Mixed neuroendocrine-non-neuroendocrine neoplasm of the colon: case report

Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) is defined as a tumor composed of cells originating from neuroendocrine cells in the embryonic intestine and elements of epithelial adenocarcinoma. To determine the differentiation grade of MiNEN, the proliferation index was used, for which at least 500 cells were examined. MiNEN is a rare neoplasm that is most frequently found in the lower gastrointestinal tract. We present a rare clinical case of surgical treatment of MiNEN of the ascending colon.

Treatment tactics of new NET G3 subgroup in first line of therapy

Considering the fact that the group of neuroendocrine carcinomas (NECs) grade 3 is heterogenous, in the year of 2017 a new subgroup of welldifferentiated neuroendocrine tumors grade 3 (NETs G3) was described. NETs G3 are tumors with more favorable prognosis and less sensitive to platinum-based chemotherapy regimens than NECs, they also have peculiar morphogenetical qualities: lower ki‑67 index (mean 35.0 %), higher somatostatin receptors expression, absence of DAXX/ATRX/MEN 1 genes mutation, p53 expression in the absence of TP53 mutation. Nowadays treatment standard for NETs G3 subgroup is still remain unclear due to lack of prospective clinical trials. At the same time taking in note historical retrospective data, NETs G3 should be treated in line with NETs G1/G2 and only patients with higher ki‑67 index can be treated as NECs with platinum-based chemotherapy. In our non-randomised phase II prospective trial, we accessed the efficacy of different chemotherapy regimens in combination with somatostatin analogues in new NETs G3 subgroup. 153 patients with IHC-confirmed neuroendocrine neoplasm diagnose were included: NETs G3 n = 53 mean ki‑67 36.4 % [21.0–60.0 %], NETs G2 n = 50 mean ki‑67 15.7 % [2.1–20.0 %], NECs n = 50 mean ki‑67 69.0 % [38.0–96.0 %]). Patients from NETs G3 subgroup received 4 chemotherapy regimens: Aranose (n = 19), Aranose (arabinopiranosilmethyl nitrosocarbamide, ALK, – cytostatic drug with a chemical structure similar to Streptozotocin and Nitrosomethylurea, approved in Russian Federation for melanoma and welldifferentiated neuroendocrine tumors treatment), XELOX (n = 8), TemCAP (n = 11), EP/EC (n = 10). mPFS in Aranose-subgroup was 19.3 ± 5.9 months (95 % CI: 7.7–30.8), in XELOX – 10.8 ± 3.6 months (3.7–17.8), in TemCAP – 14.8 ± 4.2 months (6.6–23.1) and in platinum-based regimens – 4.4 ± 1.9 months (0.6–8.2) (p = 0.01). DCR in Aranose subgroup was 73.6 % and ORR – 36.8 %, PDR – 21.1 %, in XELOX subgroup ORR was 62.5 %, SDR was 50.0 % and PDR – 25.0 %, in TemCAP subgroup DCR was 63.6 %, ORR – 9.1 %, PDR – 18.2 % and in platinum-based regimens SDR was 40.0 %, PDR – 50.0 % (p = 0.05).

The Clinical and Prognostic Factors for Biliary Neuroendocrine Neoplasm: A Study Based on the SEER Database

Background: In this study, we aimed at elucidating the postoperative survival and prognostic factors in patients with biliary neuroendocrine neoplasm (NEN).Methods: Cases of biliary system NEN and adenocarcinoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. A propensity score matching (PSM) method was used to adjust baseline differences in clinicopathological characteristics in our analysis. The Kaplan-Meier analysis was carried out for survival analysis. Results：A total of 243 patients with biliary system NEN were enrolled in this study, of which 119 patients’ lesions located in gallbladder, while the others’ located in bile duct. The postoperative overall survival of bile duct NEN is significantly longer than that of gallbladder NEN (P<0.001). For GB-NENs, surgery method (P=0.020) and lymph node metastasis (P=0.018) were identified as independent prognostic factors. In terms of AOV NENs, age (P=0.017) and lymph node metastasis (P=0.006) were identified was independent prognostic factor, while grade (P=0.002) and lymph node metastasis (P=0.036) were identified as independent prognostic factors for EBD NENs. PSM analysis indicated that patients with biliary duct NENs have better postoperative prognosis than biliary duct adenocarcinoma.Conclusions: Patients with NEN have better overall survival than patients with adenocarcinoma. Gallbladder NEN has adverse prognosis than that of biliary tract NEN. Pathological subtype, differentiation, lymph node metastasis, surgery method and lymph node resection could affect postoperative prognosis of gallbladder and biliary tract NEN.

Trends in Incidence and Survival of Patients with Pancreatic Neuroendocrine Neoplasm, 1987–2016

Background. Pancreatic neuroendocrine neoplasm (pNEN), with the lowest 5-year survival rates in neuroendocrine tumors (NETs), exerts great threat to human health. Because large-scale population research aimed at pNEN is rare, we aimed to explore the tendencies and differences of changes in incidences and survival rates of pNEN in each decade from 1987 to 2016 and evaluate the impacts of age, sex, race, socioeconomic status (SES), and grade. Methods. Data on pNEN cases from 1987 to 2016 were extracted from the Surveillance, Epidemiology, and End Results Program (SEER) database. Kaplan–Meier, Cox proportional hazards regression analyses, and relative survival rates (RSRs) were used to identify risk factors for pNEN. Results. The incidence and survival duration of pNEN increase every decade due to medical developments. The disparities of long-term survival in different age, sex, and grade groups expanded over time while that in race and SES groups narrowed. Older age and higher grade are independent risk factors for poorer survival. Females have lower incidence and longer survival than males. Prognosis of Black patients and poor (medium and high poverty) patients improved. Conclusions. This study depicted changes in incidence and survival rates of pNEN over the past three decades and evaluated potential risk factors related to pNEN, benefiting future prediction of vulnerable and clinical options.

