JNETS clinical practice guidelines for gastroenteropancreatic neuroendocrine neoplasms: diagnosis, treatment, and follow-up: a synopsis.

Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters-diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel-Lindau (VHL) disease-and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of "neuroendocrine tumor" (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published.

Optimal strategy of systemic treatment for unresectable pancreatic neuroendocrine tumors based upon opinion of Japanese experts.

BACKGROUND/OBJECTIVES: A number of therapeutic agents have been reported to be clinically useful for the management of the patients with unresectable pancreatic neuroendocrine tumors (PanNETs) including somatostatin analogues, molecular-targeted agents and cytotoxic agents. However, the optimal strategy for selection among those treatment modalities above in these patients has remained unexplored. METHODS: Japanese experts for PanNET discussed and determined the optimal treatment strategies according to the results of previously reported studies. RESULTS: The tumor volume of liver metastases and the Ki-67 labeling index were unanimously accepted as indicators of the tumor burden and tumor aggressiveness, respectively, which are two most clinically pivotal factors for determining the strategy of systemic treatment for unresectable PanNETs. In addition, for those with a relatively small tumor burden and slow disease progression, somatostatin analogues were selected as the first-line treatment agents. For those with a relatively large tumor burden and rapid tumor progression, cytotoxic agents were selected, possibly aiming at tumor shrinkage. For those of intermediate tumor volume and/or growth rate, molecular-targeted agents were selected as the first choice. Based on this strategy discussed among the experts, we tentatively prepared a MAP for proposing optimal treatment strategy and examined its validity in some patients with unresectable PanNETs. Results validated the usefulness of this MAP proposed for patients harbouring unresectable PanNETs. CONCLUSION: We herein propose a tentative MAP for optimal treatment selection for the patients harbouring unresectable PanNETs. Further large scale studies are, however, warranted to validate the usefulness of this MAP proposed in this study.

Hepatocellular carcinoma with duodenal invasion resected subsequent to multimodal therapies: A case report.

INTRODUCTION: Gastrointestinal (GI) involvement in hepatocellular carcinoma (HCC) is uncommon. In particular, HCC with duodenal invasion is known to be a rare condition. In such cases, surgical indication has been generally negative except in few reported cases. To our knowledge, this report describes the first case of HCC with duodenal invasion, resected by hepatectomy accompanied by pancreas-preserving partial duodenectomy (HPPD) following multimodal therapies including systemic sorafenib administration. CASE PRESENTATION: A 65-year-old man had been repeatedly treated for multiple HCCs by transarterial chemoembolization (TACE) and sorafenib. However, the main tumor formerly ruptured began to involve his duodenum, causing GI bleeding. The collateral vessels from the pancreatic and omental branches entered the tumor and nullified the transarterial hemostatic embolization. Hence, HPPD was performed to preserve the major Vater papilla. Histopathological examination revealed poorly-to -moderately differentiated HCC cells invading the duodenum. DISCUSSION AND CONCLUSION: HPPD treatment successfully removed HCC with duodenal invasion achieving viable tumor clearance status (R0). We underline the importance of achieving viable tumor clearance status at any time during the treatment course of patients with advanced HCC as this approach may be the only approach to enable HCC patients with duodenal invasion to resume a healthy life.

Primary jejunal Burkitt lymphoma in a child: ultrasonic detection.

Gastrointestinal Burkitt lymphoma (BL) is a highly aggressive malignancy in childhood, and early treatment is critical for its favorable prognosis. Ultrasonography is a widely accepted initial imaging workup; therefore, recognition of the sonographic features of BL should contribute to its early diagnosis and initiation of treatment. We present a 4-year-old boy with primary jejunal BL with intussusception mimicking presentation, in which initial abdominal US allowed sustainable detection and characterization of the intestinal lesion. Jejunotomy was performed and histopathological analysis revealed a 'starry sky' pattern and c-myc split signals characteristic of BL. The patient remains disease-free following chemotherapy.

Concurrent gemcitabine+S-1 neoadjuvant chemotherapy contributes to the improved survival of patients with small borderline-resectable pancreatic cancer tumors.

PURPOSES: In the surgical treatment of pancreatic cancer, margin-negative status is one of the most important determinants of survival. We conducted this study to explore surgical margin status as well as other factors affecting the survival of borderline-resectable pancreatic cancer (BRPC) patients who received neoadjuvant chemotherapy with gemcitabine and S-1. METHODS: Eighteen BRPC patients were prospectively treated with concurrent gemcitabine and S-1 neoadjuvant chemotherapy (NAC+) and 15 of these patients underwent resection. We evaluated the safety and efficacy of this treatment regimen by comparing the outcomes of these patients with those of 19 BRPC patients who did not receive neoadjuvant chemotherapy (NAC-) during the same period. RESULTS: Fifteen (83 %) of the NAC+ patients underwent pancreatectomy. The remaining three patients (17 %) had regional tumor progression or liver metastasis. Of the 15 NAC+ patients who underwent resection, 3 (20 %) had margin-positive status, whereas 9 of the 19 (43 %) NAC- patients had margin-positive status (p = 0.002). However, disease-free survival and overall survival were similar in the two groups (MST 21.7 vs. 21.1 months). NAC+ patients with tumors smaller than 30 mm had favorable overall survival (MST 43.9 vs. 23.1 months, p = 0.0321). Most recurrences developed at distant sites rather than locally in both groups. CONCLUSIONS: In the neoadjuvant setting, gemcitabine and S-1 improved the negative surgical margin rate in BRPC patients, but it did not improve survival. Thus, neoadjuvant chemotherapy should be given to BRPC patients at an earlier stage.

