilateral EACSCC showed the intrapatient genetic heterogeneity of EACSCC. In summary, this study provides the first evidence for genetic alterations of EACSCC. Our findings suggest that EACSCC mostly resembles other SCC.

DOI： 10.1111/cas.14515

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OBJECTIVES/HYPOTHESIS: The extreme rarity of temporal bone squamous cell carcinoma (TB-SCC) has delayed the accumulation of high-quality clinical evidence. For the purposes of retrospective meta-analysis in the future, a large dataset with information from various institutions would be ideal. Our objective here was to retrospectively review cases of TB-SCC encountered at a single tertiary referral center and explore survival outcomes and prognostic factors. STUDY DESIGN: Retrospective chart review. METHODS: The medical records of all TB-SCC cases were retrospectively reviewed. The resulting dataset contained 71 cases of primary cancer eligible for initial definitive (curative) treatment. RESULTS: T4 status was associated with lower disease-specific 5-year survival than T1 to T3 staging (T1: 100&#37;, T2: 92&#37;, T3: 86&#37;, T4: 51&#37;). Survival was significantly higher in operable than in inoperable cases, even when restricted to advanced (T3/T4) cancers. The tumor extension to the middle ear cavity was observed in 13/17 of T3 cases, but it was not associated with poor survival. In addition, among operable cases, negative surgical margins were associated with significantly higher survival than positive margins. CONCLUSIONS: Definitive treatments can offer disease-specific 5-year survival of over 85&#37; in T1 to T3 cases of TB-SCC. The tumor extension to the middle ear cavity is not associated with poor survival. T4 status, inoperability, nodal invasion, and positive surgical margin are identified as a predictor of poor prognosis. Still, the matter of how to deal with unresectable tumors remains an outstanding issue in the treatment of TB-SCC. LEVEL OF EVIDENCE: 4 Laryngoscope, 2020.

DOI： 10.1002/lary.28653

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An Analysis of Cases of Recurrent/Metastatic Squamous-Cell Carcinoma of the Head and Neck Treated with Nivolumab
We reviewed 38 cases of recurrent or metastatic squamous-cell carcinoma of the head and neck treated with Nivolumab in our hospital and reported the cases that developed adverse events associated with Nivolumab monotherapy. The clinical responses to Nivolumab were partial response in 9 cases, stable disease in 10 cases, and progressive disease in 12 cases. The response rate and clinical benefit were 27.3% and 57.6%. The 1-year overall survival rate and 1-year progression-free survival rate were 32.3% and 18.2%, respectively. The most common immune-related adverse events (irAEs) were liver dysfunction (n=2) and thyroid dysfunction (n=2). Other irAEs included hyperthyroidism, arthritis, and interstitial pneumonia (n=1, each). Careful follow-up is recommended in patients treated with Nivolumab monotherapy.

DOI： 10.11334/jibi.65.6_175

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OBJECTIVES: Small cell carcinomas in extrapulmonary sites (ESmCCs) are very rare. ESmCCs originating in the head and neck account for approximately 10&#37; of all ESmCCs, and there are few reports about this disease. ESmCCs have an aggressive natural history characterized by widespread metastasis. The aim of this study was to investigate the characteristics and outcomes of patients with ESmCCs of the head and neck. METHODS: The outcomes of 21 patients with ESmCCs of the head and neck treated between January 2001 and December 2015 at the authors' hospital and associated facilities were reviewed. RESULTS: There were 18 men and 3 women, and the median age was 74 years (range, 53-91 years). The tumor site was the larynx in 6 patients; the paranasal sinus in 5; the hypopharynx in 3; the oropharynx in 2; the nasopharynx in 2; and the oral cavity, salivary gland, and primary unknown in 1 patient each. The extent of the disease was staged as follows: stage I or II, 3 cases; stage III, 4 cases; stage IVA, 9 cases; stage IVB, 1 case; and stage IVC, 4 cases. The median observation time was 17 months (range, 1-103 months). Four patients (19&#37;) had distant metastasis at initial treatment, and 13 patients (62&#37;) developed distant metastasis within 3 years. Treatments were administered, including radical surgery (9 patients), radiation therapy (5 patients), chemoradiotherapy (7 patients), and chemotherapy (6 patients). The 1- and 3-year overall survival rates of patients were 56&#37; and 37&#37;, respectively. More than half of the patients died of distant metastasis. CONCLUSIONS: ESmCCs of the head and neck have a poor prognosis, similar to those of carcinomas in many other sites. Control of distant metastasis would contribute to improving the prognosis of ESmCCs of the head and neck. Further studies are required for better understanding these disease entities and their response to treatment modalities.

DOI： 10.1177/0003489419853601

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当科において遠隔転移病変に対して外科的切除を行った頭頸部扁平上皮癌症例に関して検討を行った。対象は、2000年1月から2016年12月までに九州大学耳鼻咽喉・頭頸部外科で一次根治治療を施行した頭頸部扁平上皮癌症例のうち、肺転移、肝転移に対して外科的切除を施行した26例である。原発巣の内訳は上咽頭3例、中咽頭6例、下咽頭8例、喉頭5例、口腔3例、顎下腺1例であった。転移臓器は肺が22例、肝臓が4例であった。遠隔転移巣切除後の1年全生存率は78&#37;、2年全生存率は70.9&#37;であり、遠隔転移巣に対する外科的切除が予後の改善に寄与する可能性が示された。初回治療から遠隔転移再発までが短期間であった症例では、転移巣の切除後も予後不良な傾向を認めた。遠隔転移に対する外科的切除後も慎重なフォローアップが必要と考えられる。(著者抄録)

