Impact of Prevascularization on Immunological Environment and Early Engraftment in Subcutaneous Islet Transplantation.

BACKGROUND: The utilization of islet-like cells derived from pluripotent stem cells may resolve the scarcity of islet transplantation donors. The subcutaneous space is a promising transplantation site because of its capacity for graft observation and removal, thereby ensuring safety. To guarantee subcutaneous islet transplantation, physicians should ensure ample blood supply. Numerous methodologies, including prevascularization, have been investigated to augment blood flow, but the optimal approach remains undetermined. METHODS: From C57BL/6 mice, 500 syngeneic islets were transplanted into the prevascularized subcutaneous site of recipient mice by implanting agarose rods with basic fibroblast growth factor at 1 and 2 wk. Before transplantation, the blood glucose levels, cell infiltration, and cytokine levels at the transplant site were evaluated. Furthermore, we examined the impact of the extracellular matrix capsule on graft function and the inflammatory response. RESULTS: Compared with the 1-wk group, the 2-wk group exhibited improved glycemic control, indicating that longer prevascularization enhanced transplant success. Flow cytometry analysis detected immune cells, such as neutrophils and macrophages, in the extracellular matrix capsules, whereas cytometric bead array analysis indicated the release of inflammatory and proinflammatory cytokines. Treatment with antitumor necrosis factor and anti-interleukin-6R antibodies in the 1-wk group improved graft survival, similar to the 2-wk group. CONCLUSIONS: In early prevascularization before subcutaneous transplantation, neutrophil and macrophage accumulation prevented early engraftment owing to inflammatory cytokine production.

Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes.

Second-generation antipsychotics are widely used to medicate patients with schizophrenia, but may cause metabolic side effects such as diabetes, which has been considered to result from obesity-associated insulin resistance. Olanzapine is particularly well known for this effect. However, clinical studies have suggested that olanzapine-induced hyperglycemia in certain patients cannot be explained by such a generalized mechanism. Here, we focused on the effects of olanzapine on insulin biosynthesis and secretion by mouse insulinoma MIN6 cells. Olanzapine reduced maturation of proinsulin, and thereby inhibited secretion of insulin; and specifically shifted the primary localization of proinsulin from insulin granules to the endoplasmic reticulum. This was due to olanzapine's impairment of proper disulfide bond formation in proinsulin, although direct targets of olanzapine remain undetermined. Olanzapine-induced proinsulin misfolding and subsequent decrease also occurred at the mouse level. This mechanism of olanzapine-induced ß-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine.

The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation.

BACKGROUND: Potential adverse effects, such as functional impairment of islets, render conventional immunosuppressive drugs unsuitable for use in islet transplantation. In addition, as a single therapy, they cannot prolong islet allograft survival. Here, we investigated the utility of the mitogen-activated protein kinase inhibitor trametinib and asked whether it ameliorates acute rejection of transplanted islets without the need for conventional immunosuppressants. METHODS: Islets from fully major histocompatibility complex-mismatched BALB/c mice were transplanted into streptozotocin-induced diabetic C57BL/6 mice via the portal vein. These mice received trametinib or vehicle (orally) for 28 days. Isolated islets from BALB/c mice were incubated in vitro with different concentrations of trametinib to determine viability and function. RESULTS: Trametinib (0.1 and 0.3 mg/kg) prolonged graft survival significantly (P = 0.0007 and P = 0.005, respectively) when compared with vehicle. Histologic analyses revealed that cellular infiltration of the graft by lymphocytes was inhibited significantly on day 7 (P < 0.05). In addition, trametinib suppressed functional differentiation of naive CD4+ T cells in recipients. Expression of mRNA encoding inflammatory cytokines interleukin (IL)-2, tumor necrosis factor α, and interferon γ in recipients treated with trametinib was also inhibited (P < 0.001, P < 0.05, and P < 0.01, respectively). Trametinib also increased production of IL-4 and IL-10 (P < 0.05 and P = 0.20, respectively). In vitro, islets incubated with different concentrations of trametinib exhibited no harmful effects with respect to viability and function. CONCLUSIONS: Trametinib delayed islet graft rejection by inhibiting functional differentiation of naive CD4+ T cells and regulating inflammatory cytokines. Trametinib might be a promising candidate for maintenance immunosuppressive therapy after allogeneic islet transplantation.

