Publications by authors named "Motohiko Tokuhisa"

21 Publications

  • Page 1 of 1

Safety and efficacy of peptide receptor radionuclide therapy with Lu-DOTA-Tyr-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor-positive, progressive neuroendocrine tumors.

Ann Nucl Med 2021 Sep 17. Epub 2021 Sep 17.

Department of Oncology, Oncology Division, Yokohama City University Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Purpose: Peptide receptor radionuclide therapy (PRRT) with Lu-DOTA-Tyr-octreotate (Lu-DOTATATE) is one of the most reliable treatments for unresectable, progressive neuroendocrine tumors (NETs) with somatostatin receptor expression. We have, for the first time, reported the results of the tolerability, safety, pharmacokinetics, dosimetry, and efficacy of this treatment for Japanese patients with NET.

Methods: Patients with unresectable, somatostatin receptor scintigraphy (SRS)-positive NETs were enrolled in this phase I clinical trial. They were treated with 29.6 GBq of Lu-DOTATATE (four doses of 7.4 GBq) combined with amino acid solution infusion plus octreotide long-acting release (LAR) 30 mg. The primary objective of this study was to evaluate the tolerability, safety, pharmacokinetics, and dosimetry of a single administration of this treatment in patients with SRS-positive NETs.

Results: Six Japanese patients (three men and three women; mean age 61.5 years; range 50-70 years) with SRS-positive unresectable NETs were recruited. Lu-DOTATATE was eliminated from the blood in a two-phase manner. Cumulative urinary excretion of radioactivity was 60.1% (range 49.0%-69.8%) within the initial 6 h. The cumulative renal absorbed dose for 29.6 GBq of Lu-DOTATATE was 16.8 Gy (range 12.0-21.2 Gy), and the biological effective dose was 17.0 Gy (range 12.2-21.5 Gy). Administration of Lu-DOTATATE was well tolerated, with no dose-limiting toxicities. Grade 3 lymphopenia occurred in two (33.3%) cases, but there were no other severe toxicities. Four patients achieved partial response (objective response rate, 66.7%), one patient had stable disease, and one patient had progressive disease.

Conclusion: PRRT with Lu-DOTATATE was well-tolerated and showed good outcomes in Japanese patients with unresectable NETs. Peptide receptor radionuclide therapy, Lu-DOTA-Tyr-octreotate .
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http://dx.doi.org/10.1007/s12149-021-01674-9DOI Listing
September 2021

Retrospective study of peptide receptor radionuclide therapy for Japanese patients with advanced neuroendocrine tumors.

J Hepatobiliary Pancreat Sci 2021 Jun 26. Epub 2021 Jun 26.

Department of Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Background: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is an innovative treatment for advanced somatostatin-positive neuroendocrine tumors (NETs). PRRT cannot be performed in Japan because there is no approval or insurance cover so far.

Methods: We relied on foreign institutions to perform PRRT for Japanese patients with NETs. We retrospectively evaluated the safety and efficacy of PRRT. The inclusion criteria were pathologically confirmed well-differentiated NET and visible tumor uptake on pre-therapeutic somatostatin receptor scintigraphy. Lu-DOTA-TOC was used as the standard treatment, and patients received three infusions every 8 weeks. Until the end of 2017, combination treatment with Y and Lu-DOTA-TOC was performed using the same protocol.

Results: Thirty-five patients were evaluated, and the primary lesions were pancreas, rectum, small intestine, stomach, and other locations. The partial response rate was 42.9%. Progression-free survival (PFS) was 12.8 months and overall survival was 42.8 months. There was no significant difference in PFS between front-line and late-line PRRT (11.0 months vs 28.0 months; P = .383). Severe adverse events included lymphocytopenia (20.0%) and thrombocytopenia (5.7%). Myelodysplastic syndrome occurred in one case.

Conclusion: PRRT was effective and safe for Japanese patients with advanced NETs. PRRT was equally effective as front-line and late-line treatment.
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http://dx.doi.org/10.1002/jhbp.1014DOI Listing
June 2021

Phase II study of temozolomide monotherapy in patients with extrapulmonary neuroendocrine carcinoma.

Cancer Sci 2021 May 12;112(5):1936-1942. Epub 2021 Mar 12.