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© 2019 JLO (1984) Limited. Background Parotid gland carcinoma is a rare and complicated histopathological classification. Therefore, assembling a sufficient number of cases with long-term outcomes in a single institute can present a challenge.Method The medical records of 108 parotid gland carcinoma patients who were treated at Kyushu University Hospital, Fukuoka, Japan, between 1983 and 2014 were reviewed. The survival outcomes were analysed according to clinicopathological findings.Results Forty-six patients had low clinical stage tumours (I-II), and 62 patients had high clinical stage tumours (III-IV). Fifty-two, 10 and 46 patients had low-, intermediate-and high-grade tumours, respectively. Twenty-seven of 65 cases had positive surgical margins. In high clinical stage and intermediate-to high-grade tumours, adjuvant radiation therapy was correlated with local recurrence-free survival (p = 0.0244). Intermediate-to high-grade tumours and positive surgical margins were significantly associated with disease-specific survival in multivariate analysis (p = 0.0002 and p = 0.0058).Conclusion The results of this study show that adjuvant radiation therapy is useful for improved local control in patients with high clinical stage and intermediate-to high-grade tumours.

DOI： 10.1017/S0022215119001130

Language：Japanese  

UICC/AJCC TNM分類第8版による中咽頭癌TNM分類では、(1)HPV関連の有無 (2)N節外浸潤の有無が、重要な要素となった。本邦の症例でも検証が必要であり、今回の改定に含まれない喫煙の予後への影響も含めて後方視的検討を行った。2010年1月から2015年12月に当科で根治治療を行ったHPV検索済の中咽頭扁平上皮癌110例を対象とした。HPV関連癌は52例だった。旧分類ではStage IVが全体の60&#37;を占めていたが、新分類ではStage IおよびIIが倍増しStage IVが減ったことで各病期症例数のバランスが改善した。粗生存率解析では新分類のほうが病期毎予後をより反映しており、喫煙の予後に対する影響も示唆された。(著者抄録)

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

OBJECTIVE: The usefulness of pretreatment measurement of SCC antigen in patients with head and neck SCC is still controversial. Our aim of this study was to evaluate the clinical usefulness of serum SCC antigen, SCCA1 and SCCA2 in the management of patients with head and neck SCC. METHODS: Serum samples for the analysis of SCCA1, SCCA2 and SCC antigen were taken from head and neck SCC patients before treatment. Serum SCC antigen was assayed with a solid phase immunoradiometric assay. The SCCA1 and SCCA2 protein level was determined by a sandwich ELISA. RESULTS: Fifty-two of 96 cases (54&#37;) showed evaluated serum SCC antigen levels above the upper limit. The serum SCCA2 level was significantly higher in the head and neck SCC patients than in control group, whereas there were no significant differences in the serum SCCA1 level between head and neck SCC patients and control group. 72&#37; of head and neck SCC patients demonstrated SCCA2 levels higher than 0.15, whereas 68&#37; of the control subjects had SCCA2 levels less than 0.15. CONCLUSION: The serum SCCA2 levels were increased during the progression of cancer and might be a useful tool for the management of head and neck SCC.

DOI： 10.1016/j.anl.2018.07.010

Language：Japanese  

近年増加傾向にある高齢者頭頸部扁平上皮癌患者の手術症例についてPOSSUMを用いて検討した。対象は、過去5年間(2011年9月-2016年8月)の当科における80歳以上頭頸部扁平上皮癌の手術症例21例とした。術後合併症群8例、非合併症群13例とで検討を行い、POSSUM予測合併症率は、術後合併症群で平均65&#37;、非合併症群で平均48&#37;となり、両群間には有意差は認めなかったものの術後合併症群で高い傾向を認めた。また、死亡など重篤な合併症を生じた例ではPOSSUM予測合併症率は高値を示した。POSSUM予測合併症率が高い症例では、術前に全身状態の改善や手術侵襲等を再検討し合併症率を下げるための予防策を立てることが重要であると考えられた。(著者抄録)

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

BACKGROUND: Differentiating inverted papilloma from squamous cell carcinoma (SCC) is sometimes difficult. We evaluated the clinical usefulness of serum SCCA1 and SCCA2 in the management of patients with inverted papilloma or SCC. METHODS: Serum and tissue samples for the analysis of SCCA1, SCCA2, and SCC antigen were taken from 18 patients with sinonasal inverted papilloma and 23 cases with sinonasal SCC. The SCCA1, SCCA2, and SCC antigen levels were determined. RESULTS: The serum SCCA1 concentration was significantly higher in the inverted papilloma group than in the SCC group, whereas the serum SCCA2 level was significantly higher in the SCC group than in the inverted papilloma group. CONCLUSION: Patients with sinonasal inverted papilloma predominantly express SCCA1 protein, whereas those with SCC predominantly express SCCA2. This suggests that combined measurements of both serum SCCA1 and SCCA2 concentrations can be very useful for distinguishing sinonasal inverted papilloma from SCC.

