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Open access

Chao-bin He, Yu Zhang, Zhi-yuan Cai, and Xiao-jun Lin

Aim

The role of surgery in the treatment of metastatic pancreatic neuroendocrine tumors (PNETs) was controversial. The objectives of this study were to illustrate the impact of surgery in improving the prognosis of patients with metastatic PNETs and build nomograms to predict overall survival (OS) and cancer-specific survival (CSS) based on a large population-based cohort.

Methods

Patients diagnosed with metastatic PNETs between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Nomograms for estimating OS and CSS were established based on Cox regression model and Fine and Grey’s model. The precision of the nomograms was evaluated and compared using concordance index (C-index) and the area under receiver operating characteristic (ROC) curve (AUC).

Results

The study cohort included 1966 patients with metastatic PNETs. It was shown that the surgery provided survival benefit for all groups of patients with metastatic PNETs. In the whole study cohort, 1-, 2- and 3-year OS and CSS were 51.5, 37.1 and 29.4% and 53.0, 38.9 and 31.1%, respectively. The established nomograms were well calibrated, and had good discriminative ability, with C-indexes of 0.773 for OS prediction and 0.774 for CSS prediction.

Conclusions

Patients with metastatic PNETs could benefit from surgery when the surgery tolerance was acceptable. The established nomograms could stratify patients who were categorized as tumor-node-metastasis (TNM) IV stage into groups with diverse prognoses, showing better discrimination and calibration of the established nomograms, compared with 8th TNM stage system in predicting OS and CSS for patients with metastatic PNETs.

Open access

Norra Kwong, Ellen Marqusee, Michael S Gordon, P Reed Larsen, Jeffrey R Garber, Matthew I Kim, and Erik K Alexander

Well-differentiated thyroid carcinoma (WDTC) generally has a favorable prognosis. However, patients with distant metastatic disease experience progression of disease with a higher mortality. A subset of patients not previously described may challenge the conventional dogma regarding the progressive nature of all metastatic WDTC. Through analysis of our database, we identified patients with distant metastatic WDTC and persistent, minimally progressive disease. In all patients, persistent metastatic disease was confirmed via tissue biopsy, abnormal PET scan, and/or biochemical elevations in thyroglobulin or antibody levels. Progression of disease was monitored clinically and with repeat imaging. We describe five patients with WDTC and pulmonary metastases, aged 8–43 years at diagnosis. All patients underwent initial surgery and radioactive iodine (RAI) ablation, with some receiving multiple treatments. Persistent pulmonary metastatic disease was confirmed over decades (mean 22 years, range 8–42 years) with minimal progression despite no further treatment beyond thyroid hormone suppression. Persistent disease was biopsy-proven in all patients at a mean of 9.6 years from last RAI treatment. All patients had elevated thyroglobulin or anti-thyroglobulin antibody levels, while three demonstrated metabolically active disease with positive FDG uptake on PET scan, and one patient with persistent radioactive iodine avid pulmonary metastasis 36 years after her last RAI treatment. This case series demonstrates that some patients with distant metastases, even if metabolically active and radioactive iodine resistant, remain stable for decades without further treatment. Clinical awareness of such patients and continual reassessment of disease risk following initial therapy are crucial as aggressive treatment may not be necessary.

Open access

H Vlaardingerbroek, E L T van den Akker, and A C S Hokken-Koelega

Obesity is reaching an epidemic state and has a major impact on health and economy. In most cases, obesity is caused by lifestyle factors. However, the risk of becoming obese differs highly between people. Individual's differences in lifestyle, genetic, and neuroendocrine factors play a role in satiety, hunger and regulation of body weight. In a small percentage of children and adults with obesity, an underlying hormonal or genetic cause can be found. The aim of this review is to present and compare data on the extreme ends of the obesity and undernutrition spectrum in patients with Prader–Willi syndrome (PWS), Bardet–Biedl syndrome (BBS), acquired hypothalamic obesity in craniopharyngioma patients, and anorexia nervosa. This may give more insight into the role of neuroendocrine factors and might give direction for future research in conditions of severe obesity and underweight.