Oncology Division, Yokohama City University Hospital, Yokohama, Japan.

Extrapulmonary neuroendocrine carcinoma (EPNEC) is a lethal disease with a poor prognosis. Platinum-based chemotherapy is used as the standard first-line treatment for unresectable EPNEC. Several retrospective studies have reported the results of the utilization of temozolomide (TMZ) as a drug for the second-line treatment for EPNEC. Patients with unresectable EPNEC that were resistant to platinum-based combination chemotherapy were recruited for a prospective phase II study of TMZ monotherapy. A 200 mg/m dose of TMZ was given from day 1 to day 5, every 4 weeks. Response rate (RR) was evaluated as the primary end-point. The presence of O -methylguanine DNA methyltransferase (MGMT) in EPNEC patients was also evaluated as exploratory research. Thirteen patients were enrolled in this study. Primary lesions were pancreas (n = 3), stomach (n = 3), duodenum (n = 1), colon (n = 1), gallbladder (n = 1), liver (n = 1), uterus (n = 1), bladder (n = 1), and primary unknown (n = 1). Each case was defined as pathological poorly differentiated neuroendocrine carcinoma from surgically resected and/or biopsied specimens. The median Ki-67 labeling index was 60% (range, 22%-90%). The RR was 15.4%, progression-free survival was 1.8 months (95% confidence interval [CI], 1.0-2.7), overall survival (OS) was 7.8 months (95% CI, 6.0-9.5), and OS from first-line treatment was 19.2 months (95% CI, 15.1-23.3). No grade 3 or 4 hematological toxicity had occurred and there was one case of grade 3 nausea. One case presented MGMT deficiency and this case showed partial response. Temozolomide monotherapy is a feasible, modestly effective, and safe treatment for patients with unresectable EPNEC following platinum-based chemotherapy, especially those with MGMT deficiency.
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http://dx.doi.org/10.1111/cas.14811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088944PMC
May 2021

Pathological Findings of the Host Immune Reaction in the Tumor Microenvironment of Gastroenteropancreatic Neuroendocrine Neoplasms.

Intern Med 2021 Apr 9;60(7):977-983. Epub 2020 Nov 9.

Oncology Division, Yokohama City University Hospital, Japan.

Objective Neuroendocrine neoplasms (NENs) are rare and indolent diseases, but the efficacy of treatment without surgical resection is temporary and limited. Targeted immunotherapy is an important treatment strategy in several cancers. However, the tumor and host immune reactions in the NEN microenvironment are poorly understood. Therefore, we investigated the immune checkpoint system and host immune response in pathological NEN specimens. Methods The expression of the mismatch repair proteins MSH2, MSH6, PMS2, and MLH1 was immunohistochemically detected in archival tissue samples obtained from 20 patients with gastroenteropancreatic NENs. We additionally assessed the expression of programmed death (PD)-1, PD-L1, and the tumor-infiltrating lymphocyte (TIL) markers CD8 and family of transcription factor P3 (FOXP3). Results All 20 NENs expressed the mismatch repair proteins MSH2, MSH6, PMS2, and MLH1. The PD-L1 and/or PD-1 expression in the tumor cells and/or TILs was confirmed in 75% of the cases. PD-1-, CD8-, and FOXP3-positive TILs were more frequently associated with PD-L1-positive tumors than with PD-L1 negative tumors (PD-1: 19.5 vs. 7.3, CD8: 18.1 vs. 7.1, FOXP3: 13.2 vs. 3.2, p=0.438, p=0.419, P=0.603, respectively). The number of cells positive for PD-1 tended to gradually increase in increasing grade of NENs but did not reach significance (Grade 1: 5.8, Grade 2: 10.2, NEC: 18.1, p=0.903). Conclusion NENs consistently express mismatch repair proteins but have a high expression of PD-L1 and/or PD-1 in the tumor microenvironment. NEC and PD-L1-positive NENs may be immunologically "hot" tumors, so an immunological approach may be an appropriate treatment strategy for these tumors.
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http://dx.doi.org/10.2169/internalmedicine.5648-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079921PMC
April 2021

Case Reports: Transformation of End-Stage Neuroendocrine Tumors With Uncontrollable Liver Metastasis Into a Novel or Additional Functional Phenotype.