DOI： 10.1002/hed.25351

Language：Japanese  

2007年1月から2016年12月までの10年間に、初回治療開始時に精査を行ったにもかかわらず原発巣が不明であり頸部リンパ節転移を認めた26例を対象とした。内訳はN1:1例、N2:23例、N3:2例であった。遠隔転移を認めた症例は4例であった。26例のうち、原発巣が初回手術後に判明した症例が4例、治療終了後経過観察中に判明した症例が2例、原発巣が不明のままであった症例が20例であった。全体の3年粗生存率は52%であり、N分類の進行とともに予後も不良な傾向であった。免疫組織染色が可能であった22例中7例(32%)においてp16陽性所見が認められた。7例中5例で最終的に原発巣が判明しており、内訳は中咽頭(扁桃)4例、下咽頭(梨状陥凹)1例であった。原発不明癌頸部リンパ節転移症例でp16陽性であった場合、p16陽性中咽頭癌と同様に取り扱うことが妥当なのか大規模な検証が必要と思われる。(著者抄録)

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

OBJECTIVES: Primary squamous cell carcinoma (SCC) of the thyroid is a rare disease. It usually presents with locally advanced disease and has an overall poor prognosis. In this study, we investigated the characteristics and outcomes of patients with SCC of the thyroid, and reported our experience with chemotherapy with lenvatinib in the treatment of SCC of the thyroid. METHODS: The management outcome of 10 patients who had SCC of the thyroid between January 2000 and 2015 at Kyushu University Hospital or associated facilities was reviewed. RESULTS: There were 3 males and 7 females, ranging in age from 53 to 77 years. Extent of disease was staged as follows: stage IVA, 3 cases; stage IVB, 3 cases; stage IVC, 4 cases. Only tracheostomy was applied for 2 cases, surgical resection, such as total thyroidectomy and neck dissection, for the other 8 cases. Radiotherapy following surgical treatment was applied for 9 cases. Four patients started on oral lenvatinib due to recurrent or progressive SCC of the thyroid. The one year actuarial survival rate of patients was 22.7&#37;. There was no 2-year survivor of all patients. CONCLUSIONS: Treatment should primarily be targeted at surgical resection with negative margins in patients with resectable disease. Lenvatinib may show promise to potentially extend survival.

DOI： 10.1016/j.anl.2017.07.009

Language：Japanese  

Language：Japanese  

症例は50歳、女性。1年前から嚥下時違和感を認め、画像検査の結果、食道粘膜下腫瘍と診断した。腫瘍の増大傾向があること、乳癌治療歴があり転移が否定できないこと、嚥下時違和感などの自覚症状を有していたことから、治療目的に腫瘍摘出術を行う方針とした。腫瘍は食道筋層内に局在しており、摘出標本は37×31mm大であった。術中所見および病理組織所見から頸部食道より発生した神経鞘腫と診断した。術後経過は良好で術後10日目に退院となった。術後10ヵ月が経過した現在、再発所見は認めていない。今回まれな頸部食道神経鞘腫に対して文献的考察を行ったところ、上縦隔にとどまっている腫瘍については頸部切開のみで摘出可能であり、上縦隔から中縦隔にまたがる頸胸部境界部腫瘍の場合は症例ごとにアプローチ法が選択する必要があると考えられた。(著者抄録)

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

BACKGROUND: The role of induction chemotherapy (IC) in the treatment of resectable advanced head and neck squamous cell carcinoma has not been elucidated, and the most effective IC regimen for chemoselection is still unknown. At our institute we have not used the triple combination of docetaxel, cisplatin, fluorouracil (TPF) for chemoselection, but rather the double combination of docetaxel + cisplatin (TP). The aim of this study is to report the outcome of patients with advanced hypopharyngeal cancer treated by single cycle of IC with TP followed by chemoradiation (CRT) or surgery. METHODS: A total of 29 patients with resectable advanced hypopharyngeal cancer who were treated with a single cycle of IC were entered into the study. Responders were treated by CRT while nonresponders underwent surgery. Outcomes were analyzed using the Kaplan-Meier method. RESULTS: A single cycle of IC with TP achieved response in 21 of the 29 patients. The major side effect was neutropenia which could be managed without delaying the sequential treatment. The 2-year overall survival and disease-specific survival were both 74.0&#37; (stage III 100&#37;, stage IVA 69.1&#37;). The cumulative 2-year laryngeal preservation rate was 100&#37; for stage III and 53.6&#37; for stage IVA. CONCLUSION: A single cycle of IC with the combination of docetaxel + cisplatin may be sufficient to select advanced hypopharyngeal cancer patients with radio-sensitivity. IC intended for organ preservation strategies should be low toxic. Our strategy may be a useful for providing the benefits of IC and the opportunity for curative surgery without delay.

DOI： 10.1007/s10147-016-1084-8

Language：Japanese  

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

OBJECTIVE: The aim of this study was to investigate the clinical features and prognosis of patients with squamous cell carcinoma (SCC) associated with sinonasal inverted papilloma (IP). METHODS: The medical records of 95 patients who were diagnosed with IP or SCC associated with IP were retrospectively reviewed. Out of 95 patients, 15 were diagnosed with SCC associated with IP. The clinical characteristics, treatment modalities, and survival outcomes of the patients were analyzed. RESULTS: The incidence of SCC associated with IP was 15.8&#37;. Although differential diagnosis between IP and SCC associated with IP is difficult, epistaxis may be the specific symptom in SCC associated with IP cases. The 3-year disease-specific survival rate was higher in cases with T1, 2 and 3 than in cases with T4. There was no significant difference in survival rate between maxillary sinus and other primary sites. On the other hand, there was a significant difference in survival rate between the microscopic SCC with IP cases and the other cases. In addition, the patients with <70 years old better than those with >70 years old with a 3-year disease free survival of 80&#37; versus 0&#37;. CONCLUSIONS: Some T4 patients were found to have a highly aggressive disease. Therefore, complete surgical resection followed by chemo-radiation therapy is the recommended treatment for patients with T4 disease to control of the primary tumor site.

