Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of malignancies that originate from the diffuse neuroendocrine cell system of the pancreas and gastrointestinal tract and have increasingly increased in number over the decades. GEP-NENs are roughly classified into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas; it is essential to understand the pathological classification according to the mitotic count and Ki67 proliferation index. In addition, with the advent of molecular-targeted drugs and somatostatin analogs and advances in endoscopic and surgical treatments, the multidisciplinary treatment of GEP-NENs has made great progress. In the management of GEP-NENs, accurate diagnosis is key for the proper selection among these diversified treatment methods. The evaluation of hormone-producing ability, diagnostic imaging, and histological diagnosis is central. Advances in the study of the genetic landscape have led to deeper understanding of tumor biology; it has also become possible to identify druggable mutations and predict therapeutic effects. Liquid biopsy, based on blood mRNA expression for GEP-NENs, has been developed, and is useful not only for early detection but also for assessing minimal residual disease after surgery and prediction of therapeutic effects. This review outlines the updates and future prospects of the epidemiology, diagnosis, and management of GEP-NENs.

BACKGROUND: Delayed postpolypectomy bleeding occurs more frequently after hot resection than after cold resection. OBJECTIVE: To elucidate the underlying mechanism, we performed a histological comparison of tissue after cold and hot snare resections. DESIGN: This is a prospective study, registered in the University Hospital Medical Information Network (UMIN000020104). SETTING: This study was conducted at Aizu Medical Center, Fukushima Medical University, Japan. PATIENTS: Fifteen patients scheduled to undergo resection of colorectal cancer were enrolled. INTERVENTION: On the day before surgery, 2 mucosal resections (hot and cold) of normal mucosa were performed on each patient using the same snare without saline injection. The difference was only the application of electrocautery or not. Resection sites were placed close to the cancer to be included in the surgical specimen. MAIN OUTCOME MEASURES: The primary outcome measure was the depth of destruction. Secondary outcome measures included the width of destruction, depth of the remaining submucosa, and number of vessels remaining at the resection sites. The number and diameter of vessels in undamaged submucosa were also evaluated. RESULTS: All cold resections were limited to the shallow submucosa, whereas 60% of hot resections advanced to the deep submucosa and 20% to the muscularis propria (p < 0.001). There was no significant difference in the width of destruction. The number of remaining large vessels after hot resections trended toward fewer (p = 0.15) with a decreased depth of remaining submucosa (p = 0.007). In the deep submucosa, the vessel diameter was larger (p < 0.001) and the number of large vessels was greater (p = 0.018). LIMITATIONS: Histological assessment was not blinded to the 2 reviewers. Normal mucosa was used instead of adenomatous tissue. CONCLUSIONS: Hot resection caused damage to deeper layers involving more large vessels. This may explain the mechanism for the reduced incidence of hemorrhage after cold snare polypectomy. See Video Abstract at http://links.lww.com/DCR/A631.

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (PIK3CA, 32%; TP53, 24%) and distinct (SMAD4, 20%; RET, 16%; EGFR, 12%; APC, 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and RB1 mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.

Background. Standard treatment of early gastric cancer (EGC) after endoscopic resection with risk factors of nodal metastases and incomplete resection is controversial. We investigated optimal management for the patients with potentially noncurative EGC after endoscopic resection.Methods. We retrospectively examined clinicopathological data and surgical outcomes of all patients with clinically solitary gastric adenocarcinoma who underwent curative surgery after a single peroral endoscopic resection at the Digestive Disease Center of Showa University Northern Yokohama Hospital between April 2001 and December 2012. Fisher's exact test was used for univariate analysis. For multivariate analysis, stepwise multiple linear regression was used to identify independent predictors related to lymph node metastasis and remnant of primary tumor.Results. A total of 41 patients were studied. Four patients (9.8%) had lymph node metastases. Primary tumors remained in 6 patients (14.6%). Only venous invasion was statistically significant to lymph node metastasis (P=0.017). With respect to remnant of the primary tumor, pT1b2 tumor invasion (P=0.015) and horizontal margin (P=0.013) were statistically significant.Conclusions. Surgery with limited lymphadenectomy is recommended for tumors with venous invasion or pT1b2 tumor invasion, and additional endoscopic resection may be allowed for tumors with horizontal involvement.

The neutrophil‑to‑lymphocyte ratio (NLR) has been reported to be an independent prognostic factor of unresectable advanced or metastatic colorectal cancer (uCRC). However, few studies have documented changes in NLR during chemotherapy. The current study analyzed whether a change in NLR during chemotherapy in patients with uCRC could be used as a prognostic biomarker. The present retrospective study enrolled 71 patients who received first‑line chemotherapy for uCRC between April 2012 and April 2019. The exclusion criteria were as follows: Acute infection or systemic inflammatory disease, duration of first‑line chemotherapy <3 months, curative resection after chemotherapy and treatment with granulocyte‑colony stimulating factor within 1 month. NLR, Lymphocyte‑to‑monocyte ratio (LMR), platelet‑to‑­lymphocyte ratio (PLR), lactate dehydrogenase, alkaline phosphatase (ALP), albumin, carcinoembryonic antigen (CEA) and carbohydrate antigen 19‑9 (CA19‑9) levels were calculated before chemotherapy and at 3 months after chemotherapy. Among these laboratory data, NLR, PLR, ALP, CEA and CA19‑9 levels were significantly decreased during chemotherapy. For Cox univariate analyses, these five data makers were divided into two groups: Decreased and increased (comparing before and at 3 months after chemotherapy). Only the change in NLR was significantly associated with overall survival (P=0.0002). Furthermore, the overall survival (P<0.0001) and progression‑free survival (P=0.0041) of patients with decreased NLR was increased compared with patients with increased NLR. The change in NLR from pre‑chemotherapy to 3 months following chemotherapy was determined to be a predictor of prognosis in patients with uCRC. The ability to predict prognosis at an early phase of chemotherapy may provide useful information for the selection of subsequent treatment and may improve the quality of patient life.