Front Oncol 2020 25;10:555963. Epub 2020 Sep 25.

Department of Oncology, Yokohama City University Hospital, Yokohama, Japan.

Neuroendocrine tumors (NETs) are rare, but their worldwide incidence is gradually increasing. NETs are generally heterogeneous; however, in rare cases, they have been shown to change their phenotype (i.e., nonfunctional to functional or one functional phenotype to the addition of another functional phenotype). Here, we present two cases of liver metastatic NETs with phenotype transformation at the advanced stage that led to life-threatening events. A 73-year-old woman had a small intestinal nonfunctional NET with liver metastasis. After uncontrollable liver metastasis at the advanced stage, she developed duodenal perforation with hypergastremia. The patient was treated with octreotide and proton pump inhibitors and underwent endoscopic closure for duodenal perforation, but her general condition gradually deteriorated, and she died 2 weeks after duodenal perforation. Another patient, a 50-year-old man, had a functional NET (gastrinoma) with liver metastasis and duodenal ulcer. After uncontrollable liver metastasis at the advanced stage, he developed hypoglycemia. Although octoreotide and diazoxide were administrated for hyperalimentation, his hypoglycemia was uncontrollable, and he died after 4 months owing to general deterioration. The present cases show that advanced NETs with treatment-uncontrollable liver metastasis can transform their phenotype, specifically from a nonfunctional NET into a functional NET, and from one functional NET into the addition of another functional NET. These experiences suggest that the presence of treatment-resistant liver metastasis might be a hallmark of the potential to gain novel functions.
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http://dx.doi.org/10.3389/fonc.2020.555963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544986PMC
September 2020

Real-world Treatment Outcomes of the EXTREME Regimen as First-line Therapy for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: A Multi-center Retrospective Cohort Study in Japan.

Anticancer Res 2019 Dec;39(12):6819-6827

Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University, School of Medicine, Yokohama, Japan.

Background/aim: This Japanese multiple-center retrospective study aimed to examine the real-world treatment outcomes of the EXTREME regimen as a first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

Patients And Methods: A total of 100 R/M SCCHN patients treated with the EXTREME regimen as first-line therapy were analyzed. The treatment outcomes were evaluated to compare patient and treatment characteristics with overall survival.

Results: Patients treated with carboplatin-based EXTREME regimen showed similar overall survival with less adverse effects compared to that of patients using cisplatin. The post-progression survival was significantly longer in patients treated with second-line treatment following the EXTREME regimen than in those without second-line treatment.

Conclusion: The carboplatin-based EXTREME regimen was more feasible with similar treatment outcomes compared to cisplatin-based EXTREME regimen. In addition, subsequent lines of therapy contributed to improvement of survival for R/M SCCHN patients.
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http://dx.doi.org/10.21873/anticanres.13898DOI Listing
December 2019

[Differences in Concepts between Hospital Oncologists and Home Physicians].

Gan To Kagaku Ryoho 2019 May;46(Suppl 1):115-117

Dept. of Oncology, Yokohama City University Hospital.

Although many patients with terminal cancers desire to be cared for at home, frequently, such patients cannot be shifted to home care due to their unstable symptoms. In severe cases, emergency hospitalizations may be frequently required after introducinghome medical care. We report a case of makinghome medical care difficult due to repeated emergency hospitalizations despite of the patient's deep desire. Interviews were conducted with both the oncologist in charge of the case and a home physician, and their viewpoints were compared. For patients and their families to achieve desired livingconditions, it was considered necessary to give supportive medical care that meet their desires until the end of their lives as mutual viewpoints are taken in a good balance.
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May 2019

Sarcopenia is a reliable prognostic factor in patients with advanced pancreatic cancer receiving FOLFIRINOX chemotherapy.

Pancreatology 2019 Jan 10;19(1):127-135. Epub 2018 Nov 10.

Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan.

Background/objectives: FOLFIRINOX is the reliable treatments for pancreatic cancer, but it has a relatively high toxicity and the selection of suitable patients for this regimen remains challenge. On the other hand, sarcopenia is one of the important prognostic factors of pancreatic cancer. The aim of this study was to investigate the effect of sarcopenia on overall survival (OS) and time to treatment failure (TTF) in patients with pancreatic cancer who received FOLFIRINOX.

