Adult-Onset Focal Nesidioblastosis With Nodular Formation Mimicking Insulinoma.

Nesidioblastosis is defined as the neoformation of the islets of Langerhans from the pancreatic ductal epithelium and is recognized as the most common cause of hyperinsulinemic hypoglycemia in infants. We herein report an extremely rare case of adult-onset focal nesidioblastosis with the unusual feature of hyperplastic nodular formation. A 55-year-old woman was admitted to our hospital for a tumor detected in the body of the pancreas by magnetic resonance imaging screening. Laboratory examinations showed a high insulin level in the blood. Contrast-enhanced computed tomography and the selective arterial calcium injection test suggested the presence of multiple insulinomas in the body and tail of the pancreas, and, thus, the patient underwent distal pancreatectomy. A histopathological examination of the tumor in the body of the pancreas showed the nodular hyperplasia of islet-like cell clusters. In addition, many small intralobular ductules and islet cells appeared to be budding from the proliferating ductal epithelium, forming "ductuloinsular complexes". No other abnormal lesion was detected in the remainder of the pancreas. The histopathological diagnosis was focal nesidioblastosis. The patient has remained free of the recurrence of hypoglycemic episodes for more than 31 months. The present case of rare adult-onset focal nesidioblastosis with hyperplastic nodular formation was preoperatively identified as an apparent pancreatic tumor mimicking insulinoma. Nesidioblastosis and insulinoma need to be considered in cases of hyperinsulinemic hypoglycemia, even in adult patients.

[Gastrointestinal Stromal Tumor of the Small Intestine with Dissemination Successfully Treated with Surgical Resection and Adjuvant Chemotherapy with Sunitinib-A Case Report].

We report the case of a 73-year-old woman with repeated recurrent small intestinal gastrointestinal stromal tumor(GIST) who was referred to our hospital for best supportive care. She underwent surgical resection 4 times and developed recurrent tumors that were resistant to imatinib. She complained of right lower abdominal pain caused by the recurrent tumor. We performed surgical resection of the tumor and the disseminated tumors synchronously. Histopathological findings of the resected specimen revealed a high-risk GIST. After the operation, she was administered sunitinib(50mg/day)as adjuvant therapy according to a 4-week-on/2-week-off schedule. Due to the resulting adverse effects, the schedule was changed to 1-week-on/1-week-off therapy. She showed no sign of recurrence 38months after the last surgery. Thus, surgical resection and adjuvant molecular targeted therapy may be an effective treatment strategy for recurrent GIST.

Risk Factors for Unresectable Recurrence After Up-Front Surgery for Colorectal Liver Metastasis.

BACKGROUND: There is no clear evidence that preoperative chemotherapy for resectable colorectal liver metastasis (CRLM) is superior to up-front surgery (UFS). The aim of this study was to identify the risk factors associated with poor prognosis after UFS for CRLM. METHODS: Data about consecutive patients with CRLM who underwent liver resection at Nara Medical University Hospital between January 2000 and December 2015 were retrieved from a prospective database. Recurrence that developed within 2 years after liver resection and could not be surgically resected was defined as unresectable recurrence (UR). Preoperative risk factors associated with UR after UFS were analyzed. Among the patients with the identified risk factors, the patients who were treated with UFS were compared with those who received preoperative chemotherapy via propensity score-matching analysis. RESULTS: There were 167 patients treated with UFS, and 71 of them developed UR (the UR group). The overall survival (OS) rate of the UR group was significantly worse than that of the non-UR group (5-year survival rate: 3.8 vs. 66.8%, p < 0.001). Multivariate analysis identified a primary colorectal cancer N factor of N2-3 as a risk factor for UR (hazard ratio 2.72, p = 0.004). Propensity score-matching analysis demonstrated that among patients with N2-3 primary colorectal cancer the post-initial treatment OS of the patients treated with UFS was significantly worse than that of the patients who received preoperative chemotherapy (5-year survival rate: 11.1 vs. 30.0%, p = 0.046). CONCLUSIONS: Patients with CRLM with a primary colorectal cancer N factor of N2-3 should be considered for preoperative chemotherapy.

