Isolated autoimmune adrenocorticotropic hormone deficiency: A positive predictor of survival among cancer patients treated with checkpoint inhibitors.

OBJECTIVE: We aimed to characterize cancer patients who developed isolated adrenocorticotrophic hormone (ACTH) deficiency (IAD) after treatment with checkpoint-inhibitors (CPIs), including clinical manifestations, laboratory findings and risk factors, and to evaluate the prognostic significance of this complication. DESIGN: A retrospective case-control study. METHODS: We conducted a retrospective analysis of 2225 cancer patients treated with CPIs between 2015 and 2021 in our institute. We identified a subgroup of patients with sub-normal cortisol levels due to ACTH deficiency, and comprehensively extracted all relevant data. We compared the patients survival rates using a log-rank test and a multi-variable Cox regression. RESULTS: Among 2225 patients, hypocortisolemia was documented in 99 (4.45%) patients, and 19 of them were diagnosed with IAD (0.85%). Asthenia and diarrhea were the most reported complaints (36.8%), and melanoma was the most common malignancy (68.42%) within the IAD group. In multivariable analysis, IAD was associated with better survival rates (p = .018), female gender (63.2% vs 40%, p = .041), treatment with Ipilimumab (57.9% vs. 19.4%, p < .001), and younger age (median 56 IQR 51-69, vs. median 69 IQR 60-76, p = .004). CONCLUSIONS: IAD is the dominant autoimmune etiology for cortisol deficiency among patients receiving immunotherapy and is reported for the first time as a positive predictor of survival among cancer patients treated with CPIs. In our patients, IAD development was associated with female gender, treatment with ipilimumab, and younger age.

Plasma Hemoglobin and Red Blood Cell Mass Levels as Dynamic Prognostic Markers for Progression and Survival in Pancreatic Neuroendocrine Tumors.

There are scarce data on readily available markers enabling immediate risk stratification and personalized management in patients with advanced pancreatic neuroendocrine tumors. This study explores the association of red blood cells-related parameters as prognostic markers in patients harboring pancreatic neuroendocrine tumors. Retrospective analysis of a tertiary medical center database, acquiring data of patients with pancreatic neuroendocrine tumors including demographics, tumor-related parameters and consecutive imaging results, vital status at last follow-up, and red blood cells parameters at baseline, last follow-up, and dynamics (last/baseline ratio). Univariate and multivariable analyses were performed. Sixty-seven patients were identified (mean age at diagnosis of 63±11 years, 56.7% males). Patients with disease progression had lower hemoglobin, red blood cells mass values and hematocrit at the last evaluation (p<0.001 for all comparisons), with red blood cells mass level<3.9 m/µl and a 6% and 9% relative reduction in hemoglobin and hematocrit levels, respectively, associated with an increased risk for disease progression. Similarly, patients deceased during the study period had lower hemoglobin, red blood cells mass values and hematocrit (p<0.03 for all) than those alive, at last follow-up. Eleven percent reduction in hemoglobin level was noted indicating a higher mortality risk (p=0.04). Negative hemoglobin and hematocrit dynamics were independently associated with increased risk for disease progression (p=0.03 and 0.049, respectively). In conclusion, decrease in red blood cells mass, hemoglobin and/or hematocrit levels are all associated with poor prognosis in patients with pancreatic neuroendocrine tumors. We suggest utilizing these parameters as complementary follow-up prognostic markers to radiologic imaging in this patients population.

Low risk for all-cause mortality among patients with lung neuroendocrine tumors co-diagnosed with pituitary adenomas.

PURPOSE: Lung neoplasms often co-occur with pituitary adenoma (PA). However, whether co-diagnosis of lung neuroendocrine tumors (LNETs) and PA constitute a unique entity and the impact of such co-diagnosis on patients' outcome is yet to be defined. The study objective was to compare patients' clinical characteristics with LNET to patients co-diagnosed with PA. METHODS: A Retrospective, case-control study based on the Surveillance, Epidemiology, and End Results (SEER) registry database between 2000 and 2016. A total of 2947 patients with LNET, including 2913 with LNET alone ("Sporadic") and 34 patients with both LNET and PA ("LNET-PA"). RESULTS: PA preceded LNET diagnosis in 85.3% of patients and had higher rates among LNET patients (34/2947) than with any cancer (p < 0.00001) and compared to patients with non-small cell lung cancer (NSCLC) (15/2378, p = 0.047). LNET-PA patients were younger at diagnosis compared with NSCLC patients and PA (p = 0.04). Among patients <60 years with LNET, co-diagnosis with PA was associated with lower all-cause mortality (ACM) risk (Log-rank test, p = 0.03). Adjusted ACM risk of patients with LNET-PA was lower than sporadic LNET (hazard ratio 0.553, 95% confidence interval 0.309-0.99, p = 0.046), especially among Caucasians, and lower overall-mortality risk in patients <60 years with borderline statistical significance (p = 0.071). CONCLUSIONS: Patients with both LNET and PA constitute a distinct morbidity and mortality profile than sporadic LNET, possibly suggesting an undefined MEN syndrome. Additional studies to further investigate patients' natural course and genetic profile with these neoplasms are needed.