Methods: Clinical data of consecutive patients treated with FOLFIRINOX at our institution from 2011 to 2017 was retrospectively reviewed. Skeletal muscle index (SMI) and adipose tissue index (ATI) at the third lumbar spine level was calculated from computed tomography (CT) images. The association between clinical factors (SMI and ATI), and OS and TTF were determined using univariate and multivariate analyses.

Results: We assessed 82 patients. The median OS of sarcopenia and the non-sarcopenia patients were 11.3 and 17.0 months, respectively (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.43-4.32; p = 0.001). Median TTF was 3.0 and 6.1 months in the sarcopenia and the non-sarcopenia patients, respectively (HR, 1.67; 95% CI, 1.03-2.71; p = 0.032). Multivariate analyses revealed that sarcopenia (HR, 1.37; 95% CI, 1.01-1.87; p = 0.045) was an independent prognostic factor of OS. High ATI (p = 0.022) and sarcopenic obesity (p = 0.008) were significantly associated with hematologic toxicity.

Conclusions: Sarcopenia is an independent indicator of poor prognosis in patients with pancreatic cancer who received FOLFIRINOX, while ATI and sarcopenic obesity predicted severe hematologic toxicity.
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http://dx.doi.org/10.1016/j.pan.2018.11.001DOI Listing
January 2019

Clinical Usefulness of Somatostatin Receptor Scintigraphy in Japanese Patients with Gastroenteropancreatic Neuroendocrine Tumors.

Digestion 2017 14;96(1):13-20. Epub 2017 Jun 14.

Oncology Division, Yokohama City University Hospital, Yokohama, Japan.

Background/aims: Somatostatin receptor (SSTR) scintigraphy (SRS) is the standard imaging modality for evaluation of gastroenteropancreatic neuroendocrine tumor (GEP-NET) in Western countries. However, this modality was not approved in Japan until recently. The purpose of this study was to evaluate the clinical efficacy of SRS for detecting GEP-NET in Japanese patients.

Methods: Japanese patients with advanced GEP-NET were enrolled and evaluated by the SRS and CT. We also compared SRS and immunohistochemical expression of SSTR type 2a (SSTR2a).

Results: We enrolled 16 patients and the primary sites were the pancreas in 9, the stomach in 1, the small intestine in 2, the colon in 3, and unknown in 1. SRS showed positive findings in 3 (100%) of grade 1 (G1) and in 12 (92.3%) of grade 2 (G2) lesions. In the liver, SRS and CT detected lesions in 13 and 14 cases, respectively. The concordance rate of SSTR2a expression with SRS findings was 93.8% in the whole body and 92.9% in the liver.

Conclusions: SRS could detect almost all of G1 and G2. SRS could be useful to detect lesions, with a high concordance rate with CT and pathological findings. We confirmed that SRS is a useful and reliable modality for Japanese patients.
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http://dx.doi.org/10.1159/000470838DOI Listing
April 2018

Effect of FOLFIRINOX as second-line chemotherapy for metastatic pancreatic cancer after gemcitabine-based chemotherapy failure.

Medicine (Baltimore) 2017 May;96(19):e6769

Graduate School of Medicine, Department of Oncology, Yokohama City University, Japan Shimamura Clinic and Yokohama City University Graduate School of Medicine Department of Oncology Graduate School of Medicine, Department of Gastroenterological Surgery, Yokohama City University, Japan.

Background: This study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicity, and efficacy of second-line chemotherapy with FOLFIRINOX after gemcitabine (GEM)-based chemotherapy failure in metastatic pancreatic cancer (MPC).

Methods: We studied 18 histopathologically proven MPC patients. The schedule was 85 mg/m oxaliplatin, irinotecan, and 400 mg/m leucovorin, followed by 400 mg/m 5-fluorouracil (5-FU) as a bolus on day 1 and 2400 mg/m 5-FU as a 46-hour continuous infusion biweekly. The dose of irinotecan was defined as follows: level 0: 100 mg/m, level 1: 125 mg/m, level 2: 150 mg/m, and level 3: 180 mg/m. The doses of other drugs were fixed. The primary endpoint of phase II study was the response rate (RR).

