九州大学 研究者情報
論文一覧
甲斐 昌也(かい まさや) データ更新日:2021.08.02

助教 /  九州大学病院 乳腺外科(1)


原著論文
1. 頼正恵, 山下弘幸, 定永匡子, 甲斐昌也, 小川尚洋, 野口志郎, バセドウ病を合併した原発性副甲状腺機能亢進症 原発性副甲状腺機能亢進症単独症例との比較, 内分泌外科, 23, 4, 263-266, 2006.04, バセドウ病に原発性副甲状腺機能亢進症(HPT)を合併した10症例(B+HPT群)とHPT単独の54症例(HPT群)とを比較した。血清総カルシウム(Ca)はB+HPT群:10.75±0.5mg/dl、HPT群:11.1±0.8mg/dl、血清intact PTHはB+HPT群:120±95pg/ml、HPT群:230±415pg/ml、血清リンはB+HPT群:3.55±0.48mg/dl、HPT群:3.08±0.44mg/dl、24時間尿中Ca排泄量はB+HPT群:192.9±58.3mg/dl、HPT群:274.5±103.8mg/dlであった。腫大腺の部位診断はB+HPT群:4例(40%)、HPT群:40例(74%)で可能であった。摘出甲状腺重量はB+HPT群:295±132mg、HPT群:1089±1946mgであった。バセドウ病に合併したHPTの診断は困難であり、診断には甲状腺機能の状態を考慮しなければならない。甲状腺機能更新状態ではCaが高めになり、高Ca血症を呈する症例もあ�
k!#I{9C>uA#5!G=$,@5>o2=$7$?8e$b9b�Ca血症が持続する場合は、HPTの合併を鑑別する必要があると思われた。.
2. 倉田加奈子, 甲斐昌也, 久保真, 森瞳美, 山田舞, 中房祐司, 中村雅史, 原発性乳癌非切除例における内分泌療法の意義, 癌と化学療法, 45, 11, 1645-1647, 2018.04, Abstract:ホルモン受容体陽性乳癌の手術拒否・不適格例では、有害事象が少なく、長期投与が可能な内分泌療法が選択されることがある。今回、2012~2015年に当科および関連施設においてホルモン受容体陽性乳癌と診断され、非切除かつ内分泌療法を施行したStage I~IIIの8例を対象とし、内分泌療法の意義について検討した。平均治療期間は20.1ヵ月であり、治療を中断した症例はなかった。またPDとなった症例はなく、手術拒否・不適格例においては内分泌療法も有用・安全な選択肢であると考えられた。(著者抄録).
3. Kai M, Yamashita H, Cantor T, Moriyama T, Rai M, Ogawa T, Watanabe S, Uchino S, Noguchi S, Intraoperative parathyroid hormone levels measured by intact and whole parathyroid hormone assays in patients with Graves' disease., Surgery Today, 38, 3, 214-221, 2008.04, PURPOSE: To find out if the whole parathyroid hormone (wPTH) assay has practical advantages over the intact (iPTH) assay in patients with Graves' disease. METHODS: We measured iPTH and wPTH levels before and after subtotal thyroidectomy in 111 consecutive patients (94 women and 17 men) with Graves' disease. Blood samples for assays were obtained after the induction of anesthesia (basal) and following skin closure (postoperative). RESULTS: There was a significant correlation between wPTH and iPTH in both the basal and postoperative levels. Logistic regression analyses examining the relationship between the reduction in parathyroid hormone (PTH) levels and the incidence of tetany revealed that both the wPTH and iPTH assays were significantly equally predictive of postoperative tetany. CONCLUSION: We found that both the wPTH and iPTH assays were useful for predicting postoperative tetany in patients with Graves' disease, yielding similar results.


.
4. Kai M, Onishi H, Souzaki M, Tanaka Haruo, Kubo M, Tanaka M, Katano M, Semi-quantitative evaluation of CD44(+) /CD24(-) tumor cell distribution in breast cancer tissue using a newly developed fluorescence immunohistochemical staining method
, Cancer Sci, 102, 12, 2132-2138, 2011.04, Abstract
CD44(+) /CD24(-) tumor cells are reported to contain cancer stem cells in breast cancer. The main purpose of the present study is to develop an immunohistofluorescence method that can quantitatively analyze CD44(+) /CD24(-) tumor cell distribution in breast cancer tissue and help better define the role of CD44(+) /CD24(-) tumor cells in breast cancer. The samples used were from 21 primary breast cancer patients who underwent neoadjuvant chemotherapy and 17 cases with sentinel lymph nodes that had lymph node micrometastasis. CD44(+) /CD24(-) tumor cells were distinguished at a single cell level using improved triple-staining immunohistofluorescence and a simulated laser capture microdissection method. The percentage of CD44(+) /CD24(-) cells significantly increased following neoadjuvant chemotherapy treatment (0.93% and 2.78%, before and after, respectively, P = 0.0043). The percentage of CD44(+) /CD24(-) cells was also significantly high in micrometastatic sentinel lymph nodes (0.49% and 1.91%, primary tumors and lymph nodes, respectively, P = 0.0246). The CD44(+) /CD24(-) tumor cell distribution was heterogeneous in both breast cancer tissue and lymph node metastasis. In a xenograft model using immunodeficient mice, the hedgehog signaling inhibitor cyclopamine repressed the tumorigenicity of CD44(+) /CD24(-) cells. Our results suggest that this semi-quantitative immunohistochemical analysis is valuable for detecting a small population of cells in cancer tissues and that the hedgehog signaling pathway inhibitor cyclopamine is useful for regulating the CD44(+) /CD24(-) tumor cells in breast cancer. (Cancer Sci, doi: 10.1111/j.1349-7006.2011.02063.x, 2011).

.
5. Onishi H, Kai M, Odate S, Iwasaki H, Morifuji Y, Ogino T, Morisaki T, Nakashima Y, Katano M, Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer, Cancer Sci, 102, 6, 1144-1150, 2011.04, Abstract

The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O2) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O2) or hypoxic (1% O2) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness.
.
6. Onishi H, Morifuji Y, Kai M, Suyama K, Iwasaki H, Katano M, Hedgehog inhibitor decreases chemosensitivity to 5-FU and gemcitabine under hypoxic conditions in pancreatic cancer, Cancer Sci, 103, 7, 1272-1279, 2012.04, Abstract


Pancreatic cancer is one of the deadliest types of cancer. Previously, we showed that hypoxia increases invasiveness through upregulation of Smoothened (Smo) transcription in pancreatic ductal adenocarcinoma (PDAC) cells. Here, we first evaluated whether hypoxia-induced increase in Smo contributes to the proliferation of PDAC cells. We showed that Smo, but not Gli1, inhibition decreases proliferation significantly under hypoxic conditions. To further investigate the effects of Smo on PDAC growth, cell cycle analysis was carried out. Inhibition of Smo under hypoxia led to G(0) /G(1) arrest and decreased S phase. As 5-fluorouracil (5-FU) and gemcitabine, which are first-line drugs for pancreatic cancer, are sensitive to S phase, we then evaluated whether cyclopamine-induced decreased S phase under hypoxia affected the chemosensitivity of 5-FU and gemcitabine in PDAC cells. Cyclopamine treatment under hypoxia significantly decreased chemosensitivity to 5-FU and gemcitabine under hypoxia in both in vitro and in vivo models. In contrast, cis-diamminedichloroplatinum, which is cell cycle-independent, showed significant synergistic effects. These results suggest that hypoxia-induced increase of Smo directly contributes to the proliferation of PDAC cells through a hedgehog/Gli1-independent pathway, and that decreased S phase due to the use of Smo inhibitor under hypoxia leads to chemoresistance in S phase-sensitive anticancer drugs. Our results could be very important clinically because a clinical trial using Smo inhibitors and chemotherapy drugs will begin in the near future.
.
7. Nagamatsu I, Onishi H, Matsushita S, Kubo M, Kai M, Imaizumi A, Nakano K, Hattori M, Oda Y, Tanaka M, Katano M, NOTCH4 is a potential therapeutic target for Triple-negative Breast cancer, Anticancer Res, 34, 1, 69-80, 2014.04, BACKGROUND/AIM:

The prognosis for triple-negative breast cancer (TNBC) is poor. In the present study, we evaluated whether NOTCH4 receptor is a potential new therapeutic target for TNBC.

MATERIALS AND METHODS:

In vitro proliferation and invasiveness were evaluated in TNBC cells with or without small-interfering RNA (siRNA) for NOTCH4, and with or without NOTCH4 plasmid transfection. In vivo, MDA-MB-231 cells with or without NOTCH4 siRNA were subcutaneously implanted into the flank regions of mice. The frequency of nuclear translocation of NOTCH4 was assessed by immunohistochemistry in 21 TNBC samples and 46 non-TNBC samples.

RESULTS:

NOTCH4 inhibition in TNBC cells reduced proliferation and invasiveness, and NOTCH4 overexpression in TNBC cells increased proliferation and invasiveness. NOTCH4 inhibition reduced tumour volume and tumourigenicity of mouse xenografts. TNBC cells had a higher frequency of nuclear translocation of NOTCH4 than other cells.

