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Background: Adjuvant chemotherapy with S-1 for resected pancreatic cancer demonstrated survival benefits compared with gemcitabine in the JASPAC 01 trial. We investigated the effect of these agents on health-related quality of life (HRQOL) of patients in the JASPAC 01 trial., Methods: Patients with resected pancreatic cancer were randomly assigned to receive gemcitabine (1000 mg/m 2 weekly for three of four weeks for up to six cycles) or S-1 (40, 50, or 60 mg twice daily for four of six weeks for up to four cycles). HRQOL was assessed using the EuroQol-5D-3L (EQ-5D) questionnaire at baseline, months three and six, and every 6 months thereafter. HRQOL end-points included change in EQ-5D index from baseline, responses to five items in the EQ-5D, and quality-adjusted life months up to 24 months., Results: Of randomised 385 patients, 354 patients were included in HRQOL analysis. Mean change in the EQ-5D index was similar in the S-1 and gemcitabine groups within 6 months from treatment initiation (difference, 0.024; P = 0.112), whereas corresponding mean from 12 to 24 months was better in the S-1 group than in the gemcitabine group (difference, 0.071; P < 0.001). Problems in mobility and pain/discomfort were also less frequent in the S-1 group than in the gemcitabine group in that period. Quality-adjusted life months were longer in the S-1 group than in the gemcitabine group (P < 0.001)., Conclusion: Adjuvant chemotherapy with S-1 does not improve HRQOL within 6 months from treatment initiation but does improve HRQOL thereafter and quality-adjusted life months., Clinical Trial Registration Number: UMIN000000655 at UMIN CTR., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Several studies have demonstrated the benefit of hepatectomy for treating gastric cancer (GC) with liver-limited metastases (LLM). The survival benefit of hepatectomy compared with that of systemic chemotherapy is unknown, particularly in patients with multiple LLM. This study investigated the survival benefit of hepatectomy compared with that of systemic chemotherapy administered to patients with GC with multiple LLM., Methods: We retrospectively reviewed the data of consecutive patients with GC with two or three LLM who underwent hepatectomy or received systemic chemotherapy as initial treatment at the Shizuoka Cancer Center between December 2004 and December 2015., Results: Nine of 24 patients who met the inclusion criteria underwent hepatectomy, and 15 received chemotherapy. In the hepatectomy group, all patients achieved R0 resection and none died during hospitalization. Three patients received adjuvant chemotherapy. Disease recurred in eight patients (88.9%). In the chemotherapy group, three patients underwent hepatectomy following initial chemotherapy and did not experience recurrence or death during follow-up. Median follow-up was 47.9 months and median overall survival (OS) was 38.1 and 24.8 months in the chemotherapy and hepatectomy groups, respectively. Multivariate analysis of OS, including initial treatment, revealed that unilobar liver metastasis was the only independent favorable prognostic factor., Conclusions: Although hepatectomy for patients with GC with multiple LLM is not recommended as the initial therapy, it prolonged the survival of patients with tumors controlled using systemic chemotherapy.

Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has been applied to pancreatic lesions since the 1990s, and its use is now widespread. Improvements in endoscopic devices and sampling techniques have resulted in excellent diagnostic ability for solid pancreatic lesions. However, clinical improvements alone are not responsible for it; pathological aspects have also played important roles. Rapid on-site evaluation minimizes endoscopic procedures, although its value at improving the diagnostic ratio is still debated. Diagnostic efficacy differs by sample preparations (direct smear, cytospin, liquid-based cytology, cell block, and biopsy) and by staining methods (Papanicoloau, Diff-Quik, hematoxylin-eosin, and Giemsa). Several immunocytochemistry protocols aid in diagnosing epithelial components with cytological atypia and in differentiating various tumor types. One cytopathology diagnostic system is telecytology, which uses transmitted digital images and enables real-time diagnosis of EUS-FNA samples by expert cytologists at remote locations. However, EUS-FNA samples are useful for more than just diagnoses, as molecular analysis of these samples allows the identification of prognostic markers, such as genetic alterations in K-ras and EGFR. Expression of drug-metabolizing enzymes, human equilibrative nucleoside transporter 1, correlates with the response to gemcitabine-based chemotherapy. These pathology efforts have enhanced the diagnostic efficacy of EUS-FNA, thereby leading to better outcomes for patients with pancreatic diseases.

Objectives: Taxane chemotherapy for esophageal cancer causes pneumonitis, not only by itself but also by radiation recall. This study aimed to clarify the risk of pneumonitis in patients with esophageal cancer who receive taxane therapy after chemoradiotherapy., Methods: The data of 129 patients with metastatic or recurrent esophageal cancer who initiated taxane therapy between September 2002 and June 2013 were retrospectively analyzed. Patient selection criteria were as follows: performance status ≤2, preserved organ functions, previous chemoradiotherapy with a radiation dose of ≥50 Gy, grade 0 or 1 pneumonitis at taxane initiation, and no concomitant malignancy. Logistic regression analysis was performed to identify risk factors for pneumonitis., Results: Patient characteristics were as follows: males/females, 116/13; median age, 63 years (range, 44 to 80 y); performance status of 0/1/2, 61/60/8; smoking history, 112 (88%); location of the primary tumor Ce/Ut/Mt/Lt/Ae 12/30/66/20/1; median radiation dose, 60 Gy; history of radiation pneumonitis, 39 (30%); history of other pulmonary disease, 4 (3%); and median duration between the last radiation therapy (RT) exposure and taxane initiation, 6.1 months (range, 1.0 to 71 mo). During the median observation period of 7.8 months from taxane initiation, the incidence of grade 2 and 3 pneumonitis was observed in 7 (5.4%) and 3 (2.3%) patients, respectively. No patient died of pneumonitis. The only independent risk factor for pneumonitis was a ≤4-month period between the last RT exposure and taxane initiation (P=0.03)., Conclusions: A short period between the last RT exposure and taxane initiation is an independent risk factor for pneumonitis development.

