Toru Miyake

Hyperthermic intraperitoneal chemotherapy using a combination of mitomycin C,5-fluorouracil, and oxaliplatin in patients at high risk of colorectal peritoneal metastasis: A Phase I clinical study

INTRODUCTION The drugs and protocols used for hyperthermic intraperitoneal chemotherapy (HIPEC) vary among institutions. Here we show the efficacy of the 3-drug combination of mitomycin C (MMC), 5-fluorouracil (5FU), and oxaliplatin (OHP) in an in vitro simulation of HIPEC and the safety of HIPEC with these drugs during a Phase I study of patients at high risk of developing colorectal peritoneal metastasis. METHODS To simulate HIPEC, we used HCT116 and WiDr cells to assess the growth inhibitory efficacy of MMC 2 μg/mL, 5FU 200 μg/mL, and OHP 40 μg/mL as single drugs or their combination after an exposure time of 30 min at 37 or 42 °C. In addition, nine patients underwent surgical resection of tumors and HIPEC with MMC, 5FU, and an escalating dose of OHP (90/110/130 mg/m²). Dose-limiting toxicity was monitored. RESULTS In the simulation, the 3-drug combination showed marked tumor-suppressive effects compared with those from ten times higher dose of OHP 400 μg/mL, with significant augmentation under hyperthermic conditions. No dose-limiting toxicity occurred in the clinical study. Dose escalation was completed at the final level of OHP. CONCLUSIONS The MMC-5FU-OHP combination showed marked growth inhibition against colorectal cancer cells under hyperthermic conditions in vitro. In the phase I study, the recommended dose of OHP was determined as 130 mg/m² when used with MMC and 5FU; HIPEC using MMC-5FU-OHP appears to be safe and feasible for patients at high risk of colorectal peritoneal metastasis.

Endotoxin adsorption: Direct hemoperfusion with the polymyxin B-immobilized fiber column (PMX)

Toraymyxin® is a medical device developed to adsorb circulating endotoxins in the blood using direct hemoperfusion therapy for patients with septic shock. In 1994, the Japanese National Health Insurance system approved the use of Toraymyxin for the treatment of endotoxemia and septic shock. Since then, Toraymyxin has been safely used in more than 100,000 cases in emergency and intensive care units in Japan. Toraymyxin is currently available for use in the clinical setting in 14 countries worldwide. In this study, we reviewed and introduced the development, clinical use, and efficacy of Toraymyxin and commented on its anticoagulant use and cartridge clotting issue in the treatment of severe sepsis and septic shock. We also highlighted potential new applications of Toraymyxin for longer duration therapy and pulmonary diseases.

Classification of remnant stomach shape after distal gastrectomy with Billroth-I reconstruction and a comparison of the postoperative outcomes

PurposeTo classify the shape of the remnant stomach after Billroth-I (B-I) reconstruction and evaluate the relationship between the shape of the remnant stomach and the postoperative clinical outcomes.MethodsOne hundred and ninety-five consecutive patients with gastric cancer underwent distal gastrectomy with B-I reconstruction between May 2006 and October 2014. We retrospectively reviewed their medical records and radiological findings. Finally, the shapes of the remnant stomach of 150 patients were classified as either straight type (type A) or stagnant type (type B). The clinical outcomes were compared with respect to the types of remnant stomach.ResultsThe incidence of anastomotic leakage was significantly higher in the type A group than in the type B group (9.4 vs. 1.5%, p = 0.044). The body weight change ratio after surgery was significantly lower in the type B group than in the type A group [p = 0.0068, two-way repeated measures analysis of variance (ANOVA)], while the serum albumin levels showed marginally significant improvement in the type B group compared with the type A group (p = 0.0542, two-way repeated measures ANOVA).ConclusionThe shape of the remnant stomach after distal gastrectomy with B-I reconstruction might influence the degree of anastomotic leakage and long-term nutritional status.

Fibrosis in metastatic lymph nodes is clinically correlated to poor prognosis in colorectal cancer

Background Tumor microenvironment including fibrosis has a pivotal role in cancer growth and distant metastasis. Fibrosis is a known risk factor for carcinogenesis, but its biological role in disease invasion and metastasis in colorectal cancer (CRC) remains unclear. In particular, there is no report on how fibrosis of metastatic lymph nodes (MLNs) in CRC contributes to prognosis. Methods We reviewed 94 colorectal adenocarcinoma patients with MLNs who underwent colectomy. Both the primary tumors and MLNs were analyzed for alpha-smooth muscle actin (α-SMA) expression and collagen deposition. Results Higher α-SMA expression and collagen deposition in MLNs were associated with significantly shorter relapse-free survival and overall survival in CRC patients. α-SMA expression in MLNs (HR, 1.53; p = 0.034) was independent predictive factor of overall survival in multivariate Cox proportional hazards regression analysis of clinicopathological factors. In the Stage III patient subgroup, α-SMA expression in MLNs was a strong prognostic marker (HR, 3.01; p = 0.006). On the other hand, higher α-SMA expression and collagen deposition in primary tumors were associated with short overall survival, but they were not significant factors in multivariate Cox regression analyses. In MLNs, the podoplanin signals co-localized with α-SMA expression and were confirmed by the dual immunofluorescence staining, implying that the MLN stromal cells were fibroblastic reticular cells. Conclusion Both high collagen deposition and high α-SMA expression in MLNs predicted poor prognosis in CRC.