Mitomycin C treatment improves pancreatic islet graft longevity in intraportal islet transplantation by suppressing proinflammatory response.

The in vitro culture period prior to cell transplantation (i.e. pancreatic islet transplantation) enables cell modification and is thus advantageous. However, the islet preconditioning method has not been fully explored. Here we present a simple approach for islet preconditioning that uses the antibiotic mitomycin C (MMC), which has antitumor activity, to reduce islet immunogenicity and prevent proinflammatory events in an intraportal islet transplantation model. Freshly isolated mice islets were treated for 30 min with 10 µg/mL MMC or not, cultured for 20 h and transplanted into the livers of syngeneic or allogeneic diabetic mouse recipients. In the allogeneic model, MMC preconditioning significantly prolonged graft survival without requiring immunosuppressants. In vitro, MMC treatment suppressed the expression of proinflammatory cytokines in islet allografts, while immunohistochemical studies revealed the suppression of inflammatory cell infiltration into MMC-treated allografts relative to untreated allografts. Furthermore, MMC preconditioning significantly suppressed the mRNA expression of proinflammatory cytokines into the transplant site and induced the differentiation of regulatory T cells with the ability to suppress CD4+ T cell-mediated immune responses. In conclusion, islet preconditioning with MMC prolonged graft survival in an intraportal islet transplantation model by suppressing proinflammatory events and inducing potentially regulatory lymphocytes.

Successful laparoscopic distal pancreatectomy for a large solid pseudopapillary neoplasm: A case report.

A 30-year-old Japanese woman presented at our hospital with a pancreatic tumor. Contrast-enhanced CT revealed a tumor with a 12-cm diameter in the pancreatic body and tail. In the preoperative setting, endoscopic ultrasound-guided fine-needle aspiration permitted a histopathological diagnosis of solid pseudopapillary neoplasm. Twhe patient underwent laparoscopic distal pancreatectomy with splenectomy. Our procedure involved three steps. Firstly, the splenic artery was occluded to block inflow of blood to the tumor. Then, we transected the neck of the pancreas using radical antegrade modular pancreatosplenectomy. Finally, hand-assisted laparoscopic surgery allowed us to secure the operating field and easily handle the large tumor. This enabled us to accomplish laparoscopic distal pancreatectomy, and en-bloc resection was completed. The patient was discharged without major complications. Laparoscopic distal pancreatectomy for huge solid pancreatic tumors can be completed safely.

Effect of antiplatelet therapy on patients undergoing gastroenterological surgery: thromboembolic risks versus bleeding risks during its perioperative withdrawal.

BACKGROUND: Antiplatelet agents given to prevent thromboembolic disease are frequently withdrawn prior to surgical procedures to reduce bleeding complications. This action may expose patients to increased thromboembolic morbidity and mortality. METHODS: A series of 2012 patients who had undergone gastroenterologic surgery between January 2005 and June 2010 at our institution were reviewed. Among this cohort, antiplatelet therapy (APT) was used in 519 patients (25.8 %). The perioperative management included interruption of APT 1 week before surgery and early postoperative reinstitution in patients at low thromboembolic risk, although APT was maintained until surgery in those at high thromboembolic risk. Bleeding and thromboembolic complications, as well as other outcome variables, were assessed in patients with and without APT. RESULTS: Among 519 patients with APT, 99 (19.1 %) underwent multidrug APT. Among them, 124 (23.9 %) required preoperative continuation of APT. None suffered from excessive bleeding intraoperatively. There were 19 thromboembolic events (0.9 %) in the whole cohort. Postoperative bleeding complications occurred in 37 patients (1.8 %). Multivariate analysis showed that increased postoperative bleeding complications were independently associated with multidrug APT [hazard ratio (HR) 4.3, p = 0.014], high-risk surgical procedures (HR 3.5, p = 0.003), and perioperative heparin bridging (HR 2.8, p = 0.029). High-risk surgery (HR 8.3, p < 0.001) and poor performance status (HR 4.9, p = 0.005)--but neither APT nor anticoagulation use--were significant prognostic factors for thromboembolic complications. CONCLUSIONS: Satisfactory outcomes were obtained during gastroenterologic surgery under rigorous perioperative management, including single-agent APT continuation in patients at high thromboembolic risk. Patients treated with multidrug APT still represent a challenging group, however, and need to be carefully managed to prevent perioperative complications.