Open access

David T Broome, Gauri B Gadre, Ehsan Fayazzadeh, James F Bena, and Christian Nasr

Objective:

To identify novel prognostic risk factors and compare them with other known prognostic risk factors in follicular-cell-derived thyroid carcinoma (FDTC) with distant metastases.

Methods:

A retrospective review was conducted of adult patients with metastatic FDTC seen at a tertiary care center between January 1990 and December 2010. A 15-year Kaplan–Meier survival estimate was created for overall survival (OS) and cancer-specific survival (CSS). Hazard ratios (HR) and P values from Cox proportional hazard models were used with a 95% CI.

Results:

There were 143 patients (60.1% male, 39.9% female), of whom 104 (72.7%) patients had papillary, 30 (21.0%) had follicular, 5 (3.5%) had poorly differentiated, and 4 (2.8%) had Hürthle cell cancers. Median length of follow-up was 80.0 months (range 1.0–564.0). The 15-year mortality rate was 32.2% and cancer-specific mortality was 25.2%, with OS and CSS having the same risk factors. Lung was the most common site of metastases in 53 patients (37.1%), and patients with pleural effusions had significantly lower CSS (HR = 5.21, CI = 1.79–15.12). Additional risk factors for a decreased CSS included: older age upon diagnosis (>45 years, HR = 4.15, CI = 1.43–12.02), multiple metastatic locations (HR = 3.75, CI = 1.32–10.67), and incomplete/unknown tumor resection (HR = 2.35, CI = 1.18–4.67).

Conclusion:

This study is the first to demonstrate that pleural effusion is a poor prognostic sign in patients with FDTC with distant metastases and compare this risk with other accepted prognostic variables.

Open access

B C M Hermans, J L Derks, H J M Groen, J A Stigt, R J van Suylen, L M Hillen, E C van den Broek, E J M Speel, and A-M C Dingemans

Introduction

Stage IV large cell neuroendocrine carcinoma (LCNEC) of the lung generally presents as disseminated and aggressive disease with a Ki-67 proliferation index (PI) 40–80%. LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small-cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small-cell lung carcinoma (NSCLC)-like). Here we evaluated 11 LCNEC patients with only a solitary brain metastasis and evaluate phenotype, genotype and follow-up.

Methods

Eleven LCNEC patients with solitary brain metastases were analyzed. Clinical characteristics and survival data were retrieved from medical records. Pathological analysis included histomorphological analysis, immunohistochemistry (pRB and Ki-67 PI) and next-generation sequencing (TP53, RB1, STK11, KEAP1 and MEN1).

Results

All patients had N0 or N1 disease. Median overall survival (OS) was 12 months (95% confidence interval (CI) 5.5–18.5 months). Mean Ki-67 PI was 59% (range 15–100%). In 6/11 LCNEC Ki-67 PI was ≤40%. OS was longer for Ki-67 ≤40% compared to >40% (17 months (95% CI 11–23 months) vs 5 months (95% CI 0.7–9 months), P = 0.007). Two patients were still alive at follow-up after 86 and 103 months, both had Ki-67 ≤40%. 8/11 patients could be subclassified, and both SCLC-like (n = 6) and NSCLC-like (n = 2) subtypes were present. No MEN1 mutation was found.

Conclusion

Stage IV LCNEC with a solitary brain metastasis and N0/N1 disease show in the majority of cases Ki-67 PI ≤40% and prolonged survival, distinguishing them from general LCNEC. This unique subgroup can be both of the SCLC-like and NSCLC-like subtype.

