MicroRNAs associated with postoperative outcomes in patients with limited stage neuroendocrine carcinoma of the esophagus.

Esophageal neuroendocrine carcinoma (E-NEC) is an aggressive disease with a poor prognosis. The present study aimed to assess the role of surgery in the treatment of patients with resectable E-NEC, and identify a microRNA (miRNA/miR) signature in association with positive postoperative outcomes. Between February 2017 and August 2019, 36 patients with E-NEC who underwent curative surgery at the Japan Neuroendocrine Tumor Society partner hospitals were enrolled in the study. A total of 16 (44.4%) patients achieved disease-free survival (non-relapse group), whereas 20 (55.6%) patients developed tumor relapse (relapse group) during the median follow-up time of 36.5 months (range, 1-242) after surgery with a 5-year overall survival rate of 100 and 10.8%, respectively (P<0.01). No clinicopathological parameters, such as histological type or TNM staging, were associated with tumor relapse. Microarray analysis of 2,630 miRNAs in 11 patients with sufficient quality RNA revealed 12 miRNAs (miR-1260a, -1260b, -1246, -4284, -612, -1249-3p, -296-5p, -575, -6805-3p, -12136, -6822-5p and -4454) that were differentially expressed between the relapse (n=6) and non-relapse (n=5) groups. Furthermore, the top three miRNAs (miR-1246, -1260a and -1260b) were associated with overall survival (P<0.01). These results demonstrated that surgery-based multidisciplinary treatment is effective in a distinct subpopulation of limited stage E-NEC. A specific miRNA gene set is suggested to be associated with treatment outcome.

How to treat gastrinomas in patients with multiple endocrine neoplasia type1: surgery or long-term proton pump inhibitors?

In patients with multiple endocrine neoplasia type 1 syndrome (MEN 1) and Zollinger-Ellison syndrome (ZES), gastrinomas arise from the duodenum, about 60% are multiple, and about 15% of patients have coexisting pancreatic gastrinomas, which can be localized by the selective arterial secretagogue injection test (SASI test). The guidelines (GLs) by the Japanese Neuroendocrine Tumor Society (JNETS) recommend surgical resection for functioning duodenopancreatic neuroendocrine tumors (NETs), including gastrinomas, in patients with MEN1 (Grade A, 100% agreement among members). Conversely, the GLs of the National Comprehensive Cancer Network (NCCN) in the USA recommend observation and treatment with proton pump inhibitors (PPIs) or exploratory surgery for occult gastrinomas. An international Consensus Statement (ICS) from the European Union (EU) also does not recommend resection of gastrinomas in patients with MEN1, despite some surgeons having reported surgery being curative for gastrinomas in MEN1 patients. In this review, we discuss the serious side effects and tumorigenic effects of the prolonged use of PPIs and the safety and curability of surgery, supported by our results of curative surgery for gastrinomas in 20 patients with MEN1 over 30 years. We conclude that surgery should be the first-line treatment for gastrinomas in MEN1 patients.

Phase I/II study of streptozocin monotherapy in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: This phase I/II study was conducted to evaluate the efficacy, safety and pharmacokinetics of streptozocin (STZ) in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. METHODS: Twenty-two patients received up to 4 cycles of intravenous STZ at either 500 mg/m2 once daily for 5 consecutive days every 6 weeks (daily regimen) or at 1000-1500 mg/m2 once weekly for 6 weeks (weekly regimen). Tumor response was evaluated using the modified RECIST criteria ver. 1.1, and adverse events were assessed by grade according to the National Cancer Institute CTCAE (ver. 4.0). RESULTS: Fourteen (63.6%) patients completed the study protocol. No patients had complete response; partial response in 2 (9.1%), stable disease in 17 (77.3%), non-complete response/non-progressive disease in 2 (9.1%) and only 1 (4.5%) had non-evaluable disease. Excluding the latter, the response rate in the daily and weekly regimens was 6.7% (1/15) and 16.7% (1/6), respectively, with an overall response rate of 9.5% (2/21). However, the best overall response in each patient showed that the disease control rate was 100%.Adverse events occurred in all 22 patients, including 17 grade 3 adverse events in 11 patients; however, no grade 4 or 5 adverse events were reported. Prophylactic hydration and antiemetic treatment reduced the severity and incidence of nephrotoxicity, nausea and vomiting. Plasma STZ concentrations decreased rapidly after termination of infusion, with a half-life of 32-40 min. Neither repeated administration nor dose increases affected pharmacokinetic parameters. CONCLUSIONS: STZ may be a useful option for Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