[A case of adenocarcinoma occurring in the bladder mucosa after a surgical operation for colovesical fistula].

We report a case of adenocarcinoma occurring in the bladder mucosa 6 years after a surgical operation for colovesical fistula due to colonic diverticulitis of the sigmoid colon. The patient was a 76-year-old woman who had undergone a sigmoidectomy and ligation of the colovesical fistula at the age of 70 years. She presented with a complaint of gross hematuria. Cystoscopy and computed tomography revealed bladder cancer at the site of the original colovesical fistula surgery. She underwent transurethral resection of the bladder tumor. Histopathological findings revealed intestinal adenocarcinoma in the urinary bladder. A radical partial cystectomy was subsequently performed because of a positive and involved margin. This tumor may have originated from the bladder mucosa and then replaced by intestinal metaplastic cells that originated from the same initiating event.

Does antiplatelet therapy affect outcomes of patients receiving abdominal laparoscopic surgery? Lessons from more than 1,000 laparoscopic operations in a single tertiary referral hospital.

BACKGROUND: The effect of antiplatelet therapy (APT) on surgical blood loss and perioperative complications in patients receiving abdominal laparoscopic surgery still remains unclear. STUDY DESIGN: A total of 1,075 consecutive patients undergoing abdominal laparoscopic surgery between 2005 and 2011 were reviewed. Our perioperative management protocol consisted of interruption of APT 1 week before surgery and early postoperative reinstitution in low thromboembolic risk patients (n = 160, iAPT group). Preoperative APT was maintained in patients with high thromboembolic risk or emergent situation (n = 52, cAPT group). Perioperative and outcomes variables of cAPT and iAPT groups, including bleeding and thromboembolic complications, were compared with those of patients without APT (non-APT group, n = 863). RESULTS: In this cohort, 715 basic and 360 advanced laparoscopic operations were included. No patient suffering excessive intraoperative bleeding due to continuation of APT was observed. There were 10 postoperative bleeding complications (0.9%) and 3 thromboembolic events (0.3%), but the surgery was free of both complications in the cAPT group. No significant differences were found between the groups in operative blood loss, blood transfusion rate, and the occurrence of bleeding and thromboembolic complications. Multivariable analyses showed that multiple antiplatelet agents (p = 0.015) and intraoperative blood transfusion (p = 0.046) were significant prognostic factors for postoperative bleeding complications. Increased thromboembolic complications were independently associated with high New York Heart Association class (p = 0.019) and history of cerebral infarction (p = 0.048), but not associated with APT use. CONCLUSIONS: Abdominal laparoscopic operations were successfully performed without any increase in severe complications in patients with APT compared with the non-APT group under our rigorous perioperative assessment and management. Maintenance of single APT should be considered in patients with high thromboembolic risk, even when an abdominal laparoscopic approach is considered.

Intractable intraoperative bleeding requiring platelet transfusion during emergent cholecystectomy in a patient with dual antiplatelet therapy after drug-eluting coronary stent implantation (with video).

