Takashi Kobayashi

Outcome after pancreatectomy and islet autotransplantation in a pediatric population.

Objectives: Little is known regarding outcomes after pancreatectomy and islet autotransplantation for chronic pancreatitis in pediatric patients. In this study, we document pain control and metabolic course after this procedure in a pediatric population. Materials and Methods: We reviewed medical records for 24 patients 18 years old or younger who underwent pancreatectomy with islet autotransplantation at the University of Minnesota from July 1989 through June 2006. Patients and/or their parents were invited to participate in a follow-up telephone survey. Primary outcome measures were narcotics and insulin use at follow-up. We compared outcomes in patients undergoing surgery as preadolescents (<13 years old) versus adolescents. Results: Follow-up information was available on 18 of 24 patients. All of the patients required narcotics before surgery. Of the 18, only 7 (39%) were still taking narcotics at the time of the survey. At 1 year posttransplant, 78% of patients had islet graft function with full function (insulin independent) in 56% and partial function (once-daily insulin use only) in 22%. By Cox regression analysis, important predictors of insulin independence were islet yield >2000 islet equivalents per kilogram and lack of prior pancreatic surgery (P = 0.011). Preadolescents were less likely to require chronic narcotic therapy at follow-up (P = 0.05) and were more likely to maintain graft function (P = 0.02) compared with adolescents. Conclusions: Pancreatectomy can relieve pain in pediatric patients with chronic pancreatitis and the majority can withdraw from narcotics. Islet autotransplantation can prevent or reduce the severity of diabetes in about three fourths of patients. Outcome goals were reached in a higher proportion of younger than older children.

Stereotactic ablative body radiotherapy for previously untreated solitary hepatocellular carcinoma

Stereotactic ablative body radiotherapy (SABR) is a relatively new treatment for hepatocellular carcinoma (HCC). The outcomes of SABR for previously untreated solitary HCC unfit for ablation and surgical resection were evaluated.

Correlation of pancreatic histopathologic findings and islet yield in children with chronic pancreatitis undergoing total pancreatectomy and islet autotransplantation

Objectives: The probability of insulin independence after intraportal islet autotransplantation (IAT) for chronic pancreatitis (CP) treated by total pancreatectomy (TP) relates to the number of islets isolated from the excised pancreas. Our goal was to correlate the islet yield with the histopathologic findings and the clinical parameters in pediatric (age, <19 years) CP patients undergoing TP-IAT. Methods: Eighteen pediatric CP patients aged 5 to 18 years (median, 15.6 years) who underwent TP-IAT were studied. Demographics and clinical history came from medical records. Histopathologic specimens from the pancreas were evaluated for presence and severity of fibrosis, acinar cell atrophy, inflammation, and nesidioblastosis by a surgical pathologist blinded to clinical information. Results: Fibrosis and acinar atrophy negatively correlated with islet yield (P = 0.02, r = −0.50), particularly in hereditary CP (P = 0.01). Previous duct drainage surgeries also had a strong negative correlation (P = 0.01). Islet yield was better in younger (preteen) children (P = 0.02, r = −0.61) and in those with pancreatitis of shorter duration (P = 0.04, r = −0.39). Conclusions: For preserving beta cell mass, it is best to perform TP-IAT early in the course of CP in children, and prior drainage procedures should be avoided to maximize the number of islets available, especially in hereditary disease.

Correlation of histopathology, islet yield, and islet graft function after islet autotransplantation in chronic pancreatitis.