Background/objective: Whether gastrojejunostomy (GJJ) or duodenal stent (DS) placement is preferable for treatment of gastric outlet obstruction (GOO) in patients with unresectable pancreatic cancer is unclear. We compared the usefulness of GJJ with that of DS placement in these patients., Methods: We retrospectively reviewed 66 consecutive patients with unresectable pancreatic cancer who underwent GJJ or DS placement for symptomatic GOO., Results: We analyzed 30 patients who underwent GJJ and 23 who underwent DS placement. Peritoneal metastasis was more common in the DS group. Median survival after the first intervention was similar in both groups. Although clinical success (maintaining a GOO Scoring System score ≥2 for more than 7 days) rate was significantly higher in the GJJ group (100% vs. 81%), clinical benefit (maintaining a score ≥2 for more than half of their survival after the first intervention) rate was similar between the GJJ and DS groups (66.7% vs. 69.7%), even among patients who survived for ≥90 days (73.3% vs. 75.0%). Further, the proportion of patients who could receive planned chemotherapy after the first intervention was higher and the time to administration of chemotherapy was significantly shorter in the DS group (9 vs. 32 days). Major complication rate was similar in both groups., Conclusions: These findings suggest that DS placement is as effective as GJJ for the treatment of GOO in patients with unresectable pancreatic cancer, even in those with a long life expectancy. DS placement might be more beneficial than GJJ in patients for whom chemotherapy is planned., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background Lanreotide is a long-acting somatostatin analog with demonstrated efficacy against enteropancreatic neuroendocrine tumor (NET) in the phase III (CLARINET) study. Materials and Methods In this single-arm study, Japanese patients with grade (G) 1/G2 NET received lanreotide (120 mg/4 weeks) for 48 weeks. Those who completed the study were enrolled in a long-term extension study. The primary endpoint was the clinical benefit rate (CBR) defined as a complete response, partial response (PR), or stable disease (SD) over 24-weeks. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and pharmacokinetics. Results Thirty-two patients were recruited at 10 sites. The full analysis set (FAS) comprised 28 patients. Primary tumors were located in pancreas (12 patients), foregut (non-pancreas, lung; 1), midgut (2), hindgut (8), and unknown (5). Four patients had gastrinoma of the functional NET, and 3 had multiple endocrine neoplasia type 1. In the FAS, 39.3% had progressive disease at baseline. The CBR at 24 weeks was 64.3% (95% confidence interval; CI: 44.1-81.4), and median PFS was 36.3 weeks (95% CI: 24.1-53.1). PR was confirmed in 1 patient at 60 weeks during the extension study (ORR: 3.6%). Frequent adverse events related to lanreotide included injection site induration (28.1%), faeces pale (18.8%), flatulence (12.5%), and diabetes mellitus (12.5%). Conclusions The efficacy and safety of lanreotide in this study indicated its usefulness as a treatment option for Japanese NET patients., Trial Registration: JapicCTI-132,375, JapicCTI-142,698.

Purpose: To determine the effect of low-dose cyclosporine (CyA) treatment for patients with chronic Vogt-Koyanagi-Harada (VKH) disease resistance to systemic corticosteroid treatment. Methods: We retrospectively evaluated patients diagnosed with chronic VKH disease resistance to systemic corticosteroid treatment at Japan Community Health Care Organization (JCHO) Osaka Hospital between March 2013 and March 2016. We followed the observation with systemic low-dose CyA (100 mg once daily) treatment of these patients. The patients were divided into two groups, anterior ocular inflammation group and posterior ocular inflammation group. Demographic data were reviewed, including age, gender, the existence of inflammation at the initial visit and three months after CyA treatment, and side effect. Results: Twenty-three eyes of thirteen patients with chronic VKH disease were included in this study (11 women, 2 men; mean age, 54.6±11.9 years). Nine cases showed anterior ocular inflammation and seven cases showed posterior ocular inflammation (includes overlapping cases). Thirteen of fourteen eyes in the anterior ocular inflammation group subsided at three months after CyA treatment, and ten of thirteen eyes in the posterior ocular inflammation group subsided at three months after treatment. We had to stop the treatment in one patient because of severe increase of serum triglyceride. Conclusions: Low-dose CyA treatment was effective in patients with chronic VKH resistance to systemic corticosteroid treatment. Our results suggest that this treatment was more effective in the anterior ocular inflammation group than in the posterior ocular inflammation group; however, a larger number of patients and longer observation periods are needed to confirm these results.

Purpose: To report two cases of Vogt-Koyanagi-Harada disease (VKH) resistant to systemic corticosteroid therapy, effectively treated with systemic cyclosporine. Case 1: A 52-year-old man diagnosed as VKH was administered oral corticosteroids (40 mg/day), following steroid pulse therapy. Since there was no significant improvement, he underwent a second course of steroid pulse therapy and oral corticosteroid administration (40 mg/day). However, there was still no improvement, and a combination therapy of both oral corticosteroids (40 mg/day) and cyclosporine 200 mg (3 mg/kg) was administered. As a result, the inflammation subsided and the dosage of the drugs was tapered successfully. Case 2: A 50-year-old man diagnosed as VKH underwent two courses of steroid pulse therapy, which did not improve significantly. We performed combination therapy of both corticosteroids and cyclosporine, similar to the case described above and obtained good results. Conclusion: Our experience of these two cases indicates that systemic cyclosporine treatment was effective in the management of VKH patients resistant to conventional systemic corticosteroid therapy.