DOI： 10.1016/j.anl.2016.04.004

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

The identification of prognostic biomarkers and their underlying mechanisms of action remain of great interest in breast cancer biology. Using global miRNA profiling of 71 lymph node-negative invasive ductal breast cancers and 5 normal mammary epithelial tissues, we identified miR-449a to be highly overexpressed in the malignant breast tissue. Its expression was significantly associated with increased incidence of patient relapse, decreased overall survival, and decreased disease-free survival. In vitro, miR-449a promoted breast cancer cell proliferation, clonogenic survival, migration, and invasion. By utilizing a tri-modal in silico approach for target identification, Cysteine-Rich Protein 2 (CRIP2; a transcription factor) was identified as a direct target of miR-449a, corroborated using qRT-PCR, Western blot, and luciferase reporter assays. MDA-MB-231 cells stably transfected with CRIP2 demonstrated a significant reduction in cell viability, migration, and invasion, as well as decreased tumor growth and angiogenesis in mouse xenograft models. Our data revealed that overexpression of miR-449a suppresses CRIP2, which then affects the tumor vasculature, likely via NF-κB/p65 complex-mediated transcription of VEGF. These finding define an oncogenic function of miR-449a in human breast cancer, and highlight the importance of this pathway in driving aggressive behaviour.

DOI： 10.18632/oncotarget.7753

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

Reports of drug-induced interstitial pneumonia caused by Cetuximab have been increasing. Pneumocystis pneumonia is important as a differential diagnosis of drug-induced interstitial pneumonia. We report herein on a 64-year-old man with pneumocystis pneumonia after cetuximab-based bioradiotherapy for laryngeal cancer. After radiotherapy, the patient developed multi-drug resistant pneumonia. Chest CT imaging revealed diffuse ground-glass opacities in the lung field. He was diagnosed as having pneumocystis pneumonia based on the bronchoalveolar lavage (BAL) findings, and then his symptoms improved after treatment with Trimethoprim/Sulfamethoxazole. It is important to assess the risk factor for pneumocystis pneumonia for early its detection and treatment.

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

Cervical cancer is the third most common cancer in women worldwide. In the present study, global microRNA profiling for 79 cervical cancer patient samples led to the identification of miR-218 down-regulation in cervical cancer tissues compared to normal cervical tissues. Lower miR-218 expression was associated significantly with worse overall survival (OS), disease-free survival (DFS), and pelvic/aortic lymph node recurrence. In vitro, miR-218 over-expression decreased clonogenicity, migration, and invasion. Survivin (BIRC5) was subsequently identified as an important cervical cancer target of miR-218 using in silico prediction, mRNA profiling, and quantitative real-time PCR (qRT-PCR). Concordant with miR-218 over-expression, survivin knockdown by siRNA decreased clonogenicity, migration, and invasion. YM155, a small molecule survivin inhibitor, significantly suppressed tumor growth and lymph node metastasis in vivo. Our findings demonstrate that the miR-218~survivin axis inhibits cervical cancer progression by regulating clonogenicity, migration, and invasion, and suggest that the inhibition of survivin could be a potential therapeutic strategy to improve outcome in this disease.

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

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

BACKGROUND: TP53 is one of the most widely known cancer suppressor genes. Mutations in TP53 are ubiquitously observed in almost all cancers. Incidences of mutations range from ~15-70 &#37; in patients with hepatocellular carcinoma (HCC). Moreover, patients with mutated TP53 have poorer prognoses than those with wild-type TP53; therefore, it would be beneficial to predict the prognosis of HCC patients with wild-type TP53. We previously reported that PICT1, coding a nucleolus protein, regulates TP53 through indirect association. METHODS: In this study, we examined PICT1 expression levels and the status of TP53 in 51 primary HCC tissues in order to determine the clinical significance of PICT1 expression and the function of PICT1 in HCC cells. RESULTS: We detected 6 mutations in the 51 samples. In 45 patients with wild-type TP53, those with high PICT1 expression (n = 11) had poorer prognoses than those with low PICT1 expression (n = 34), and there were no significant associations with other clinicopathological factors. According to gene set enrichment analysis, PICT1 expression was inversely correlated with the gene set of TP53. In vitro assays indicated that suppression of PICT1 expression caused an increase in TP53 expression, reduction in cell proliferation, and arrest at the G1 phase of the cell cycle in HCC cells expressing wild-type TP53. CONCLUSIONS: PICT1 should be a useful prognostic marker in HCC patients having wild-type TP53. Furthermore, PICT1 may become a promising therapeutic target because of its ability to increase the expression and activation of TP53.

DOI： 10.1245/s10434-013-2958-x

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

Background: The TP53 pathway is frequently inactivated in human cancers. PICT1 (also known as GLTSCR2) is a novel regulator of the MDM2-TP53 pathway via its interaction with the ribosomal protein RPL11 in the nucleolus. However, the clinical significance of PICT1 in gastric cancer remains unknown.
Methods: To evaluate PICT1 function, we used shRNA to inhibit PICT1 expression in gastric cancer cells that expressed wild-type TP53. PICT1 expression and TP53 mutation status were quantified in 110 cases of primary gastric cancer to explore the impact of PICT1 expression levels on gastric cancer.
Results: Deficiency of PICT1 significantly impaired cell proliferation and colony formation via TP53-mediated cell cycle arrest. Following induction of PICT1 deficiency, RPL11 translocated out of the nucleolus. Of the 110 gastric cancer samples tested, 70 (63.6&#37;) and 40 (36.4&#37;) tumours expressed wild-type and mutant TP53, respectively. In gastric cancer patients with wild-type TP53 tumours, patients with relatively low PICT1 expression levels had a better prognosis compared with high expression level patients (P = 0.046).
Conclusion: The findings suggest that PICT1 has a crucial role in gastric cancer progression by regulating the MDM2-TP53 pathway through RPL11. Clinically, PICT1 expression is a novel prognostic parameter in gastric cancer patients with wild-type TP53 tumours.