Somatostatin Receptor 2 Expression Profiles and Their Correlation with the Efficacy of Somatostatin Analogues in Gastrointestinal Neuroendocrine Tumors.

Somatostatin analogues (SSAs) are widely used to treat gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Somatostatin receptor 2 (SSTR2) immunoreactivity serves as a predictive marker of the therapeutic efficacy of SSAs in pancreatic NETs. However, SSTR2 expression profiles in tumor cells and their association with the therapeutic efficacy of SSAs remains virtually unknown in gastrointestinal NETs (GI-NETs). Therefore, we evaluated the association between SSTR2 immunoreactivity and embryological origin and proliferative activity in 132 resected surgical tissues of GI-NETs. The correlation between SSAs' therapeutic efficacy and SSTR2 immunoreactivity was evaluated in 14 GI-NETs treated with SSAs. SSTR2 immunoreactivity was evaluated using Volante scores, immunoreactive scores, and digital image analysis (DIA). SSTR2 immunoreactivity was significantly negatively and positively correlated with the Ki-67 labeling index in foregut and hindgut NETs, respectively. In the normal mucosa, neuroendocrine cells in the rectum had significantly lower positive rates of SSTR2 than those in the stomach and duodenum. SSTR2 expression profiles in GI-NETs could differ by primary sites, while the difference of those between foregut and hindgut NETs might be derived from the SSTR2 status of normal neuroendocrine cell counterparts. In addition, DIA could provide a good alternative for predicting response to SSAs in evaluating SSTR2 immunoreactivity of GI-NETs.

Nationwide registry for patients with neuroendocrine neoplasm of pancreas, gastrointestinal tract, lungs, bronchi, or thymus in Japan.

BACKGROUND: Neuroendocrine neoplasm (NEN) is a comparatively rare tumor that has been considered indolent. Due to these characteristics, detailed epidemiological data have not been analyzed in Japan. To elucidate the present status of NEN diagnosis and treatment in Japan, we started a registry cohort study in January 2015. METHODS: Patients pathologically diagnosed with NENs of the pancreas, gastrointestinal tract, lungs, bronchi, or thymus after January 2012 were enrolled in this registry after the date of ethics review committee approval in each hospital or institute. Follow-up was continued for enrolled patients. RESULTS: During 5 years of enrollment between January 2015 and December 2019, a total of 1526 participants from 63 departments were enrolled in this registry (mean, 305.2 participants/year), covering approximately 5.8% of the annual incidence of NENs in Japan. For pancreatic NEN, 41.9% of patients had metastasis and the dominant metastatic site was the liver, at twice the rate of lymph node metastasis in the current registry. In contrast, the frequency of lymph node metastasis from gastrointestinal (GI)-NEN was similar to that of the liver. The distribution of WHO 2019-based grades varied according to the primary site. Low-to-intermediate grade (G1-G2) was dominant for duodenal, jejunal/ileal, rectal, and pancreatic NENs, whereas high grade (G3 or NEC) was dominant for esophageal, stomach, and colon NENs. For PanNENs, G3 and NEC accounted only for 1.6% and 2.9%, respectively. CONCLUSIONS: These cohort data provide crucial information for clinical research to clarify the characteristics of NENs in Japan.

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.

O6-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms.