Background: TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common treatment-related adverse event of TAS-102 is bone marrow suppression, which leads to neutropenia. The potential predictive value of neutropenia caused by cytotoxic drugs has been reported in various types of cancer., Methods: We retrospectively analyzed 95 consecutive patients with metastatic colorectal cancer who received TAS-102 at 2 Japanese institutions between May 2014 and May 2015. To evaluate the association between efficacy and neutropenia, patients were divided into 4 categories according to the grade of neutropenia during the first cycle of TAS-102: Category A (grade 0-1), B (grade 2-4), C (grade 0-2), and D (grade 3-4)., Results: Patient characteristics were as follows: median age, 64 years; male, 58%; Eastern Cooperative Oncology Group performance status 0 to 1, 91%; primary site colon, 49%; KRAS exon 2 wild, 57%; and number of metastatic site ≥ 3, 55%. The disease control rate was significantly different between Category A and B (29.2% vs. 52.6%; P = .045) and between Category C and D (30.9% vs. 72.2%; P = .002). In multivariate analysis, Category D remained a significant predictive factor for progression-free survival compared with Category C (4.3 vs. 2.0 months; hazard ratio, 0.45; P = .01)., Conclusion: Neutropenia caused by TAS-102 during the first cycle was associated with better efficacy. Neutropenia may be a surrogate marker for adequate antitumor doses of TAS-102., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Although irinotecan monotherapy is often used in third-line treatment after the failure of taxanes in Japanese clinical practice, its survival benefit is still unclear. The aim of this study is to investigate the efficacy and safety of irinotecan monotherapy as third-line treatment., Methods: Clinical data from consecutive patients in whom irinotecan had been initiated as third-line treatment between December 2003 and July 2015 in Shizuoka Cancer Center were retrospectively analyzed. Patients who were refractory or intolerant to fluoropyrimidine with or without platinum in first-line treatment and subsequent therapy with taxanes were included in this study. Irinotecan was administered at 150 mg/m(2) every 2 weeks., Results: The data of 50 patients who met the inclusion criteria were analyzed. The overall response rate was 18.4 % (7/38) among the patients with measurable disease. The median progression-free survival time was 66 days, and the median survival time was 180 days from the initiation of irinotecan therapy. The major grade 3 or 4 adverse events including neutropenia, fatigue, and anorexia were observed in 12 (24 %), 8 (16 %), and 7 (14 %), respectively. No treatment-related deaths occurred. Thirteen patients (26 %) required a dose reduction to 120 mg/m(2) or less from the initiation of irinotecan., Conclusions: This study suggests that irinotecan as third-line treatment has an anti-tumor effect and is feasible with optimal dose modification for advanced gastric cancer.

Background: Although adjuvant chemotherapy with gemcitabine is standard care for resected pancreatic cancer, S-1 has shown non-inferiority to gemcitabine for advanced disease. We aimed to investigate the non-inferiority of S-1 to gemcitabine as adjuvant chemotherapy for pancreatic cancer in terms of overall survival., Methods: We did a randomised, open-label, multicentre, non-inferiority phase 3 trial undertaken at 33 hospitals in Japan. Patients who had histologically proven invasive ductal carcinoma of the pancreas, pathologically documented stage I-III, and no local residual or microscopic residual tumour, and were aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive gemcitabine (1000 mg/m(2), intravenously administered on days 1, 8, and 15, every 4 weeks [one cycle], for up to six cycles) or S-1 (40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles) at the data centre by a modified minimisation method, balancing residual tumour status, nodal status, and institutions. The primary outcome was overall survival in the two treatment groups, assessed in the per-protocol population, excluding ineligible patients and those not receiving the allocated treatment. The protocol prespecified that the superiority of S-1 with respect to overall survival was also to be assessed in the per-protocol population by a log-rank test, if the non-inferiority of S-1 was verified. We estimated overall and relapse-free survival using the Kaplan-Meier methods, and assessed non-inferiority of S-1 to gemcitabine using the Cox proportional hazard model. The expected hazard ratio (HR) for mortality was 0.87 with a non-inferiority margin of 1.25 (power 80%; one-sided type I error 2.5%). This trial is registered at UMIN CTR (UMIN000000655)., Findings: 385 patients were randomly assigned to treatment between April 11, 2007, and June 29, 2010 (193 to the gemcitabine group and 192 to the S-1 group). Of these, three were exlcuded because of ineligibility and five did not receive chemotherapy. The per-protocol population therefore consisted of 190 patients in the gemcitabine group and 187 patients in the S-1 group. On Sept 15, 2012, following the recommendation from the independent data and safety monitoring committee, this study was discontinued because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been finished. Analysis with the follow-up data on Jan 15, 2016, showed HR of mortality was 0.57 (95% CI 0.44-0.72, pnon-inferiority<0.0001, p<0.0001 for superiority), associated with 5-year overall survival of 24.4% (18.6-30.8) in the gemcitabine group and 44.1% (36.9-51.1) in the S-1 group. Grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase were observed more frequently in the gemcitabine group, whereas stomatitis and diarrhoea were more frequently experienced in the S-1 group., Interpretation: Adjuvant chemotherapy with S-1 can be a new standard care for resected pancreatic cancer in Japanese patients. These results should be assessed in non-Asian patients., Funding: Pharma Valley Center, Shizuoka Industrial Foundation, Taiho Pharmaceutical., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Watering eyes is a common late adverse event associated with S-1 chemotherapy; however, the frequency and predictive factors are not known., Methods: This study included 304 consecutive gastric cancer patients treated with adjuvant S-1 monotherapy for 1 year at Shizuoka Cancer Center. We retrospectively evaluated the frequency of watering eyes, and explored other nonhematological adverse events during the first course of S-1 monotherapy which could become predictive factors for watering eyes., Results: The severest grade of watering eyes during S-1 monotherapy was grade 2 in 41 patients (13.5 %) and grade 3 in 36 patients (11.8 %). The median time to onset of grade 2 and grade 3 watering eyes was 82 days (range 6-344 days) and 249 days (range 84-653 days), respectively, and the median cumulative S-1 dose at the onset of grade 2 and grade 3 watering eyes was 4174 mg/m(2) (range 491-16,095 mg/m(2)) and 10,243 mg/m(2) (range 4943-16,341 mg/m(2)), respectively. Multivariate analysis showed that anorexia (odds ratio 2.37, P = 0.008), oral mucositis (odds ratio 3.86, P = 0.0003), skin hyperpigmentation (odds ratio 3.84, P = 0.0001), and rash (odds ratio 3.76, P = 0.01) observed during the first course were significantly associated with watering eyes., Conclusion: The risk of watering eyes was higher in patients who also had anorexia, oral mucositis, skin hyperpigmentation, or rash during first course of S-1 monotherapy than in those without them.

Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Background: The influence of resection of the primary lesion on the prognosis of patients with incurable stage IV colorectal cancer is unclear., Methods: We retrospectively analyzed 158 asymptomatic patients with incurable stage IV colorectal cancer who received systemic chemotherapy in our center from 2002 to 2009, either without (chemotherapy group; n = 112) or after (resection group; n = 46) primary tumor resection. Primary tumor resection was performed if the fiberscope did not pass through the primary lesion. Survival was compared between the 2 groups, and the actual surgical intervention was assessed., Results: At a median follow-up period of 26 months (range 7-91 months), the median survival times were 19.9 months in the resection group and 19.0 months in the chemotherapy group (HR = 0.81, 95 % CI 0.53-1.19, p = 0.29). Among the tumor resection group, 8 (17 %) experienced postoperative complications, with all showing improvement after conservative treatment. In the chemotherapy group, 18 patients (21 %) required surgical interventions for symptoms associated with progression of the primary tumor., Conclusions: Resection of the primary tumor in asymptomatic patients with incurable stage IV colorectal cancer was safe, but had no effect on prognosis.

The FOLFIRINOX combination of chemotherapy drugs had not been fully evaluated for Japanese pancreatic cancer patients. Therefore, we carried out a phase II study to examine the efficacy and safety of FOLFIRINOX in chemotherapy-naïve Japanese patients with metastatic pancreatic cancer. FOLFIRINOX (i.v. infusion of 85 mg/m(2) oxaliplatin, 180 mg/m(2) irinotecan, and 200 mg/m(2) l-leucovorin, followed by a bolus of 400 mg/m(2) fluorouracil and a 46-h continuous infusion of 2400 mg/m(2) fluorouracil) was given every 2 weeks. The primary endpoint was the response rate. The 36 enrolled patients received a median of eight (range, 1-25) treatment cycles. The response rate was 38.9% (95% confidence interval [CI], 23.1-56.5); median overall survival, 10.7 months (95% CI, 6.9-13.2); and median progression-free survival, 5.6 months (95% CI, 3.0-7.8). Major grade 3 or 4 toxicities included neutropenia (77.8%), febrile neutropenia (22.2%), thrombocytopenia (11.1%), anemia (11.1%), anorexia (11.1%), diarrhea (8.3%), nausea (8.3%), elevated alanine aminotransferase levels (8.3%), and peripheral sensory neuropathy (5.6%). Febrile neutropenia occurred only during the first cycle. There were no treatment-related deaths. FOLFIRINOX can be a standard regimen showing favorable efficacy and acceptable toxicity profile in chemotherapy-naïve Japanese patients with metastatic pancreatic cancer., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Objective: Breast, gastric and lung cancers are the most common cancers that cause pulmonary lymphangitis carcinomatosa. However, little is known about the clinical features of pulmonary lymphangitis carcinomatosa in advanced gastric cancer., Methods: We retrospectively reviewed the data throughout the clinical courses of 33 patients with gastric cancer who developed pulmonary lymphangitis carcinomatosa. Pulmonary lymphangitis carcinomatosa was confirmed by both a pulmonologist and a diagnostic radiologist on the basis of computed tomography findings of interstitial patterns such as thickening or irregularity of interlobular septa and bronchovascular bundles., Results: The median age of the 33 patients was 55 years old (range, 25-73 years). The percentages of female patients, those with performance status 3 or 4, and those with respiratory symptoms at diagnosis were 70, 36 and 76%, respectively. The histologically diffuse type of gastric cancer accounted for 85% of cases. Mediastinal lymph node, peritoneal and bone metastases were found in 64, 61 and 39% of patients, respectively. Disseminated intravascular coagulation was noted in 21% of patients. The median survival time of the 18 chemotherapy-naïve patients treated with chemotherapy was 5.7 months (range, 0.4-37.0 months). Two patients obtained symptomatic relief, and one patient treated with S-1 + cisplatin + sunitinib survived >3 years., Conclusions: Pulmonary lymphangitis carcinomatosa caused by gastric cancer has some specific clinicopathological features. While the prognosis of gastric cancer patients with pulmonary lymphangitis carcinomatosa is extremely poor, some patients may have survival benefit from chemotherapy., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Previous Phase 1 studies have shown the acceptable safety profile of ganitumab-a fully human monoclonal antibody to insulin-like growth factor Type 1 receptor-in patients with advanced solid tumors. However, ganitumab 20 mg/kg in combination with gemcitabine had not been administered to patients with metastatic pancreatic cancer. To evaluate the safety, tolerability, pharmacokinetics and antitumor activity of ganitumab 20 mg/kg combined with gemcitabine 1000 mg/m(2) as first-line therapy in patients with metastatic pancreatic cancer, we conducted a Phase 1b study., Methods: Eligible patients were adults with previously untreated metastatic adenocarcinoma of the pancreas. Patients received gemcitabine 1000 mg/m(2) on Days 1, 8 and 15 plus ganitumab 20 mg/kg on Days 1 and 15 of each 28-day cycle. Gemcitabine was administered intravenously over 30-60 min. Ganitumab was administered intravenously over 60 min after completing gemcitabine infusion., Results: Six patients were enrolled and received the study treatment. All patients had thrombocytopenia and leukopenia. Other most common adverse events were neutropenia and nausea. One patient had a dose-limiting toxicity defined as Grade 3 neutropenia with fever. Exposure to ganitumab 20 mg/kg was not affected by the administration of gemcitabine. No apparent pharmacokinetic drug-drug interaction was observed. No anti-ganitumab antibodies were detected. Five patients had a measurable tumor region at baseline. Of these, four patients had a best response of stable disease., Conclusions: Ganitumab 20 mg/kg combined with gemcitabine 1000 mg/m(2) was tolerable and showed an acceptable safety profile in patients with untreated metastatic pancreatic cancer.

