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Purpose: Peripheral sensory neuropathy (PSN) and thrombocytopenia are the main dose-limiting toxicities of oxaliplatin for the treatment of advanced gastric cancer (AGC). Because the risk factors for those toxicities in practice have not been clarified, we conducted this prospective study., Methods: AGC patients who received oxaliplatin-based therapy at any of seven institutions participating in the Kyushu Medical Oncology Group were assessed after we obtained written informed consent., Results: A total of 60 patients including 39 males and 21 females were examined. The median age was 66 years. The numbers of patients receiving oxaliplatin as the first, second, or third and later lines of therapy were 39, 16, and 5, respectively. An initial dose of 130, 100, or < 100 mg/m 2 oxaliplatin was administered to 12, 39, and 9 patients, respectively. S-1 or capecitabine as a concomitant drug was administered in 54 and 6 patients, respectively. In multivariate analysis, the comorbidity of diabetes mellitus was associated with ≥ grade 2 thrombocytopenia (p = 0.035). No significant risk factor was associated with ≥ grade 2 PSN. However, the accumulated dose of oxaliplatin exhibited a strong correlation with ≥ grade 2 PSN (p = 0.0043), and the predicted accumulated dose of oxaliplatin in which 10% of patients developed ≥ grade 2 PSN was 800 mg/m 2 . The frequency of PSN in subsequent paclitaxel therapy in patients with ≥ grade 2 or worse PSN in oxaliplatin-based chemotherapy did not increase compared to those with none or grade 1 PSN in oxaliplatin., Conclusion: Thrombocytopenia in AGC patients with diabetes mellitus should be carefully monitored during oxaliplatin-based therapy.

Purpose: Standard therapy for advanced small bowel adenocarcinoma (SBA) has not yet been established. The present study assessed the efficacy and safety of chemotherapy (CT) in association with molecular targeting approaches for SBA., Methods: The histories of 33 advanced SBA patients from six different institutions in Japan, who received CT from 2008 to 2016, were retrospectively examined for background, clinical course and outcome., Results: Median patient age was 65 years (range 39-83). Primary tumor was located in the duodenum in 21 patients (67%), the ampulla of Vater in three patients (9%), the jejunum in seven patients (21%) and the ileum in one patient (3%). Histologically, well-to-moderately and poorly differentiated adenocarcinoma were identified in 20 (61%) and nine (27%) patients, respectively. Thirteen patients received a single CT regimen, seven patients received two types of CT regimen, and 13 patients received three or more CT regimens. As first-line CT, modified FOLFOX6, capecitabine plus oxaliplatin, and S-1 plus cisplatin were employed in 13, 1, and 4 patients, respectively. The response rate (RR) and median progression-free survival (PFS) were 25% and 6.0 months, respectively. Median overall survival (OS) was 13.0 months. Nine out of the 33 patients received bevacizumab-containing CT and three received cetuximab-containing CT. Median OS of bevacizumab-containing CT patients was 21.9 months. No unexpected serious adverse events were observed., Conclusions: The analysis indicates that combination CT for advanced SBA is associated with modest efficacy and safety, and bevacizumab-containing CT may contribute to favorable outcome in these patients.

Purpose: Investigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies., Methods: AZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80-400, 360-480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients., Results: Forty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade ≥3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years., Conclusions: Intermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363.

Purpose: Extrapulmonary neuroendocrine carcinomas (EPNEC) are rarely observed and are associated with poor outcomes. Based on the clinicopathological similarity, treatment used for small cell lung carcinoma has also been employed for EPNEC, but the response to such therapy has not been well examined. The goal of this study was to investigate amrubicin (AMR) monotherapy as a salvage therapy for EPNEC arising from digestive organs., Methods: Patients with EPNEC of the digestive organs who had prior platinum-based chemotherapy and were subsequently treated with AMR between July 2005 and December 2013 at any one of four institutions were retrospectively examined to characterize the safety and efficacy of AMR., Results: Thirteen patients (ten males, three females; median age 64 years) were examined. Primary cancer sites included stomach (n = 6), rectum (n = 3), esophagus (n = 2), liver (n = 1) and pancreas (n = 1). Prior irinotecan- and etoposide-containing chemotherapies were used in ten and six patients, respectively. Median initial dose of AMR was 40 mg/m(2)/day for three consecutive days, and median of treatment cycles was 4 (range 1-9). The objective response rate (ORR) was 38.5%. Median progression-free survival (PFS) and overall survival (OS) were 107 (range 22-275) and 215 days (range 71-535), respectively. Common severe adverse events (grade 3/4) were neutropenia (84.6%) and febrile neutropenia (30.8%). Patient with longer platinum-free interval (>90 days) exhibited longer PFS and OS than those with shorter platinum-free interval (190 vs. 63 days and 348 vs. 145 days, respectively)., Conclusions: AMR showed evidence of clinical activity and safety when used for the treatment of EPNEC. It might be especially useful for populations with sensitive relapse.

