Prognosis after surgery for multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors:Functionality matters

Background: Metastasized pancreatic neuroendocrine tumors are the leading cause of death in patients with multiple endocrine neoplasia type 1. Aside from tumor size, prognostic factors of pancreatic neuroendocrine tumors are largely unknown. The present study aimed to assess whether the prognosis of patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors differs from those with resected multiple endocrine neoplasia type 1-related insulinomas and assessed factors associated with prognosis.Methods: Patients who underwent resection of a multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors between 1990 and 2016 were identified in 2 databases: the DutchMEN Study Group and the International MEN1 Insulinoma Study Group databases. Cox regression was performed to compare liver metastases-free survival of patients with a nonfunctioning pancreatic neuroendocrine tumors versus those with an insulinoma and to identify factors associated with liver metastases-free survival.Results: Out of 153 patients with multiple endocrine neoplasia type 1, 61 underwent resection for a nonfunctioning pancreatic neuroendocrine tumor and 92 for an insulinoma. Of the patients with resected lymph nodes, 56% (18/32) of nonfunctioning pancreatic neuroendocrine tumors had lymph node metastases compared to 10% (4/41) of insulinomas (P =.001). Estimated 10-year liver metastases-free survival was 63% (95% confidence interval 42%–76%) for nonfunctioning pancreatic neuroendocrine tumors and 87% (72%–91%) for insulinomas. After adjustment for size, World Health Organization tumor grade, and age, nonfunctioning pancreatic neuroendocrine tumors had an increased risk for liver metastases or death (hazard ratio 3.04 [1.47–6.30]). In pancreatic neuroendocrine tumors ≥2 cm, nonfunctioning pancreatic neuroendocrine tumors (2.99 [1.22–7.33]) and World Health Organization grade 2 (2.95 [1.02–8.50]) were associated with liver metastases-free survival.Conclusion: Patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors had a significantly lower liver metastases-free survival than patients with insulinomas. Postoperative counseling and follow-up regimens should be tumor type specific and at least consider size and World Health Organization grade.</p

Conceptualizing and measuring distance in international business research:Recurring questions and best practice guidelines

Distance is a central concept in international business research, yet there is debate about the construct as well as its operationalization. In this editorial, we address three of the most important recurring questions posed by authors, editors, and reviewers by examining the theory, methods, and data of distance research. We discuss (1) how to theorize on distance, and (2) what method and (3) what data to use when constructing a distance index. We develop practical recommendations grounded in theory, illustrating and supporting them by calculating cross-country distance indices for all available country pairs and two of the most used distance indices: cultural and institutional. We show that, whereas a specific method to calculate distance may matter to some extent, the choice for a specific cultural or institutional framework to measure cultural or institutional distance has a major impact on country-pair distances. Overall, this editorial highlights the importance of matching data and method to the theoretical argument.</p

Prognosis after surgery for multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: Functionality matters

Background: Metastasized pancreatic neuroendocrine tumors are the leading cause of death in patients with multiple endocrine neoplasia type 1. Aside from tumor size, prognostic factors of pancreatic neuroendocrine tumors are largely unknown. The present study aimed to assess whether the prognosis of patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors differs from those with resected multiple endocrine neoplasia type 1-related insulinomas and assessed factors associated with prognosis. Methods: Patients who underwent resection of a multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors between 1990 and 2016 were identified in 2 databases: the DutchMEN Study Group and the International MEN1 Insulinoma Study Group databases. Cox regression was performed to compare liver metastases-free survival of patients with a nonfunctioning pancreatic neuroendocrine tumors versus those with an insulinoma and to identify factors associated with liver metastases-free survival. Results: Out of 153 patients with multiple endocrine neoplasia type 1, 61 underwent resection for a nonfunctioning pancreatic neuroendocrine tumor and 92 for an insulinoma. Of the patients with resected lymph nodes, 56% (18/32) of nonfunctioning pancreatic neuroendocrine tumors had lymph node metastases compared to 10% (4/41) of insulinomas (P = .001). Estimated 10-year liver metastases-free survival was 63% (95% confidence interval 42%–76%) for nonfunctioning pancreatic neuroendocrine tumors and 87% (72%–91%) for insulinomas. After adjustment for size, World Health Organization tumor grade, and age, nonfunctioning pancreatic neuroendocrine tumors had an increased risk for liver metastases or death (hazard ratio 3.04 [1.47–6.30]). In pancreatic neuroendocrine tumors ≥2 cm, nonfunctioning pancreatic neuroendocrine tumors (2.99 [1.22–7.33]) and World Health Organization grade 2 (2.95 [1.02–8.50]) were associated with liver metastases-free survival. Conclusion: Patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors had a significantly lower liver metastases-free survival than patients with insulinomas. Postoperative counseling and follow-up regimens should be tumor type specific and at least consider size and World Health Organization grade

