Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy.

Oxaliplatin is widely used as a key drug in the treatment of colorectal cancer. However, its administration is associated with the dose-limiting adverse effect, peripheral neuropathy. Platinum accumulation in the dorsal root ganglion (DRG) is the major mechanism responsible for oxaliplatin-induced neuropathy. Some drug transporters have been identified as platinum complex transporters in kidney or tumor cells, but not yet in DRG. In the present study, we investigated oxaliplatin transporters and their contribution to peripheral neuropathy. We identified 12 platinum transporters expressed in DRG with real-time PCR, and their transiently overexpressing cells were established. After exposure to oxaliplatin, the accumulation of platinum in these overexpressing cells was evaluated using a coupled plasma mass spectrometer. Octn1/2- and Mate1-expressing cells showed the intracellular accumulation of oxaliplatin. In an animal study, peripheral neuropathy developed after the administration of oxaliplatin (4 mg/kg, intravenously, twice a week) to siRNA-injected rats (0.5 nmol, intrathecally, once a week) was demonstrated with the von Frey test. The knockdown of Octn1 in DRG ameliorated peripheral neuropathy, and decreased platinum accumulation in DRG, whereas the knockdown of Octn2 did not. Mate1 siRNA-injected rats developed more severe neuropathy than control rats. These results indicate that Octn1 and Mate1 are involved in platinum accumulation at DRG and oxaliplatin-induced peripheral neuropathy.

Ulcerative Colitis-associated Spondyloarthritis Successfully Treated with Infliximab in the Absence of Enhanced TNF-α Responses.

Although concurrent occurrence of spondyloarthritis (SpA) and ulcerative colitis (UC) is sometimes seen, the profiles of cytokines have been poorly understood in UC-associated SpA. We herein report a case of UC-associated SpA successfully treated with infliximab (IFX). Profiles of cytokines in the serum and colonic mucosa were characterized by an enhanced expression of IL-6 but not tumor necrosis factor (TNF)-α. Successful induction of remission by IFX was associated with the downregulation of IL-6 expression but no significant alteration in TNF-α expression. These findings suggest that some cases of UC-associated SpA might be driven by IL-6, and IFX might be effective in cases lacking enhanced TNF-α responses.

Laparoscopic distal gastrectomy for advanced gastric cancer with situs inversus totalis: a case report.

BACKGROUND: Situs inversus totalis (SIT) is a relatively rare condition, in which the thoracic and abdominal organs are reversed or mirrored from their normal positions. Here, we reported a case of a patient with SIT and advanced gastric cancer with lymph node metastasis who underwent laparoscopic distal gastrectomy (LDG). CASE PRESENTATION: A 67-year-old man with SIT was clinically diagnosed with T3N2M0 advanced gastric cancer located in the middle gastric body. Three-dimensional reconstruction of computed tomography angiogram revealed that the common hepatic artery originated from the superior mesenteric artery. The patient underwent LDG with D2 lymph node dissection and Roux-en-Y reconstruction. The postoperative course was uneventful. CONCLUSION: This case report showed that LDG could be safely performed on a patient even under complex conditions, such as advanced gastric cancer with lymph node metastasis with SIT and vascular anomalies.

Laparoscopic Left Hepatectomy for Ruptured Hepatocellular Carcinoma Controlled After Transcatheter Arterial Embolization: Case Report and Review of the Literature.

BACKGROUND: Although spontaneous tumour rupture is a life-threatening complication of hepatocellular carcinoma (HCC), staged hepatectomy for HCC controlled after transcatheter arterial embolization (TAE) could provide a better prognosis. Laparoscopic liver resection (LLR) has been accepted worldwide and has been expanded from minor resection to anatomical major resection. We herein report the first case of pure laparoscopic left hepatectomy for ruptured HCC controlled after TAE. CASE REPORT: A 66-year-old man was transferred to our Institute because of abdominal pain and decreased consciousness. Ruptured HCC in segment IV and massive intra-abdominal haemorrhage were diagnosed. Emergency TAE was performed, achieving haemostasis. Reduction of intra-abdominal haemorrhage was confirmed at the 3-month follow-up, and no intrahepatic metastasis or peritoneal dissemination was present. Therefore, we performed elective laparoscopic left hepatectomy for the remaining HCC 110 days after TAE. Although dense adhesion was found in the upper right peritoneal cavity and greater omentum enveloping the remaining haemorrhage on the underside of the liver, there was no disseminated involvement in the peritoneal cavity. The operative time was 194 minutes, and intraoperative blood loss was 100 g. The postoperative course was uneventful, and the patient was discharged on postoperative day 6. CONCLUSION: Major LLR may be an option for staged hepatectomy in patients with ruptured HCC controlled after TAE.

Exenatide Facilitates Recovery from Oxaliplatin-Induced Peripheral Neuropathy in Rats.

BACKGROUND: Oxaliplatin has widely been used as a key drug in the treatment of colorectal cancer; however, it causes peripheral neuropathy. Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, is an incretin mimetic secreted from ileal L cells, which is clinically used to treat type 2 diabetes mellitus. GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems. In this study, we investigated the effects of exenatide on oxaliplatin-induced neuropathy in rats and cultured cells. METHODS: Oxaliplatin (4 mg/kg) was administered intravenously twice per week for 4 weeks, and mechanical allodynia was evaluated using the von Frey test in rats. Axonal degeneration was assessed by toluidine blue staining of sciatic nerves. RESULTS: Repeated administration of oxaliplatin caused mechanical allodynia from day 14 to 49. Although the co-administration of extended-release exenatide (100 µg/kg) could not inhibit the incidence of oxaliplatin-induced mechanical allodynia, it facilitated recovery from the oxaliplatin-induced neuropathy with reparation of axonal degeneration. Inhibition of neurite outgrowth was evaluated in cultured pheochromocytoma 12 (PC12) cells. Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells. Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice. CONCLUSION: These results suggest that exenatide may be useful for treating peripheral neuropathy induced by oxaliplatin in colorectal cancer patients with type 2 diabetes.

Oxaliplatin induces hypomyelination and reduced neuregulin 1 expression in the rat sciatic nerve.

Oxaliplatin causes severe peripheral neuropathy. In this study, we examined hypomyelination in the peripheral nerve in oxaliplatin-induced neuropathy rat model. Gene expression of neuregulin 1 (NRG1), a myelination regulatory factor, is reduced in the dorsal root ganglion (DRG) in DNA microarray analysis. Oxaliplatin increased the g-ratio and reduced levels of myelin protein zero in sciatic nerve, suggesting the hypomyelination. Moreover, oxaliplatin reduced NRG1 mRNA levels in the DRG and decreased levels of cleaved NRG1 type III protein in the sciatic nerve. Our results indicate that oxaliplatin induces hypomyelination and reduced NRG1 expression.