Background: The number of cases of metastatic colorectal cancer treated by chemotherapy without primary tumor resection has recently increased. However, evaluation of primary tumor response by computed tomography is difficult in such cases. In this study, the usefulness of evaluation of primary tumor response to chemotherapy by endoscopy was investigated., Methods: This retrospective analysis was performed at the Shizuoka Cancer Center and included 31 patients (88 evaluations) with metastatic colorectal cancer. Computed tomography and endoscopy were performed concomitantly between September 2002 and June 2006. Patients were treated by systemic chemotherapy without prophylactic primary tumor resection. Definitions of primary tumor response were as follows: (1) complete response, confirmed by colorectal biopsy; (2) progressive disease, enlargement of at least one of five tumor parameters; and (3) neither (1) nor (2). Computed tomography was performed to evaluate primary tumor response according to the Response Evaluation Criteria in Solid Tumors and to identify colorectal stenosis secondary to primary tumors., Results: The rate of concordance between endoscopy and computed tomography for evaluation of primary tumor response was 75%. Colorectal stenosis was detected 14 times by endoscopy (9 cases) and 3 times by computed tomography (3 cases). Of the 7 patients in whom surgery was required, 6 exhibited stenotic symptoms before endoscopic detection., Conclusions: With regard to primary tumor response evaluation, a high concordance rate was observed between endoscopy and computed tomography, although endoscopic evaluation appeared more sensitive in detecting colorectal stenosis requiring surgical treatment.

Background: An oxaliplatin-based regimen as the adjuvant treatment for stage III colon cancer demonstrated a survival advantage over fluorouracil (FU) and leucovorin (LV) in the MOSAIC and NSABP C-07 trials. For adjuvant treatment after the resection of metastases from colorectal cancer), active chemotherapy regimens such as FOLFOX are recommended. However, the safety data of FOLFOX are insufficient for its use after metastasectomy of colorectal cancer in Japanese patients. The aim of this study was to evaluate the safety of mFOLFOX6 for adjuvant treatment after the resection of metastases from colorectal cancer., Methods: Among 67 consecutive patients who received mFOLFOX6 as the adjuvant treatment after resection of metastases from colorectal cancer between September 2002 and March 2009 in our institution, 51 patients who had not received preoperative chemotherapy were reviewed. The mFOLFOX6 treatment comprised oxaliplatin 85 mg/m(2) and l-leucovorin 200 mg/m(2) given intravenously over a 2-h period on day 1, followed by a 5-FU bolus of 400 mg/m(2) and a 46-h infusion of 5-FU 2400 mg/m(2), every 2 weeks for up to 12 cycles., Results: National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI-CTC) grade 3-4 toxicities per patient were: peripheral neuropathy 8%, allergic reaction 4%, aspartate transaminase (AST) 4%, febrile neutropenia 4%, nausea 2%, anorexia 2%, fatigue 2%, alanine transaminase (ALT) 2%, bilirubin 2%, neutrophils 49%, leukocytes 6%, and hemoglobin 2%; 71% of the patients completed the scheduled 12 cycles., Conclusion: Adjuvant therapy with mFOLFOX6 after resection of metastases from colorectal cancer is feasible for Japanese patients.

Background: Although S-1 plus cisplatin (SP) therapy is recognized as the standard treatment for advanced gastric cancer (AGC) in Japan, its safety and efficacy in elderly patients have not been investigated sufficiently., Methods: We retrospectively reviewed the data of 58 patients with AGC selected from 82 consecutive patients who were ≥70 years old and were treated with SP or S-1 monotherapy as the first-line therapy. In SP, S-1 (40 mg/m(2), bid) was administered for 3 weeks and cisplatin (60 mg/m(2)) on day 8, every 5 weeks. In S-1 monotherapy, S-1 (40 mg/m(2), bid) was administered for 4 weeks, every 6 weeks., Results: SP and S-1 was administered in 21 and 37 patients, respectively. There were some differences in patient characteristics between the treatment groups, such as histological type (P = 0.16); the presence of liver metastasis (P = 0.07); and the presence of peritoneal metastasis (P = 0.02). The incidences of grade 3/4 hematological toxicities were 57% (12/21) in the SP and 35% (13/37) in the S-1 group (P = 0.17). Those of non-hematological toxicities were 14% (3/21) and 14% (5/37) for anorexia, 10% (2/21) and 14% (5/37) for fatigue, and 5% (1/21) and 5% (2/37) for nausea in the SP and S-1 groups, respectively. Median progression-free survival and median overall survival in the SP and S-1 groups were 5.0 and 5.2 months, and 14.4 and 10.9 months, respectively., Conclusion: SP and S-1 therapy were both feasible in elderly patients, though there is the risk of a high incidence of hematological toxicities.