Does anatomic resection improve the postoperative outcomes of solitary hepatocellular carcinomas located on the liver surface?

BACKGROUND: It is unclear whether anatomic resection achieves better outcomes than nonanatomic resection in patients with hepatocellular carcinoma. This study aimed to compare the outcomes of anatomic resection and nonanatomic resection for hepatocellular carcinoma located on the liver surface via one-to-one propensity score-matching analysis. METHODS: Data from all consecutive patients who underwent liver resection for primary solitary hepatocellular carcinoma at Nara Medical University Hospital, Japan, January 2007- December 2015 were retrieved. Superficial hepatocellular carcinomas were defined as hepatocellular carcinoma that extended to a depth of < 3 cm from the liver surface and measured < 5 cm in diameter. The prognoses of the patients with superficial hepatocellular carcinoma who underwent anatomic resection and nonanatomic resection were compared. RESULTS: In this study 23 patients with superficial hepatocellular carcinoma underwent anatomic resection and 70 patients who underwent nonanatomic resection. The recurrence-free survival rate of the patients who underwent anatomic resection was better than that of the patients who underwent nonanatomic resection (P = .006), while no such difference was observed for nonsuperficial hepatocellular carcinoma. After the propensity score-matching procedure, the resected liver volume and operation time were the only background or clinical characteristics to exhibit significant differences between the anatomic resection (n = 20) and nonanatomic resection groups (n = 20). The recurrence-free survivial rate of the patients who underwent anatomic resection was significantly than that of the patients that underwent nonanatomic resections (P = .030), but overall survival did not differ significantly between the groups (P = .182). CONCLUSION: Anatomic resection decreases the risk of tumor recurrence and improves recurrence-free survival compared with nonanatomic resection in patients with superficial hepatocellular carcinoma.

Long-term observation and treatment of a widespread intraductal papillary neoplasm of the bile duct extending from the intrapancreatic bile duct to the bilateral intrahepatic bile duct: A case report.

INTRODUCTION: Few studies have reported the long-term outcomes of surgical resected intraductal papillary neoplasm of the bile duct (IPNB). Here, we describe the long-term observation and treatment of a case of widespread IPNB. PRESENTATION OF CASE: A 57-year-old male was referred to our hospital due to jaundice and dilation of the intrahepatic bile duct. Computed tomography showed dilation and irregularities of the right intrahepatic and extrahepatic bile ducts together with a 3cm nodule in the common hepatic duct. Peroral cholangioscopy revealed mucinous discharge from the ampulla of Vater, which resulted in a diagnosis of IPNB. A biopsy of the nodule and the bile duct revealed papillary adenoma in all of them. Right hepatectomy, caudate lobectomy, extrahepatic bile duct resection, and left hepaticojejunostomy were performed. The nodule was histologically diagnosed as papillary carcinoma in situ, and R0 resection was performed. However, mucus production from the papillary adenoma in the B3 and B4 was observed. We carefully managed the patient's biliary tract by inserting a biliary drainage tube into the segment 2, and he has survived for more than 7 years since the initial treatment. DISCUSSION: Mucus might be produced after the surgical resection of IPNB even if s surgical margin was benign. Five-year survival rate of benign IPNB was reported from 85% to 100%. That might be caused by difference of the postoperative management of the biliary tract. CONCLUSIONS: Careful management of the biliary tract should be performed after surgical resection of IPNB.

Risk Factors for Postoperative Ascites in Patients Undergoing Liver Resection for Hepatocellular Carcinoma.