Results: We initially evaluated 6 patients in a phase I study. One patient developed neutropenia and 1 patient developed hyperglycemia and severe infection. Accordingly, level 1 was chosen as the MTD. According to a phase II study, the RR was 22.2% and the disease control rate was 61.1%. The progression-free survival and overall survival were 2.8 (range, 0.7-19.1) and 9.8 (2.4-19.8) months, respectively. The most common severe adverse event was neutropenia (66.7%). Febrile neutropenia occurred in 1 (5.6%) case.

Conclusion: The recommended dose was 85 mg/m oxaliplatin, 100 mg/m irinotecan, and 400 mg/m leucovorin, followed by 400 mg/m 5-FU as a bolus on day 1 and 2400 mg/m 5-FU as a 46-hour continuous infusion. These results indicate that second-line FOLFIRINOX is a marginally effective treatment for GEM-based chemotherapy failure cases.
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http://dx.doi.org/10.1097/MD.0000000000006769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428587PMC
May 2017

Sorafenib Monotherapy in a Patient with Unresectable Hepatic Epithelioid Hemangioendothelioma.

Case Rep Oncol 2016 Jan-Apr;9(1):134-7. Epub 2016 Feb 19.

Department of Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

A 49-year-old Japanese man had multiple huge masses (max. size 60 mm diameter) in his liver. These tumors were pathologically diagnosed by tumor biopsy as epithelioid hemangioendotheliomas of the liver. In this case, multiple liver tumors existed in both lobes. Also this patient did not agree to receive surgical resection including liver transplantation. Chemotherapy with sorafenib at a dose of 400 mg/body twice a day was started. About 6 months later, CT findings revealed that these tumors were shrinking slightly; 33 months later, the tumors obviously showed a partial response in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST). Also 60 months later, the partial response continued with sorafenib monotherapy.
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http://dx.doi.org/10.1159/000443986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899657PMC
June 2016

Exosomal miRNAs from Peritoneum Lavage Fluid as Potential Prognostic Biomarkers of Peritoneal Metastasis in Gastric Cancer.

PLoS One 2015 24;10(7):e0130472. Epub 2015 Jul 24.

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Peritoneal metastasis is the most frequent type of recurrence in patients with gastric cancer (GC) and is associated with poor prognosis. Peritoneal lavage cytology, used to evaluate the risk of peritoneal metastasis, has low sensitivity. Here, we assessed the diagnostic potential of exosomal miRNA profiles in peritoneal fluid for the prediction of peritoneal dissemination in GC. Total RNA was extracted from exosomes isolated from six gastric malignant ascites (MA) samples, 24 peritoneal lavage fluid (PLF) samples, and culture supernatants (CM) of two human gastric carcinoma cell lines that differ in their potential for peritoneal metastasis. Expression of exosomal miRNAs was evaluated with Agilent Human miRNA microarrays and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The microarray analysis indicated a low variability in the number and signal intensity of miRNAs detected among the samples. In the six MA fluids, miR-21 showed the highest signal intensity. We identified five miRNAs (miR-1225-5p, miR-320c, miR-1202, miR-1207-5p, and miR-4270) with high expression in MA samples, the PLF of serosa-invasive GC, and the CM of a highly metastatic GC cell line; these candidate miRNA species appear to be related to peritoneal dissemination. Differential expression of miR-21, miR-320c, and miR-1225-5p was validated in the PLF of serosa-invasive and non-invasive GC by qRT-PCR and miR-21 and miR-1225-5p were confirmed to be associated with serosal invasion in GC. PLF can be used to profile the expression of exosomal miRNAs. Our findings suggest that miR-21 and miR-1225-5p may serve as biomarkers of peritoneal recurrence after curative GC resection, thus providing a novel approach to early diagnosis of peritoneal dissemination of GC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130472PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514651PMC
May 2016

Endoscopic inside stent placement is suitable as a bridging treatment for preoperative biliary tract cancer.

BMC Gastroenterol 2015 Feb 5;15. Epub 2015 Feb 5.