Background: Leptomeningeal carcinomatosis (LMC) is a rare but devastating complication of gastric cancer., Methods: The subjects were 12 gastric cancer patients who were diagnosed as having LMC at the Shizuoka Cancer Center between October 2002 and March 2009. We conducted a retrospective survey of the medical records of the study subjects and collected data on the clinical features, treatment modalities employed/outcomes, and survival of the patients., Results: Of the 12 patients, 9 (75%) were male, and the median age was 63 years. Histopathologically, the majority of the patients (83%) had diffuse-type adenocarcinoma. At the time of diagnosis of the LMC, the other major sites of metastasis were the peritoneum (75%) and lymph nodes (50%). The median duration from the diagnosis of gastric cancer to the diagnosis of LMC was 15.6 months. While the treatment strategy changed with time, intrathecal chemotherapy (n = 10), followed by whole brain irradiation (n = 7) and subsequent ventriculo-peritoneal shunt (n = 3) was performed in 10 of the patients. Improvement of neurological functions was observed in 6 of the 10 patients. The median overall survival time from the diagnosis of LMC in all the 12 patients was 60 days. One patient survived for a considerably long period of 532 days., Conclusions: Multidisciplinary treatment, including ventriculo-peritoneal shunt for LMC secondary to gastric cancer, may benefit selected patients, but further accumulation of clinical cases is necessary.

Objective: Since 2007, S-1 plus cisplatin therapy has been recognized as the standard first-line treatment for advanced gastric cancer in Japan. However, no standard regimen has been established for patients refractory to first-line treatment. Furthermore, irinotecan and paclitaxel are considered key drugs for second-line treatment. Several studies have investigated the efficacy and tolerability of combination therapy with oxaliplatin, 5-fluorouracil and leucovorin (modified FOLFOX-6) for advanced gastric cancer. Here, we examined the efficacy and toxicity of modified FOLFOX-6 therapy in heavily pretreated patients with advanced gastric cancer refractory to 5-fluorouracil, irinotecan, cisplatin and taxanes., Methods: Fourteen patients with advanced gastric cancer refractory to 5-fluorouracil, irinotecan, cisplatin and taxanes were included in the study. In modified FOLFOX-6 therapy, 85 mg/m(2) oxaliplatin, 400 mg/m(2) 5-fluorouracil and 200 mg/m(2) leucovorin on Day 1 were administered biweekly by intravenous infusion, followed by the administration of 2400 mg/m(2) 5-fluorouracil by a 46-h continuous infusion., Results: The median age of the patients was 59 years (range, 22-74). A median of 5.5 (range, 1-13) chemotherapy cycles were administered. The overall response rate was 23.1% in patients with measurable lesions. Of the 12 patients with advanced gastric cancer refractory to cisplatin, 2 showed partial response (response rate, 18.2%). The progression-free survival was 90 days, and the median survival time from the initiation of modified FOLFOX-6 therapy was 268 days. Grade 3-4 toxicities most commonly observed included neutropenia (57%), anaemia (14%), thrombocytopenia (21%) and hyperammonaemia (7%)., Conclusions: Modified FOLFOX-6 therapy in patients refractory to 5-fluorouracil, irinotecan, cisplatin and taxanes may be a potential advanced gastric cancer therapeutic strategy.

Objective: The objective was to determine the maximum tolerated dose and the dose-limiting toxicity of panobinostat (LBH589) when administered as a single agent to adult patients with advanced solid tumors or cutaneous T-cell lymphoma whose disease had progressed despite standard therapy or for whom no standard therapy existed., Methods: Panobinostat was administered orally once daily on Monday, Wednesday, and Friday of each week. A total of 13 patients were treated with one of three initial doses: 10 mg (n = 3), 15 mg (n = 4), or 20 mg (n = 6)., Results: No dose-limiting toxicity was observed in 12 evaluable patients. The most frequently reported adverse events, regardless of whether they were related to the study drug, were diarrhea and nausea in 10 patients (76.9%). Thrombocytopenia was reported in 12 of 13 patients (92.3%). Five of 11 patients (45.4%) had stable disease., Conclusion: Panobinostat administered orally once daily on Monday, Wednesday, and Friday of each week was well tolerated at doses up to 20 mg in Japanese patients. Dose escalation did not proceed after exploration of the 20 mg dose due to emerging global clinical data at that time.

Background/purpose: Complications from biliary drainage in biliary tract cancer (BTC) may influence the relative dose intensity of chemotherapy or increase adverse events during chemotherapy. BT22 was a randomized phase II trial, the results of which were consistent with those of a phase III trial in non-Japanese that demonstrated the effectiveness of gemcitabine plus cisplatin combination therapy (GC) in BTC. The purpose of this exploratory analysis of the BT22 study was to identify the possible effects of biliary drainage on the efficacy and safety of GC or gemcitabine monotherapy (G)., Patients and Methods: The 83 BTC patients who received GC or G in BT22 were retrospectively analysed in two subgroups dependent upon whether biliary drainage was performed before study entry. Efficacy and safety of treatment (GC vs. G) were compared in these two groups., Results: The GC arm had a higher 1-year survival rate and longer median survival time (MST) than the G arm independent of prior biliary drainage. Patients in the drainage subgroup developed cholangitis more frequently, however, the frequency of grade 3/4 adverse events did not differ between the treatment regimens with/without drainage., Conclusions: Biliary drainage before chemotherapy did not affect the therapeutic efficacy or tolerability of chemotherapy using G or GC., (© 2012 International Hepato-Pancreato-Biliary Association.)