Objective: The number of islets available (yield) is an important predictor of insulin independence after islet autotransplantation (IAT) done at the time of total pancreatectomy to treat painful chronic pancreatitis. The aim of this study was to correlate histopathologic findings with islet yield and graft function. Methods: Pancreatic histopathology was examined in 105 adults who underwent pancreatectomy and IAT; postoperative insulin use was known in 53 cases. Histologic degree of fibrosis, acinar atrophy, inflammation, and nesidioblastosis were scored by a surgical pathologist. The correlation of histopathology with islet yield and graft function was evaluated. Results: Patients received a median of 2968 islet equivalents per kilogram. Fibrosis and acinar atrophy correlated negatively with islet yield (P < 0.001, r = −0.67), as did inflammation (P < 0.001, r = −0.43). There was a positive correlation of islet yield (P < 0.0001, r = 0.64) and a negative correlation of fibrosis (P = 0.006, r = −0.43) and acinar atrophy (P = 0.006, r = −0.42) with islet graft function. Conclusion: More severe histopathologic changes were associated with a lower islet yield and lower likelihood of insulin independence. Total pancreatectomy and IAT should not be delayed in patients with painful chronic pancreatitis refractory to medical therapy; otherwise progressive damage to the pancreas may limit islet yield and increase the risk of diabetes.Abbreviations: IAT - islet autotransplantation, CP - chronic pancreatitis

Sphingosine-1-Phosphate Transporters as Targets for Cancer Therapy

Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, the recruitment of immune cells, angiogenesis, and lymphangiogenesis, all of which are involved in cancer progression. S1P is generated inside cancer cells by sphingosine kinases then exported outside of the cell into the tumor microenvironment where it binds to any of five G protein coupled receptors and proceeds to regulate a variety of functions. We have recently reported on the mechanisms underlying the “inside-out” signaling of S1P, its export through the plasma membrane, and its interaction with cell surface receptors. Membrane lipids, including S1P, do not spontaneously exchange through lipid bilayers since the polar head groups do not readily go through the hydrophobic interior of the plasma membrane. Instead, specific transporter proteins exist on the membrane to exchange these lipids. This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporters in cancer and in the tumor microenvironment. Based on our research and the emerging understanding of the role of S1P signaling in cancer and in the tumor microenvironment, S1P transporters and S1P signaling hold promise as new therapeutic targets for cancer drug development.

Genomic landscape of colorectal cancer in Japan: Clinical implications of comprehensive genomic sequencing for precision medicine

BackgroundComprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).MethodsUsing next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.ResultsThe 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.ConclusionsUse of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.

DNA damage response and sphingolipid signaling in liver diseases

Patients with unresectable hepatocellular carcinoma (HCC) cannot generally be cured by systemic chemotherapy or radiotherapy due to their poor response to conventional therapeutic agents. The development of novel and efficient targeted therapies to increase their treatment options depends on the elucidation of the molecular mechanisms that underlie the pathogenesis of HCC. The DNA damage response (DDR) is a network of cell-signaling events that are triggered by DNA damage. Its dysregulation is thought to be one of the key mechanisms underlying the generation of HCC. Sphingosine-1-phosphate (S1P), a lipid mediator, has emerged as an important signaling molecule that has been found to be involved in many cellular functions. In the liver, the alteration of S1P signaling potentially affects the DDR pathways. In this review, we explore the role of the DDR in hepatocarcinogenesis of various etiologies, including hepatitis B and C infection and non-alcoholic steatohepatitis. Furthermore, we discuss the metabolism and functions of S1P that may affect the hepatic DDR. The elucidation of the pathogenic role of S1P may create new avenues of research into therapeutic strategies for patients with HCC.

Management of major portosystemic shunting in small-for-size adult living-related donor liver transplantation with a left-sided graft liver