CONCLUSION:

NOTCH4 is a new potential therapeutic target for triple-negative breast cancer.
.
8. Mori H, Kubo M, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Miyazaki T, Oda Y, Otsuka T, Nakamura M, BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline-Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer, PLoS One, 10.1371/journal.pone.0167016 , 11, 12, e0167016, 2016.04, BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1-mutated tumors, in a large cohort of TNBC cases. MethodsThe BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA). The tumor subtypes were determined immunohistochemically using resected specimens. ResultsOf the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4%) tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003). There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter
recurrence-free survival (RFS) compared with the non-BRCAness group (P = 0.04) and had a shorter overall survival (OS) although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS). Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC.ConclusionsThe 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs..
9. Mori H, Kubo M, Yamaguchi R, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Oda Y, Nakamura M, The combination of PD-L1 expression and decreased tumor- infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer, Oncotarget, 8, 9, 15584-15592, 2017.04, This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD- L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs- low tumors (P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival (P = 0.0018) and overall survival (P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PD-
L1-positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies..
10. Torata N, Kubo M, Miura D, Ohuchida K, Mizuuchi Y, Fujimura Y, Hayakawa E, Kai M, Oda Y, Mizumoto K, Hashizume M, Nakamura M, Visualizing Energy Charge in Breast Carcinoma Tissues by MALDI Mass-spectrometry Imaging Profiles of Low-molecular-weight Metabolites, Anticancer Res, doi:10.21873/anticanres.12723, 38, 7, 4267-4272, 2018.04, Abstract
BACKGROUND/AIM:
Metabolomics is widely used for biomarker discovery, but conventional mass-spectrometry extraction procedures lose the spatial localization of metabolites. In this study, we directly analyzed breast carcinoma tissues embedded in frozen tissue microarrays (fTMAs) using MALDI mass-spectrometry imaging (MALDI-MSI).
MATERIALS AND METHODS:
A total of 119 breast tissues (84 carcinoma and 35 normal) were used. MSI data were extracted from each tissue.
RESULTS:
Overall, 185 of 1,915 peaks which were commonly detected in 60% of target areas were subjected to further analysis. One hundred and fifty-two peaks of carcinoma showed significantly higher intensity than normal. Comparing metabolite profiles from carcinoma and normal tissues, energy charge (EC) and the sum of adenosine phosphate compound (AXP) indicated significantly higher intensities in cancerous tissues than normal. But comparisons of EC and AXP among lymph node metastasis, tumor size and tumor subtypes indicated no significant differences.
CONCLUSION:
Breast carcinoma tissues had higher EC and AXP values than normal. MALDI-MSI could be a tool for characterizing breast carcinoma.
.
11. Mori H, Kubo M, Kai M, Kurata K, Yamada M, Nakamura M, Efficacy and Safety of Bi-weekly Pegfilgrastim for Dose-dense Chemotherapy-induced Neutropenia in Breast Cancer Patients, Anticancer Res, 10.21873/anticanres.12740 , 38, 7, 4381-4386, 2018.04, Abstract
BACKGROUND/AIM:
The dose-dense doxorubicin and cyclophosphamide (ddAC) for patients with HER-2-negative breast cancer is recommended by the National Comprehensive Cancer Network guideline in US. However, there are little data on serum G-CSF concentrations in patients undergoing bi-weekly dose-dense therapy with pegfilgrastim. The objective of this study was to compare the serum G-CSF concentrations in patients receiving pegfilgrastim in bi- or tri-weekly regimens.
PATIENTS AND METHODS:
This study included 26 patients who received ddAC or docetaxel and cyclophosphamide (TC) for primary breast cancer. Serum G-CSF concentrations were measured by ELISA.
RESULTS:
Serum G-CSF concentrations peaked in the second week of ddAC cases and in the ninth week of TC cases. Neutrophils gradually increased until the sixth week in ddAC cases, while they were slightly decreased during the first three weeks in TC cases. Treatments were completed without febrile neutropenia or treatment delays.
CONCLUSION:
Primary prophylactic pegfilgrastim administrations increased serum G-CSF concentrations, helping to maintain the absolute neutrophil counts that are required to undergo chemotherapy. The treatment of ddAC with 3.6 mg pegfilgrastim is completely safe for female Japanese patients.
.
12. Mori H, Kubo M, Kai M, Velasquez VV, Kurata K, Yamada M, Okido M, Kuroki S, Oda Y, Nakamura M, BRCAness Combined With a Family History of Cancer Is Associated With a Poor Prognosis for Breast Cancer Patients With a High Risk of BRCA Mutations, Clin Breast Cancer, 10.1016/j.clbc.2018.05.008, 18, 5, e1217-e1227, 2018.04.
13. Mori H, Kubo M, Kai M, Yamada M, Kurata K, Kawaji H, Kaneshiro K, Osako T, Nishimura R, Arima N, Okido M, Kishimoto J, Oda Y, Nakamura M, T-bet+ lymphocytes infiltration as an independent better prognostic indicator for triple-negative breast cancer, Breast Cancer Res Treat, 10.1007/s10549-019-05256-2, 176, 3, 569-577, 2019.04, Purpose T-box transcription factor 21 (T-bet), which is the master regulator of effector T-cell activation, is derived by stimulation of T-cell receptors. In this study, we focused on T-bet and examined the function of activated T cells.Methods This study included 242 patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. The immunohistochemistry scoring for CD8 and T-bet expression on tumor-infiltrating lymphocytes (TILs) was defined as ≥ 30 per 6.25 × 10-3 mm2.Results Of the 242 TNBC cases, CD8 was positively expressed in 127 (52.5%) tumors, and T-bet was positively expressed in 67 (27.7%) tumors. T-bet expression was significantly correlated with CD8 expression (p < 0.0001). Patients with T-bet+ tumors had longer overall survival (OS) compared with patients with T-bet- tumors (p = 0.047). The combination of CD8+ and T-b
et+ was associated with a better recurrence-free survival (RFS) and OS compared to CD8+/T-bet- tumors (p = 0.037 and p = 0.024, respectively). Adjuvant chemotherapy provided significantly greater benefit to patients with T-bet+ tumors (p = 0.031 for RFS, p = 0.0003 for OS). Multivariate analysis revealed that T-bet expression on TILs was an independent and positive prognostic indicator (HR = 0.36, 95% confidence interval (CI) 0.12–0.94, p = 0.037 for RFS, HR = 0.30, 95% CI 0.07–0.95, p = 0.039 for OS).Conclusions OS was significantly improved for patients with high T-bet-expressing TILs in TNBC. Thus, T-bet may be a predictive indicator for survival and various immunotherapy strategies in TNBC..
14. Kurata K, Kubo M, Kai M, Mori H, Kawaji H, Kaneshiro K, Yamada M, Nishimura R, Osako T, Arima N, Okido M, Oda Y, Nakamura M, Microsatellite instability in Japanese female patients with triple-negative breast cancer, Breast Cancer, 10.1007/s12282-019-01043-5 , 27, 3, 490-498, 2020.04, Abstract
Background: It is important to identify biomarkers for triple-negative breast cancers (TNBCs). Recently, pembrolizumab, an immune checkpoint inhibitor (ICI) for programmed cell death 1 (PD-1), was approved as a treatment strategy for unresectable or metastatic tumor with high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency, such as malignant melanoma, non-small cell lung cancer, renal cell cancer and urothelial cancer. In addition, results from clinical trials suggested that ICI was a promising treatment for TNBCs with accumulated mutations. However, the frequency of MSI in Japanese TNBCs still remains unclear. We aimed to analyze the presence of MSI-H in TNBCs as a biomarker for ICI therapy.
Methods: In this study, we retrospectively evaluated the MSI of 228 TNBCs using an innovative method, MSI Analysis System Version 1.2 (Promega), consisting of 5 microsatellite markers: BAT-26, NR-21, BAT-25, MONO-27 and NR-24 without a normal tissue control.
Results: Among 228 tumors, 222 (97.4%) were microsatellite stable, 4 (1.7%) low-frequency MSI and 2 (0.9%) MSI-H, respectively. Two MSI-H tumors were potentially aggressive pathologically as indicated by nuclear grade 3 and high Ki-67 (> 30%), and were classified as basal-like and non-BRCA-like, but were not consistent regarding tumor-infiltrating lymphocytes, CD8 and PD-L1 expression.
Conclusions: Although we found that MSI-H was uncommon (0.9%) in TNBCs, potential targets for ICIs exist in TNBCs. Therefore, MSI-H breast cancer patients should be picked up using not only conventional methods but also platforms for comprehensive genomic profiling.
.
15. 頼正恵, 山下弘幸, 定永匡子, 甲斐昌也, 小川尚洋, 野口志郎, バセドウ病を合併した原発性副甲状腺機能亢進症 原発性副甲状腺機能亢進症単独症例との比較, 内分泌外科, 23, 4, 263-266, 2006.04, バセドウ病に原発性副甲状腺機能亢進症(HPT)を合併した10症例(B+HPT群)とHPT単独の54症例(HPT群)とを比較した。血清総カルシウム(Ca)はB+HPT群:10.75±0.5mg/dl、HPT群:11.1±0.8mg/dl、血清intact PTHはB+HPT群:120±95pg/ml、HPT群:230±415pg/ml、血清リンはB+HPT群:3.55±0.48mg/dl、HPT群:3.08±0.44mg/dl、24時間尿中Ca排泄量はB+HPT群:192.9±58.3mg/dl、HPT群:274.5±103.8mg/dlであった。腫大腺の部位診断はB+HPT群:4例(40%)、HPT群:40例(74%)で可能であった。摘出甲状腺重量はB+HPT群:295±132mg、HPT群:1089±1946mgであった。バセドウ病に合併したHPTの診断は困難であり、診断には甲状腺機能の状態を考慮しなければならない。甲状腺機能更新状態ではCaが高めになり、高Ca血症を呈する症例もあ�
k!#I{9C>uA#5!G=$,@5>o2=$7$?8e$b9b�Ca血症が持続する場合は、HPTの合併を鑑別する必要があると思われた。.
16. 倉田加奈子, 甲斐昌也, 久保真, 森瞳美, 山田舞, 中房祐司, 中村雅史, 原発性乳癌非切除例における内分泌療法の意義, 癌と化学療法, 45, 11, 1645-1647, 2018.04, Abstract:ホルモン受容体陽性乳癌の手術拒否・不適格例では、有害事象が少なく、長期投与が可能な内分泌療法が選択されることがある。今回、2012~2015年に当科および関連施設においてホルモン受容体陽性乳癌と診断され、非切除かつ内分泌療法を施行したStage I~IIIの8例を対象とし、内分泌療法の意義について検討した。平均治療期間は20.1ヵ月であり、治療を中断した症例はなかった。またPDとなった症例はなく、手術拒否・不適格例においては内分泌療法も有用・安全な選択肢であると考えられた。(著者抄録).
17. Makino I, Chijiiwa K, Kondo K, Ohuchida J, Kai M, Prognostic benefit of selective portal vein occlusion during hepatic resection for hepatocellular carcinoma, Surgery, 137, 6, 626-631, 2005.04, The aim of this study was to clarify whether the types of portal vein (PV) occlusion during hepatectomy affect the long-term outcome in patients with hepatocellular carcinoma (HCC). METHODS: Eighty-six patients who had undergone curative hepatic resection for HCC were divided on the basis of the type of PV occlusion into 2 groups: total PV occlusion (TPVO, n = 56) and selective PV occlusion (SPVO, n = 30) groups. The recurrence-free survival was compared between the groups, and factors affecting recurrence-free survival were examined by univariate analyses followed by multivariate analyses. Moreover, the patients with a single nodular HCC less than 5 cm in diameter were abstracted from both groups, and the recurrence-free survival rate was compared. RESULTS: The patients and tumor-related factors were similar in the TPVO and SPVO groups. The recurrence-free survival was better in the SPVO group than in the TPVO group (median recurrence-free survival time, 1520 vs 561 days, P = .017). The type of PV occlusion was a significant factor for recurrence-free survival by univariate analysis but did not reach significance ( P = .052) by multivariate analysis. In the selected patients who had a single nodular HCC less than 5 cm in diameter, the recurrence-free survival was also significantly better in the SPVO group than in the TPVO group (median recurrence-free survival time, 2613 vs 1003 days, P = .018). CONCLUSIONS: Hepatectomy under selective PV occlusion seems to improve the recurrence-free survival in patients with HCC.
.
18. Eto T, Chijiiwa K, Hidaka H, Ohuchida J, Kai M, Kondo K, Hotokezaka M, Sum of the longest diameters of metastatic liver tumors is a possible new prognostic factor after hepatectomy in patients with colorectal liver metastases, Hepatogastroenterology, 53, 72, 909-912, 2006.04, BACKGROUND/AIMS: Although the size and number of the metastatic liver tumors have been considered to be prognostic factors after hepatectomy in patients with colorectal liver metastases, the importance of these parameters is still controversial. The aim of this study was to evaluate the importance of the new factor, namely, the sum of longest diameters of the metastatic liver tumors (SLD). METHODOLOGY: The medical records of 59 patients who had undergone hepatic resection for colorectal liver metastases were abstracted and these patients were completely followed-up. RESULTS: The overall 5-year survival rate after hepatectomy was 38.5%, and median survival time was 25.9 months. The significant prognostic factors by the univariate analysis were the extents of vessel permeation and lymph node metastasis of primary colorectal carcinoma, the presence of extrahepatic metastasis, the longest diameter and SLD of the liver tumor, surgical margin of the liver, and the serum level of carcinoembryonic antigen. Multivariate analysis showed that SLD (P=0.026) and extrahepatic distant organ metastasis (P=0.008) were the independent prognostic factor. CONCLUSIONS: SLD is a useful and significant predictor for survival after hepatectomy in patients with colorectal liver metastases.