Tumor Macroscopic Morphology Is an Important Prognostic Factor in Predicting Chemotherapeutic Efficacy and Clinical Outcomes of Patients With Colorectal Neuroendocrine Neoplasms, One Multicenter Retrospective Cohort Study

Background and AimsLocally advanced and metastatic colorectal neuroendocrine neoplasm (NEN) is a rare disease with a dismal prognosis. We aimed to explore the value of the macroscopic morphology of NENs in the management of TNM stage II-IV colorectal NENs, which has not been fully elucidated in previous reports.MethodsWe retrospectively enrolled 125 eligible patients with TNM stage II-IV colorectal NENs who were diagnosed between 2000 and 2020 from three Chinese hospitals. All were categorized into either protruding or ulcerative NEN groups through endoscopic evaluation of their macroscopic morphology. Clinicopathological data were collected and compared between the two groups. Survival analysis was performed to assess the survival outcomes between the two groups.ResultsA total of 77 and 48 patients had protruding and ulcerative NENs, respectively. Patients with ulcerative NENs had a larger median tumor size (P&lt;0.001) and higher median Ki-67 index (P&lt;0.001), and a larger proportion of these patients had grade G3 disease (P=0.001) and poorly differentiated neoplasms (P=0.001), as well as higher frequencies of T3 and T4 tumors (P=0.006) than patients with protruding NENs. In addition, patients with ulcerative NENs showed a much lower response to first-line chemotherapy [50% (95% CI: 27.3% - 72.7%) versus 20% (95% CI: 3.1% - 36.9%), P=0.03] and a worse 3-year progression-free survival (PFS) rate [19.7% (95% CI: 7.2% - 32.2%) versus 49.5% (95% CI: 37.5% - 61.5%), P=0.001] and 3-year overall survival (OS) rate [30.7% (95% CI: 15.6% - 45.8%) versus 76.9% (95% CI: 66.5% - 87.3%), P&lt;0.001] than those with protruding NENs. The multivariate analysis results indicated that the macroscopic shape of NENs was an independent prognostic factor affecting both PFS (HR = 1.760, 95% CI: 1.024 – 3.026, P = 0.04) and OS (HR = 2.280, 95% CI: 1.123 – 4.628, P = 0.02).ConclusionsUlcerative NENs were more malignant and chemotherapy resistant than protruding NENs. Tumor macroscopic morphology is a valuable prognostic factor for stage II-IV colorectal NENs.

PD-1 Blockade Elicits Ongoing Remission in Two Cases of Refractory Microsatellite-Stable Cancer Harboring a POLE Mutation

Introduction: In the last decade immune checkpoint therapy has led to a break-through in the treatment of cancer across all entities, while molecular markers have grown in importance for the choice of the appropriate chemotherapeutic agents. Accordingly, in 2017 the U.S. Food and Drug Administration (FDA) approved the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, a tissue agnostic cancer drug, for the treatment of cancer that displays microsatellite instability (MSI), regardless of histological entity and site of origin. However, a growing number of studies report that cases of microsatellite stable (MSS) tumors harboring a DNA polymerase ε (POLE) mutation, a gene associated with proofreading deficiency, leading to an increased tumor mutational burden (TMB), likewise benefit from immune checkpoint therapy. Case report: Here we present two cases - one advanced adenocarcinoma of the ileum and one mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN), both MSS and carrying a POLE mutation - that were refractory to initial chemotherapy but responded on immunotherapy with pembrolizumab. Conclusion: Colorectal cancer is a clinically and molecularly heterogenic disease which requires comprehensive genetic testing to screen for rare genetic alterations like POLE mutations to detect tumors harboring an ultramutator phenotype especially in patients that are refractory to standard chemotherapy.

Gallium-68-somatostatin receptor PET/CT parameters as potential prognosticators for clinical time to progression after peptide receptor radionuclide therapy: a cohort study

Background Early [68Ga]Ga-DOTA-TOC PET/CT imaging after peptide receptor radionuclide therapy (PRRT) in neuroendocrine neoplasm patients is often used as a prognosticator for survival, but lacks validity. This study investigates the prognostic value of changes in PET parameters after PRRT. Methods Baseline and follow-up [68Ga]Ga-DOTA-TOC PET/CT scans of all patients treated with PRRT were delineated automatically. Total lesion somatostatin receptor expression (TL-SSTR) and somatostatin receptor expressing tumor volume (SSTR-TV) were used as covariates in Cox proportional hazard models to predict time-to-new treatment. Results In twenty patients, median time-to-new treatment was 19.3 months (range [3.8; 36.2]). Absolute and percentual changes in both PET parameters were not associated with time-to-new treatment. A significant relation between independent baseline and follow-up SSTR-TV and follow-up TL-SSTR, and time-to-new treatment was identified. Conclusions Automatically derived [68Ga]Ga-DOTA-TOC PET/CT parameters are easy to acquire and may be of prognostic value after completing PRRT. Acquiring SSTR-TV or TL-SSTR parameters at baseline and during follow-up can be of value in identifying a patient’s prognosis.