Prognosis after surgery for multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: Functionality matters

Background: Metastasized pancreatic neuroendocrine tumors are the leading cause of death in patients with multiple endocrine neoplasia type 1. Aside from tumor size, prognostic factors of pancreatic neuroendocrine tumors are largely unknown. The present study aimed to assess whether the prognosis of patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors differs from those with resected multiple endocrine neoplasia type 1-related insulinomas and assessed factors associated with prognosis. Methods: Patients who underwent resection of a multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors between 1990 and 2016 were identified in 2 databases: the DutchMEN Study Group and the International MEN1 Insulinoma Study Group databases. Cox regression was performed to compare liver metastases-free survival of patients with a nonfunctioning pancreatic neuroendocrine tumors versus those with an insulinoma and to identify factors associated with liver metastases-free survival. Results: Out of 153 patients with multiple endocrine neoplasia type 1, 61 underwent resection for a nonfunctioning pancreatic neuroendocrine tumor and 92 for an insulinoma. Of the patients with resected lymph nodes, 56% (18/32) of nonfunctioning pancreatic neuroendocrine tumors had lymph node metastases compared to 10% (4/41) of insulinomas (P =.001). Estimated 10-year liver metastases-free survival was 63% (95% confidence interval 42%–76%) for nonfunctioning pancreatic neuroendocrine tumors and 87% (72%–91%) for insulinomas. After adjustment for size, World Health Organization tumor grade, and age, nonfunctioning pancreatic neuroendocrine tumors had an increased risk for liver metastases or death (hazard ratio 3.04 [1.47–6.30]). In pancreatic neuroendocrine tumors ≥2 cm, nonfunctioning pancreatic neuroendocrine tumors (2.99 [1.22–7.33]) and World Health Organization grade 2 (2.95 [1.02–8.50]) were associated with liver metastases-free survival. Conclusion: Patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors had a significantly lower liver metastases-free survival than patients with insulinomas. Postoperative counseling and follow-up regimens should be tumor type specific and at least consider size and World Health Organization grade

Prognosis after surgery for multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: Functionality matters

Background: Metastasized pancreatic neuroendocrine tumors are the leading cause of death in patients with multiple endocrine neoplasia type 1. Aside from tumor size, prognostic factors of pancreatic neuroendocrine tumors are largely unknown. The present study aimed to assess whether the prognosis of patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors differs from those with resected multiple endocrine neoplasia type 1-related insulinomas and assessed factors associated with prognosis. Methods: Patients who underwent resection of a multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors between 1990 and 2016 were identified in 2 databases: the DutchMEN Study Group and the International MEN1 Insulinoma Study Group databases. Cox regression was performed to compare liver metastases-free survival of patients with a nonfunctioning pancreatic neuroendocrine tumors versus those with an insulinoma and to identify factors associated with liver metastases-free survival. Results: Out of 153 patients with multiple endocrine neoplasia type 1, 61 underwent resection for a nonfunctioning pancreatic neuroendocrine tumor and 92 for an insulinoma. Of the patients with resected lymph nodes, 56% (18/32) of nonfunctioning pancreatic neuroendocrine tumors had lymph node metastases compared to 10% (4/41) of insulinomas (P =.001). Estimated 10-year liver metastases-free survival was 63% (95% confidence interval 42%–76%) for nonfunctioning pancreatic neuroendocrine tumors and 87% (72%–91%) for insulinomas. After adjustment for size, World Health Organization tumor grade, and age, nonfunctioning pancreatic neuroendocrine tumors had an increased risk for liver metastases or death (hazard ratio 3.04 [1.47–6.30]). In pancreatic neuroendocrine tumors ≥2 cm, nonfunctioning pancreatic neuroendocrine tumors (2.99 [1.22–7.33]) and World Health Organization grade 2 (2.95 [1.02–8.50]) were associated with liver metastases-free survival. Conclusion: Patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors had a significantly lower liver metastases-free survival than patients with insulinomas. Postoperative counseling and follow-up regimens should be tumor type specific and at least consider size and World Health Organization grade

Early and Late Complications After Surgery for MEN1-related Nonfunctioning Pancreatic Neuroendocrine Tumors

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Qualitative elastography can replace thyroid nodule fine-needle aspiration in patients with soft thyroid nodules. A systematic review and meta-analysis