Backgrounds: The effectiveness of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has not been fully evaluated in the diagnosis of autoimmune pancreatitis (AIP)., Aim: To evaluate the effectiveness of EUS-FNA using 22-gauge needles in the diagnosis of AIP., Methods: EUS-FNA was examined in 85 patients with pancreatic mass, including 64 patients with pancreatic cancer and 21 patients with AIP. We investigated ability of EUS-FNA using 22-gauge needle for the differential diagnosis between AIP and pancreatic cancer. We also compared the factors concerning FNA procedures (number of needle passes, size of lesion, device, and amount of obtained pancreatic tissue) between two diseases., Results: Tissues obtained from 21 patients with AIP, although none of them demonstrated histology suspicious for malignancy, did not show histological evidence definitive for AIP. The amount of obtained pancreatic tissue was almost equal between two diseases in each pancreatic location. Sensitivity, specificity, overall accuracy, and negative predictive value of histological diagnosis of pancreatic cancer were 92.2%, 100%, 94.1%, and 80.8%, respectively., Conclusion: EUS-FNA using 22-gauge needle distinguished benign from malignant pancreatic mass with >90% of accuracy, regardless of the location. Hence, it was helpful for the clinical diagnosis of AIP, however not providing satisfactory samples for the histological diagnosis of AIP., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Although concurrent chemoradiotherapy (CRT) is a standard treatment for esophageal cancer invading adjacent structures (T4-EC), arterio-esophageal fistula (AEF) occurs occasionally as a critical adverse event of T4-EC with CRT. The frequency, clinical course, and risk factors of AEF related to CRT are not well known., Methods: We retrospectively analyzed 48 patients with T4-EC invasion of the aorta who were treated with 5-fluorouracil, cisplatin, and concurrent radiotherapy at our institution between September 2002 and April 2009. Treatment-related AEF was defined as AEF without obvious tumor progression. We evaluated the frequency, clinical courses, and risk factors of AEF., Results: The median survival time was 10.6 months with a median follow-up time of 33.3 months. The 2-year survival rate was 25%. Treatment-related AEF was observed in 7 patients (14.6%) and 4 of them died of massive bleeding due to aortic AEF. In the other 3 patients with non-aortic AEF, hemorrhage could be arrested by transcatheter arterial embolization (TAE). In the univariate analysis of risk factors for AEF, lower serum cholesterol level was a risk factor for AEF (OR 14.7; 95% CI 1.58-137; P = 0.008)., Conclusions: Although CRT has a curative potential even for patients with T4-EC invading the aorta, we should be aware of the relatively high incidence of treatment-related AEF. TAE may be successful in rescuing a non-aortic AEF patient. Low serum cholesterol level may be a risk factor for AEF, but further investigation is needed.

Background: Although S-1 is effective against advanced gastric cancer (AGC), its efficacy in elderly patients has not yet been investigated sufficiently. We assessed the efficacy and safety of S-1 monotherapy in elderly patients with AGC., Methods: We conducted a retrospective review of the data of 153 patients with unresectable/recurrent gastric adenocarcinoma who received S-1 monotherapy as first-line chemotherapy at our institution. S-1 was administered orally twice daily at the dose of 40 mg/m², on days 1-28, every 6 weeks. We categorized the patients into three groups, the young (≤65 years old), the middle-aged (66-75 years old), and the elderly (≥76 years old); and the drug toxicity, objective responses, progression-free survivals, and overall survivals were compared among the three groups., Results: The incidence of leukopenia of grade 3 or greater in the three groups was 7%, 5%, and 13%, and that of anemia was 9%, 18%, and 27%, respectively. In regard to nonhematological toxicities, the incidence of nausea of grade 3 or greater was 3%, 5%, and 13%; that of fatigue was 5%, 11%, and 20%; and that of anorexia was 5%, 6%, and 27%, respectively. As for the treatment efficacy, the objective response rates, median progressionfree survivals, and overall survivals in the young, middle-aged, and elderly groups were 53%, 46%, and 33%; 7.8, 5.6, and 3.9 months; and 16.9, 17.1; and 7.7 months, respectively., Conclusion: Although S-1 monotherapy showed moderate efficacy in elderly (≥76 years) patients with AGC, patients in this age group showed higher incidences of severe toxicities than the younger patients.

The incidence of pancreatic endocrine tumor (PET)accounts for 1 approximately 2% of total pancreatic tumors and 0. 4 approximately 1. 5% of autopsy cases, reflecting the recently increasing trend. According to WHO criteria(2004), PET is classified by the type of hormone produced by the tumor and its biological behavior. Together with the classical clinical images and hormone markers, 11C-5-HTP-Positron emission tomography, OctreoScan ([(111)In-DTPA0]octreotide)scintigram, SACI-test and IOUS are used for diagnosis. Surgery is the treatment of choice, if supposed to be curative and tolerable. In case of a well-differentiated endocrine tumor, with no indication of resection or IVR, somatostatin analog is another therapy showing stable disease status for a long period. Systemic chemotherapy, including 5-FU+streptozotocin, and streptozotocin+doxorubicin, are used in cases of well -differentiated endocrine carcinoma, and cisplatin+etoposide are applied for poorly-differentiated endocrine carcinoma (or small cell carcinoma). Recent studies focus on molecular target therapy including small molecules and monoclonal antibody, such as tyrosine kinase inhibitor, anti-VEGF antibody and moor inhibitor.

Background: Pancreatitis is the most common and serious complication to occur after endoscopic retrograde cholangiopancreatography (ERCP). It is often associated with additional diagnostic modalities and/or treatment of obstructive jaundice. The aim of this study was to determine the risk of post-ERCP pancreatitis associated with pancreaticobiliary examination and endoscopic biliary drainage (EBD)., Methods: A total of 740 consecutive ERCP procedures performed in 477 patients were analysed for the occurrence of pancreatitis. These included 470 EBD procedures and 167 procedures to further evaluate the pancreaticobiliary tract using brush cytology and/or biopsy, intraductal ultrasound and/or peroral cholangioscopy or peroral pancreatoscopy. The occurrence of post-ERCP pancreatitis was analysed retrospectively., Results: The overall incidence of post-ERCP pancreatitis was 3.9% (29 of 740 procedures). The risk factors for post-ERCP pancreatitis were: being female (6.5%; odds ratio [OR] 2.5, P= 0.02); first EBD procedure without endoscopic sphincterotomy (ES) (6.9%; OR 3.0, P= 0.003), and performing additional diagnostic procedures on the pancreatobiliary duct (9.6%; OR 4.6, P < 0.0001). Pancreatitis after subsequent draining procedures was rare (0.4%; OR for first-time drainage 16.6, P= 0.0003). Furthermore, pancreatitis was not recognized in 59 patients who underwent ES. Seven patients with post-EBD pancreatitis were treated with additional ES., Conclusions: Invasive diagnostic examinations of the pancreaticobiliary duct and first-time perampullary biliary drainage without ES were high-risk factors for post-ERCP pancreatitis. Endoscopic sphincterotomy may be of use to prevent post-EBD pancreatitis.