BACKGROUND: Postoperative ascites is a common complication after liver resection. This study aimed to identify the risk factors for ascites in patients after liver resection and the relationship between postoperative ascites and other complications. METHODS: We retrospectively analyzed data that were obtained from 266 patients who underwent liver resection for treating hepatocellular carcinoma between 2008 and 2015. Postoperative ascites was defined as a daily ascitic fluid drainage exceeding 500 mL on postoperative day 3 or later. The participants were categorized and analyzed with respect to the presence or absence of postoperative ascites. RESULTS: Overall, 17 (6.4%) patients developed postoperative ascites. A multivariate analysis identified that three significant factors-serum albumin, platelet count, and operation duration-were associated with the development of postoperative ascites. Sixteen (94.1%) of the 17 patients with postoperative ascites experienced other associated complications. The patients with ascites had more pleural effusion (70.6 vs. 17.7%, P < 0.001) than the patients without ascites. Postoperative morbidity, except for pleural effusion, was similar between the groups. The postoperative hospital stay duration was significantly longer in patients with ascites than in those without ascites. CONCLUSIONS: Postoperative ascites frequently occurred in patients with decreased liver functional reserve. Moreover, the presence of ascites was associated with significantly increased pleural effusion rates, and postoperative hospital stay duration was significantly prolonged.

The safety of the early removal of prophylactic drainage after liver resection based solely on predetermined criteria: a propensity score analysis.

BACKGROUND: Prophylactic drainage after liver resection remains a common practice amongst hepatic surgeons. However, there is little information about the optimal timing of drain removal. METHODS: From April 2008 to December 2012 (conventional group), the drains were removed based on the treating surgeon's view. From January 2013 to April 2016 (ERP group), the drains were removed on POD 3 if the bile concentration of the drain discharge was less than three times the serum bilirubin on POD 3, and the amount of drain discharge was <500 ml on POD 3. The postoperative outcomes of the two groups were compared using one-to-one propensity score-matching analysis. RESULTS: One hundred nine patients were extracted from ERP group (n = 226) and conventional group (n = 246). The time to drain removal was significantly shorter in the ERP group than in the conventional group (3 days vs. 5 days, P < 0.001). The frequency of delayed bile leakage or the appearance of symptomatic abdominal fluid collection after drain removal did not differ between the two groups (3% vs. 4%, P = 0.791). CONCLUSION: Drain removal on POD 3 based on the volume and bile concentration is safe.

The Administration of Celecoxib as an Analgesic after Liver Resection Is Safe.

BACKGROUND: There are a few studies that have evaluated postoperative analgesia. The aim of this study was to evaluate the safety of administering celecoxib to manage postoperative pain after liver surgery. METHODS: The cases of patients who underwent liver resection at Nara Medical University from April 2008 to December 2015 were retrospectively analyzed. From January 2013 to December 2015, celecoxib was routinely administered (600 mg/day on postoperative day (POD) 2 and 400 mg/day from POD 3-7), whereas celecoxib was not administered from April 2008 to December 2012. The patients' baseline characteristics, the operative procedures, and postoperative complications were analyzed. RESULTS: In total, 207 patients were administered celecoxib (celecoxib group), whereas 246 were not (non-celecoxib group). The preoperative serum total bilirubin and creatinine levels and indocyanine green retention rate at 15 min values of the 2 groups were similar. Similar incidences of overall and major complications (Clavien-Dindo classification ≥grade IIIa) were seen in both groups (33.8 vs. 36.2%, p = 0.601 and 12.1 vs. 12.6%, p = 0.866, respectively). No significant differences in the incidences of gastrointestinal bleeding, acute renal failure, or portal vein thrombosis were observed between the groups. CONCLUSIONS: The use of celecoxib for postoperative analgesia in the early period after liver resection is safe.

The prognosis of liver resection for patients with four or more colorectal liver metastases has not improved in the era of modern chemotherapy.

BACKGROUND AND OBJECTIVES: The impact of perioperative chemotherapy on patients with multiple colorectal liver metastases (CRLM) remains unclear. We attempted to examine whether the introduction of modern chemotherapies has improved the prognosis of patients that undergo liver resection for ≥4 CRLM. METHODS: Between January 1990 and December 2013, 194 patients underwent liver resection for CRLM at our institution. The outcomes of the patients with ≥4 and 1-3 CRLM were compared before and after 2005, when modern chemotherapies were introduced to Japan. RESULTS: There were 50 and 144 patients with ≥4 (Group 1) and 1-3 (Group 2) CRLM, respectively. The overall survival (OS) rate of Group 1 was significantly worse than that of Group 2 (P = 0.0007). The OS rate of Group 2 was significantly better after 2005 than before 2004 (P = 0.039), while no such differences were observed in Group 1. Multivariate analysis identified three prognostic factors in Group 1: a serum carcinoembryonic antigen level of ≥20 ng/ml (P = 0.018), a serum cancer antigen 19-9 level of ≥100 U/ml (P = 0.018), and a primary colorectal cancer N factor of ≥N2 (P = 0.023). CONCLUSIONS: The prognosis of patients with ≥4 CRLM that undergo liver resection has not improved despite the development of modern chemotherapies. J. Surg. Oncol. 2016;114:959-965. © 2016 Wiley Periodicals, Inc.