BACKGROUND: Streptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ. METHODS: In this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs). RESULTS: In GI-NETs, MGMT scores of ≥2 and ≥ 3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥ 6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but none of the included GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki-67 labeling index (GLUT2 score: P = 0.0045, ρ = - 0.4570; MGMT score: P = 0.0064, ρ = - 0.4399; H-score: P = 0.0110, ρ = - 0.4135) and MGMT immunoreactivity were significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy. CONCLUSION: The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients.

Correction to: Phase II study of sunitinib in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumor.

In the original publication of this article, the license subtype should be CC BY and not CC BY-NC.

Multi-center clinical evaluation of streptozocin-based chemotherapy for advanced pancreatic neuroendocrine tumors in Japan: focus on weekly regimens and monotherapy.

PURPOSE: Streptozocin (STZ) is a key agent for treating advanced pancreatic neuroendocrine tumors (pNET). Most STZ regimens for pNET are daily and also include 5-fluorouracil (5FU), whereas STZ monotherapy and weekly regimens have also been applied in daily practice in Japan. The present study aimed to evaluate responses to weekly regimens and to STZ monotherapy, and to identify a predictive marker of a response to STZ. METHODS: Clinical data regarding STZ-based chemotherapy for pNET were collected between 2015 and 2017 at 25 facilities. We analyzed the effects, safety, progression-free survival (PFS), and factors that correlate with responses to STZ. RESULTS: The overall objective response rate (ORR) of 110 patients who underwent STZ-based chemotherapy (monotherapy, 81.8%; weekly regimen 46.4%) was 21.8%, and PFS was 9.8 months. The ORR of weekly vs. daily regimens was 21.6 vs. 22.0% (P = 1.000), and that of monotherapy vs. combination therapy was 21.1 vs. 25.0% (P = 0.766). A Ki67 proliferation index (Ki67) of > 5% was a predictive marker of a response to STZ (P = 0.017), whereas regimen type, mono- or combination therapy, treatment line and liver tumor burden were not associated with responses. The frequencies of Grade ≥ 3 nausea and hematological adverse events were significantly lower for monotherapy than combination therapy (P = 0.032). CONCLUSIONS: The effects of weekly STZ monotherapy on pNET are comparable to those previously reported and the toxicity profile was acceptable. Ki67 > 5% was the sole predictive marker of an objective response.

[A Case of Esophageal Carcinoma with Large Intramural Metastasis to the Stomach].

We report a rare case of esophageal carcinoma with gastric wall metastasis. A 73-year-old man with dysphagia underwent endoscopy and upper GI series and chest-abdominal computed tomography, revealing esophageal carcinoma and gastric cancer, which was diagnosed as squamous cell carcinoma by biopsy. The esophageal carcinoma was located in the lower thoracic esophagus(Lt). Total gastrectomy was performed. The resected specimen showed a type 3 tumor measuring 7×7 cm in the anterior wall of the stomach. Pathologically, the depth of invasion of the stomach was SE. He died 3 months after the operation. Esophageal carcinoma with gastric intramural metastasis is very rare and has a dismal prognosis. We report a rare case of esophageal carcinoma with large intramural metastasis to the stomach.

A primary hepatic gastrinoma accompanied by hyperplasia of multi-nodular Brunner's glands.

