International Validation of a Nomogram to Predict Recurrence after Resection of Grade 1 and 2 Nonfunctioning Pancreatic Neuroendocrine Tumors

Background: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors. Methods: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1-2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel's C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence. Results: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78-88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70-0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80). Conclusions: External validity of this prediction model for recurrence after curative surgery for grade 1-2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com

Pancreatic Neuroendocrine Tumors : Surgical Treatment and Follow-up

Pancreatic neuroendocrine tumors (Pan-NET), are rare, heterogenous and derive from the hormone producing cells in the pancreas. The functioning tumors that overproduce hormones cause clinical syndromes with specific symptoms due to the hormonal production. However, the majority of patients have non-functioning tumors, and in lack of symptoms, these more often present with, or develop, liver metastases. This thesis focuses on treatment of metastasized pan-NET, stage IV, from a surgical perspective. As some patients operated on for localized disease eventually experience recurrence, it would also be beneficial to be able to predict which patients that are at a higher risk for recurrence.          In paper I, outcome after primary tumor resection in pan-NET patients, stage IV, was evaluated. An association between primary tumor resection and prolonged survival was found in patients, both before and after propensity score match. In paper II, outcome after hepatic resection and thermal hepatic ablation of liver metastases, in patients previously subjected to primary tumor resection, was scrutinized. Survival rates were significantly higher in the hepatic resection/thermal hepatic ablation group, and in a multivariable analysis, hepatic resection/thermal hepatic ablation remained a significant positive prognostic factor for prolonged survival. In paper III, patients with unresectable liver metastases, eligible for liver transplantation were investigated. A very small group of all pan-NET stage IV patients was eligible for liver transplantation and even fewer patients met any of the current selection criteria for liver transplantation. The survival rates for these patients, only subjected to multimodal treatment, were comparable to the survival rates after liver transplantation, presented in previously published studies. In paper IV, an external validation of a prediction model for recurrence after resection of non-metastatic, non-functioning, grade 1-2 tumors, was performed. The model performed well in the validation and is available online. To conclude, both primary tumor resection and surgical and ablative treatment of liver metastases in stage IV pan-NET, were associated with prolonged survival in analyses controlling for bias and possible confounders. However, the evidence base to perform liver transplantation in patients with pan-NET is weak. A prediction model for recurrence after radical surgery of non-metastatic pan-NET was externally validated with success. Our findings provide additional knowledge regarding treatment of stage IV pan-NET and could also help us predict which patients that will recur after surgery

Adverse childhood experiences and mental health problems in a nationally representative study of heterosexual, homosexual and bisexual Danes

Non‐heterosexual persons more often report adverse childhood experiences (ACEs) than heterosexuals, and they generally bear a greater burden of mental health challenges. However, population‐based data on this topic are scarce. In a nationally representative study within the Project SEXUS, one of the world's largest cohort studies on sexual health, we used data from 57,479 individuals in Denmark to explore the interplay between ACEs and mental health problems among self‐identified heterosexual, homosexual and bisexual persons, and among self‐identified heterosexuals with or without same‐sex sexual experience. Compared to heterosexuals, non‐heterosexual persons were more likely to report most of the studied ACEs, with odds ratios (ORs) for the ACE category “abuse” ranging from 1.38 to 1.75 for homosexual women, from 1.76 to 2.65 for homosexual men, from 2.52 to 3.64 for bisexual women, and from 1.58 to 6.07 for bisexual men. Furthermore, non‐heterosexual persons had consistently and statistically significantly higher odds for mental health problems (ORs: 1.50 to 4.63). Combinations of ACEs with a non‐heterosexual identity resulted in markedly elevated odds for mental health problems, particularly among bisexual individuals. This included high odds for suicidal thoughts/attempts among bisexual persons with a history of “neglect” (women: OR=12.82; men: OR=35.24) and “abuse” (women: OR=11.81; men: OR=11.65). Among self‐identified heterosexuals, combinations of ACEs with same‐sex sexual experience were associated with consistently elevated odds for mental health problems (ORs: 2.22 to 12.04). The greater burden of ACEs among self‐identified homosexuals and, most notably, bisexuals may account for part of their excess risk of mental health problems. These findings emphasize the public health importance of preventive measures to minimize the burden of ACEs and avert their harmful long‐term effects. Moreover, they highlight the need to safeguard the welfare of children and adolescents with non‐conforming expressions of sexuality