DOI： 10.1038/bjc.2013.561

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

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

Circulating tumor cells (CTC) in blood have attracted attention both as potential seeds for metastasis and as biomarkers. However, most CTC detection systems might miss epithelial-mesenchymal transition (EMT)-induced metastatic cells because detection is based on epithelial markers. First, to discover novel markers capable of detecting CTCs in which EMT has not been repressed, microarray analysis of 132 colorectal cancers (CRC) from Japanese patients was conducted, and 2,969 genes were detected that were overexpressed relative to normal colon mucosa. From the detected genes, we selected those that were overexpressed CRC with distant metastasis. Then, we analyzed the CRC metastasis-specific genes (n = 22) to determine whether they were expressed in normal circulation. As a result, PLS3 was discovered as a CTC marker that was expressed in metastatic CRC cells but not in normal circulation. Using fluorescent immunocytochemistry, we validated that PLS3 was expressed in EMT-induced CTC in peripheral blood from patients with CRC with distant metastasis. PLS3-expressing cells were detected in the peripheral blood of approximately one-third of an independent set of 711 Japanese patients with CRC. Multivariate analysis showed that PLS3-positive CTC was independently associated with prognosis in the training set (n = 381) and the validation set [n = 330; HR = 2.17; 95&#37; confidence interval (CI) = 1.38-3.40 and HR = 3.92; 95&#37; CI = 2.27-6.85]. The association between PLS3-positive CTC and prognosis was particularly strong in patients with Dukes B (HR = 4.07; 95&#37; CI = 1.50-11.57) and Dukes C (HR = 2.57; 95&#37; CI = 1.42-4.63). PLS3 is a novel marker for metastatic CRC cells, and it possesses significant prognostic value.

DOI： 10.1158/0008-5472.CAN-12-0326

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

The functions of many long non-coding RNAs (ncRNAs) in human cancers have not yet been elucidated. The long ncRNA HOTAIR is expressed from the developmental HOXC locus located on chromosome 12q13.13. Previous reports have demonstrated that HOTAIR associates with chromatin modifications in cooperation with the Polycomb complex PRC2, and promotes breast and colorectal cancer metastasis. In this study, we examined the clinical significance of HOTAIR expression in patients with hepatocellular carcinoma (HCC). HOTAIR expression was detected in primary HCCs in 13 out of 64 patients. Patients with HOTAIR expression had significantly poorer prognoses and a larger primary tumor size than those without HOTAIR expression, similar to studies in breast and colorectal cancers. Moreover, introduction of human HOTAIR into liver cancer cells revealed that HOTAIR promoted more rapid proliferation compared to control cells. Thus, although the clinical significance of HOTAIR expression in HCC may not be as pronounced as that in breast and colorectal cancers, the current study demonstrates that HOTAIR expression is associated with HCC progression, warranting further studies.

DOI： 10.3892/or.2012.2219

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

The mammalian target of rapamycin (mTOR) is a downstream integrator of essential pathways. mTOR signaling is frequently dysregulated in a variety of human cancers, and in silico analysis has revealed two miR-144 binding sites in the mTOR 3' untranslated region. We investigated the clinicopathologic magnitude of the mTOR pathway regulating microRNA, miR-144 in colorectal cancer (CRC) cases. The regulation of mTOR by miR-144 was examined with inhibitor miR-144-transfected cells. We also investigated changes in sensitivity to the mTOR inhibitor, rapamycin, in inhibitor miR-144-transfected cells. Quantitative RT-PCR was used to evaluate the clinicopathologic significance of miR-144 expression in 137 CRC. Furthermore, we assessed the correlation between CRC prognosis and the expression of 16 genes in the Akt/mTOR pathway. In vitro assays showed that mTOR is a direct target of miR-144, and downregulation of miR-144 facilitated proliferation of CRC cell line, HT29. In addition, the viability of HT29 cells with downregulated miR-144 expression was significantly reduced with rapamycin treatment. Low expression levels of miR-144 were associated with enhanced malignant potential such as venous invasion (P = 0.0013), liver metastasis (P = 0.08), liver recurrence (P = 0.0058) and poor prognosis (P = 0.0041). Multivariate analysis indicated that low miR-144 expression was an independent prognostic factor for survival. Among many genes consisting of the mTOR pathway, only high expression of Rictor was associated with poor prognosis of CRC. miR-144 is a meaningful prognostic marker. Downregulation of miR-144 leads to poor prognosis of CRC patients via activation of the mTOR signaling pathway.