.
19. Hotokezaka M, Chijiiwa K, Kondo K, Kai M, Eto T-A, Hidaka H, Jimi S-I, Maehara N, Ohuchida J, Matsumoto K, Nakao H, Video Monitoring and Slide and Video Presentations as Tools for Surgical Education, Hepatogastroenterology, 55, 86-87, 1519-1522, 2008.04, Abstract
BACKGROUND/AIMS: To provide medical students with good visualization and understanding of surgical procedures, we used video monitoring (Monitor) in the operating room and slide (Slide) and video (Video) presentation in the conferences. The purpose of this study was to evaluate the effect of these visual aids on surgical education.

METHODOLOGY: One hundred and twenty-nine fifth- and sixth-year medical students completed a questionnaire regarding their visualization of, understanding of, and interest in all surgical procedures observed and procedures pertaining to their assigned patients. The score was collected on a Likert-type scores ranged from 1 for "poor" to 5 for "excellent".

RESULTS: Visualization and understanding scores were significantly lower for direct observation than for Monitor (p<0.01 and p<0.001), Slide (p<0.001 and p<0.001) and Video (p<0.001 and p<0.001). Interest scores did not differ between observation methods. For all observation methods, understanding of and interest in the surgical procedures were significantly greater in relation to assigned patients than in relation to all patients observed.

CONCLUSIONS: Video monitoring and slide and video presentations enhance students' understanding of and interest in surgical procedures. Contributing to the care of assigned patient also increases understanding of and interest in general surgery.

.
20. Otani K, Chijiiwa K, Kai M, Ohuchida J, Nagano M, Tsuchiya K, Kondo K, Outcome of surgical treatment of hilar cholangiocarcinoma., J Gastrointest Surg., 12, 6, 1033-1040, 2008.04, To evaluate surgical results and the effect of adjuvant chemotherapy in cases of hilar cholangiocarcinoma, we retrospectively analyzed 27 consecutive patients who underwent surgical resection (eight bile duct resections, 18 bile duct resections plus hepatectomy, one hepatopancreaticoduodenectomy). There was no operative mortality, and the morbidity was 37%. Curative resection (R0 resection) was achieved in 20 (74%) patients. Overall survival at 3 and 5 years was 44% and 27%, significantly higher than that of 47 patients who did not undergo resection (3.5% and 0% at 3 and 5 years, p < 0.0001). Survival of patients with positive margins (R1/2 resection) was poor; there were no 5-year survivors. However, survival was better than that of patients who did not undergo resection (median survival: 22 vs 9 months, p = 0.0007). Univariate analysis identified lymph node metastasis as a negative prognostic factor (p = 0.043). Median survival of patients who un
d!
erwent adjuvant chemotherapy was significantly longer than that of patients who did not (42 vs. 22 months, p = 0.0428). Resection should be considered as the first option for hilar cholangiocarcinoma. There appears to be a survival advantage ev.
21. Hotokezaka M, Chijiiwa K, Kondo K, Kai M, Eto T-A, Hidaka H, Jimi S-I, Maehara N, Ohuchida J, Matsumoto K, Nakao H, Medical Students’ Attitudes to Laparoscopic surgery, Hepato-Gastroenterology, 55, 86-87, 1541-1544, 2008.04, Abstract
BACKGROUND/AIMS: The purpose of the present study was to evaluate the attitude of medical students to laparosocopic surgery.

METHODOLOGY: Two hundred and seven medical students completed a questionnaire regarding their visualization of, understanding of, and interest in observation of laparoscopic surgery via laparoscopic monitor (laparoscopic observation) and of open surgery, either directly (open direct observation), or via video monitor observation (open monitor observation). They were also asked about their willingness to become an operator (operator). Responses to each item were given as Likert-type scores ranging from 1 to 5.

RESULTS: The visualization score was significantly lower for open direct observation than for open monitor observation (P<0.001) and laparoscopic observation (P<0.001), with the significantly lower score for open monitor observation than for laparoscopic observation (P<0.001). The understanding score was significantly lower for open direct observation than for open monitor observation (P<0.01) and laparoscopic observation (P<0.01). Interest scores did not differ between the three observation methods. The operator score was significantly higher for open surgery than for laparoscopic surgery.

CONCLUSIONS: Laparoscopic surgery provides good visualization of the operative field. However, students' interest in laparoscopic surgery is similar to those of open surgery.

.
22. Kai M, Yamashita H, Cantor T, Moriyama T, Rai M, Ogawa T, Watanabe S, Uchino S, Noguchi S, Intraoperative parathyroid hormone levels measured by intact and whole parathyroid hormone assays in patients with Graves' disease., Surgery Today, 38, 3, 214-221, 2008.04, PURPOSE: To find out if the whole parathyroid hormone (wPTH) assay has practical advantages over the intact (iPTH) assay in patients with Graves' disease. METHODS: We measured iPTH and wPTH levels before and after subtotal thyroidectomy in 111 consecutive patients (94 women and 17 men) with Graves' disease. Blood samples for assays were obtained after the induction of anesthesia (basal) and following skin closure (postoperative). RESULTS: There was a significant correlation between wPTH and iPTH in both the basal and postoperative levels. Logistic regression analyses examining the relationship between the reduction in parathyroid hormone (PTH) levels and the incidence of tetany revealed that both the wPTH and iPTH assays were significantly equally predictive of postoperative tetany. CONCLUSION: We found that both the wPTH and iPTH assays were useful for predicting postoperative tetany in patients with Graves' disease, yielding similar results.