BACKGROUND: Primary hepatic gastrinoma causing severe ulcerogenic syndrome is extremely rare. Herein, we report a case of primary hepatic gastrinoma accompanied by hyperplasia of multi-nodular Brunner's glands in a patient who instead, preoperatively, was suspected of having multiple duodenal gastrinomas and hepatic metastasis. CASE PRESENTATION: A 57-year-old woman consulted a clinic complaining of melena, intermittent abdominal pain, diarrhea, and vomiting which had persisted for about 3 years. Six months before her presentation, she underwent segmental resection of the jejunum for acute peritonitis due to the spontaneous jejunal perforation. A blood test revealed that her serum immunoreactive gastrin (IRG) level was 12,037 pg/mL. Subsequently, she was transferred to our hospital. On computed tomography (CT), a hypervascular tumor of 23 mm in the segment 5 (S5) region of the liver was visualized. A selective arterial secretagogue injection test (SASI test) was performed twice. The first SASI test revealed that the hepatic tumor was a gastrinoma, and there was no gastrinoma in the duodeno-pancreatic region. Additionally, somatostatin receptor scintigraphy only visualized the tumor in the liver. However, the second SASI test, which was performed during the administration of a proton pump inhibitor and a somatostatin analog (octreotide acetate), revealed that there may have been gastrinomas existing not only in the liver but also in the upper part of the duodenum or the head of the pancreas. Duodenal endoscopy revealed multiple submucosal tumors in the first and the second portion of the duodenum, although a pathological examination of biopsied specimens obtained from the duodenal lesions was negative for malignant cells. Multiple endocrine neoplasia type 1 (MEN1) was excluded from her family history, and serum levels of both intact parathyroid hormone (iPTH) and calcium were within normal ranges. An anterior segmentectomy of the liver and pancreas-preserving total duodenectomy were performed on September 9, 2013. Postoperatively, her serum immunoreactive gastrin level decreased to less than 50 pg/mL. Pathological study of the resected specimens revealed a gastrinoma in the liver, but no gastrinoma in the duodenum. Interestingly, the duodenal submucosal tumor-like lesions were hyperplastic Brunner's glands. Postoperatively, she has been well without recurrence of hypergastrinemia for 4 years. CONCLUSION: We report a case of primary hepatic gastrinoma in a patient who has been cured for 4 years postoperatively. The diagnosis was somewhat difficult due to the coexisting, multiple hyperplastic Brunner's glands of the duodenum mimicking the submucosal neuroendocrine tumors, which might have developed due to long-term hypergastrinemia.

Rb Loss and KRAS Mutation Are Predictors of the Response to Platinum-Based Chemotherapy in Pancreatic Neuroendocrine Neoplasm with Grade 3: A Japanese Multicenter Pancreatic NEN-G3 Study.

Purpose: Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival.Experimental Design: A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype [NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3)] were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed.Results: Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (P < 0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, P = 0.006; mutated KRAS, 77% versus wild type, 23%, P = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (P = 0.035).Conclusions: NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3. Clin Cancer Res; 23(16); 4625-32. ©2017 AACR.

Advances in the diagnosis and treatment of pancreatic neuroendocrine neoplasms in Japan.

Several new developments have occurred in the field of pancreatic neuroendocrine neoplasm (PNEN) recently in Japan. First, the utility of chromogranin A (CgA), useful for the diagnosis and monitoring of the treatment response of neuroendocrine neoplasm (NEN), has been demonstrated in Japan. For PNEN diagnosis and treatment, grading and correct histological diagnosis according to the WHO 2010 classification is important. Regarding the histological diagnosis, the advent of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has enabled correct pathological diagnosis and suitable treatment for the affected tissue. Furthermore, EUS-FNA has also facilitates the assessment of the presence or absence of gene mutations. In addition, patients who have a well-differentiated neuroendocrine tumor (NET) showing a Ki-67 index of higher than 20 % according to the WHO 2010 classification, have also been identified, and their responses to treatment were found to be different from those of patients with poorly differentiated neuroendocrine carcinoma (NEC). Therefore, the concept of NET G3 was proposed. Additionally, somatostatin receptor type 2 is expressed in several cases of NET, and somatostatin receptor scintigraphy (111In-octreoscan) has also been approved in Japan. This advancement will undoubtedly contribute to the localization diagnosis, the identification of remote metastasis, and assessments of the treatment responses of PNEN. Finally, regarding the treatment strategy for PNEN, the management of liver metastasis is important. The advent of novel molecular-targeted agents has dramatically improved the prognosis of advanced PNEN. Multimodality therapy that accounts for the tumor stage, degree of tumor differentiation, tumor volume, and speed of tumor growth is required.

[Recurrent Gastric Carcinoma(Endocrine Cell Type)Successfully Treated with Multidisciplinary Therapy - A Case Report].