(68)Ga-DOTATOC-PET/CT for effective diagnosis and treatment of pancreatic tail gastrinoma with multiple liver metastases: a case report.

A 40-year-old man admitted to our hospital with diarrhea underwent abdominal computed tomography (CT) which showed multiple masses in the liver and pancreatic tail. Although there were no abnormal accumulations with fluorodeoxyglucose ((18)F) positron emission tomography (FDG-PET), (68)Ga-DOTATOC-PET/CT detected obvious abnormal accumulations for the both lobes of liver and pancreatic tail tumors. The serum gastrin was markedly high, and liver tumor biopsy demonstrated the presence of malignant cells with round nuclei that were positive for gastrin and somatostatin receptor. The patient was diagnosed with pancreatic tail gastrinoma with multiple liver metastases and treated with octreotide, everolimus, and a proton pump inhibitor which functionally controlled tumor growth. This case demonstrates (68)Ga-DOTATOC-PET/CT as a useful modality for the localization, qualitative diagnosis, and treatment of gastrinoma.

Determinants of surgical resection for pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (pNETs) include functioning and non-functional tumors. Functioning tumors consist of tumors that produce a variety of hormones and their clinical effects. Therefore, determinants of resection of pNETs should be discussed for each group of tumors. Less than 10% of insulinomas are malignant, therefore more than 90% of the cases can be cured by surgical resection. Lymphadenectomy is generally not necessary in insulinoma operation. If preoperative localization of the insulinoma is completed, enucleation from the pancreatic body or tail, and distal pancreatectomy can be performed safely by laparoscopy. When preoperative localization of a sporadic insulinoma is not confirmed, surgical exploration is needed. Intraoperative localization of a tumor, intraoperative insulin sampling and frozen section are required. The crucial purpose of surgical resection is to control inappropriate insulin secretion by removing all insulinomas. Gastrinomas are usually located in the duodenum or pancreas, which secrete gastrin and cause Zollinger-Ellison syndrome (ZES). Duodenal gastrinomas are usually small, therefore they are not seen on preoperative imaging studies or endoscopic ultrasound, and can be found only at surgery if a duodenotomy is performed. In addition, lymph node metastasis is found in 40-60% of cases. Therefore, the experienced surgeons should direct operation for gastrinomas. Surgical exploration with duodenotomy should be performed at a laparotomy. Other functioning pNETs can occur in the pancreas or in other locations. Curative resection is always recommended whenever possible after optimal symptomatic control of the clinical syndrome by medical treatment. Indications for surgery depend on clinical symptom control, tumor size, location, extent, malignancy and presence of metastasis. A lot of non-functioning pNETs are found incidentally according to the quality improvement of imaging techniques. Localized, small, malignant non-functioning pNETs should be operated on aggressively, while in possibly benign tumors smaller than 2 cm the surgical risk-benefit ratio should be carefully weighted. Surgical liver resection is generally proposed in curative intent to all patients with operable metastases from G1 or G2 pNET. The benefits of surgical resection of liver metastases have been demonstrated in terms of overall survival and quality of life. Complete resection is associated with better long-term survival.

PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors.

The molecular mechanisms underlying the development of pancreatic neuroendocrine tumors (PanNETs) have not been well defined. We report here that the genomic region of the PHLDA3 gene undergoes loss of heterozygosity (LOH) at a remarkably high frequency in human PanNETs, and this genetic change is correlated with disease progression and poor prognosis. We also show that the PHLDA3 locus undergoes methylation in addition to LOH, suggesting that a two-hit inactivation of the PHLDA3 gene is required for PanNET development. We demonstrate that PHLDA3 represses Akt activity and Akt-regulated biological processes in pancreatic endocrine tissues, and that PHLDA3-deficient mice develop islet hyperplasia. In addition, we show that the tumor-suppressing pathway mediated by MEN1, a well-known tumor suppressor of PanNETs, is dependent on the pathway mediated by PHLDA3, and inactivation of PHLDA3 and MEN1 cooperatively contribute to PanNET development. Collectively, these results indicate the existence of a novel PHLDA3-mediated pathway of tumor suppression that is important in the development of PanNETs.

Natural history of branch duct intraductal papillary mucinous neoplasm with mural nodules: a Japan Pancreas Society multicenter study.