.
23. Kondo K, Chijiiwa K, Funagayama M, Kai M, Otani K, Ohuchida J, Hepatic resection is justified for elderly patients with hepatocellular carcinoma., World J Surg., 32, 10, 2223-2229, 2008.04, BACKGROUND: Hepatic resection is one of the main treatment modalities for patients with hepatocellular carcinoma (HCC); however, surgery is generally stressful and often is avoided for elderly patients. This retrospective study was designed to determine whether the indications for hepatic resection in younger patients with HCC are applicable to elderly patients. METHODS: Subjects were 294 patients in whom 319 hepatic resections were performed for HCC (male/female ratio, 238/81; age range, 18-83 years). The patients were divided into two groups according to age at the time of surgery: 70 years or older (n = 109) and 69 years or younger (n = 210). Surgical strategy and postoperative follow-up methods did not differ between groups. The incidence and severity of postoperative complications classified by the Clavien system were compared between the two groups. Postoperative survival was compared between the two groups and between subgroups based on Japan I
n!
tegrated Staging (JIS) scores. HCC-related death rates also were compared. RESULTS: No significant between-group difference was found in background liver function or type of hepatic resection. Differences were found in performance status and type of hepatitis virus infection. No difference was observed in the incidence or severity of postoperative complications. Postoperative survival was similar between the two age-based study groups and between the JIS-based subgroups. HCC-related death rates did not differ between groups. CONCLUSIONS: The absence of differences in postoperative outcomes between groups suggests that hepatic resection is justified for HCC in selected patients aged 70 years or older..
24. Kondo K, Chijiiwa K, Funagayama M, Kai M, Otani K, Ohuchida J, Differences in long-term outcome and prognostic factors according to viral status in patients with hepatocellular carcinoma treated by surgery., J Gastrointest Surg, 12, 3, 468-476, 2008.04, Long-term postoperative survival and prognostic factors were examined retrospectively in patients with hepatocellular carcinoma (HCC) with serum hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCVAb) and in those without virus infection. Subjects were 265 consecutive HCC patients treated surgically at one institution during the period 1990 to 2006. Postoperative survival was analyzed and compared between HBsAg-positive (B-HCC), HCVAb-positive (C-HCC), and hepatitis B- and C-negative (NBNC-HCC) patients. Prognostic factors for overall and recurrence-free survival were also analyzed. Overall and recurrence-free survival rates were significantly higher in the NBNC-HCC group than in the C-HCC group. Significant prognostic factors for overall survival identified by univariate and multivariate analyses were age, serum alkaline phosphatase (ALP) level, tumor multiplicity, portal vein invasion (Vp), hepatic vein invasion (Vv), and operative blood
!
loss in the B-HCC group; serum albumin level, ALP level, tumor size, and Vv in the C-HCC group; and tumor multiplicity in the NBNC-HCC group. Significant factors for recurrence-free survival were age, ALP level, tumor multiplicity, Vp, and operation time in the B-HCC group; ALP level, prothrombin time, tumor size, Vv, and width of the surgical margin in the C-HCC group; and age, tumor size, tumor multiplicity, and Vp in the NBNC-HCC group. Thus, postoperative survival and prognostic factors in cases of HCC differ according to the presence of serologic viral markers..
25. Chijiiwa K, Imamura N, Ohuchida J, Hiyoshi M, Nagano M, Otani K, Kai M, Kondo K, Prospective randomized controlled study of gastric emptying assessed by (13)C-acetate breath test after pylorus-preserving pancreaticoduodenectomy: comparison between antecolic and vertical retrocolic duodenojejunostomy, J Hepatobiliary Pancreat Surg, 16, 1, 49-55, 2009.04, BACKGROUND/PURPOSE: To examine whether vertical retrocolic duodenojejunostomy is superior to antecolic duodenojejunostomy with respect to gastric emptying in a prospective, randomized, controlled study of patients undergoing pylorus-preserving pancreaticoduodenectomy (PpPD). METHODS: Thirty-five patients undergoing PpPD between March 2005 and July 2007 were enrolled in the study. All provided informed consent. During PpPD, the patients were randomly assigned to either the antecolic (antecolic group, n = 17) or vertical retrocolic route (vertical retrocolic group, n = 18) just before the reconstruction. Each patient ingested (13)C-acetate in a liquid meal before surgery and on postoperative day (POD) 30. Gastric emptying variables (Tmax, T1/2) were determined and compared between groups. RESULTS: Clinical delayed gastric emptying, defined as an inability of patients to take in an appropriate amount of solid food orally by POD 14, was found in 1 of 17 p
a!
tients (6%) in the antecolic group and in 4 of 18 patients (22%) in the vertical retrocolic group, but the difference was not significant (P = 0.34). Tmax and T1/2 on POD 30 were prolonged in both groups in comparison to preoperative levels, but no significant difference was found between the two groups. Follow-up examinations revealed that gastric emptying had recovered to the preoperative level by POD 30 in approximately 80% of the patients, regardless of the reconstruction route. CONCLUSIONS: Vertical retrocolic duodenojejunostomy does not seem to offer an advantage with respect to gastric emptying..
26. Kai M, Onishi H, Souzaki M, Tanaka Haruo, Kubo M, Tanaka M, Katano M, Semi-quantitative evaluation of CD44(+) /CD24(-) tumor cell distribution in breast cancer tissue using a newly developed fluorescence immunohistochemical staining method
, Cancer Sci. , 102, 12, 2132-2138, 2011.04, Abstract
CD44(+) /CD24(-) tumor cells are reported to contain cancer stem cells in breast cancer. The main purpose of the present study is to develop an immunohistofluorescence method that can quantitatively analyze CD44(+) /CD24(-) tumor cell distribution in breast cancer tissue and help better define the role of CD44(+) /CD24(-) tumor cells in breast cancer. The samples used were from 21 primary breast cancer patients who underwent neoadjuvant chemotherapy and 17 cases with sentinel lymph nodes that had lymph node micrometastasis. CD44(+) /CD24(-) tumor cells were distinguished at a single cell level using improved triple-staining immunohistofluorescence and a simulated laser capture microdissection method. The percentage of CD44(+) /CD24(-) cells significantly increased following neoadjuvant chemotherapy treatment (0.93% and 2.78%, before and after, respectively, P = 0.0043). The percentage of CD44(+) /CD24(-) cells was also significantly high in micrometastatic sentinel lymph nodes (0.49% and 1.91%, primary tumors and lymph nodes, respectively, P = 0.0246). The CD44(+) /CD24(-) tumor cell distribution was heterogeneous in both breast cancer tissue and lymph node metastasis. In a xenograft model using immunodeficient mice, the hedgehog signaling inhibitor cyclopamine repressed the tumorigenicity of CD44(+) /CD24(-) cells. Our results suggest that this semi-quantitative immunohistochemical analysis is valuable for detecting a small population of cells in cancer tissues and that the hedgehog signaling pathway inhibitor cyclopamine is useful for regulating the CD44(+) /CD24(-) tumor cells in breast cancer. (Cancer Sci, doi: 10.1111/j.1349-7006.2011.02063.x, 2011).

.
27. Onishi H, Kai M, Odate S, Iwasaki H, Morifuji Y, Ogino T, Morisaki T, Nakashima Y, Katano M, Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer, Cancer Sci, 102, 6, 1144-1150, 2011.04, Abstract

The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O2) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O2) or hypoxic (1% O2) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness.
.
28. Fujii Y, Ohuchida J, Chijiiwa K, Yano K, Imamura N, Nagano M, Hiyoshi M, Otani K, Kai M, Kondo K, Verification of Tokyo Guidelines for diagnosis and management of acute cholangitis, J Hepatobiliary Pancreat Sci, 19, 4, 487-491, 2012.04, BACKGROUND:This study aimed to verify diagnostic criteria and severity assessment of the Tokyo Guidelines for acute cholangitis.METHODS:We re-examined whether acute cholangitis was concomitant with gallstones according to the Tokyo Guidelines in 248 patients with choledocholithiasis. Our conventional diagnoses based on physician decision were compared with diagnoses from the Tokyo Guidelines. Problems with severity grade criteria were also evaluated.RESULTS:In total, 53 cases of acute cholangitis were determined by using the Tokyo Guidelines, including three false-negative and seven false-positive cases (acute cholecystitis or pancreatitis was concomitant with choledocholithiasis). Sensitivity, specificity, and accuracy were 94%, 96%, and 96%, respectively. Forty of the 53 patients underwent biliary drainage (mean interval between admission and drainage, 1.4 days). Severity grades were mild in 10, moderate in 30, and severe in 13 patients. Of these 13 patient
s with severe disease, 2 had chronic renal failure, 1 had liver cirrhosis, and 1 had severe acute pancreatitis and liver cirrhosis. No patients died, irrespective of severity grade.CONCLUSIONS:Acute cholangitis should be carefully diagnosed when other inflammatory disease is concomitant with choledocholithiasis. A few patients have absolute acute cholangitis even when they do not meet Tokyo Guidelines diagnostic criteria. Classification into mild or moderate grade using the Tokyo Guidelines is difficult when early biliary drainage is routinely performed. When determining severity grade, clinicians must distinguish between organ dysfunction associated with cholangitis itself and that associated with the underlying/concomitant disease. Apart from a few problems like these, the Tokyo Guidelines are mostly acceptable for the diagnosis and management of acute cholangitis..
29. Otani K, Chijiiwa K, Kai M, Ohuchida J, Nagano M, Kondo K, Role of hilar resection in the treatment of hilar cholangiocarcinoma, Hepatogastroenterology, 59, 115, 696-700, 2012.04, BACKGROUND/AIMS:The aim of this study was to clarify the role of bile duct resection without hepatectomy (hilar resection) in hilar cholangiocarcinoma.METHODOLOGY:We retrospectively compared surgical results for hilar cholangiocarcinoma between 8 patients treated with hilar resection and 21 patients treated with hepatectomy.RESULTS:All hilar resections were performed for Bismuth type I or II tumors with T2 or less lesions, whereas hepatectomy was done for type III or IV tumors excluding one type II tumor. R0 resection was equally achieved in both groups (62.5% in hilar resection group and 76.2% in hepatectomy group, p=0.469) and overall 5-year survival rates were comparable (21.9% vs. 23.6%, p=0.874). With respect to gross tumor appearance, R0 resection was achieved in all patients with papillary tumor in both groups with the excellent 5-year survivals (100% vs. 100%). In patients with nodular and flat tumors, R0 resection was achieved less frequently in the
hilar resection vs. hepatectomy group (50% vs. 77.8%) mainly due to failure to clear the proximal ductal margin, resulting in poorer 5-year survival (0% vs. 18.7%).CONCLUSIONS:Hilar resection may be indicated for papillary T1 or 2 tumors in Bismuth type I or II cholangiocarcinoma..
30. Onishi H, Morifuji Y, Kai M, Suyama K, Iwasaki H, Katano M, Hedgehog inhibitor decreases chemosensitivity to 5-FU and gemcitabine under hypoxic conditions in pancreatic cancer, Cancer Sci, 103, 7, 1272-1279, 2012.04, Abstract