Medical Oncology Division, Yokohama City University School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Background: Endoscopic biliary stenting (EBS) is one of the most important palliative treatments for biliary tract cancer. However, reflux cholangitis arising from bacterial adherence to the inner wall of the stent must be avoided. We evaluated the use of EBS above the sphincter of Oddi to determine whether reflux cholangitis could be prevented in preoperative cases.

Methods: Fifty-seven patients with primary biliary tract cancer were retrospectively recruited for the evaluation of stent placement either above (n = 25; inside stent group) or across (n = 32; conventional stent group) the sphincter of Oddi. We compared the stent patency periods prior to the time of surgical resection.

Results: The preoperative periods were 96.3 days in the conventional stent group and 96.8 days in the inside stent group (P = 0.979). Obstructive jaundice and/or acute cholangitis occurred in 7 patients (28.0%) in the inside stent group and in 15 patients (46.9%) in the conventional stent group during the preoperative period (P = 0.150). The average patency periods of the stents were 85.2 days (range, 13-387 days) for the inside stent group and 49.1 days (range, 9-136 days) for the conventional stent group (log-rank test: P = 0.009). The mean numbers of re-interventions because of stent occlusion were 0.32 for the inside stent group and 1.03 for the conventional stent group (P = 0.026). Post-endoscopic retrograde cholangiopancreatography complications occurred in 2 patients in the inside stent group and 4 patients in the conventional stent group (P = 0.516). Postoperative liver abscess occurred in 1 patient in the inside stent group and 5 patients in the conventional stent group (P = 0.968). Inside stent placement was the only significant preventative factor associated with stent obstruction based on univariate (hazard ratio [HR], 0.286; 95% confidence interval [CI], 0.114-0.719; P = 0.008) and multivariate (HR, 0.292; 95% CI, 0.114-0.750; P = 0.011) analyses.

Conclusion: Temporary plastic stent placement above the sphincter of Oddi is a better bridging treatment than conventional stent placement in preoperative primary biliary tract cancer.
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http://dx.doi.org/10.1186/s12876-015-0233-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323119PMC
February 2015

[A case of post-operative recurrence of pancreatic cancer in the residual pancreas treated by resection of the residual pancreas following radiological complete response achieved with second-line FOLFIRINOX].

Gan To Kagaku Ryoho 2014 Jul;41(7):901-4

Division of Clinical Oncology, Yokohama City University Hospital.

A 65-year-old woman with carcinoma of the pancreatic body underwent Whipple's operation. After surgery, adjuvant chemotherapy with gemcitabine alone, and S-1 combined with gemcitabine was conducted. But one year later, a recurrent tumor was detected in the pancreatic tail. We administered FOLFIRINOX treatment for the recurrent tumor. After 6 courses, FOLFIRINOX treatment resulted in a partial response, and after 9 courses, a radiological complete response was achieved. We could then perform total pancreatotectomy and resection of the metastatic liver tumor. FOLFIRINOX as a second-line treat- ment was effective and safe in this case. In cases of gemcitabine and/or S-1 failure, FOLFIRINOX treatment should be considered.
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July 2014

Does resection of primary lesions show survival benefit for stage IV colorectal cancer patients with unresectable metastases?

Hepatogastroenterology 2013 Nov-Dec;60(128):1945-9

Background/aims: The aims of the current retrospective cohort study were to compare OS of the primary resection (R-g) and the non-resection group (NR-g) after 2005.

Methodology: Ninety-five patients with stage IV colorectal cancer with unresectable distant metastases were divided into 2 groups; R-g; 37 and NR-g; 58.

Results: The only significant difference in clinical factors between the 2 was R0 resection rate (p = 0.007). The MST in R-g was superior to that in NR-g, 30.7 vs. 21.9 months (p = 0.031). After excluding the patients that underwent R0 resection, there was no difference in OS between the 2; however, the MST was 28.6 months in R-g and 17.1 months in NR-g.

Conclusions: The advantage of resection of the primary is still unclear and a well-designed randomized Phase III study is expected. However, the current results suggest that resection of the primary lesion before intensive chemotherapy had some benefit for prognosis.
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May 2014

Biweekly Docetaxel and S-1 combination chemotherapy as first-line treatment for elderly patients with advanced gastric cancer.