Laparoscopic resection of a hepatic mucinous cystic neoplasm: A case report.

INTRODUCTION: We aimed to present a case of hepatic mucinous cystic neoplasm (MCN-H) that was completely resected by laparoscopy. PRESENTATION OF CASE: A 47-year-old female exhibited mild elevation of serum liver enzyme levels. Abdominal computed tomography revealed a 45-mm multilocular cystic tumor in segment IV of the liver, along with intermittent border calcification and minimal wall thickness. Magnetic resonance imaging revealed fluid-to-fluid level in the cystic tumor, thereby increasing the suspicion of a mild hemorrhage. The patient underwent laparoscopic liver resection (LLR) with a diagnosis of suspected mucinous cystic neoplasm of the liver. The entire tumor was successfully resected with a laparoscopic approach. The resected specimen was a 4.2×3.3×2.2-cm cystic tumor. Histological findings revealed mucin-producing singular epithelium and ovarian-like stroma. The tumor was diagnosed as a MCN-H with no malignancy. DISCUSSION: This is the first report in which a MCN-H was completely resected by laparoscopy. MCN-H is rare and is observed in only<5% of liver cystic tumors. MCN-H has been reported to have the malignant potential. And complete resection might be a good treatment option. Along with technical development, LLR has been indicated for benign liver tumors to date. Benign liver tumors are commonly observed in young females. The smaller incisions of the laparoscopic approach might provide cosmetic advantages for patients. CONCLUSION: We presented the first case of a MCN-H completely resected by laparoscopy. Benign tumors and tumors with malignant potential might be good indications for a laparoscopic surgery.

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice.

AIMS/HYPOTHESIS: Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined. METHODS: Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors. RESULTS: We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue's response to clear the pancreas from insufficiently reprogrammed cells. CONCLUSIONS/INTERPRETATION: Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications.

[A Case of Advanced Hepatocellular Carcinoma, Its Disease Progression Could Be Controlled by Multimodal Treatment].

The patient was a 73-year-old man, diagnosed with advanced huge hepatocellular carcinoma with a tumor thrombus extending into the inferior vena cava and extrahepatic metastases. Radiation therapy(50 Gy)was applied for the bone metastases, primary tumor, and tumor thrombus, and the patient received a cisplatin transcatheter arterial infusion(100mg/ body, 5 courses). Sorafenib was administered orally once the local lesion was under control. The tumor showed a partial response according to the RECIST criteria, but the tumor thrombus in the inferior vena cava almost disappeared. The presence of a tumor thrombus in the inferior vena cava must be regarded as an oncologic emergency. Acisplatin transcatheter arterial infusion and radiation therapy may be treatment options for unresectable cases.

[Huge Hepatocellular Carcinoma with Portal Vein and Inferior Vena Cava Thrombi Treated with Curative Liver Resection and Perioperative Hepatic Arterial Infusion Chemotherapy - A Case Report].