Pancreatic cancer is one of the deadliest types of cancer. Previously, we showed that hypoxia increases invasiveness through upregulation of Smoothened (Smo) transcription in pancreatic ductal adenocarcinoma (PDAC) cells. Here, we first evaluated whether hypoxia-induced increase in Smo contributes to the proliferation of PDAC cells. We showed that Smo, but not Gli1, inhibition decreases proliferation significantly under hypoxic conditions. To further investigate the effects of Smo on PDAC growth, cell cycle analysis was carried out. Inhibition of Smo under hypoxia led to G(0) /G(1) arrest and decreased S phase. As 5-fluorouracil (5-FU) and gemcitabine, which are first-line drugs for pancreatic cancer, are sensitive to S phase, we then evaluated whether cyclopamine-induced decreased S phase under hypoxia affected the chemosensitivity of 5-FU and gemcitabine in PDAC cells. Cyclopamine treatment under hypoxia significantly decreased chemosensitivity to 5-FU and gemcitabine under hypoxia in both in vitro and in vivo models. In contrast, cis-diamminedichloroplatinum, which is cell cycle-independent, showed significant synergistic effects. These results suggest that hypoxia-induced increase of Smo directly contributes to the proliferation of PDAC cells through a hedgehog/Gli1-independent pathway, and that decreased S phase due to the use of Smo inhibitor under hypoxia leads to chemoresistance in S phase-sensitive anticancer drugs. Our results could be very important clinically because a clinical trial using Smo inhibitors and chemotherapy drugs will begin in the near future.
.
31. Kondo K, Chijiiwa Y, Otani K, Kai M, Ohuchida J, Chijiiwa K, Characteristics and surgical outcome of HCC patients with low platelet count, Hepatogastroenterology, 59, 119, 2269-2272, 2012.04, BACKGROUND/AIMS:Hepatocellular carcinoma (HCC) patients often have low platelet count (LPC). The aim of this study was to determine unique features of HCC patients with LPC.METHODOLOGY:HCC patients who underwent surgery were divided into two groups: LPC group (platelet count ≤100,000/mm³, n=84) and control group (platelet count >100,000/mm³, n=240). Surgical outcomes, risk factors for postoperative complications and prognostic factors were retrospectively compared.RESULTS:HCC patients with LPC had poorer liver function, smaller tumors, less anatomical resection and more frequent postoperative liver failure than control group patients. Postoperative survival was not different between the two groups. Tumor invasion to the main branch or trunk of portal vein (Vp3, 4) was the only risk factor for postoperative substantial complications in the LPC group. Postoperative survival was worse in patients with tumor diameter ≥4 cm or multiple tum
ors and in those who underwent preoperative transcatheter arterial chemoembolization (TACE) in the LPC group by multivariate analysis. Among them, preoperative TACE were not prognostic factors in the control group.CONCLUSIONS:In HCC patients with LPC, Vp3, 4 patients should be carefully monitored after surgery and preoperative TACE is not recommended for long-term postoperative survival..
32. Kondo K, Chijiiwa K, Ohuchida J, Kai M, Fujii Y, Otani K, Hiyoshi M, Nagano M, Imamura N, Selection of prophylactic antibiotics according to the microorganisms isolated from surgical site infections (SSIs) in a previous series of surgeries reduces SSI incidence after pancreaticoduodenectomy, J Hepatobiliary Pancreat Sci, 20, 3, 286-293, 2013.04, BACKGROUND:The incidence of surgical site infections (SSIs) is high after pancreaticoduodenectomy (PD).METHODS:We divided 116 consecutive patients who underwent PD into an early group (n = 58) and a later group (n = 58) according to time of surgery. In both groups, endoscopic retrograde biliary drainage was mainly employed for the patients with obstructive jaundice. In the later group, prophylactic antibiotics were selected according to the susceptibility of microorganisms isolated from SSIs in the early group. The incidence of SSIs was compared between the groups.RESULTS:The background characteristics (including methods of preoperative biliary drainage and microorganisms in the bile obtained before or during operation) of the patients were not significantly different between the groups, except for the serum albumin level, which was lower in the later group than in the early group (P = 0.0026). The incidence of SSIs was significantly lower in the later group
(24.1 %) than in the early group (46.6 %) (P = 0.0116). Belonging to the later group was one independent negative risk factor for SSI.CONCLUSIONS:Selection of prophylactic antibiotics on the basis of microorganisms isolated from SSIs in the early group contributed to the reduced incidence of SSIs in the later group after PD..
33. Nagamatsu I, Onishi H, Matsushita S, Kubo M, Kai M, Imaizumi A, Nakano K, Hattori M, Oda Y, Tanaka M, Katano M, NOTCH4 is a potential therapeutic target for Triple-negative Breast cancer, Anticancer Res, 34, 1, 69-80, 2014.04, BACKGROUND/AIM:

The prognosis for triple-negative breast cancer (TNBC) is poor. In the present study, we evaluated whether NOTCH4 receptor is a potential new therapeutic target for TNBC.

MATERIALS AND METHODS:

In vitro proliferation and invasiveness were evaluated in TNBC cells with or without small-interfering RNA (siRNA) for NOTCH4, and with or without NOTCH4 plasmid transfection. In vivo, MDA-MB-231 cells with or without NOTCH4 siRNA were subcutaneously implanted into the flank regions of mice. The frequency of nuclear translocation of NOTCH4 was assessed by immunohistochemistry in 21 TNBC samples and 46 non-TNBC samples.

RESULTS:

NOTCH4 inhibition in TNBC cells reduced proliferation and invasiveness, and NOTCH4 overexpression in TNBC cells increased proliferation and invasiveness. NOTCH4 inhibition reduced tumour volume and tumourigenicity of mouse xenografts. TNBC cells had a higher frequency of nuclear translocation of NOTCH4 than other cells.

CONCLUSION:

NOTCH4 is a new potential therapeutic target for triple-negative breast cancer.
.
34. Mori H, Kubo M, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Miyazaki T, Oda Y, Otsuka T, Nakamura M, BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline-Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer, Plos One, 11, 12, e0167016, 2016.04, BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1-mutated tumors, in a large cohort of TNBC cases. MethodsThe BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA). The tumor subtypes were determined immunohistochemically using resected specimens. ResultsOf the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4%) tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003). There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter
recurrence-free survival (RFS) compared with the non-BRCAness group (P = 0.04) and had a shorter overall survival (OS) although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS). Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC.ConclusionsThe 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs..
35. Mori H, Kubo M, Yamaguchi R, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Oda Y, Nakamura M, The combination of PD-L1 expression and decreased tumor- infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer, Oncotarget, 8, 9, 15584-15592, 2017.04, This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD- L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs- low tumors (P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival (P = 0.0018) and overall survival (P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PD-
L1-positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies..
36. Nobuhiro Torata, Makoto Kubo, Daisuke Miura, Kenoki Ohuchida, Yusuke Mizuuchi, Yoshinori Fujimura, Eisuke Hayakawa, Masaya Kai, Yoshinao Oda, Kazuhiro Mizumoto, Makoto Hashizume, Masafumi Nakamura, Visualizing Energy Charge in Breast Carcinoma Tissues by MALDI Mass-spectrometry Imaging Profiles of Low-molecular-weight Metabolites, Anticancer Res, doi:10.21873/anticanres.12723, 38, 7, 4267-4272, 2018.04, Abstract
BACKGROUND/AIM:
Metabolomics is widely used for biomarker discovery, but conventional mass-spectrometry extraction procedures lose the spatial localization of metabolites. In this study, we directly analyzed breast carcinoma tissues embedded in frozen tissue microarrays (fTMAs) using MALDI mass-spectrometry imaging (MALDI-MSI).
MATERIALS AND METHODS:
A total of 119 breast tissues (84 carcinoma and 35 normal) were used. MSI data were extracted from each tissue.
RESULTS:
Overall, 185 of 1,915 peaks which were commonly detected in 60% of target areas were subjected to further analysis. One hundred and fifty-two peaks of carcinoma showed significantly higher intensity than normal. Comparing metabolite profiles from carcinoma and normal tissues, energy charge (EC) and the sum of adenosine phosphate compound (AXP) indicated significantly higher intensities in cancerous tissues than normal. But comparisons of EC and AXP among lymph node metastasis, tumor size and tumor subtypes indicated no significant differences.
CONCLUSION:
Breast carcinoma tissues had higher EC and AXP values than normal. MALDI-MSI could be a tool for characterizing breast carcinoma.
.
37. Mori H, Kubo M, Kai M, Kurata K, Yamada M, Nakamura M, Efficacy and Safety of Bi-weekly Pegfilgrastim for Dose-dense Chemotherapy-induced Neutropenia in Breast Cancer Patients, Anticancer Research, 10.21873/anticanres.12740 , 38, 7, 4381-4386, 2018.04, Abstract
BACKGROUND/AIM:
The dose-dense doxorubicin and cyclophosphamide (ddAC) for patients with HER-2-negative breast cancer is recommended by the National Comprehensive Cancer Network guideline in US. However, there are little data on serum G-CSF concentrations in patients undergoing bi-weekly dose-dense therapy with pegfilgrastim. The objective of this study was to compare the serum G-CSF concentrations in patients receiving pegfilgrastim in bi- or tri-weekly regimens.
PATIENTS AND METHODS:
This study included 26 patients who received ddAC or docetaxel and cyclophosphamide (TC) for primary breast cancer. Serum G-CSF concentrations were measured by ELISA.
RESULTS:
Serum G-CSF concentrations peaked in the second week of ddAC cases and in the ninth week of TC cases. Neutrophils gradually increased until the sixth week in ddAC cases, while they were slightly decreased during the first three weeks in TC cases. Treatments were completed without febrile neutropenia or treatment delays.
CONCLUSION:
Primary prophylactic pegfilgrastim administrations increased serum G-CSF concentrations, helping to maintain the absolute neutrophil counts that are required to undergo chemotherapy. The treatment of ddAC with 3.6 mg pegfilgrastim is completely safe for female Japanese patients.
.
38. Mori H, Kubo M, Kai M, Velasquez VV, Kurata K, Yamada M, Okido M, Kuroki S, Oda Y, Nakamura M, BRCAness Combined With a Family History of Cancer Is Associated With a Poor Prognosis for Breast Cancer Patients With a High Risk of BRCA Mutations, Clin Breast Cancer., 10.1016/j.clbc.2018.05.008, 18, 5, e1217-e1227, 2018.04.
39. Mori H, Kubo M, Yamaguchi R, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Oda Y, Nakamura M, The combination of PD-L1 expression and decreased tumor- infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer, Oncotarget, 8, 9, 15584-15592, 2017.04, This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD- L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs- low tumors (P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival (P = 0.0018) and overall survival (P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PD-
L1-positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies..
40. Mori H, Kubo M, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Miyazaki T, Oda Y, Otsuka T, Nakamura M, BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline-Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer, Plos One, 11, 12, e0167016, 2016.04, BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1-mutated tumors, in a large cohort of TNBC cases. MethodsThe BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA). The tumor subtypes were determined immunohistochemically using resected specimens. ResultsOf the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4%) tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003). There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter
recurrence-free survival (RFS) compared with the non-BRCAness group (P = 0.04) and had a shorter overall survival (OS) although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS). Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC.ConclusionsThe 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs..
41. Kai M, Kanaya N, Wu Sv, Mendez C, Nguyen D, Luu T, Chen S, Trageting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin., Breast cancer Res. and Treat, 151, 2, 2015.06.
42. Nagamatsu I, Onishi H, Matsushita S, Kubo M, Kai M, Imaizumi A, Nakano K, Hattori M, Oda Y, Tanaka M, Katano M, NOTCH4 is a potential therapeutic target for Triple-negative Breast cancer, Anticancer Res, 34, 1, 69-80, 2014.04, BACKGROUND/AIM:

The prognosis for triple-negative breast cancer (TNBC) is poor. In the present study, we evaluated whether NOTCH4 receptor is a potential new therapeutic target for TNBC.

MATERIALS AND METHODS:

In vitro proliferation and invasiveness were evaluated in TNBC cells with or without small-interfering RNA (siRNA) for NOTCH4, and with or without NOTCH4 plasmid transfection. In vivo, MDA-MB-231 cells with or without NOTCH4 siRNA were subcutaneously implanted into the flank regions of mice. The frequency of nuclear translocation of NOTCH4 was assessed by immunohistochemistry in 21 TNBC samples and 46 non-TNBC samples.

RESULTS:

NOTCH4 inhibition in TNBC cells reduced proliferation and invasiveness, and NOTCH4 overexpression in TNBC cells increased proliferation and invasiveness. NOTCH4 inhibition reduced tumour volume and tumourigenicity of mouse xenografts. TNBC cells had a higher frequency of nuclear translocation of NOTCH4 than other cells.

CONCLUSION:

NOTCH4 is a new potential therapeutic target for triple-negative breast cancer.
.
43. Kondo K, Chijiiwa K, Ohuchida J, Kai M, Fujii Y, Otani K, Hiyoshi M, Nagano M, Imamura N, Selection of prophylactic antibiotics according to the microorganisms isolated from surgical site infections (SSIs) in a previous series of surgeries reduces SSI incidence after pancreaticoduodenectomy, J Hepatobiliary Pancreat Sci, 20, 3, 286-293, 2013.04, BACKGROUND:The incidence of surgical site infections (SSIs) is high after pancreaticoduodenectomy (PD).METHODS:We divided 116 consecutive patients who underwent PD into an early group (n = 58) and a later group (n = 58) according to time of surgery. In both groups, endoscopic retrograde biliary drainage was mainly employed for the patients with obstructive jaundice. In the later group, prophylactic antibiotics were selected according to the susceptibility of microorganisms isolated from SSIs in the early group. The incidence of SSIs was compared between the groups.RESULTS:The background characteristics (including methods of preoperative biliary drainage and microorganisms in the bile obtained before or during operation) of the patients were not significantly different between the groups, except for the serum albumin level, which was lower in the later group than in the early group (P = 0.0026). The incidence of SSIs was significantly lower in the later group
(24.1 %) than in the early group (46.6 %) (P = 0.0116). Belonging to the later group was one independent negative risk factor for SSI.CONCLUSIONS:Selection of prophylactic antibiotics on the basis of microorganisms isolated from SSIs in the early group contributed to the reduced incidence of SSIs in the later group after PD..
44. Kondo K, Chijiiwa Y, Otani K, Kai M, Ohuchida J, Chijiiwa K, Characteristics and surgical outcome of HCC patients with low platelet count, Hepatogastroenterology, 59, 119, 2269-2272, 2012.04, BACKGROUND/AIMS:Hepatocellular carcinoma (HCC) patients often have low platelet count (LPC). The aim of this study was to determine unique features of HCC patients with LPC.METHODOLOGY:HCC patients who underwent surgery were divided into two groups: LPC group (platelet count ≤100,000/mm³, n=84) and control group (platelet count >100,000/mm³, n=240). Surgical outcomes, risk factors for postoperative complications and prognostic factors were retrospectively compared.RESULTS:HCC patients with LPC had poorer liver function, smaller tumors, less anatomical resection and more frequent postoperative liver failure than control group patients. Postoperative survival was not different between the two groups. Tumor invasion to the main branch or trunk of portal vein (Vp3, 4) was the only risk factor for postoperative substantial complications in the LPC group. Postoperative survival was worse in patients with tumor diameter ≥4 cm or multiple tum
ors and in those who underwent preoperative transcatheter arterial chemoembolization (TACE) in the LPC group by multivariate analysis. Among them, preoperative TACE were not prognostic factors in the control group.CONCLUSIONS:In HCC patients with LPC, Vp3, 4 patients should be carefully monitored after surgery and preoperative TACE is not recommended for long-term postoperative survival..
45. Onishi H, Morifuji Y, Kai M, Suyama K, Iwasaki H, Katano M, Hedgehog inhibitor decreases chemosensitivity to 5-FU and gemcitabine under hypoxic conditions in pancreatic cancer, Cancer Sci, 103, 7, 1272-1279, 2012.04, Abstract


Pancreatic cancer is one of the deadliest types of cancer. Previously, we showed that hypoxia increases invasiveness through upregulation of Smoothened (Smo) transcription in pancreatic ductal adenocarcinoma (PDAC) cells. Here, we first evaluated whether hypoxia-induced increase in Smo contributes to the proliferation of PDAC cells. We showed that Smo, but not Gli1, inhibition decreases proliferation significantly under hypoxic conditions. To further investigate the effects of Smo on PDAC growth, cell cycle analysis was carried out. Inhibition of Smo under hypoxia led to G(0) /G(1) arrest and decreased S phase. As 5-fluorouracil (5-FU) and gemcitabine, which are first-line drugs for pancreatic cancer, are sensitive to S phase, we then evaluated whether cyclopamine-induced decreased S phase under hypoxia affected the chemosensitivity of 5-FU and gemcitabine in PDAC cells. Cyclopamine treatment under hypoxia significantly decreased chemosensitivity to 5-FU and gemcitabine under hypoxia in both in vitro and in vivo models. In contrast, cis-diamminedichloroplatinum, which is cell cycle-independent, showed significant synergistic effects. These results suggest that hypoxia-induced increase of Smo directly contributes to the proliferation of PDAC cells through a hedgehog/Gli1-independent pathway, and that decreased S phase due to the use of Smo inhibitor under hypoxia leads to chemoresistance in S phase-sensitive anticancer drugs. Our results could be very important clinically because a clinical trial using Smo inhibitors and chemotherapy drugs will begin in the near future.
.
46. Otani K, Chijiiwa K, Kai M, Ohuchida J, Nagano M, Kondo K, Role of hilar resection in the treatment of hilar cholangiocarcinoma, Hepatogastroenterology, 59, 115, 696-700, 2012.04, BACKGROUND/AIMS:The aim of this study was to clarify the role of bile duct resection without hepatectomy (hilar resection) in hilar cholangiocarcinoma.METHODOLOGY:We retrospectively compared surgical results for hilar cholangiocarcinoma between 8 patients treated with hilar resection and 21 patients treated with hepatectomy.RESULTS:All hilar resections were performed for Bismuth type I or II tumors with T2 or less lesions, whereas hepatectomy was done for type III or IV tumors excluding one type II tumor. R0 resection was equally achieved in both groups (62.5% in hilar resection group and 76.2% in hepatectomy group, p=0.469) and overall 5-year survival rates were comparable (21.9% vs. 23.6%, p=0.874). With respect to gross tumor appearance, R0 resection was achieved in all patients with papillary tumor in both groups with the excellent 5-year survivals (100% vs. 100%). In patients with nodular and flat tumors, R0 resection was achieved less frequently in the
hilar resection vs. hepatectomy group (50% vs. 77.8%) mainly due to failure to clear the proximal ductal margin, resulting in poorer 5-year survival (0% vs. 18.7%).CONCLUSIONS:Hilar resection may be indicated for papillary T1 or 2 tumors in Bismuth type I or II cholangiocarcinoma..
47. Fujii Y, Ohuchida J, Chijiiwa K, Yano K, Imamura N, Nagano M, Hiyoshi M, Otani K, Kai M, Kondo K, Verification of Tokyo Guidelines for diagnosis and management of acute cholangitis, J Hepatobiliary Pancreat Sci, 19, 4, 487-491, 2012.04, BACKGROUND:This study aimed to verify diagnostic criteria and severity assessment of the Tokyo Guidelines for acute cholangitis.METHODS:We re-examined whether acute cholangitis was concomitant with gallstones according to the Tokyo Guidelines in 248 patients with choledocholithiasis. Our conventional diagnoses based on physician decision were compared with diagnoses from the Tokyo Guidelines. Problems with severity grade criteria were also evaluated.RESULTS:In total, 53 cases of acute cholangitis were determined by using the Tokyo Guidelines, including three false-negative and seven false-positive cases (acute cholecystitis or pancreatitis was concomitant with choledocholithiasis). Sensitivity, specificity, and accuracy were 94%, 96%, and 96%, respectively. Forty of the 53 patients underwent biliary drainage (mean interval between admission and drainage, 1.4 days). Severity grades were mild in 10, moderate in 30, and severe in 13 patients. Of these 13 patient
s with severe disease, 2 had chronic renal failure, 1 had liver cirrhosis, and 1 had severe acute pancreatitis and liver cirrhosis. No patients died, irrespective of severity grade.CONCLUSIONS:Acute cholangitis should be carefully diagnosed when other inflammatory disease is concomitant with choledocholithiasis. A few patients have absolute acute cholangitis even when they do not meet Tokyo Guidelines diagnostic criteria. Classification into mild or moderate grade using the Tokyo Guidelines is difficult when early biliary drainage is routinely performed. When determining severity grade, clinicians must distinguish between organ dysfunction associated with cholangitis itself and that associated with the underlying/concomitant disease. Apart from a few problems like these, the Tokyo Guidelines are mostly acceptable for the diagnosis and management of acute cholangitis..
48. Onishi H, Kai M, Odate S, Iwasaki H, Morifuji Y, Ogino T, Morisaki T, Nakashima Y, Katano M, Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer, Cancer Sci, 102, 6, 1144-1150, 2011.04, Abstract