Anticancer Res 2013 Feb;33(2):697-704

Department of Surgery, Gastroenterological Center, Yokohama City University, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan.

Background/aim: This study assessed the toxicity and activity of biweekly docetaxel and S-1 combination therapy in elderly patients with advanced gastric cancer.

Patients And Methods: One-hundred and thirteen patients were enrolled: 35 were 75 years old or more. The objective response rate, toxicity, progression-free survival (PFS), and overall survival (OS) were compared.

Results: Dose reduction was significantly frequent in the elderly group (24/35 versus 25/78, p<0.001). The overall response rate was 54.9%. Out of these, 18 (15.9%) underwent gastrectomy (13 R0 gastrectomy). The median OS was 17.3 months and the median PFS was 8.0 months. Neutropenia was the most frequently observed hematological toxicity at grade 3 and 4 (34.5%), followed by leukopenia (24.8%). Most non-hematological toxicities were of grade 1 or 2. There were no significant differences in overall response rate, median OS, median PFS, or toxicities between the two groups.

Conclusion: This combination offers favourable survival benefits with controllable tolerance for therapy of AGC in the elderly.
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February 2013

Low-dose docetaxel and cisplatin combination chemotherapy for stage II/III gastric cancer showing resistance to S-1 adjuvant chemotherapy: a phase I study.

J Chemother 2012 Dec;24(6):364-8

Department of Surgery, Gastroenterological Center, Yokohama City University, Yokohama, Japan.

To establish a safe, long-term regimen of docetaxel (DOC) and cisplatin (CDDP) in an outpatient setting for gastric cancer refractory to S-1 adjuvant chemotherapy, a dose-escalating phase I study was conducted. Cohorts of patients were treated with escalating doses of DOC (starting at 20 mg/m² per week with 5 mg/m² increments) and a fixed dose of CDDP (25 mg/m²). Drugs were administered on days 1, 8, and 15. A cycle of this treatment was 28 days. In total, 52 courses were performed, and the mean number of courses was 5.3. Two of the four patients at dose level 3 showed dose-limiting toxicities (grade 4 neutropenia, and grade 3 anorexia and dehydration). The recommended dose (RD) of DOC was therefore defined as 25 mg/m². There is a need for a phase II clinical trial using this regimen in patients with S-1-refractory stage II/III gastric cancer.
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http://dx.doi.org/10.1179/1973947812Y.0000000042DOI Listing
December 2012

Significance of thoracoscopy-assisted surgery with a minithoracotomy and hand-assisted laparoscopic surgery for esophageal cancer: the experience of a single surgeon.

J Gastrointest Surg 2011 Nov 10;15(11):1939-51. Epub 2011 Sep 10.

Department of Surgery, Gastroenterological Center, Yokohama City University, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan.

Background: This retrospective study evaluated the surgical learning curve and outcomes of thoracolaparoscopic esophagectomy.

Patients And Methods: The study group comprised a series of 92 patients with preoperatively diagnosed resectable thoracic esophageal cancer. Additionally, the surgical outcomes in 79 esophageal cancer patients receiving open esophagectomies were compared. All patients underwent thoracolaparoscopic esophagectomy in the lateral decubitus position. The short- and long-term outcomes were evaluated, and the surgical learning curve was assessed.

Results: The total operation time was 477.8 ± 102.2 min, the thoracoscopic time was 157.9 ± 61.3 min, the total blood loss was 554.4 ± 280.5 ml, and the number of retrieved lymph nodes was 34.3 ± 14.3. Postoperative morbidity was observed in 23 patients. After the surgeon's first 40 cases, the surgical technique and short-term outcomes were stable. The 5-year disease-specific survival was 66.6% and the 5-year overall survival was 64.6% in patients receiving R0 thoracolaparoscopic esophagectomy. Comparison of 5-year disease-specific survival rate according to tumor-node-metastasis stage between patients receiving R0 thoracolaparoscopic esophagectomy and conventional open esophagectomy showed that there were no significant differences in survival in any stage between the two groups. Loco-regional recurrence was observed in 6 patients, distant recurrence in seven, and combined recurrence in nine after R0 thoracolaparoscopic esophagectomy. There was no significant difference in the pattern of recurrence between the two groups.