Social capital is an important resource that can be mobilized for purposive action or competitive gain. The distribution of social capital in social-ecological systems can determine who is more productive at extracting ecological resources and who emerges as influential in guiding their management, thereby empowering some while disempowering others. Despite its importance, the factors that contribute to variation in social capital among individuals have not been widely studied. We adopt a network perspective to examine what determines social capital among individuals in social-ecological systems. We begin by identifying network measures of social capital relevant for individuals in this context, and review existing evidence concerning their determinants. Using a complete social network dataset from Hawaii's longline fishery, we employ social network analysis and other statistical methods to empirically estimate these measures and determine the extent to which individual stakeholder attributes explain variation within them. We find that ethnicity is the strongest predictor of social capital. Measures of human capital (i.e., education, experience), years living in the community, and information-sharing attitudes are also important. Surprisingly, we find that when controlling for other factors, industry leaders and formal fishery representatives are generally not well connected. Our results offer new quantitative insights on the relationship between stakeholder diversity, social networks, and social capital in a coupled social-ecological system, which can aid in identifying barriers and opportunities for action to overcome resource management problems. Our results also have implications for achieving resource governance that is not only ecologically and economically sustainable, but also equitable.

Purpose: AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing activity with gemcitabine in xenograft models., Methods: This open-label, Phase I, dose-escalation study evaluated the safety, pharmacokinetics (PK) and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours (NCT00937664). Patients received intravenous AZD7762 alone on days 1 and 8 of a 14-day cycle (cycle 0), followed by AZD7762 plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of 22-day cycles, in ascending AZD7762 dose cohorts., Results: Twenty patients received AZD7762 at doses of 6 mg (n = 3), 9 mg (n = 3), 21 mg (n = 6) and 30 mg (n = 8). Dose-limiting toxicities occurred in 2/6 evaluable patients in the 30-mg cohort: one, CTCAE grade 3 elevated troponin T (cycle 0: AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated aspartate aminotransferase and alanine aminotransferase (cycle 1: combination therapy). The 30 mg dose was therefore regarded as non-tolerable. The most common adverse events (AEs) in cycle 0 (AZD7762 monotherapy) were bradycardia (50 %), hypertension (25 %) and fatigue (15 %). Overall, the most common AEs were bradycardia (55 %), neutropenia (45 %) and hypertension, fatigue and rash (30 % each). Grade ≥3 AEs were reported in 11 patients, the most common being neutropenia (45 %) and leukopenia (25 %). AZD7762 exposure increased approximately linearly. Gemcitabine did not appear to affect AZD7762 PK. There were no objective responses; five patients (all lung cancer) had stable disease., Conclusions: The maximum tolerated dose of AZD7762 in combination with gemcitabine, 1,000 mg/m(2) was determined as 21 mg in Japanese patients.

Purpose: The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan has been reported to be a promising regimen for advanced colorectal cancer. However, the safety and efficacy of bevacizumab (BV) to combine with irinotecan and S-1 has not been determined. The aim of the study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BV combined with irinotecan plus S-1, and to observe the safety and efficacy of this regimen as second-line chemotherapy in patients with advanced colorectal cancer., Methods: This study initially had been planned as a phase I/II study. Eighty mg/m(2) of irinotecan on days 1 and 8, 80 mg/m(2) of S-1 for 14 consecutive days, and two doses of BV (Level 1; 10 mg/kg, Level -1; 7.5 mg/kg) were administered on day 1 every 3 weeks., Results: Fourteen patients were enrolled in phase I of the study between January 2008 and September 2010. Dose-limiting toxicities were diarrhea, abdominal pain, and infection. The MTD and RD of BV were determined to be 10 mg/kg and 7.5 mg/kg, respectively. The main adverse events were leukopenia, anorexia, and diarrhea. There were no treatment-related deaths. An independent review committee was scheduled to evaluate safety in phase I, but this trial closed early due to toxicity., Conclusions: This study identified the risk of gastrointestinal toxicity with the combination of irinotecan, S-1 and BV as second-line chemotherapy in patients with advanced colorectal cancer.