Distinct Prognostic Factors in Sporadic and Multiple Endocrine Neoplasia Type 1-Related Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PNET) may develop sporadically or in the context of hereditary syndromes. In patients with multiple endocrine neoplasia type 1 (MEN1), PNET is the leading cause of death. Our aim was to compare the mortality risk in sporadic and MEN1-related PNETs and identify high-risk populations. A retrospective Surveillance, Epidemiology, and End Results database analysis of patients with PNET was used. Patients with MEN1 were defined by syn/metachronous pituitary adenoma. Clinical data were retrieved, and all-cause mortality (ACM) risk was compared in univariate and multivariable analyses. The cohort included 569 patients (46.6% males) with sporadic (n=542) and MEN1-related (n=27) PNETs. Age at diagnosis of MEN1-related PNET was significantly younger than with sporadic PNETs (mean age 49.2±16.7 vs. 61.6±12.7 years, respectively; p < 0.001). Survival analysis showed a trend for a better outcome in patients with MEN1-related vs. sporadic PNET (Log-rank, p=0.09) and in subgroup analysis for patients with advanced disease (p=0.08). Furthermore, among patients followed expectantly, those with MEN1-related PNET had lower ACM risk than their sporadic counterparts (p=0.08). Multivariable analysis demonstrated lower ACM risk in patients diagnosed with MEN1 (hazard ratio 0.35, 95% confidence interval 0.11-1.2, p=0.09), further supporting the trend detected in the univariate analysis. In conclusion, our study demonstrates the distinct clinical profile of patients with MEN1-related PNET compared to sporadic disease and emphasizes the expertise required to accurately manage patients with PNET in this rare context. The cautious decision-making required before embarking on surgical intervention is further emphasized in this robust analysis of a large cancer database.

Long-term outcomes in MEN-1 patients with pancreatic neuroendocrine neoplasms: an Israeli specialist center experience.

PURPOSE: The decreased life expectancy of MEN-1 patients is mainly related to pancreatic neuroendocrine tumors (pNETs). At best, limited data is available on the natural history of MEN-1-associated pNETs, as these tumors are rare and have a wide range of biologic behavior. Our study aims to explore the clinical course of patients with MEN-1-associated pNETs and the long-term outcomes. METHODS: This longitudinal study was conducted on the MEN-1 cohort treated at our referral center over a 22-year period (1996-2018). Relevant clinical data were retrospectively analysed. RESULTS: Among the 33 MEN-1 patients included in our study, pNETs were identified in 21 subjects with a penetrance of 48% by the age of 50. Non-functioning and functioning pNETs were diagnosed in sixteen (76%) and five (24%) patients, respectively. Two-thirds of the patients had multifocal tumors. The median number of pancreatic macroscopic lesions per individual was 4.0 ± 3.9 (range 1-8) with a mean size of 1.3 ± 2.1 cm (range 0.5-10). The metastatic rate according to the dominant pNET lesion reached 100%, 62% and 6% for tumors sized > 4 cm, 2.1-4 cm, and 1-2 cm, respectively. Over the study period, one or more therapeutic interventions for pNETs were required in 20 out of the 21 patients. pNET-related metastatic complication was the main cause of death within this MEN-1 cohort. The overall survival rate for the pNETs patients was 86% during a mean follow-up period of 8.0 ± 4.6 years. CONCLUSIONS: In our MEN-1 cohort, non-functioning pNETs were the most frequent type of pancreaticoduodenal tumor, and the tumor size correlated with the risks of metastasis and death. Increased awareness, early diagnosis, and a multidisciplinary approach may improve the associated morbidity and mortality in these patients.

Anatomic site as prognostic marker of pancreatic neuroendocrine tumors: a cohort study.