The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O2) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O2) or hypoxic (1% O2) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness.
.
49. Kai M, Onishi H, Souzaki M, Tanaka Haruo, Kubo M, Tanaka M, Katano M, Semi-quantitative evaluation of CD44(+) /CD24(-) tumor cell distribution in breast cancer tissue using a newly developed fluorescence immunohistochemical staining method
, Cancer Sci. , 102, 12, 2132-2138, 2011.04, Abstract
CD44(+) /CD24(-) tumor cells are reported to contain cancer stem cells in breast cancer. The main purpose of the present study is to develop an immunohistofluorescence method that can quantitatively analyze CD44(+) /CD24(-) tumor cell distribution in breast cancer tissue and help better define the role of CD44(+) /CD24(-) tumor cells in breast cancer. The samples used were from 21 primary breast cancer patients who underwent neoadjuvant chemotherapy and 17 cases with sentinel lymph nodes that had lymph node micrometastasis. CD44(+) /CD24(-) tumor cells were distinguished at a single cell level using improved triple-staining immunohistofluorescence and a simulated laser capture microdissection method. The percentage of CD44(+) /CD24(-) cells significantly increased following neoadjuvant chemotherapy treatment (0.93% and 2.78%, before and after, respectively, P = 0.0043). The percentage of CD44(+) /CD24(-) cells was also significantly high in micrometastatic sentinel lymph nodes (0.49% and 1.91%, primary tumors and lymph nodes, respectively, P = 0.0246). The CD44(+) /CD24(-) tumor cell distribution was heterogeneous in both breast cancer tissue and lymph node metastasis. In a xenograft model using immunodeficient mice, the hedgehog signaling inhibitor cyclopamine repressed the tumorigenicity of CD44(+) /CD24(-) cells. Our results suggest that this semi-quantitative immunohistochemical analysis is valuable for detecting a small population of cells in cancer tissues and that the hedgehog signaling pathway inhibitor cyclopamine is useful for regulating the CD44(+) /CD24(-) tumor cells in breast cancer. (Cancer Sci, doi: 10.1111/j.1349-7006.2011.02063.x, 2011).

.
50. Chijiiwa K, Imamura N, Ohuchida J, Hiyoshi M, Nagano M, Otani K, Kai M, Kondo K, Prospective randomized controlled study of gastric emptying assessed by (13)C-acetate breath test after pylorus-preserving pancreaticoduodenectomy: comparison between antecolic and vertical retrocolic duodenojejunostomy, J Hepatobiliary Pancreat Surg, 16, 1, 49-55, 2009.04, BACKGROUND/PURPOSE: To examine whether vertical retrocolic duodenojejunostomy is superior to antecolic duodenojejunostomy with respect to gastric emptying in a prospective, randomized, controlled study of patients undergoing pylorus-preserving pancreaticoduodenectomy (PpPD). METHODS: Thirty-five patients undergoing PpPD between March 2005 and July 2007 were enrolled in the study. All provided informed consent. During PpPD, the patients were randomly assigned to either the antecolic (antecolic group, n = 17) or vertical retrocolic route (vertical retrocolic group, n = 18) just before the reconstruction. Each patient ingested (13)C-acetate in a liquid meal before surgery and on postoperative day (POD) 30. Gastric emptying variables (Tmax, T1/2) were determined and compared between groups. RESULTS: Clinical delayed gastric emptying, defined as an inability of patients to take in an appropriate amount of solid food orally by POD 14, was found in 1 of 17 p
a!
tients (6%) in the antecolic group and in 4 of 18 patients (22%) in the vertical retrocolic group, but the difference was not significant (P = 0.34). Tmax and T1/2 on POD 30 were prolonged in both groups in comparison to preoperative levels, but no significant difference was found between the two groups. Follow-up examinations revealed that gastric emptying had recovered to the preoperative level by POD 30 in approximately 80% of the patients, regardless of the reconstruction route. CONCLUSIONS: Vertical retrocolic duodenojejunostomy does not seem to offer an advantage with respect to gastric emptying..
51. Kondo K, Chijiiwa K, Funagayama M, Kai M, Otani K, Ohuchida J, Differences in long-term outcome and prognostic factors according to viral status in patients with hepatocellular carcinoma treated by surgery., J Gastrointest Surg, 12, 3, 468-476, 2008.04, Long-term postoperative survival and prognostic factors were examined retrospectively in patients with hepatocellular carcinoma (HCC) with serum hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCVAb) and in those without virus infection. Subjects were 265 consecutive HCC patients treated surgically at one institution during the period 1990 to 2006. Postoperative survival was analyzed and compared between HBsAg-positive (B-HCC), HCVAb-positive (C-HCC), and hepatitis B- and C-negative (NBNC-HCC) patients. Prognostic factors for overall and recurrence-free survival were also analyzed. Overall and recurrence-free survival rates were significantly higher in the NBNC-HCC group than in the C-HCC group. Significant prognostic factors for overall survival identified by univariate and multivariate analyses were age, serum alkaline phosphatase (ALP) level, tumor multiplicity, portal vein invasion (Vp), hepatic vein invasion (Vv), and operative blood
!
loss in the B-HCC group; serum albumin level, ALP level, tumor size, and Vv in the C-HCC group; and tumor multiplicity in the NBNC-HCC group. Significant factors for recurrence-free survival were age, ALP level, tumor multiplicity, Vp, and operation time in the B-HCC group; ALP level, prothrombin time, tumor size, Vv, and width of the surgical margin in the C-HCC group; and age, tumor size, tumor multiplicity, and Vp in the NBNC-HCC group. Thus, postoperative survival and prognostic factors in cases of HCC differ according to the presence of serologic viral markers..
52. Kondo K, Chijiiwa K, Funagayama M, Kai M, Otani K, Ohuchida J, Hepatic resection is justified for elderly patients with hepatocellular carcinoma., World J Surg., 32, 10, 2223-2229, 2008.04, BACKGROUND: Hepatic resection is one of the main treatment modalities for patients with hepatocellular carcinoma (HCC); however, surgery is generally stressful and often is avoided for elderly patients. This retrospective study was designed to determine whether the indications for hepatic resection in younger patients with HCC are applicable to elderly patients. METHODS: Subjects were 294 patients in whom 319 hepatic resections were performed for HCC (male/female ratio, 238/81; age range, 18-83 years). The patients were divided into two groups according to age at the time of surgery: 70 years or older (n = 109) and 69 years or younger (n = 210). Surgical strategy and postoperative follow-up methods did not differ between groups. The incidence and severity of postoperative complications classified by the Clavien system were compared between the two groups. Postoperative survival was compared between the two groups and between subgroups based on Japan I
n!
tegrated Staging (JIS) scores. HCC-related death rates also were compared. RESULTS: No significant between-group difference was found in background liver function or type of hepatic resection. Differences were found in performance status and type of hepatitis virus infection. No difference was observed in the incidence or severity of postoperative complications. Postoperative survival was similar between the two age-based study groups and between the JIS-based subgroups. HCC-related death rates did not differ between groups. CONCLUSIONS: The absence of differences in postoperative outcomes between groups suggests that hepatic resection is justified for HCC in selected patients aged 70 years or older..
53. Kai M, Yamashita H, Cantor T, Moriyama T, Rai M, Ogawa T, Watanabe S, Uchino S, Noguchi S, Intraoperative parathyroid hormone levels measured by intact and whole parathyroid hormone assays in patients with Graves' disease., Surgery Today, 38, 3, 214-221, 2008.04, PURPOSE: To find out if the whole parathyroid hormone (wPTH) assay has practical advantages over the intact (iPTH) assay in patients with Graves' disease. METHODS: We measured iPTH and wPTH levels before and after subtotal thyroidectomy in 111 consecutive patients (94 women and 17 men) with Graves' disease. Blood samples for assays were obtained after the induction of anesthesia (basal) and following skin closure (postoperative). RESULTS: There was a significant correlation between wPTH and iPTH in both the basal and postoperative levels. Logistic regression analyses examining the relationship between the reduction in parathyroid hormone (PTH) levels and the incidence of tetany revealed that both the wPTH and iPTH assays were significantly equally predictive of postoperative tetany. CONCLUSION: We found that both the wPTH and iPTH assays were useful for predicting postoperative tetany in patients with Graves' disease, yielding similar results.