Context: Only a minority of thyroid nodules is malignant; nevertheless, many invasive diagnostic procedures are performed to distinguish between benign and malignant nodules. Qualitative ultrasound elastography is a non-invasive technique to evaluate thyroid nodules. Objective: To investigate the diagnostic value of qualitative elastography in distinguishing benign from malignant thyroid nodules in patients referred for fine-needle aspiration (FNA). Data sources: A systematic literature search (PubMed, Embase and Cochrane Library) was performed. Study selection: Included studies reported thyroid nodule elastography color scores and the related cytologic or histologic findings in patients with a thyroid nodule referred for FNA. Data extraction: Two independent reviewers extracted study data and assessed study quality. Pooled sensitivities and specificities of different populations were calculated using a bivariate Bayesian framework. Data Synthesis: Twenty studies including thyroid nodules were analyzed. Pooled results of elastography indicate a summary sensitivity of 85% (95% confidence interval [CI], 79-90%) and specificity of 80% (95% CI, 73-86%). The respective pooled negative predictive and positive predictive values were 97% (95% CI, 94-98%) and 40% (95% CI, 34-48%). The pretest probability of a benign nodule was 82%. Only 3.7% of the false-negative nodules was a follicular thyroid carcinoma. A pooled negative predictive value of 99% (95% CI, 97-100%) was found when only complete soft nodules (Asteria elastography 1) were classified as benign, which included 14% of the studied population. Conclusions: Elastography has a fair specificity and sensitivity for diagnostic accuracy. Its major strength entails the detection of benignity, especially when only completely soft nodules are qualified as benign. The outcomes of our analysis show that FNA could safely be omitted in patients referred for analysis of their thyroid nodule when elastography shows it to be completely soft (Asteria elastography 1). This could prevent unnecessary invasive diagnostic procedures in a substantial portion of patients

Digital PCR-Based T-cell Quantification-Assisted Deconvolution of the Microenvironment Reveals that Activated Macrophages Drive Tumor Inflammation in Uveal Melanoma

Uveal melanoma progression can be predicted by gene expression profiles enabling a clear subdivision between tumors with a good (class I) and a poor (class II) prognosis. Poor prognosis uveal melanoma can be subdivided by expression of immune-related genes; however, it is unclear whether this subclassification is justified; therefore, T cells in uveal melanoma specimens were quantified using a digital PCR approach. Absolute T-cell quantification revealed that T-cell influx is present in all uveal melanomas associated with a poor prognosis. However, this infiltrate is only accompanied by differential immune-related gene expression profiles in uveal melanoma with the highest T-cell infiltrate. Molecular deconvolution of the immune profile revealed that a large proportion of the T-cell-related gene expression signature does not originate from lymphocytes but is derived from other immune cells, especially macrophages. Expression of the lymphocyte-homing chemokine CXCL10 by activated macrophages correlated with T-cell infiltration and thereby explains the correlation of T-cell numbers and macrophages. This was validated by in situ analysis of CXCL10 in uveal melanoma tissue with high T-cell counts. Surprisingly, CXCL10 or any of the other genes in the activated macrophage-cluster was correlated with reduced survival due to uveal melanoma metastasis. This effect was independent of the T-cell infiltrate, which reveals a role for activated macrophages in metastasis formation independent of their role in tumor inflammation.Implications: The current report uses an innovative digital PCR method to study the immune environment and demonstrates that absolute T-cell quantification and expression profiles can dissect disparate immune components. Mol Cancer Res; 1-10. ©2018 AACR

Prognostic Factors for Survival of MEN1 Patients with Duodenopancreatic Tumors Metastatic to the Liver: Results from the DMSG

Objective: Duodenopancreatic neuroendocrine tumors (DP-NETs) develop in a majority of patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Overall survival (OS) and prognostic factors for patients with liver metastases from DP-NETs are not known. Methods: This was a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population treated between 1990 and 2014. OS was assessed with time to event analysis, and prognostic factors were evaluated. Results: A total of 56% of the MEN1 patients (n = 220) were diagnosed with a DP-NET, of who 34 (15%) developed DP-NET liver metastases. Median age at liver metastases diagnosis was 53 years (range 31-74). Of those patients, 16 patients (47%) had died after a median follow up of 4 years (range 0.3-12.3). OS at 2, 5, and 10 years were 91%, 65%, and 50%, respectively. A trend towards worse survival was seen in males compared to females (5-year OS 58% versus 75%, P =.07) and also in patients with multiple liver metastases compared to patients with solitary liver metastasis (59 versus 83%, P =.09). Conclusion: Despite the fairly indolent course of DP-NET liver metastases in MEN1 patients, half of the population was deceased after 10 years. Sex and tumor load at diagnosis of liver metastases are possible prognostic factors for worse survival