Open access

T Szarvas, B Jardin-Watelet, N Bourgoin, M J Hoffmann, P Nyirády, C Oláh, T Széll, A Csizmarik, B Hadaschik, and H Reis

Recently, a neuroendocrine-like molecular subtype has been discovered in muscle-invasive urothelial bladder cancer (BC). Chromogranin A (CGA) is a widely used tissue and serum marker in neuroendocrine tumors. Our aim was to evaluate serum CGA (sCGA) concentrations and their associations with clinical and follow-up data in BC and renal cell carcinoma (RCC). sCGA concentrations were analyzed in the following cohorts: (1) BC training set (n = 188), (2) BC validation set (n = 125), (3) RCC patients (n = 77), (4) healthy controls (n = 97). CGA immunohistochemistry and RT-qPCR analyses were performed in 20 selected FFPE and 29 frozen BC tissue samples. Acquired data were correlated with clinicopathological parameters including comorbidities with known effect on sCGA as well as with patients’ follow-up data. sCGA levels were significantly higher in BC but not in RCC patients compared to healthy controls. High sCGA levels were independently associated with poor overall and disease-specific survival both in the BC training (P < 0.001, P = 0.002) and validation set (P = 0.009, P = 0.017). sCGA levels were inversely correlated with glomerulus filtrating rate (GFR) and linearly correlated with creatinine clearance and urea concentrations. These correlations were not related to the prognostic value of sCGA. Tissue CGA levels were low to absent independently of sCGA concentrations. Our results demonstrate elevated levels and an independent prognostic value for sCGA in BC but not in RCC. Despite the significant correlation between sCGA and GFR, the prognostic relevance of sCGA seems not related to impaired renal function or other comorbidities.

Open access

Hanbaro Kim, Ki Byung Song, Dae Wook Hwang, Jae Hoon Lee, Shadi Alshammary, and Song Cheol Kim

This study aimed to evaluate the evolving trends in clinicopathological features of pancreatic neuroendocrine tumors and to analyze the predictors of recurrence after curative resection. Data collected retrospectively from a single center between January 1990 and December 2017 were analyzed. Patients were categorized chronologically into three groups for evolving time-trend analysis. Overall, 542 patients (300 female, 55.4%) underwent surgical resection for pancreatic neuroendocrine tumors, including 435 (80.3%) with non-functional tumors. Time-trend analysis revealed that the surgically resected pancreatic neuroendocrine tumor number increased consistently; however, the incidental non-functional pancreatic neuroendocrine tumor number also increased over time (P < 0.001). The 5- and 10-year disease-free survival rates were 86.4 and 81.3%, respectively. The overall recurrence rate was 13.7%, and the most common site of recurrence was the liver. The median time to recurrence after primary surgery was 19.0 (range 0.8–236.3) months, and the median survival time after recurrence was 22.6 (range 0.4–126.9) months. On multivariate analysis, grade G3 pancreatic neuroendocrine tumors (hazard ratio 4.51; P < 0.001), lymph node metastasis (hazard ratio 2.46; P = 0.009), lymphovascular invasion (hazard ratio 3.62; P = 0.004), perineural invasion (hazard ratio 2.61; P = 0.004) and resection margin (hazard ratio 4.20; P = 0.003) were independent prognostic factors of disease-free survival. The surgically resected pancreatic neuroendocrine tumor number increased over time mainly because of an increase in incidentally discovered non-functional pancreatic neuroendocrine tumors. Grade G3 pancreatic neuroendocrine tumors, lymph node metastasis, lymphovascular invasion, perineural invasion and a positive resection margin were significant predictors of worse disease-free survival in patients with surgically resected pancreatic neuroendocrine tumors.