OBJECTIVE: This study aimed to elucidate the natural history of intraductal papillary mucinous neoplasm (IPMN) of the pancreas with mural nodules (MNs) in branch duct IPMN (BD-IPMN). METHODS: Among the 402 registered patients with BD-IPMN on long-term follow-up at 10 institutions in Japan, 53 patients with MNs of less than 10 mm in height detected by endosonography were included in this study. The morphological changes of the BD-IPMN in these patients and histologic findings of the resected specimen were investigated. RESULTS: The median height of the MNs at the initial diagnosis was 3 mm (range, 1-8 mm), and 12 (23%) of the 53 patients showed an increase in the height of the MNs during follow-up (mean duration, 42 months). Six patients underwent surgery because of an increase in the height of MNs, yielding high-grade dysplasia in 1 patient and low-grade dysplasia in 5 patients. No patients developed invasive carcinoma derived from IPMN, and distinct pancreatic ductal adenocarcinoma developed in 1 (2%) patient. The incidence of the development of malignancy in BD-IPMNs, including distinct pancreatic ductal adenocarcinoma, was similar to that of those without MNs. CONCLUSIONS: In patients who have BD-IPMN with MNs of less than 10 mm in height, observation instead of immediate resection is considered to be possible.

GPR119 expression in normal human tissues and islet cell tumors: evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function.

OBJECTIVE: GPR119 is reportedly involved in regulating glucose metabolism and food intake in rodents, but little is known about its expression and functional significance in humans. To begin to assess the potential clinical importance of GPR119, the distribution of GPR119 gene expression in humans was examined. MATERIALS/METHODS: Expression of GPR119 mRNA in fresh samples of normal human pancreas (n=19) and pancreatic islets (n=3) and in insulinomas (n=2) and glucagonomas (n=2), all collected at surgery, was compared with the mRNA expression of various receptors highly expressed and operative in human pancreatic islets. RESULTS: GPR119 mRNA was most abundant in the pancreas, followed by the duodenum, stomach, jejunum, ileum and colon. Pancreatic levels of GPR119 mRNA were similar to those of GPR40 mRNA and were higher than those of GLP1R and SUR1 mRNA, which are strongly expressed in human pancreatic islets. Moreover, levels of GPR119 mRNA in pancreatic islets were more than 10 times higher than in adjacent pancreatic tissue, as were levels of GPR40 mRNA. GPR119 mRNA was also abundant in two cases of insulinoma and two cases of glucagonoma, but was undetectable in a pancreatic acinar cell tumor. Similar results were obtained with mouse pancreatic islets, MIN6 insulinoma cells and alpha-TC glucagonoma cells. CONCLUSIONS: The results provide evidence of an islet-gastrointestinal distribution of GPR119, its expression in pancreatic beta and alpha cells, and its possible involvement in islet function. They also provide the basis for a better understanding of the potential clinical importance of GPR119.

[Resection of cholangiolocellular carcinoma successfully responding to neoadjuvant hepatic arterial infusion chemotherapy - report of a case].

A 78-year-old man who had hepatitis C was examined by computed tomography(CT)because of prostate cancer, and was found to have a liver tumor 8. 0 cm in size at S4/S8. The view of the liver tumor was enhanced by CTHA image and washed out by CTAP image. It was suspected to have invaded the RHV and MHV. The pathological examination of the liver biopsy sample revealed cholangiocellular carcinoma or cholangiolocellular carcinoma. Hepatic arterial infusion chemotherapy with gemcitabine and cisplatin was performed. The size of the tumor reduced to 6. 0 cm and the invasion to the RHV was no longer evident. Hepatic resection for the middle two segments was performed after 3 months of chemotherapy. After a histological examination of the resected specimen, the patient was given the final diagnosis of cholangiolocellular carcinoma. Over 50% of the tumor was estimated as necrosis by chemotherapy, indicating that the gemcitabine and cisplatin regimen was remarkably effective. The patient is alive with no evidence of recurrence.

Successful neoadjuvant treatment with radiochemotherapy and systemic chemotherapy for the locally advanced pancreatic head cancer: report of a case.

A 49-year-old man was admitted to the hospital for the upper abdominal pain and was diagnosed as unresectable pancreatic head cancer because of the invasion around the superior mesenteric artery. He was treated with radiochemotherapy, followed by systemic gemcitabine alone for 3 courses. He was further treated with systemic gemcitabine plus S­1 combination therapy for 5 courses. CT examination after these treatments showed a dramatic reduction of the tumor at the head of the pancreas and a pancreatoduodenectomy was performed. Pathologically, there was no residual malignant tumor. He has had no recurrent tumor up until now. Several studies of gemcitabine plus S-1 combination therapy show higher response rates for unresectable tumors. The current case indicates the effectiveness of the radiochemotherapy and gemcitabine plus S­1 combination therapy for locally advanced pancreatic head cancer as a neoadjuvant setting. We consider that multidisciplinary treatment including gemcitabine plus S­1 therapy may prolong the survival time by curative operation.