DOI： 10.1093/carcin/bgs288

Language：Japanese  

【最新疾患モデルと病態解明、創薬応用研究、細胞医薬創製研究の最前線 最新疾患モデル動物、ヒト化マウス、モデル細胞、ES・iPS細胞を利用した病態解明から創薬まで】 (第2章)各種病態モデルと創薬研究 腫瘍性疾患 PICT1による核小体ストレス経路を介したp53と腫瘍進展制御 腫瘍予後マーカーや今後の創薬応用に向けて
p53は,DNAストレス,発がんストレスのほかに核小体ストレスによっても活性化されることが近年わかってきた。核小体ストレス刺激後には,RPL11などの一部のリボソームタンパク質が核小体から核質に局在変化し,核質にいるMDM2と結合してその機能を抑制し,p53が蓄積される。われわれは核小体にありRPL11の局在を制御するPICT1を見出し,この分子がp53を制御し,がんの良い予後マーカーとなることを見出した。今後PICT1の発現制御やPICT1とRPL11との結合様式の研究により,新規抗腫瘍薬が生まれることが期待される。(著者抄録)

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

Cell growth demands new protein synthesis, which requires nucleolar ribosomal functions. Ribosome biogenesis consumes a large proportion of the cell's resources and energy, and so is tightly regulated through an intricate signaling network to guarantee fidelity. Thus, events that impair ribosome biogenesis cause nucleolar stress. In response to this stress, several nucleolar ribosomal proteins (RPs) translocate to the nucleoplasm and bind to MDM2. MDM2-mediated ubiquitination and degradation of the tumor suppressor p53 is then blocked, resulting in p53 accumulation and the induction of p53-dependent cell cycle arrest and apoptosis. Nucleolar stress is therefore a quality control surveillance mechanism that monitors the synthesis and assembly of the rRNA and protein components of ribosomes. Although nucleolar stress signaling pathways have been extensively analyzed, critical questions remain about their regulatory mechanisms. For example, how do RPs translocate from the nucleolus to the nucleoplasm to exert their functions, and do these p53-regulating RPs influence the prognosis of human cancer patients? Our laboratory recently identified the nucleolar protein PICT1 as a novel regulator of nucleolar stress. PICT1 sequesters the ribosomal protein RPL11 in the nucleolus, preventing it from binding to MDM2. MDM2 is then free to degrade p53, favoring tumor cell growth. Accordingly, the level of PICT1 in a tumor is becoming a useful prognostic marker for human cancers. This review summarizes the evidence that links nucleolar stress to tumorigenesis, and casts PICT1 as an oncogenic player in human cancer biology.

DOI： 10.1111/j.1349-7006.2012.02219.x

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

The aim of this study was to identify and evaluate novel prognostic markers for gastric cancer. Differential mRNA displays comparing paired tumor/normal stomach samples were assessed. Several differentially expressed cDNA fragments of candidate genes were identified, and one of these was further studied using quantitative reverse transcription-PCR in 140 human gastric carcinomas. To evaluate protein expression, immunohistochemical staining was performed in selected cases. One of the genes abundantly expressed in tumor tissue on the differential mRNA displays was identified as histone deacetylase 1 (HDAC). HDAC was overexpressed in the tumor tissue in 77&#37; of the cases as determined by quantitative reverse transcription-PCR. Immunohistochemical staining revealed analogous results, showing strong expression in cancer cells. Patients were then classified into high (n=78) and low (n=62) expression groups according to the mean value of HDAC expression. High frequencies of lymph vessel and vascular vessel permeations, and advanced stage of the disease were recognized in the high expression group compared to the low expression group (p<0.05). Prognosis was significantly worse for the high expression group than for the low expression group (p<0.05), and multi-variate analysis demonstrated that HDAC expression was an independent prognostic factor. Although not significantly different, lymph node metastasis was recognized more frequently in the high expression group (p=0.07). In conclusion, the findings show that HDAC expression is associated with aggressive behavior of primary gastric cancer, and imply that determination of the HDAC expression status is useful for predicting prognosis in patients with gastric cancer.

DOI： 10.3892/or.2011.1361

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

The functional impact of recently discovered long noncoding RNAs (ncRNAs) in human cancer remains to be clarified. One long ncRNA which has attracted attention is the Hox transcript antisense intergenic RNA termed HOTAIR, a long ncRNA expressed from the developmental HOXC locus located on chromosome 12q13.13. In cooperation with Polycomb complex PRC2, the HOTAIR long ncRNA is reported to reprogram chromatin organization and promote breast cancer metastasis. In this study, we examined the status and function of HOTAIR in patients with stage IV colorectal cancer (CRC) who have liver metastases and a poor prognosis. HOTAIR expression levels were higher in cancerous tissues than in corresponding noncancerous tissues and high HOTAIR expression correlated tightly with the presence of liver metastasis. Moreover, patients with high HOTAIR expression had a relatively poorer prognosis. In a subset of 32 CRC specimens, gene set enrichment analysis using cDNA array data revealed a close correlation between expression of HOTAIR and members of the PRC2 complex (SUZ12, EZH2, and H3K27me3). Our findings suggest that HOTAIR expression is associated with a genome-wide reprogramming of PRC2 function not only in breast cancer but also in CRC, where upregulation of this long ncRNA may be a critical element in metastatic progression.

DOI： 10.1158/0008-5472.CAN-11-1021

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

Language：English   Publishing type：Research paper (other academic)  

DOI： 10.1158/1538-7445.FBCR11-PR9

Language：English  

核小体を起点とする新規p53経路制御因子PICT1とその異常による腫瘍制御(Regulation of p53 pathway and Tumor Growth by Novel Nucleolar Protein PICT1)

Language：English  

食道癌における転移関連遺伝子FOXC2の臨床病理学的意義(FOXC2 is a Novel Prognostic Factor in Human Esophageal Squamous Cell Carcinoma)