The prognosis of hepatocellular carcinoma(HCC)with main portal vein(MPV)and/or the inferior vena cava(IVC)tumor thrombi is dismal. The management of HCC with severe tumor thrombus is complicated. In this study, we report a case of HCC with tumor thrombi in the MPV and IVC that was successfullytreated via liver resection and perioperative hepatic arterial infusion chemotherapy(HAI). A 68-year-old man was referred to our institution to treat huge HCC lesion in the right lobe of the liver. Abdominal computed tomography(CT)revealed a tumor(12 cm in diameter)in the right hepatic lobe and tumor thrombi in the MPV and IVC. The patient was initiallytreated with HAI(cisplatin 100mg/body). After 3 courses of HAI, the tumor was dramaticallyreduced in size, and the thrombus in the IVC had disappeared; however, the thrombus in the MPV remained. Therefore, we performed right hepatectomy, wedge resection of the IVC, combined resection of the MPV, and portal vein reconstruction. The histopathological findings of the resected specimen revealed that viable cancer cells were observed onlyin an 8×8mm lesion. Subsequently, HAI was performed as adjuvant therapy for 3 courses. The patient died of other causes 2 years 3 months after surgery. There was no sign of recurrence at the time of death. This case suggested that perioperative HAI and liver resection mayrepresent an effective treatment strategyfor HCC with severe tumor thrombus.

Huge hepatocellular carcinoma with multiple intrahepatic metastases: An aggressive multimodal treatment.

INTRODUCTION: Huge hepatocellular carcinoma (HCC) possesses a potential risk for spontaneous rupture, which leads to a life-threatening complication with a high mortality rate. In addition, a large HCC is frequently accompanied by intrahepatic metastases. PRESENTATION OF CASE: We describe, the case of a 74-year-old woman with a huge extrahepatically expanding HCC with multiple intrahepatic metastases who was treated by liver resection with repeated transcatheter arterial chemoembolization (TACE). To prevent tumor rupture or bleeding, we performed right hepatectomy. After the operation, TACE was applied for multiple intrahepatic metastases in the remnant liver. Furthermore, the elevated protein induced vitamin K absence (PIVKA II) level had decreased to limits within the normal range. Three months after the first TACE, computed tomography revealed several recurrences in the liver. TACE was applied for the second and third time and the tumors were well controlled. DISCUSSION: Although, liver resection is occasionally performed for patients with huge HCC to avoid spontaneous tumor rupture, only surgical approach might not be sufficient for such advanced HCC. To achieve long-term survival, it is necessary to control the residual intrahepatic tumors. We could control multiple intrahepatic metastases with repeated TACEs after hepatectomy. CONCLUSION: Multimodal treatment involving hepatectomy and TACE might be a good treatment strategy for patients with huge HCC with multiple intrahepatic metastases if the tumors are localized in the liver without distant or peritoneal metastasis.

Hepatic artery injury during left hepatic trisectionectomy for colorectal liver metastasis treated by portal vein arterialization.

Portal vein arterialization (PVA) has been applied as a salvage procedure in hepatopancreatobiliary surgeries, including transplantation and liver resection, with revascularization for malignancies. Here we describe the use PVA as a salvage procedure following accidental injury of the hepatic artery to the remnant liver occurred during left hepatic trisectionectomy for colorectal liver metastases (CRLM). A 60-year-old man with cancer of the sigmoid colon and initially unresectable CRLM received 11 cycles of hepatic arterial infusion chemotherapy with 5-fluorouracil (1500mg/week), after which CRLM was downstaged to resectable. One month after laparoscopic sigmoidectomy, a left trisectionectomy and wedge resection of segment 6 were performed. The posterior branch of the right hepatic artery, the only feeding artery to the remnant liver, was injured and totally dissected. Because microsurgical reconstruction of the artery was impossible, PVA was used; PVA is the sole known procedure available when hepatic artery reconstruction is impossible. The patient then suffered portal hypertension, and closure of arterio-portal anastomosis using an interventional technique with angiography was eventually performed on postoperative day 73. Therefore, it is considered that because PVA is associated with severe postoperative portal hypertension, closure of the arterio-portal shunt should be performed as soon as possible on diagnosing portal hypertension.

Reprogramming Mouse Cells With a Pancreatic Duct Phenotype to Insulin-Producing ß-Like Cells.