We present a case of pancreatic carcinoma with strongly suspected coexisting autoimmune pancreatitis (AIP). The patient presented with a chief complaint of icterus and weight loss, and was referred to our institution after a pancreatic lesion was found. Blood test showed elevation of serum bilirubin, hepato-biliary enzyme, glucose and tumor markers, and also high levels of serum IgG4 (344 mg/dl, normal 4.8-105 mg/dl) and anti-DNA antibody (14 IU/ml, normal <6.0 IU/ml). Ultrasonography demonstrated an enlarged pancreas with smooth borders and low internal echo density. Enhanced computed tomography (CT) showed a sausage-shaped pancreas without definitive metastasis to the surrounding lymph nodes and liver. Imaging of the pancreatic duct, including endoscopic retrograde pancreatography (ERP) and magnetic resonance cholangiopancreatography (MRCP), showed stenosis of the main pancreatic duct at the pancreatic head as well as a long segment of narrowing at the body and no dilatation at the tail. Tissues from these stenotic sites and open biopsy from pancreatic body showed infiltrating adenocarcinoma and dense fibrosis. To date, only a small number of reports have described pancreatic carcinoma accompanied with AIP. It is important to confirm diagnosis with histology in cases of suspicious autoimmune pancreatitis, even when the clinical images are compatible with AIP.

Background/aims: Autoimmune pancreatitis (AIP) is an IgG4-related systemic disease often accompanied with a variety of lesions outside of the pancreas and is treated with steroid therapy. The aim of this study is to analyze the usefulness of positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) in the evaluation of distribution and activity of systemic lesions of AIP during steroid therapy., Methods: Eleven cases of AIP had their FDG-PET images evaluated before and 3 months after steroid therapy and another 2 cases only before therapy. AIP activity was determined by the level of serum markers, IgG and IgG4, and compared with findings of PET., Results: In all 13 cases of AIP, a moderate to intense level of FDG accumulation was recognized in the pancreatic lesion before steroid therapy. Of 13 patients, 11 (84.6%) showed FDG accumulation in the multiple organs, such as mediastinal and other lymph nodes, salivary gland, biliary tract, prostate, and aortic wall. In 11 patients who underwent PET before and after steroid therapy, FDG accumulation was diminished in almost all systemic lesions, with a mean of maximum standardized uptake value (SUV(max)) in the pancreatic lesion from 5.12 to 2.69. Similar to the SUV level, serum IgG and IgG4 were decreased in most of the cases after steroid therapy., Conclusions: FDG-PET is an effective modality to evaluate the response of steroid therapy and the distribution and activity of various systemic lesions of AIP., (Copyright 2009 S. Karger AG, Basel.)

Background: Many studies of concurrent chemoradiation therapy with 5-fluorouracil (5-FU) for locally advanced pancreatic cancer have been reported with a median survival time of approximately 10 months. Recently, gemcitabine (GEM) has been administered immediately after chemoradiation. The clinical outcome of chemoradiation therapy in conjunction with 5-FU and second-line chemotherapy with GEM after disease progression has not been clarified., Methods: Patients with locally advanced pancreatic cancer were treated with concurrent radiation therapy (1.8 Gy/fraction; total dose, 50.4 Gy) with 5-FU (200 mg/m(2) every day) until disease progression, followed by GEM (1000 mg/m(2), days 1, 8, 15, and every 4 weeks) as second-line therapy., Results: Of the 18 patients with locally advanced pancreatic cancer who received chemoradiation therapy with 5-FU, there were three partial responses, giving a response rate of 17%. The median time to progression was 170 days. The median survival time was 443 days. During chemoradiation therapy, the incidences of grade 3 or 4 anorexia, nausea, mucositis, and gastric ulcer were 33%, 22%, 17%, and 17%, respectively. Sixteen patients received second-line chemotherapy with GEM, of whom one patient had a partial response. The median time to progression from the initiation of GEM was 113 days, and median overall survival time was 231 days. Major toxicities were hematological toxicities: grade 3 or 4 leukopenia in 75% and anemia in 31%., Conclusions: The treatment strategy with concurrent chemoradiation and maintenance chemotherapy with 5-FU followed by second-line chemotherapy with GEM may be an option for locally advanced pancreatic cancer.

We report a patient with chemotherapy-naïve advanced pancreatic cancer having multiple liver metastases which dramatically responded to S-1, an oral fluoropyrimidine. The patient was enrolled in the "Late Phase II Clinical Study of S-1 in Patients with Advanced Pancreatic Cancer." Anti-tumor efficacy after the first four courses of S-1 monotherapy was confirmed to be partial response (PR) in overall response by Response Evaluation Criteria in Solid Tumors (RECIST). Grade 3 neutropenia was observed, but no other severe toxicities were noted. On the basis of the results of the late phase II clinical study, S-1 is a promising agent for systemic chemotherapy against advanced pancreatic cancers because of its excellent efficacy, high tolerability, and convenient route of oral administration.

We experienced a case of pancreaticobiliary maljunction in monozygotic twins. While one of the twins suffered from gallbladder cancer with poor prognosis, the other was not associated with biliary malignancy. Ultrasonography, endoscopic ultrasonography, and magnetic resonance cholangiopancreatography are effective in diagnosis of this disorder before occurrence of biliary cancers. This case is not only of academic interest for familial occurrence, but also of clinical interest in the early detection of pancreaticobiliary maljunction.