Overall Survival in Patients with Stage IV Pan-NET Eligible for Liver Transplantation

BACKGROUND: The use of liver transplantation (LT) in patients with stage IV neuroendocrine pancreatic tumors (pan-NET) is under debate. Previous studies report a 5-year survival of 27-53% after LT in pan-NET and up to 92.7% in patients with mixed NETs. This study aimed to determine survival rates of patients with stage IV pan-NET meeting criteria for LT while only subjected to multimodal treatment. METHODS: Medical records of patients with pan-NET diagnosed from 2000 to 2021 at a tertiary referral center were evaluated for eligibility. Patients without liver metastases, who did not undergo primary tumor surgery, age > 75 years and with grade 3 tumors were excluded. The patients were divided into groups; all included patients, patients meeting the Milan, the United Network for Organ Sharing (UNOS) or the European Neuroendocrine Tumor Society (ENETS) criteria for LT. Kaplan-Meier survival analysis was used to calculate overall survival. RESULTS: Out of 519 patients with pan-NET, 41 patients were included. Mean follow-up time was 5.4 years. Overall survival was 9.3 years (95% Cl 6.8-11.7), and 5-year survival was 64.7% (95% CI 48.2-81.2). Patients meeting the Milan, ENETS and UNOS criteria for LT had a 5-year survival of 64.9% (95% CI 32.2-97.6), 85.7% (95% CI 59.8-100.0) and 55.4% (95% CI 26.0-84.8), respectively. CONCLUSIONS: In patients with stage IV pan-NET, grade 1 and 2, with no extra abdominal disease, 5-year survival was 64.7% (95% CI 48.2-81.2). As these survival rates exceed previously published series of LT for pan-NET, the evidence base for this treatment is very weak

Benefit of Primary Tumor Resection in Stage IV, Grade 1 and 2, Pancreatic Neuroendocrine Tumors

Objective:. To determine the association of primary tumor resection in stage IV pancreatic neuroendocrine tumors (Pan-NET) and survival in a propensity-score matched study. Background:. Pan-NET are often diagnosed with stage IV disease. The oncologic benefit from primary tumor resection in this scenario is debated and previous studies show contradictory results. Methods:. Patients from 3 tertiary referral centers from January 1, 1985, through December 31, 2019: Uppsala University Hospital (Uppsala, Sweden), Sahlgrenska University Hospital (Gothenburg, Sweden), and Brigham and Women’s Hospital/Dana-Farber Cancer Institute (Boston, USA) were assessed for eligibility. Patients with sporadic, grade 1 and 2, stage IV pan-NET, with baseline 2000–2019 were divided between those undergoing primary tumor resection combined with oncologic treatment (surgery group [SG]), and those who received oncologic treatment without primary tumor resection (non-SG). A propensity-score matching was performed to account for the variability in the extent of metastatic disease and comorbidity. Primary outcome was overall survival. Results:. Patients with stage IV Pan-NET (n = 733) were assessed for eligibility, 194 were included. Patients were divided into a SG (n = 65) and a non-SG (n = 129). Two isonumerical groups with 50 patients in each group remained after propensity-score matching. The 5-year survival was 65.4% (95% CI, 51.5-79.3) in the matched SG and 47.8% (95% CI, 30.6-65.0) in the matched non-SG (log-rank, P = 0.043). Conclusions:. Resection of the primary tumor in patients with stage IV Pan-NET and G1/G2 grade was associated with prolonged overall survival compared to nonoperative management. A surgically aggressive regime should be considered where resection is not contraindicated

International Validation of a Nomogram to Predict Recurrence after Resection of Grade 1 and 2 Nonfunctioning Pancreatic Neuroendocrine Tumors

BACKGROUND: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors. METHODS: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1-2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel's C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence. RESULTS: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78-88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70-0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80). CONCLUSIONS: External validity of this prediction model for recurrence after curative surgery for grade 1-2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com