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

PURPOSE: The profiles of microRNAs change significantly in gastric cancer. MiR-146a is reported to be a tumor suppressor in pancreatic cancer, breast cancer, and prostate cancer. We investigated the clinical significance of miR-146a in gastric cancer, in particular focusing on hypothetical miR-146a target genes, such as epidermal growth factor receptor (EGFR) and interleukin-1 receptor-associated kinase (IRAK1). EXPERIMENTAL DESIGN: We examined miR-146a levels in 90 gastric cancer samples by q-real-time (qRT)-PCR and analyzed the association between miR-146a levels and clinicopathologic factors and prognosis. The regulation of EGFR and IRAK1 by miR-146a was examined with miR-146a-transfected gastric cancer cells. Moreover, we analyzed the association between miR-146a levels and the G/C single nucleotide polymorphism (SNP) within pre-miR-146a seed sequences in 76 gastric cancer samples, using direct sequencing of genomic DNA. RESULTS: In 90 clinical samples of gastric cancer, miR-146a levels in cancer tissues were significantly lower than those in the corresponding noncancerous tissue (P < 0.001). Lower levels of miR-146a were associated with lymph node metastasis and venous invasion (P < 0.05). Moreover, a lower level of miR-146a was an independent prognostic factor for overall survival (P = 0.003). Ectopic expression of miR-146a inhibited migration and invasion and downregulated EGFR and IRAK1 expression in gastric cancer cells. In addition, G/C SNP within the pre-miR-146a seed sequence significantly reduced miR-146a levels in the GG genotype compared with the CC genotype. CONCLUSIONS: MiR-146a contains an SNP, which is associated with mature miR-146a expression. MiR-146a targeting of EGFR and IRAK1 is an independent prognostic factor in gastric cancer cases.

DOI： 10.1158/1078-0432.CCR-10-2866

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

Cyclin D1 plays important roles in esophageal squamous cell carcinoma (ESCC) cases by amplification of the 11q13.3 locus. FBXO31 is a subunit of the SCF ubiquitin ligase, which targets cyclin D1 for degradation. In this study, we clarified the clinical significance of FBXO31 and characterized the association between cyclin D1 and FBXO31 in ESCC cases. Total RNA was extracted from tumor tissues obtained from 68 ESCC patients who underwent surgical resection. FBXO31 expression levels were determined by quantitative RT-PCR, and both FBXO31 and cyclin D1 protein expression and localization were evaluated by immunohistochemistry (IHC). Furthermore, using CGH and gene expression array data of another subset, we validated the association between cyclin D1 genomic amplification and FBXO31 expression levels. Higher FBXO31 expression levels significantly correlated with depth of tumor invasion and clinical stage (P<0.05). In addition, the FBXO31 high expression group showed a significantly poorer prognosis than the low expression group (P<0.001). Multivariate analysis indicated that FBXO31 expression was an independent prognostic factor [relative risk (RR): 1.79, confidence interval (CI): 1.14-3.01, P=0.01]. Using IHC, concordant expression was observed between cyclin D1 and FBXO31 in the nucleus and cytoplasm, respectively. CGH array indicated that cases having cyclin D1 with increased copy number were significantly associated with elevated FBXO31 expression levels (P<0.05). FBXO31 could be a novel and robust prognostic marker for ESCC.

DOI： 10.3892/ijo.2011.1018

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

PICT1 (also known as GLTSCR2) is considered a tumor suppressor because it stabilizes phosphatase and tensin homolog (PTEN), but individuals with oligodendrogliomas lacking chromosome 19q13, where PICT1 is located, have better prognoses than other oligodendroglioma patients. To clarify the function of PICT1, we generated Pict1-deficient mice and embryonic stem (ES) cells. Pict1 is a nucleolar protein essential for embryogenesis and ES cell survival. Even without DNA damage, Pict1 loss led to p53-dependent arrest of cell cycle phase G(1) and apoptosis. Pict1-deficient cells accumulated p53, owing to impaired Mdm2 function. Pict1 binds Rpl11, and Rpl11 is released from nucleoli in the absence of Pict1. In Pict1-deficient cells, increased binding of Rpl11 to Mdm2 blocks Mdm2-mediated ubiquitination of p53. In human cancer, individuals whose tumors express less PICT1 have better prognoses. When PICT1 is depleted in tumor cells with intact P53 signaling, the cells grow more slowly and accumulate P53. Thus, PICT1 is a potent regulator of the MDM2-P53 pathway and promotes tumor progression by retaining RPL11 in the nucleolus.

DOI： 10.1038/nm.2392

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

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

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

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核小体を起点としp53の制御に関わる腫瘍関連遺伝子の同定

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p53の制御に関わる新規腫瘍関連遺伝子の同定(Identification of a novel gene which regulates MDM2-p53 pathway and tumor growth)

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孤立性線維性腫瘍は間葉系由来の腫瘍であるが鼻、副鼻腔での報告はまれである。中鼻甲介を基部とした孤立性線維性腫瘍の1例を経験したので報告する。症例は59歳、女性で徐々に出現した鼻背部の腫脹を主訴に当科を受診した。生検で孤立性線維性腫瘍の診断であった。易出血性であったがDenker法に内視鏡を併用することによって安全に摘出可能であった。術後病理で悪性所見を認めず、12ヵ月経過した。現在再発は認めていない。(著者抄録)

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Neck dissection after concurrent chemoradiotherapy for head and neck squamous cell carcinoma with cervical metastases
To examine the effect of preoperative concurrent chemoradiotherapy for head and neck squamous cell carcinoma with cervical metastases, we reviewed pN, the locoregional recurrence rate, and the salvage rate of recurrence cases at our institution. The average term from concurrent chemoradiotherapy to neck dissection was 3.1 weeks. The pN0 rate was 62&#37; for all cases. For the recurrence rate of primary tumor, there was no significant difference -in the degree of progress of -primary tumor at the start of treatment, but in the pN (+) cases, there was significantly more progress than in the pN0 cases (p<0.05). The pN (+) rate was 38&#37; after concurrent chemoradiotherapy, so it is necessary for the case to show cervical metastasis at the start of treatment in order to perform neck dissection. Furthermore, it appears that pN (+) cases are at higher risk of recurrence of primary tumor and so require careful follow-up.