OBJECTIVE: Patients with pancreatic neuroendocrine tumors (PNET) have variable prognosis, even with comparable tumor grade and stage. In the current study we aimed to evaluate the prognostic utility of the intrapancreatic PNET anatomical site. DESIGN: Cohort study based on the Surveillance Epidemiology and End Results database. METHODS: Patients diagnosed with non-functioning PNET between 2004 and 2015 were compared by anatomic site for disease-specific mortality and all-cause mortality, using log-rank test and by multivariable cox regression analysis. RESULTS: Overall, 4171 patients (1839 women (44.1%), median age strata 60-64 years, range 10-14 to ≥85 years) were included in our analysis. Patients with PNETs located at the head vs body/tail of the pancreas had comparable tumor diameter, as well as ethnicity, gender and age distributions, but had higher rates of grade III and IV NET (13.2 vs 6.6% and 4.4 vs 1.9%, respectively, P < 0.001). NETs located at the head vs body/tail of pancreas were more likely to be locally advanced (32.2 vs 19.9%) with no difference in distant metastases (36.4 vs 33.5%, respectively, P < 0.001). Patients with NETs of the head vs. body/tail of the pancreas had higher disease-specific mortality risk in univariate (log-rank test, P < 0.001) and multivariable analysis (hazard ratio (HR): 1.34, 95% confidence interval: 1.10-1.65, P = 0.004). Multivariable analysis for all-cause mortality also showed increased risk for patients with pancreatic head vs. body/tail PNET (HR: 1.23, P = 0.013). CONCLUSIONS: PNET anatomical location is associated with the mortality risk and should be considered as a prognostic factor, and as an additional consideration in directing patients management.

Lower all-cause mortality rates in patients harboring pituitary carcinoma following the introduction of temozolomide.

OBJECTIVE: To evaluate the impact of temozolomide (TMZ) introduction on the survival of patients with pituitary carcinoma (PC) compared to aggressive pituitary adenoma (APA). METHODS: Retrospective analysis of the Surveillance Epidemiology and End-Results database (SEER), including patients diagnosed with PC or APA between 1973 and 2015. Age-adjusted Kaplan-Meier analyses were performed, comparing all-cause mortality (ACM) rates before the year 2006, the time of TMZ introduction ("period 1"), and afterwards ("period 2"), in patients harboring PC and APA. RESULTS: Among 107 patients, 18 (16.8%) harbored PC. The prevalence of PC and APA was comparable between genders, ethnicities and age strata. Patients harboring any pituitary tumor (PC or APA) had comparable risk for ACM and disease-specific mortality between the two time periods. However, among patients harboring PC, the risk for ACM was significantly lower in period 2 vs. period 1 (p = 0.021), becoming comparable to the risk of ACM in patients diagnosed with APA (p = 0.48). CONCLUSIONS: In this large cancer-database-based analysis we observed improved overall survival in patients harboring PC in the years following the introduction of TMZ.

The prognosis and management of neuroendocrine neoplasms-related metastatic bone disease: lessons from clinical practice.

PURPOSE: To study the evolution and optimal management of metastatic bone disease (mBD) in patients with neuroendocrine neoplasms (NENs). METHODS: Seventy-four patients were recruited from four NEN centers in this observational multicenter study. RESULTS: Pancreas and small bowel were the most common primaries (30 and 27%, respectively). Almost all gastrointestinal (GI)-NENs were grades 1 and 2, whereas bronchopulmonary-thymic were atypical carcinoids. Thirty-two (43%) patients had synchronous metastatic bone disease (mBD) and three patients reported bone-specific symptoms; metachronous mBD developed at a median of 35 (range: 4-395) months. Thirty-six (86%) of patients with metachronous mBD had stage IV disease at diagnosis. Somatostatin receptor functional imaging and computed tomography were the modalities mostly used for mBD identification. Fifty-two patients received assessable bone-related therapy (bisphosphonates, denosumab, local radiotherapy, and radionuclide treatment). Improvement in mBD was seen in 5, stable disease in 22, and deterioration in 25 patients. The presence of synchronous mBD and the negative outcome of bone-related therapy negatively affected overall survival (OS). In the multivariate analysis, the stronger predictor of OS was the outcome of bone-related therapy (HR: 4.753; 95% CI: 1.589-14.213). Bisphosphonates therapy was the mostly used bone-specific treatment but its monthly administration did not affect OS. At last follow-up, 39 patients were alive with OS 50 (14-463) months. CONCLUSIONS: Early investigation for mBD offers a prognostic marker of patients with NENs, since synchronous mBD has a negative impact on survival. The outcome of bone-related therapy affects OS but the monthly administration of bisphosphonates did not show a benefit over less intense schemes.