5-fluorouracil combined with cisplatin and mitomycin C as an optimized regimen for hyperthermic intraperitoneal chemotherapy in gastric cancer

Optimized drug regimens for hyperthermic intraperitoneal chemotherapy (HIPEC) have not been standardized completely in patients with advanced gastric cancer (GC). We evaluated an optimized anti‐tumor protocol comprising 5‐fluorouracil (5‐FU) combined with cisplatin (CDDP) and mitomycin C (MMC) in vitro for clinical use of HIPEC.

In vivo antitumor function of tumor antigen-specific CTLs generated in the presence of OX40 co-stimulation in vitro : CTLs generated in the presence of OX40

Adoptive cell transfer (ACT) is an emerging and promising cancer immunotherapy that has been improved through various approaches. Here, we described the distinctive characteristics and functions of tumor Ag‐specific effector CD8+ T‐cells, co‐cultured with a tumor‐specific peptide and a stimulatory anti‐OX40 antibody, before being used for ACT therapy in tumor‐bearing mouse recipients. Splenic T‐cells were obtained from wild‐type FVB/N mice that had been injected with a HER2/neu (neu)‐expressing tumor and a neu‐vaccine. The cells were then incubated for 7 days in vitro with a major histocompatibility complex (MHC) class I peptide derived from neu, in the presence or absence of an agonistic anti‐OX40 monoclonal antibody, before CD8+ T cells were isolated for use in ACT therapy. The proliferative ability of OX40‐driven tumor Ag‐specific effector CD8+ T‐cells in vitro was less than that of non‐OX40‐driven tumor Ag‐specific effector CD8+ T‐cells, but they expressed significantly more early T‐cell differentiation markers, such as CD27, CD62L and CCR7, and significantly higher levels of Bcl‐2, an anti‐apoptotic protein. These OX40‐driven tumor Ag‐specific effector CD8+ T‐cells, when transferred into tumor‐bearing recipients, demonstrated potent proliferation capability and successfully eradicated the established tumor. In addition, these cells exhibited long‐term antitumor function, and appeared to be established as memory T‐cells. Our findings suggest a possible in vitro approach for improving the efficacy of ACT, which is simple, requires only a small amount of modulator, and can potentially avoid several toxicities associated with co‐stimulation in vivo.

A pilot study: The association between physical activity level using by accelerometer and postoperative complications after hepatic resection

Recently, accelerometers measuring physical activity level have been available to the public. In the present study, it was examined whether the accelerometer could evaluate postoperative outcomes for 12 patients subjected to hepatic resection from August-November 2016. The association was evaluated between the changing pattern of activity level until the postoperative day (POD) 7 and the occurrence of postoperative complications. The median age of patients was 79 years (range, 58-85). Postoperative complications were identified in 6 patients. The activity level in patients with complications was low from POD 1 and was significantly lower than patients without complications following POD 6. The changing pattern of activity level with all included patients could be divided into the following 3 types: Increase type, bell curve type and flat type. Patients without complications exhibited an accelerated increase of postoperative activity level, categorized as increase type. Bell curve type and flat type demonstrated delay of recovery in postoperative activity levels, and were suggested to be associated with the occurrence of postoperative complications. These findings may provide rationale for larger sample studies to evaluate whether physical activity level measured via accelerometer may be a surrogate marker for postoperative complications.

Severe mental retardation patient with a de novo chromosomal deletion 5q14-22 can be a carrier of a rectal and duodenal cancer associated with over 200 colorectal polyps: A case report

Introduction: Familial adenomatous polyposis (FAP) caused by a de novo 5q chromosomal deletion is rare, and precise cytogenetic analysis utilizing comparative genomic hybridization (CGH) arrays have been performed in few cases. Case presentation: We herein present the case of a 38-year-old man with advanced rectal and duodenal cancer, FAP, and severe mental retardation caused by a de novo chromosomal deletion at 5q14-22. He was referred to our outpatient clinic because of a positive fecal occult blood test result. He was found to have advanced rectal cancer, with over 200 colorectal polyps, and duodenal cancer. He underwent laparoscopic total proctocolectomy with definitive ileostomy followed by partial resection of the duodenum. Comparative genomic hybridization to characterize deleted genes identified a large 5q deletion expanding approximately 24.9 Mbp, including the APC gene. Conclusion: Patients who harbor a chromosomal deletion involving 5q21 are at risk of developing rectal cancer and polyposis. Th...

History and current status of polymyxin B-immobilized fiber column for treatment of severe sepsis and septic shock

Toraymyxin® (Toray Medical Co., Ltd, Tokyo, Japan) has been developed as a direct hemoperfusion column that contains polymyxin B‐immobilized fiber to bind endotoxins in patients’ blood. Toraymyxin was approved by the Japanese National Health Insurance system for the treatment of endotoxemia and septic shock in 1994. Since then, PMX (defined as direct hemoperfusion with Toraymyxin) has been safely used in more than 100 000 cases in emergency and intensive care units in Japan. Toraymyxin is currently available for use in clinical settings in 12 countries outside of Japan. We reviewed and analyzed the development, clinical use, and efficacy of Toraymyxin, and assessed the current status of Toraymyxin use for the treatment of severe sepsis and septic shock. Our review shows that PMX appeared to be effective in improving hemodynamics and respiratory function in septic shock requiring emergency abdominal surgery. Recent large‐scale ranomized controlled trialscould not demonstrate whether prognosis is improved by PMX. However, the latest meta‐analysis revealed that PMX significantly decreased mortality in patients with severe sepsis and septic shock. Combination of PMX with continuous hemodiafiltration and longer duration of PMX might be an effective strategy to improve survival in such patients.