Reprogramming technology has opened the possibility of converting one cell type into another by forced expression of transgenes. Transduction of adenoviral vectors encoding 3 pancreatic transcription factors, Pdx1, Ngn3, and MafA, into mouse pancreas results in direct reprogramming of exocrine cells to insulin-producing ß-like cells. We hypothesized that cultured adult pancreatic duct cells could be reprogrammed to become insulin-producing ß-cells by adenoviral-mediated expression of this same combination of factors. Exocrine were isolated from adult mouse insulin 1 promoter (MIP)-green fluorescent protein (GFP) transgenic mice to allow new insulin-expressing cells to be detected by GFP fluorescence. Cultured cells were transduced by an adenoviral vector carrying a polycistronic construct Ngn3/Pdx1/MafA/mCherry (Ad-M3C) or mCherry sequence alone as a control vector. In addition, the effects of glucagon-like peptide-1 (GLP-1) receptor agonist, exendin-4 (Ex-4) on the reprogramming process were examined. GFP(+) cells appeared 2 days after Ad-M3C transduction; the reprogramming efficiency was 8.6 ± 2.6% by day 4 after transduction. Ad-M3C also resulted in increased expression of ß-cell markers insulin 1 and 2, with enhancement by Ex-4. Expression of other ß-cell markers, neuroD and GLP-1 receptor, were also significantly up-regulated. The amount of insulin release into the media and insulin content of the cells were significantly higher in the Ad-M3C-transduced cells; this too was enhanced by Ex-4. The transduced cells did not secrete insulin in response to increased glucose, indicating incomplete differentiation to ß-cells. Thus, cultured murine adult pancreatic cells with a duct phenotype can be directly reprogrammed to insulin-producing ß-like cells by adenoviral delivery of 3 pancreatic transcription factors.

Eosinophilic cholangitis coexisted with idiopathic thrombocytopenic purpura: Report of a case.

Eosinophilic cholangitis is a rare disease of which only 31 cases have been reported. Eosinophilic infiltration causes stricture of the bile duct diffusely or locally, and the imaging of eosinophilic cholangitis resembles primary sclerosing cholangitis or cancer of the bile tract. For eosinophilic cholangitis, treatment with steroid is effective and the prognosis is good. Therefore, its accurate diagnosis is very important. Here, we describe a patient with eosinophilic cholangitis who was also diagnosed with idiopathic thrombocytopenic purpura (ITP). He was treated for ITP using prednisolone, the unexpected sudden interruption of which caused severe deterioration of eosinophilic cholangitis and acute cholecystitis. Cholecystectomy and choledochojejunostomy were performed, and the addition of treatment by prednisolone resulted in a good clinical course. This is the first report on eosinophilic cholangitis coexisting with ITP.

Direct Reprogramming for Pancreatic Beta-Cells Using Key Developmental Genes.

Direct reprogramming is a promising approach for regenerative medicine whereby one cell type is directly converted into another without going through a multipotent or pluripotent stage. This reprogramming approach has been extensively explored for the generation of functional insulin-secreting cells from non-beta-cells with the aim of developing novel cell therapies for the treatment of people with diabetes lacking sufficient endogenous beta-cells. A common approach for such conversion studies is the introduction of key regulators that are important in controlling beta-cell development and maintenance. In this review, we will summarize the recent advances in the field of beta-cell reprogramming and discuss the challenges of creating functional and long-lasting beta-cells.

Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells.

Direct lineage conversion is a promising approach to generate therapeutically important cell types for disease modeling and tissue repair. However, the survival and function of lineage-reprogrammed cells in vivo over the long term has not been examined. Here, using an improved method for in vivo conversion of adult mouse pancreatic acinar cells toward beta cells, we show that induced beta cells persist for up to 13 months (the length of the experiment), form pancreatic islet-like structures and support normoglycemia in diabetic mice. Detailed molecular analyses of induced beta cells over 7 months reveal that global DNA methylation changes occur within 10 d, whereas the transcriptional network evolves over 2 months to resemble that of endogenous beta cells and remains stable thereafter. Progressive gain of beta-cell function occurs over 7 months, as measured by glucose-regulated insulin release and suppression of hyperglycemia. These studies demonstrate that lineage-reprogrammed cells persist for >1 year and undergo epigenetic, transcriptional, anatomical and functional development toward a beta-cell phenotype.