Current treatment strategies for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

BACKGROUND: Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of ~ 6.9/100,000. NETs arise throughout the body from cells of the diffuse endocrine system. More than half originate from endocrine cells of the gastrointestinal tract and the pancreas, thus being referred to as gastroenteropancreatic NETs (GEP NETs). The only treatment that offers a cure is surgery, however most patients are diagnosed with metastatic disease, and curative surgery is usually not an option.Since the majority of patients are not candidate for curative surgery, they can be offered long-term systemic treatment, for both symptomatic relief and tumor growth suppression. Evidence based treatment options include somatostatin analogues, everolimus (an mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor), peptide receptor radionuclide therapy (PRRT), chemotherapy, etc., alone or combined with cytoreductive procedures (surgery or liver directed procedures). However, there is an increasing need for novel therapies. Other treatment options being investigated are immunotherapy and epigenetic assessment that may lead to more personalized interventions. Following first line therapy with somatostatin analogues, there is no clear information to date indicating a preferred treatment sequence, and therefore the treatment approach should be individualized based on each NET patient characteristics. CONCLUSIONS: NET patients are increasingly diagnosed throughout the world, usually with metastatic disease and requiring systemic therapy. We believe that each patient should be therefore thoroughly evaluated and individually discussed by a multidisciplinary and dedicated NET-expert team, updated with all treatment options including ongoing clinical trials, and before selecting the proper treatment sequence.

Update in the Therapy of Advanced Neuroendocrine Tumors.

OPINION STATEMENT: Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of ~ 6.9/100,000. NETs arise throughout the body from cells of the diffuse endocrine system. More than half originate from endocrine cells of the gastrointestinal tract and the pancreas, thus being referred to as gastroenteropancreatic NETs (GEP-NETs). The only treatment that offers a cure is surgery; however, most patients are diagnosed with metastatic disease, and curative surgery is usually not an option. These patients can be offered long-term systemic treatment, for both symptomatic relief and tumor growth suppression. Evidence-based treatment options include somatostatin analogs, everolimus (a mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor), and peptide receptor radionuclide therapy, alone or combined with cytoreductive procedures (surgery or liver-directed procedures). Other treatment options being investigated are immunotherapy and epigenetic assessment that may lead to more personalized interventions. We believe that each patient should be thoroughly evaluated and their case discussed by a multidisciplinary team that is up-to-date with all treatment modalities including ongoing clinical trials, before selecting the proper treatment option.

Erectile dysfunction severity might be associated with poor cardiovascular prognosis in diabetic men.

INTRODUCTION: Although erectile dysfunction (ED) might be associated with coronary heart disease (CHD), there is no evidence it predicts poor cardiovascular prognosis. On the other hand, an abnormal heart rate profile during exercise stress testing predicts poor cardiovascular prognosis in high-risk patients, such as diabetic men, even in the absence of CHD. AIM: In order to study if ED predicts poor cardiovascular prognosis in high-risk patients, we examined the association between ED and heart rate profile during exercise stress testing in diabetic men with no CHD. MAIN OUTCOME MEASURES: Erectile dysfunction severity, exercise capacity during exercise stress testing, and heart rate decrease after exercise stress testing. METHODS: A retrospective study. The medical charts of diabetic men with vascular ED from a single-sex clinic were reviewed, as well as the medical charts of body mass index (BMI)- and age-matched diabetic men without ED going through routine check-ups. All men underwent routine treadmill stress testing according to the Bruce protocol in order to characterize heart rate profile during exercise. The Sexual Health Inventory for Men (SHIM) questionnaire was used to characterize ED. RESULTS: Included were 18 diabetic men with ED (SHIM questionnaire scores 5-21) and 18 diabetic men without ED (SHIM questionnaire scores 22-25), 40 years of age or older. None of the men had signs of coronary insufficiency during exercise treadmill stress testing. Although the two groups did not statistically differ with respect to the mean age, the mean BMI, the prevalence of cardiovascular risk factors, and the mean exercise treadmill stress testing findings, the SHIM questionnaire scores were significantly associated with low metabolic equivalents (r = 0.51, P = 0.03) and delayed heart rate recovery during the first 2 minutes after exercise (r = 0.55, P = 0.018) only among diabetic men with ED. CONCLUSIONS: Erectile dysfunction severity might be associated with poor cardiovascular prognosis in adult diabetic men with no CHD.