Conclusions: Thoracolaparoscopic esophagectomy for esophageal cancer was technically feasible and oncologically satisfactory, according to the surgical learning curve.
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http://dx.doi.org/10.1007/s11605-011-1664-xDOI Listing
November 2011

Indication for hepatic resection in the treatment of liver metastasis from gastric cancer.

Anticancer Res 2010 Jun;30(6):2367-76

Department of Surgery, Gastroenterological Center, Yokohama City University, 4-57, Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan.

Background: The significance of hepatic resection for liver metastasis after gastric cancer is not well established. This study aimed to evaluate the effect of hepatic resection in such patients.

Patients And Methods: A retrospective analysis was performed on the outcome of 63 patients with liver metastases without other non-curative factors of gastric cancer who underwent gastrectomy with or without hepatic resection.

Results: Overall 1-, 3-, and 5-year survival rates were 61.9%, 17.2%, and 10.3%, respectively, with a median survival time of 16 months. This increased to 82.3%, 46.4%, and 37.1%, respectively, with a median survival time of 31.2 months in patients who underwent hepatic resection. Multivariate analysis showed that hepatic resection was an independent prognostic factor. Moreover, unilobar liver metastases significantly influenced favorable prognosis in patients receiving hepatic resection by univariate analysis.

Conclusion: In patients with liver metastases, hepatic resection may be a therapeutic option in the presence of unilobar liver metastases.
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June 2010

Effect of obesity on laparoscopy-assisted distal gastrectomy compared with open distal gastrectomy for gastric cancer.

J Surg Oncol 2010 Aug;102(2):141-7

Department of Surgery, Yokohama City University, Gastroenterological Center, Minami-ku, Yokohama, Japan.

Background And Objectives: This study compared surgical outcomes between patients undergoing laparoscopy-assisted distal gastrectomy (LADG) and those undergoing open distal gastrectomy (ODG) from the viewpoint of obesity.

Methods: Between June 2002 and May 2008, 146 patients with preoperatively diagnosed early gastric cancer who underwent LADG (n = 90) or ODG (n = 56) were enrolled in this study and compared in terms of clinicopathological findings and operative outcome. The visceral fat area (VFA) and subcutaneous fat area (SFA) were assessed as identifiers of obesity using FatScan software. The relationship between obesity and operative outcomes after LADG and ODG was evaluated.

Results: There were no significant correlations between intraoperative blood loss (IBL) and any obesity-related factors, or between operation time (OT) and any obesity-related factors in the LADG group. There was a significant correlation between IBL and BMI (r = 0.486, P = 0.0001), IBL and VFA (r = 0.456, P = 0.0003), IBL and SFA (r = 0.311, P = 0.0193), OT and BMI (r = 0.406, P = 0.0017), OT and VFA (r = 0.314, P = 0.0178), and between OT and SFA (r = 0.382, P = 0.0034) in the ODG group.

Conclusions: LADG may be a useful operative manipulation that is not influenced by obesity, whereas ODG may be influenced by obesity even after reaching the surgical plateau.
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http://dx.doi.org/10.1002/jso.21582DOI Listing
August 2010

[A case of drug-induced interstitial pneumonitis after adjuvant chemotherapy with gemcitabine for bile duct cancer].

Gan To Kagaku Ryoho 2010 May;37(5):923-6

Dept. of Surgery, Fujisawa Municipal Hospital.

A 70-year-old man received pancreaticoduodenectomy for bile duct cancer and had been administered gemcitabine for 1 year as adjuvant chemotherapy. He complained of shortness of breath on effort and was admitted for gemcitabine-induced interstitial pneumonitis. His respiratory status was worsening after admission, so he was transferred in the intensive-care unit and required mechanical ventilator and steroid pulse therapy with 1,000 mg/day of methylprednisolone. His symptoms and radiological findings were dramatically improved. The patient could be discharged on the 24th day after admission. Interstitial pneumonitis induced by gemcitabine is rare, but could lead to severe complications, which could develop after long-term administration and should be treated by corticosteroid as soon as possible.
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May 2010
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