PurposeWe investigated the mechanisms of small-for-size graft syndrome by time-lag ligation, a novel approach to treating major portosystemic shunts in small-for-size adult living-related donor liver transplantation (LRDLT) using left-sided graft liver.MethodsFive patients with end-stage liver failure and major splenorenal shunting underwent LRDLT using left lobe grafts. The average graft volume to recipient body weight (GV/RBW) ratio was 0.68 ± 0.14. Two patients underwent time-lag ligation of their splenorenal (SR) shunts on postoperative days (PODs) 8 and 14, respectively. The shunts of the other three patients were untreated.ResultsThe portal pressures in the first patient who underwent time-lag ligation rose above 300 mmH2O and remained there for 2 weeks. Thus, we ligated the SR shunt in the second patient on POD 14, resulting in an increase from 177 mmH2O to 258 mmH2O, but it decreased again thereafter. In the other three patients, the SR shunt was not ligated because portal blood flow volumes remained sufficient. Total bilirubin levels in the first time-lag ligation patient rose to 16 mg/dl, paralleling the rise in portal pressures. Although they increased after ligation in the second patient, they did not exceed 10 mg/dl.ConclusionsWe recommend time-lag ligation if portal venous blood flow decreases in the early post-transplant period, but not until at least 2 weeks after transplantation. If the portal venous blood flow does not decrease, early postoperative ligation is unnecessary. If there are no major portosystemic shunts, making a portosystemic shunt might decompress excessive portal hypertension. With donor safety priority in LRDLT, novel approaches must be developed to enable the use of smaller donor grafts. We describe a potential means of using left lobe grafts in adult LRDLT.

Is early enteral nutrition initiated within 24 hours better for the postoperative course in esophageal cancer surgery

Background Early enteral nutrition within 24 h after surgery has become a recommended procedure. In the present study, we retrospectively examined whether initiating EN within 24 h after esophagectomy improves the postoperative course. Methods Among 103 patients who underwent thoracic esophagectomy for esophageal cancer, we enrolled the cases in which EN was initiated within 72 h after surgery. The patients were divided into two groups: EN started within 24 h (Group D1) and EN started at 24 - 72 h (Group D2-3). Clinical factors including days for first fecal passage, dose of postoperative albumin infusion, difference in serum albumin between pre- and postoperation, incidence of postoperative infection, and use of total parenteral nutrition were compared. Statistical analyses were performed by the Mann-Whitney U test and Chi square test, with significance defined as P < 0.05. Results There was no significant difference between the groups in clinical factors. While pneumonia was significantly more frequent in Group D1 than in Group D2-3 (P = 0.0308), the frequency of infectious complications was comparable between the groups. Conclusion Initiating EN within 24 h showed no advantage for the postoperative course in esophageal cancer, and thus EN should be scheduled within 24 - 72 h, based on the patient condition.

Feasibility of Auxiliary Partial Living Donor Liver Transplantation for Fulminant Hepatic Failure as an Aid for Small-for-Size Graft : Single Center Experience

Auxiliary partial orthotopic liver transplantation (APOLT) or heterotopic auxiliary partial liver transplantation (HAPLT) was initially indicated for potentially reversible fulminant hepatic failure (FHF). We started auxiliary partial living donor liver transplantation (LDLT) for FHF in February 2002. Since then, 5 FHF patients (3 females and 2 males) underwent auxiliary partial LDLT: 3 cases of APOLT and 2 cases of HAPLT. All of them received a small-for-size graft: graft-to-recipient weight ratio (GRWR) < or = 1.0%. The etiologies of FHF were hepatitis B virus (HBV) in 1, Wilsons disease in 1, and unknown origin in 3 cases. Three were the acute type and 2 the subacute type of FHF. Median age was 45 years (range, 14-54 years). Blood type was identical in all cases. A left lobe graft was used in 4 instances and a right lobe graft in 1 case. Median GRWR was 0.74 (range, 0.42-0.85). Median follow-up was 42 months (range, 3 days to 70 months). Three of 5 patients (60%) were alive (at 42, 67, and 70 months) and 1 was free of immunosuppression after sufficient recovery of the native liver. Two cases succumbed: 1 at postoperative day 3 because of cytomegalovirus pneumonia and 1 at 10 months after APOLT because of sepsis. Complications were seen in all 5 patients: Relaparotomy for hemostasis in 3, decompression surgery of the abdominal cavity in 1, rehepaticojejunostomy in 1, and biliary strictures in 2 cases. Auxiliary partial LDLT may be a choice as an aid for a small-for-size graft in FHF.