A 62-year-old woman was diagnosed with carcinoma of the stomach at another hospital. Distal gastrectomy with D2 dissection was performed and she was referred to our hospital. Histopathological and immunopathological examinations showed the tumor to be composed of adenocarcinoma and neuroendocrine carcinoma. The patient was followed until 4 months after the operation when an abdominal computed tomographic(CT)scan showed a metastatic tumor at S2 and S5/6 of the liver. No other organ metastases were found, and a hepatectomy was performed. The primary tumor of the stomach consisted of adenocarcinoma and neuroendocrine carcinoma; however, the resected metastatic liver tumor consisted of only neuroendocrine carcinoma. Liver and lung metastases appeared 2 months after the operation, and we started chemotherapy with VP-16 and cisplatin. After 8 courses of treatment, the lung metastases showed a CR, and the liver metastasis was SD. She is alive without lung metastases 9 months after the hepatectomy.

[A Case of Rectal Cancer Successfully Treated with Surgery and Stereotactic Radiotherapy for Metachronous Lung Metastases].

A 64-year-old woman underwent polypectomy for a rectal polyp(Isp). Pathological findings were invasion of the submucosa( 3,500 mm diameter), and she underwent anterior resection for rectal cancer(RS, pT1b, pN0, cM0, Stage I )without adjuvant chemotherapy. Lung masses were found in her right(8mm)and left lung(7mm). The tumors enlarged during the 4 month follow-up period. We decided to perform left partial pneumonectomy. The tumor was diagnosed as a lung metastasis from colon cancer by pathology. Because the right tumor was located towards the center, performing right pneumonectomy would have been quite invasive and we feared occult metastases. We decided to apply SRT(50 Gy)to the right tumor. The tumor shrunk and became a scar after treatment. There were no complications such as radiation pneumonitis. The patient was in good health without any recurrence for 12 months after SRT. Surgical resection is an optimal method to control lung metastasis from colon cancer if the lesion is operable. However, in the case of a tumor centrally located, surgical resection may cause deterioration of lung function. There are also cases with contraindications for surgery due to co-morbidities. In addition, there is no consensus on observation periods to exclude occult metastases. SRT can be an effective treatment for lung metastases from colon cancer when there are bilateral lung metastases and no metastases outside the lungs.

A case of insulinoma with non-alcoholic fatty liver disease: Roles of hyperphagia and hyperinsulinemia in pathogenesis of the disease.

Nonalcoholic fatty liver disease (NAFLD) is a serious health-related condition all over the world; the number of patients is increasing in Asian countries including Japan. Better understanding of its pathophysiology is required to develop effective therapeutics, as patients may go on to develop non-alcoholic steatohepatitis and hepatocellular carcinomas. While NAFLD is believed to be associated with metabolic risk factors such as obesity, diabetes, and dyslipidemia, its etiology remains largely unknown and the development or co-existence of NAFLD in patients with insulinoma has not been investigated. A 33-year-old male with an insulinoma, who had been hypoglycemic during the previous four years, developed abnormally elevated levels of liver enzymes and histological fatty liver characteristic of NAFLD by the time of admission to our hospital for resection of an insulinoma. His medical records for the previous eight years revealed that his bodyweight had increased gradually from 60 kg to 71 kg for seven years and then acutely increased to 79 kg in the latest one-year period. This sudden increase was thought to be due to the patient's self-described overeating of fruits to forestall hypoglycemia. Fresh fruits are rich in fructose, and the patient's triglycerides, alanine and aspartate transaminases showed an acute increase in the previous one-year period. After resection of the insulinoma, the levels of these parameters all were mostly restored, which suggests that hyperinsulinemia and subsequent hyperphagia played a role in the development of NAFLD in this case. This is the first report of patient with NAFLD and an insulinoma.

Diagnosis of functioning pancreaticoduodenal neuroendocrine tumors.