We report a case of an aneurysm of a persistent sciatic artery which caused buttock pain. Preoperative diagnosis is very difficult. However, awareness of the presence of this rare embryonic abnormality is important, especially in elderly persons with atherosclerotic changes. Sagittal magnetic resonance imaging (MRI) was very useful in reaching this diagnosis.

The cardiac effect of granisetron, a selective 5-hydroxytryptamine3 receptor antagonist, on 12 patients with bone and soft-tissue sarcomas treated by cytotoxic chemotherapy consisting of multiple courses was examined. Of the 12 patients, 4 showed significant electrocardiographical changes, including sinus bradycardia, integral change of P-waves, junctional escape beat, and atrioventricular (AV) block with Wenckebach phenomenon, indicating stimulatory regulation of the vagus nerve. These changes were observed in each patient after several courses of chemotherapy but not in the first course. There was no correlation between the electrocardiographical changes and the chemotherapeutic agents used or the type of tumor present. A patient with osteosarcoma showed persistent bradycardia in three courses, all protocols of which contained high-dose methotrexate. From these findings we conclude that the cardiac responses may be due to stimulated activity of the vagal efferent nerve, which is regulated reflexly by afferent nerve activity suppressed by granisetron. On the other hand, the antiemetic efficacy of granisetron was satisfactory. These results suggest that careful observation of the heart is necessary when granisetron is used, especially for chemotherapy consisting of repeated multiple courses.

A Japanese man, who was 61 years of age, presented with multiple neurilemmoma in both legs which had arisen from different levels of both sciatic nerves. There were no clinical findings relating to von Recklinghausen's disease in the patient or his siblings. Multiple neurilemmoma may be the result of embryonic metameric anomalies. The condition may be distinguished from von Recklinghausen's disease by the distribution of the lesions and genetic analysis.

We describe a simple bone cyst in a patient who had an osteoblastic lesion which had been discovered 1 1/2 years earlier. Curettage and drilling proved effective treatment. We suggest that increased regional blood flow, in association with bone formation, produces a hydrodynamic disorder followed by venous obstruction leading to the formation of a bone cyst.

Curettage without bone graft was performed in 17 patients with benign bone tumors and tumor-like lesions. New bone formation with uniformly increased radiodensity appeared in serial plain radiographs within 3 months after the operation. The average period before full weight could be borne on the lower extremities was 14 weeks. Computed tomography revealed that the central part of the bone lesions persisted without bone formation. The thickening of cortical bone was predominant. These data indicate that enough mechanical strength for daily activity will be recovered by bone within 4 months after curettage without any filler, although remodeling continues for over a year. It is suggested that bone graft and implantation of "biomaterials" are not necessary in patients, especially younger ones, with benign bone tumors or tumorous conditions.

We report a case of multiple, simple bone cysts in long tubular, short tubular, and flat bones. The internal pressure of the cysts and the oxygen tension of cyst fluid were measured simultaneously. These values were similar to those of typical solitary cysts in other patients. Curettage and bone graft onto the calcaneal cyst were effective, although steroid injection therapy into the metacarpal cyst had no effect. Piercing the ulnar and radial cysts a number of times was uniformly effective. These results may suggest that venous obstruction of the lesions play an important role in the etiology of multiple simple cysts, as shown in typical bone cysts. However, we could not exclude the possibility that simple bone cysts, solitary or multiple, represent some kind of secondary forms of other disorders, or that a simple bone cyst is a heterogeneous entity.

We report the long-term results with ten patients with simple bone cysts with special retrospective reference to the radiographic evidence of healing after hole drilling. Cortical thickening was initially observed within 3 months, and minimal new bone formation around Kirschner wires left in situ was observed within 4 months. New bone formation gradually progressed from the cyst wall and around the wire. Consolidation of a cyst cavity was uniformly observed 6-7 months after drilling. In several patients residual cysts were seen between the wire and cortical shell. In younger patients, a cystic cavity reappeared after extraction of the wire, although complete radiographic healing had been observed. These findings suggest that a Kirschner wire plays an important role in preventing relapse of simple bone cysts after hole drilling.