"Present and future of immunotherapy in Neuroendocrine Tumors".

Immunotherapy, so promising in many neoplasms, still does not have a precise role in the treatment of neuroendocrine neoplasms (NENs). In this article, we provide an overview on the current knowledge about immunotherapy with immune checkpoint inhibitors (ICIs) applied to NENs, evaluating future perspectives in this setting of tumors.Evidence so far available for ICIs in gastroenteropancreatic (GEP)-NENs is definitively not as robust as for other tumors such as Small Cell Lung Cancer or Merkel Cell Carcinoma. In fact, with regard to the well-differentiated forms of NENs (NETs), the results obtained nowadays have been disappointing. However, the near future, might reserve interesting results for ICIs in GEP-NEN from a total of nine different ICI drugs, used throughout 19 randomised controlled trials. Such numbers highlight the growing attention gathering around NENs and ICIs, in response to the need of stronger evidences supporting such therapy.For the future, the most important aspect will be to study strategies that can make NETs more susceptible to response to ICI and, thus, enhance the effectiveness of these treatments. Therefore, the combination of conventional therapy, target therapy and immunotherapy deserve attention and warrant to be explored. A sequential chemotherapy, possibly inducing an increase in tumor mutational burden and tested before immunotherapy, could be a hypothesis deserving more consideration. A radiation treatment that increases tumor-infiltrating lymphocytes, could be another approach to explore before ICIs in NENs. Equally essential will be the identification of biomarkers useful for selecting patients potentially responsive to this type of treatment.

Determining the relationship between load markers and non-contact injuries during the competitive season among professional and semi-professional basketball players.

This study examined the association and predictive ability of internal load markers (based on rating of perceived exertion, RPE) with non-contact injuries in basketball. 35 basketball players (age: 24 ± 6 years, stature: 196 ± 9 cm, body mass: 91 ± 12 kg) were prospectively followed during 1 or 2 seasons, during which non-contact injuries were recorded. Markers examined were: mean weekly RPE, weekly load, exposure, week-to-week load change, acute:chronic 1:2, 1:3, 1:4 load ratio. A generalized estimating equations analysis was used to determine association with non-contact injury in the subsequent week. Prediction was examined with receiver operating characteristic curve, area under the curve (AUC) and Youden index. No associations were found between load markers and non-contact injuries (all p > 0.05); load markers showed no injury predictive ability (AUC range: 0.468-537; Youden index range: 0.019-132). In conclusion, the load markers selected are not associated with non-contact injuries and they cannot be used to predict injuries in basketball.

Prognostic Effect of Lymph Node Metastases and Mesenteric Deposits in Neuroendocrine Tumors of the Small Bowel.

Well-differentiated, low-grade neuroendocrine tumors (NETs) are the most frequent tumor types of the small bowel. Despite their generally indolent growth patterns and grade, these tumors tend to metastasize; indeed, at presentation, approximately 50% show nodal metastases and 30% of patients have distant metastases, even though they potentially show long survival. Little is available in the literature concerning the optimal nodal yield in small-bowel resections, and the clinical significance of nodal metastases and lymph node ratio (LNR) at this site is still debated. The aim of this review, through a systematic literature search, is to explore and analyze data regarding nodal status, adequacy of lymphadenectomy, and LNR on the prognosis of small bowel NETs using defined end points (progression-free survival, recurrence-free survival, and overall survival). Some surgical series have demonstrated that extended regional mesenteric lymphadenectomy, together with primary tumor resection, is associated with improved patient survival, and LNR is proving a prognostically important parameter. The new feature of mesenteric tumor deposits (MTDs; neoplastic deposits found in the mesenteric perivisceral adipose tissue that are not LN associated) seems to be a better prognostic predictor in small-bowel NETs compared to nodal metastases, and this feature is explored and critiqued in this review. In particular, increasing number of tumor deposits is correlated with increased risk of disease-specific death, and MTDs seem to correlate with peritoneal carcinomatosis.

Immune Checkpoint Inhibitors: New Weapons Against Medullary Thyroid Cancer?