.
54. Hotokezaka M, Chijiiwa K, Kondo K, Kai M, Eto T-A, Hidaka H, Jimi S-I, Maehara N, Ohuchida J, Matsumoto K, Nakao H, Medical Students’ Attitudes to Laparoscopic surgery, Hepato-Gastroenterology, 55, 86-87, 1541-1544, 2008.04, Abstract
BACKGROUND/AIMS: The purpose of the present study was to evaluate the attitude of medical students to laparosocopic surgery.

METHODOLOGY: Two hundred and seven medical students completed a questionnaire regarding their visualization of, understanding of, and interest in observation of laparoscopic surgery via laparoscopic monitor (laparoscopic observation) and of open surgery, either directly (open direct observation), or via video monitor observation (open monitor observation). They were also asked about their willingness to become an operator (operator). Responses to each item were given as Likert-type scores ranging from 1 to 5.

RESULTS: The visualization score was significantly lower for open direct observation than for open monitor observation (P<0.001) and laparoscopic observation (P<0.001), with the significantly lower score for open monitor observation than for laparoscopic observation (P<0.001). The understanding score was significantly lower for open direct observation than for open monitor observation (P<0.01) and laparoscopic observation (P<0.01). Interest scores did not differ between the three observation methods. The operator score was significantly higher for open surgery than for laparoscopic surgery.

CONCLUSIONS: Laparoscopic surgery provides good visualization of the operative field. However, students' interest in laparoscopic surgery is similar to those of open surgery.

.
55. Otani K, Chijiiwa K, Kai M, Ohuchida J, Nagano M, Tsuchiya K, Kondo K, Outcome of surgical treatment of hilar cholangiocarcinoma., J Gastrointest Surg., 12, 6, 1033-1040, 2008.04, To evaluate surgical results and the effect of adjuvant chemotherapy in cases of hilar cholangiocarcinoma, we retrospectively analyzed 27 consecutive patients who underwent surgical resection (eight bile duct resections, 18 bile duct resections plus hepatectomy, one hepatopancreaticoduodenectomy). There was no operative mortality, and the morbidity was 37%. Curative resection (R0 resection) was achieved in 20 (74%) patients. Overall survival at 3 and 5 years was 44% and 27%, significantly higher than that of 47 patients who did not undergo resection (3.5% and 0% at 3 and 5 years, p < 0.0001). Survival of patients with positive margins (R1/2 resection) was poor; there were no 5-year survivors. However, survival was better than that of patients who did not undergo resection (median survival: 22 vs 9 months, p = 0.0007). Univariate analysis identified lymph node metastasis as a negative prognostic factor (p = 0.043). Median survival of patients who un
d!
erwent adjuvant chemotherapy was significantly longer than that of patients who did not (42 vs. 22 months, p = 0.0428). Resection should be considered as the first option for hilar cholangiocarcinoma. There appears to be a survival advantage ev.
56. Hotokezaka M, Chijiiwa K, Kondo K, Kai M, Eto T-A, Hidaka H, Jimi S-I, Maehara N, Ohuchida J, Matsumoto K, Nakao H, Video Monitoring and Slide and Video Presentations as Tools for Surgical Education, Hepatogastroenterology, 55, 86-87, 1519-1522, 2008.04, Abstract
BACKGROUND/AIMS: To provide medical students with good visualization and understanding of surgical procedures, we used video monitoring (Monitor) in the operating room and slide (Slide) and video (Video) presentation in the conferences. The purpose of this study was to evaluate the effect of these visual aids on surgical education.

METHODOLOGY: One hundred and twenty-nine fifth- and sixth-year medical students completed a questionnaire regarding their visualization of, understanding of, and interest in all surgical procedures observed and procedures pertaining to their assigned patients. The score was collected on a Likert-type scores ranged from 1 for "poor" to 5 for "excellent".

RESULTS: Visualization and understanding scores were significantly lower for direct observation than for Monitor (p<0.01 and p<0.001), Slide (p<0.001 and p<0.001) and Video (p<0.001 and p<0.001). Interest scores did not differ between observation methods. For all observation methods, understanding of and interest in the surgical procedures were significantly greater in relation to assigned patients than in relation to all patients observed.

CONCLUSIONS: Video monitoring and slide and video presentations enhance students' understanding of and interest in surgical procedures. Contributing to the care of assigned patient also increases understanding of and interest in general surgery.

.
57. Eto T, Chijiiwa K, Hidaka H, Ohuchida J, Kai M, Kondo K, Hotokezaka M, Sum of the longest diameters of metastatic liver tumors is a possible new prognostic factor after hepatectomy in patients with colorectal liver metastases, Hepatogastroenterology, 53, 72, 909-912, 2006.04, BACKGROUND/AIMS: Although the size and number of the metastatic liver tumors have been considered to be prognostic factors after hepatectomy in patients with colorectal liver metastases, the importance of these parameters is still controversial. The aim of this study was to evaluate the importance of the new factor, namely, the sum of longest diameters of the metastatic liver tumors (SLD). METHODOLOGY: The medical records of 59 patients who had undergone hepatic resection for colorectal liver metastases were abstracted and these patients were completely followed-up. RESULTS: The overall 5-year survival rate after hepatectomy was 38.5%, and median survival time was 25.9 months. The significant prognostic factors by the univariate analysis were the extents of vessel permeation and lymph node metastasis of primary colorectal carcinoma, the presence of extrahepatic metastasis, the longest diameter and SLD of the liver tumor, surgical margin of the liver, and the serum level of carcinoembryonic antigen. Multivariate analysis showed that SLD (P=0.026) and extrahepatic distant organ metastasis (P=0.008) were the independent prognostic factor. CONCLUSIONS: SLD is a useful and significant predictor for survival after hepatectomy in patients with colorectal liver metastases.

.
58. 頼正恵, 山下弘幸, 定永匡子, 甲斐昌也, 小川尚洋, 野口志郎, バセドウ病を合併した原発性副甲状腺機能亢進症 原発性副甲状腺機能亢進症単独症例との比較, 内分泌外科, 23, 4, 263-266, 2006.04, バセドウ病に原発性副甲状腺機能亢進症(HPT)を合併した10症例(B+HPT群)とHPT単独の54症例(HPT群)とを比較した。血清総カルシウム(Ca)はB+HPT群:10.75±0.5mg/dl、HPT群:11.1±0.8mg/dl、血清intact PTHはB+HPT群:120±95pg/ml、HPT群:230±415pg/ml、血清リンはB+HPT群:3.55±0.48mg/dl、HPT群:3.08±0.44mg/dl、24時間尿中Ca排泄量はB+HPT群:192.9±58.3mg/dl、HPT群:274.5±103.8mg/dlであった。腫大腺の部位診断はB+HPT群:4例(40%)、HPT群:40例(74%)で可能であった。摘出甲状腺重量はB+HPT群:295±132mg、HPT群:1089±1946mgであった。バセドウ病に合併したHPTの診断は困難であり、診断には甲状腺機能の状態を考慮しなければならない。甲状腺機能更新状態ではCaが高めになり、高Ca血症を呈する症例もあ�
k!#I{9C>uA#5!G=$,@5>o2=$7$?8e$b9b�Ca血症が持続する場合は、HPTの合併を鑑別する必要があると思われた。.
59. Makino I, Chijiiwa K, Kondo K, Ohuchida J, Kai M, Prognostic benefit of selective portal vein occlusion during hepatic resection for hepatocellular carcinoma, Surgery, 137, 6, 626-631, 2005.04, The aim of this study was to clarify whether the types of portal vein (PV) occlusion during hepatectomy affect the long-term outcome in patients with hepatocellular carcinoma (HCC). METHODS: Eighty-six patients who had undergone curative hepatic resection for HCC were divided on the basis of the type of PV occlusion into 2 groups: total PV occlusion (TPVO, n = 56) and selective PV occlusion (SPVO, n = 30) groups. The recurrence-free survival was compared between the groups, and factors affecting recurrence-free survival were examined by univariate analyses followed by multivariate analyses. Moreover, the patients with a single nodular HCC less than 5 cm in diameter were abstracted from both groups, and the recurrence-free survival rate was compared. RESULTS: The patients and tumor-related factors were similar in the TPVO and SPVO groups. The recurrence-free survival was better in the SPVO group than in the TPVO group (median recurrence-free survival time, 1520 vs 561 days, P = .017). The type of PV occlusion was a significant factor for recurrence-free survival by univariate analysis but did not reach significance ( P = .052) by multivariate analysis. In the selected patients who had a single nodular HCC less than 5 cm in diameter, the recurrence-free survival was also significantly better in the SPVO group than in the TPVO group (median recurrence-free survival time, 2613 vs 1003 days, P = .018). CONCLUSIONS: Hepatectomy under selective PV occlusion seems to improve the recurrence-free survival in patients with HCC.
.

九大関連コンテンツ

pure2017年10月2日から、「九州大学研究者情報」を補完するデータベースとして、Elsevier社の「Pure」による研究業績の公開を開始しました。
 
 
九州大学知的財産本部「九州大学Seeds集」