Functioning pancreaticoduodenal neuroendocrine tumors (PD-NETs) are popular in a textbook, but they are still unfamiliar to a general clinician, and delay of diagnosis or misdiagnosis has been reported even today. It is a consensus that sporadic functioning PD-NET is cured only by surgical resection. So, early detection and early resection is the gold standard for the treatment of functioning PD-NET. Functioning PD-NETs in patients with multiple endocrine neoplasia type 1 (MEN 1) are often multiple. You should check about MEN 1 whenever you encountered multiple PD-NET. They are diagnosed in younger age than sporadic cases. In most cases they are accompanied with numerous microscopic or macroscopic nonfunctioning P-NETs, which are potentially metastatic and the most common cause of death in MEN 1 patients.

Streptozocin chemotherapy for advanced/metastatic well-differentiated neuroendocrine tumors: an analysis of a multi-center survey in Japan.

BACKGROUND: Neuroendocrine tumors (NETs) are believed to be relatively rare and to follow a generally indolent course. However, liver metastases are common in NET patients and the outcome of NET liver metastasis is poor. In Western countries, streptozocin (STZ) has been established as a first-line anticancer drug for unresectable NET; however, STZ cannot be used in daily practice in Japan. The aim of the present study was to determine the status of STZ usage in Japan and to evaluate the effectiveness and safety of STZ chemotherapy in Japanese NET patients. METHODS: A retrospective multi-center survey was conducted. Five institutions with experience performing STZ chemotherapy participated in the study. The patient demographics, tumor characteristics, context of STZ chemotherapy, and patient outcome were collected and assessed. RESULTS: Fifty-four patients were enrolled. The main recipients of STZ chemotherapy were middle-aged patients with pancreatic NET and unresectable liver metastases. The predominant regimen was the weekly/bi-weekly intravenous administration of STZ combined with other oral anticancer agents. STZ monotherapy was used in one-fourth of the patients. The median progression-free and overall survival periods were 11.8 and 38.7 months, respectively, and sustained stable disease was obtained in some selected patients. The adverse events profile was mild and tolerable. CONCLUSIONS: Our survey showed the clinical benefit and safety of STZ therapy for Japanese patients with unresectable NET. Therefore, we recommend that STZ, which is the only cytotoxic agent available against NET, should be used in daily practice in Japan.

Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis.

BACKGROUND: Although neuroendocrine tumors (NETs) are rare, the number of patients with NET is increasing. However, in Japan, there have been no epidemiological studies on NET since 2005; thus, the prevalence of NET remains unknown. METHODS: We reported the epidemiology of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [pancreatic neuroendocrine tumors (PNETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005. Here, we conducted the second nationwide survey on patients with GEP-NETs who received treatment in 2010. RESULTS: A total of 3,379 patients received treatment for PNETs in 2010, representing a 1.2-fold increase in the number of patients from 2005 to 2010. The prevalence was estimated to be 2.69/100,000, with an annual onset incidence of 1.27/100,000 in 2010. Non-functioning tumor (NF)-PNETs comprised 65.5% of cases followed by insulinoma (20.9%) and gastrinoma (8.2%). Interestingly, the number of patients with NF-PNETs increased ~1.8 fold since 2005. A total of 19.9% of patients exhibited distant metastasis at initial diagnosis; 4.3% had complications with multiple endocrine neoplasia type 1 (MEN-1), and only 4.0% had NF-PNETs associated with MEN-1. Meanwhile, an estimated 8,088 patients received treatment for GI-NETs, representing a ~1.8-fold increase since 2005. The prevalence was estimated to be 6.42/100,000, with an annual onset incidence of 3.51/100,000. The locations of GI-NETs varied: foregut, 26.1%; midgut, 3.6%; and hindgut, 70.3%. Distant metastasis and complications with MEN-1 were observed in 6.0 and 0.42% at initial diagnosis, respectively. The frequency of carcinoid syndrome in patients with GI-NETs was 3.2%. CONCLUSION: We clarified the epidemiological changes in GEP-NETs from 2005 to 2010 in Japan.