DOI： 10.5981/jjhnc.34.557

Language：Japanese  

Country：Japan  

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Country：Japan  

副咽頭間隙腫瘍は、画像検査の普及により近年その報告は増加している。手術治療が第1選択だが解剖学的特殊性から手術アプローチ法の選択に苦慮することもある。今回、われわれは1994年から2017年の24年間に当科にて手術加療した副咽頭間隙腫瘍症例76例について腫瘍部位(茎突前区・後区)と術後合併症を中心に臨床検討を行った。全体で53例(70%)になんらかの合併症が認められ、特に後区発生腫瘍では迷走神経麻痺が17例(63%)、Horner症候群は9例(33%)にみられ、また長期経過においても症状が遷延しやすかった。(著者抄録)

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症例は63歳、女性。40年数年前から関節リウマチを罹患しており、10年以上メトトレキサート(Methotrexate:MTX)、タクロリムスを服用していた。201X年8月下旬に左耳下部腫脹と疼痛を認めたため、近医内科クリニックより総合病院耳鼻咽喉科を紹介受診した。造影MRIにて左耳下腺深葉に腫瘍性病変を認め、穿刺吸引細胞診にてclass IIIbの結果であった。悪性の可能性が否定できないため、手術加療目的に九州大学病院耳鼻咽喉科紹介受診となった。耳下腺原発悪性腫瘍が疑われたため、10月6日に左耳下腺全摘術を施行した。永久病理診断の結果、組織型はDiffuse Large B Cell Lymphoma(DLBCL)、EBER陽性であったためMTX関連リンパ増殖性疾患と診断した。術後MTX内服を中止し、以後再燃は認めていない。本邦では関節リウマチ罹患者の多くがMTXを服用している。MTX服用中の関節リウマチ患者に頭頸部腫瘍性病変を認めた場合は、本症を十分に念頭に置き、診断、治療に当たる必要である。(著者抄録)

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Country：Japan  

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大腸癌におけるゲノムワイド発癌関連多型解析の結果

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Country：Japan  

好中球減少性腸炎から回盲弁狭窄を来たしイレウスを発症した1例

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Country：Japan  

術前放射線化学療法後に根治術を行った膵癌の5例

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αリポ酸誘導体(DHLHZn)の癌幹細胞様細胞を介した抗腫瘍効果の検討

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Country：Japan  

乳癌、胃癌におけるCD47発現の臨床学的重要性

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Country：Japan  

大腸癌症例におけるNEK2発現の重要性

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肝細胞癌におけるlincRNA HOTAIRの発現と臨床病理学的因子との関連

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Country：Japan  

胃癌症例におけるRFWD2の機能解析

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胃癌骨髄・原発巣におけるHistone mRNAおよびmiR-760発現変化

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Country：Japan  

17q25.1領域遺伝子発現解析による食道上皮癌原因遺伝子の同定

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Country：Japan  

F-box protein FBXO31の胃がんにおける発現低下の重要性(The significance of down regulation of F-box protein FBXO31 in gastric cancer)

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Country：Japan  

miR-144によるmTOR制御と大腸癌の予後

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ゲノム解析から選択されたADH1BまたはALDH2遺伝子多型は、飲酒と喫煙により食道扁平上皮癌罹患に強く相関する

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大腸癌のゲノムにおけるmicroRNA領域の変異とその臨床病理学的意義

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大腸癌間質におけるマイクロRNA-遺伝子pathwayの包括的解析

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早期・進行胃癌症例骨髄のWhole transcriptome解析による比較検討

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Country：Japan  

消化管再生に向けたヒト腸管in vitro培養法の確立

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消化管再生に向けたヒト腸管in vitro培養法の確立

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胃 胃癌においてHER2を制御するマイクロRNAの検討

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Country：Japan  

胃癌におけるマイクロRNAmiR-125aの臨床病理学的意義

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Country：Japan  

胃癌原発巣・骨髄におけるhistone family遺伝子発現の検討

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Country：Japan  

食道扁平上皮癌における17q25.1 TOC locus上の全転写産物解析(Analysis of all transcripts in TOC locus on chromosome 17q25.1 in esophageal squamous cell carcinoma)

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Country：Japan  

食道癌における細胞外マトリックス関連遺伝子Fibronectin発現の臨床病理学的意義

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大腸癌におけるmiR-144の臨床的意義(Clinical significance of miR-144 expression in colorectal cancer patients)

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Country：Japan  

大腸癌におけるmicroRNA-125b発現の臨床的意義の検討

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Country：Japan  

浸潤・転移 食道癌におけるFN1発現の意義(Invasion and metastasis Fibronectin 1 is a bona-fide prognostic marker in esophageal cancer cases)

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Country：Japan  

背景肝におけるFbxw7発現の低下は、肝癌患者の予後不良因子である(Lower expression of Fbxw7 mRNA in non-cancerous liver tissue predicts poorer outcome of patients with HCC)

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Country：Japan  

食道癌および大腸癌細胞におけるゲノム変化の横断的解析及びその臨床病理学的意義(Transversal analysis of genomic alteration and following gene expression change of esophageal and colorectal cancer)

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Country：Japan  

食道癌における上皮間葉移行関連因子FN1発現の臨床的意義について

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