We report a case of a 76-year-old man, receiving dual antiplatelet therapy (DAPT) with aspirin and ticlopidine for the past 6 years after implantation of drug-eluting coronary stent, developed a severe hypochondriac pain. After diagnosing severe acute cholecystitis by an enhanced CT, emergent laparotomy under continuation of DAPT was attempted. During the operation, intractable bleeding from the adhesiolysed liver surface was encountered, which required platelet transfusion. Subtotal cholecystectomy with abdominal drainage was performed, and the patient recovered without any postoperative bleeding or thromboembolic complications. Like the present case, the final decision should be made to perform platelet transfusion when life-threatening DAPT-induced intraoperative bleeding occurs during an emergent surgery, despite the elevated risk of stent thrombosis.

[A case of unresectable hilar cholangiocarcinoma successfully treated by gemcitabine and S-1 combination chemotherapy].

A 52-year-old male was presented with obstructive jaundice and liver dysfunction. He was diagnosed as hilar cholangiocarcinoma involving the confluence of the right and left hepatic duct and bifurcation of the main portal vein trunk. Swollen lymph nodes in the hepatoduodenal ligament were also detected. ERBD tubes were placed in each B2, 3, and 5 branch. GEM and S-1 combination chemotherapy was carried out for four months. As a reduction in the primary tumor and lymph nodes was observed on CT scan surgical exploration was conducted, and an extended left hepatectomy with partial resection of the portal vein and regional lymph node dissection was achieved. The postoperative course was uneventful, and the patient remained free of recurrence, 34 months after the original diagnosis was made, and 29 months after surgical resection. Thus, GEM and S-1 combination chemotherapy is one of the options for the management of advanced hilar cholangiocarcinoma.

[A long survival of a patient with poor performance status who suffered from advanced right breast cancer with multiple lung metastases controlled by trastuzumab as a key drug].

We report a case of a 60-year-old woman with poor performance status (PS). She suffered from advanced right breast cancer with multiple lung metastases, which was controlled by chemotherapy with trastuzumab as the key drug. The patient presented with a 4 cm-sized large right breast mass. Her PS was poor due to progressive spinocerebellar degeneration. The biopsy specimen of the breast mass showed scirrhous type of the invasive ductal carcinoma (ER+, HER2 2+). Multiple lung metastases were also detected by computed tomography. Considering her poor PS, the patient was treated with mild systemic therapy using trastuzumab as the key drug. A different drug response was achieved between the breast mass and lung metastatic lesions, and the tumors were maintained as stable disease (SD) during first 18 months. However, she finally passed away due to respiratory failure resulting from lung metastasis, 33 months after starting treatment. The autopsy findings showed a difference of HER2 expression between the breast tumor and lung metastatic lesions. It must be recognized that differences of HER2 expression between the primary tumor and metastatic lesions are sometimes demonstrated in patients with breast cancer, and that trastuzumab can be used as a key drug in some patients as in the current case.

Undifferentiated carcinoma of the common bile duct with intraductal tumor thrombi: report of a case.

We report a case of undifferentiated carcinoma of the common bile duct with intraductal tumor thrombi. A 73-year-old man presented with general malaise. Abdominal computed tomography and magnetic resonance imaging revealed a mass in the distal common bile duct, accompanied by dilatation of the intra- and extrahepatic bile ducts. The patient underwent pancreaticoduodenectomy with regional lymphadenectomy. Gross examination revealed that the distal common bile duct was obstructed by an elastic hard mass, 3.2 × 2.6 cm, accompanied by intraductal tumor thrombi. Microscopically, the nodule was well defined and composed of atypical large tumor cells with bizarre nuclei and little cytoplasm. Immunohistochemically, the tumor cells were diffusely positive for cytokeratin-7 and CAM5.2, but negative for CD56, chromogranin A, and synaptophysin. Thus, a histological diagnosis of undifferentiated carcinoma of the common bile duct was made. The patient recovered uneventfully and has remained free of any signs of recurrence for 18 months since the operation. Undifferentiated carcinomas of the extrahepatic bile duct can be detected early, with the chance of a good prognosis; however, because their biologic growth behavior is still considered aggressive, careful observation after surgery and the initiation of multidisciplinary treatment against recurrence are necessary.