Open access

Elham Barazeghi, Per Hellman, Gunnar Westin, and Peter Stålberg

Small intestinal neuroendocrine tumors (SI-NETs) are small, slow growing neoplasms with loss of one copy of chromosome 18 as a common event. Frequently mutated genes on chromosome 18 or elsewhere have not been found so far. The aim of this study was to investigate a possible tumor suppressor role of the transmembrane receptor type tyrosine phosphatase PTPµ (PTPRM at 18p11) in SI-NETs. Immunohistochemistry, quantitative RT-PCR, colony formation assay and quantitative CpG methylation analysis by pyrosequencing were performed. Undetectable/very low levels of PTPRM or aberrant pattern of immunostaining, with both negative and positive areas, were detected in the majority of tumors (33/40), and a significantly reduced mRNA expression in metastases compared to primary tumors was observed. Both the DNA methylation inhibitor 5-aza-2′-deoxycytidine and the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) induced PTPRM expression in CNDT2.5 and KRJ-I SI-NET cells. CpG methylation of upstream regulatory regions, the promoter region and the exon 1/intron 1 boundary was detected by pyrosequencing analysis of the two cell lines and not in the analyzed SI-NETs. Overexpression of PTPRM in the SI-NET cell lines reduced cell growth and cell proliferation and induced apoptosis. The tyrosine phosphatase activity of PTPRM was not involved in cell growth inhibition. The results support a role for PTPRM as a dysregulated candidate tumor suppressor gene in SI-NETs and further analyses of the involved mechanisms are warranted.

Open access

Juan Carlos Juárez-Cruz, Miriam Daniela Zuñiga-Eulogio, Monserrat Olea-Flores, Eduardo Castañeda-Saucedo, Miguel Ángel Mendoza-Catalán, Carlos Ortuño-Pineda, Ma Elena Moreno-Godínez, Sócrates Villegas-Comonfort, Teresita Padilla-Benavides, and Napoleón Navarro-Tito

Breast cancer is the most common invasive neoplasia, and the second leading cause of the cancer deaths in women worldwide. Mammary tumorigenesis is severely linked to obesity, one potential connection is leptin. Leptin is a hormone secreted by adipocytes, which contributes to the progression of breast cancer. Cell migration, metalloproteases secretion, and invasion are cellular processes associated with various stages of metastasis. These processes are regulated by the kinases FAK and Src. In this study, we utilized the breast cancer cell lines MCF7 and MDA-MB-231 to determine the effect of leptin on FAK and Src kinases activation, cell migration, metalloprotease secretion, and invasion. We found that leptin activates FAK and Src and induces the localization of FAK to the focal adhesions. Interestingly, leptin promotes the activation of FAK through a Src- and STAT3-dependent canonical pathway. Specific inhibitors of FAK, Src and STAT3 showed that the effect exerted by leptin in cell migration in breast cancer cells is dependent on these proteins. Moreover, we established that leptin promotes the secretion of the extracellular matrix remodelers, MMP-2 and MMP-9 and invasion in a FAK and Src-dependent manner. Our findings strongly suggest that leptin promotes the development of a more aggressive invasive phenotype in mammary cancer cells.

Open access

Shan Wu, Jianjun Zhou, Jing Guo, Zhan Hua, Jianchen Li, and Zai Wang

Angiogenesis has a pivotal role in the growth and metastasis of pancreatic neuroendocrine tumors (PNETs). Apatinib inhibits angiogenesis as a highly selective KDR inhibitor and has been used to treat advanced gastric cancer and malignancies in clinical settings. However, the efficacy of apatinib in PNETs remains unclear. The aim of this study was to compare the antitumor efficacy of apatinib with that of the standard PNET drug sunitinib in our subcutaneous and liver metastasis models of insulinoma and non-functional PNET. Our results revealed that apatinib had a generally comparable or even superior antitumor effect to that of sunitinib on primary PNET, and it inhibited angiogenesis without directly causing tumor cell cytotoxicity. Apatinib inhibited the tumor in a dose-dependent manner, and the high dose was well tolerated in mice. We also found that the apatinib efficacy in liver metastasis models was cell-type (disease) selective. Although apatinib efficiently inhibited INR1G9-represented non-functional PNET liver metastasis, it led to the emergence of a hypoxic area in the INS-1-represented insulinoma and promoted liver metastasis. Our study demonstrated that apatinib has promise for clinical applications in certain malignant PNETs, and the application of anti-angiogenesis drugs to benign insulinomas may require careful consideration.