Medullary thyroid carcinoma is a rare neuroendocrine neoplasm that originates from thyroid C cells. Surgery, with complete resection of the tumor, is the only curative approach. However, in most cases, the tumor recurs at locoregional or metastatic level. In this setting, the management remains challenging. In recent years, the immune checkpoint inhibitors have provided promise for changing the cancer treatment paradigm through the application of new approaches that enhance the body's natural antitumor defenses. The aim of this review is to summarize and discuss available data on efficacy and safety of the Food and Drug Administration-approved immune checkpoint inhibitors in patients with medullary thyroid carcinoma. After an extensive search, we found 7 useful data sources (one single-case report, one short article with very preliminary data, five ongoing registered clinical trials). Despite the lack of published evidence regarding the use of immune check point inhibitors, it must be considered that all the ongoing registered clinical trials saw first light in the last three years, thus indicating a growing interest of researchers in this field. Results coming from these trials, and hopefully, in the next future, from additional trials, will help to clarify whether this class of drugs may represent a new weapon in favor of patients with medullary thyroid carcinoma.

Left Ventricular Mass Reduction by a Low-Sodium Diet in Treated Hypertensive Patients.

OBJECTIVE: To evaluate the left ventricular mass (LVM) reduction induced by dietary sodium restriction. PATIENTS AND METHODS: A simple sodium-restricted diet was advised in 138 treated hypertensives. They had to avoid common salt loads, such as cheese and salt-preserved meat, and were switched from regular to salt-free bread. Blood pressure (BP), 24-h urinary sodium (UNaV) and LVM were recorded at baseline, after 2 months. and after 2years. RESULTS: In 76 patients UNaV decreased in the recommended range after 2 months and remained low at 2 years. In 62 patients UNaV levels decreased after 2 months and then increased back to baseline at 2 years. Initially the two groups did not differ in terms of BP (134.3 ± 16.10 / 80.84 ± 12.23 vs.134.2 ± 16.67 / 81.55 ± 11.18 mmHg, mean ± SD), body weight (72.64 ± 15.17 vs.73.79 ± 12.69 kg), UNaV (161.0 ± 42.22 vs.158.2 ± 48.66 mEq/24 h), and LVM index (LVMI; 97.09 ± 20.42 vs.97.31 ± 18.91 g/m2). After 2years. they did not differ in terms of BP (125.3 ± 10.69 / 74.97 ± 7.67 vs.124.5 ± 9.95 / 75.21 ± 7.64 mmHg) and body weight (71.14 ± 14.29 vs.71.50 ± 11.87 kg). Significant differences were seen for UNaV (97.3 ± 23.01 vs.152.6 ± 49.96 mEq/24 h) and LVMI (86.38 ± 18.17 vs.103.1 ± 21.06 g/m2). Multiple regression analysis: UNaV directly and independently predicted LVMI variations, either as absolute values (R2 = 0.369; ß = 0.611; p < 0.001), or changes from baseline to +2years. (R2 = 0.454; ß = 0.677; p < 0.001). Systolic BP was a weaker predictor of LVMI (R2 = 0.369; ß = 0.168; p = 0.027; R2 = 0.454; ß = 0.012; p = 0.890), whereas diastolic BP was not correlated with LVMI. The prevalence of left ventricular hypertrophy decreased (29/76 to 15/76) in the first group while it increased in the less compliant patients (25/62 to 36/62; Chi2p = 0.002). CONCLUSION: LVM seems linked to sodium consumption in patients already under proper BP control by medications.

Cross-sectional and prospective study on anti-Müllerian hormone changes in a cohort of pre-menopausal women with a history of differentiated thyroid cancer.

BACKGROUND: Anti-Müllerian hormone (AMH) decreases acutely after post-surgical radioactive iodine (RAI) ablation in females with differentiated thyroid cancer (DTC). AIM: We performed a cross-sectional and prospective study on AMH levels in pre-menopausal females with a history of DTC. METHODS: Fifty-nine females after surgery and RAI (group 1) and 30 females after surgery alone (group 2) were studied. The control group consisted of 141 healthy women (group 3). The prospective study was performed in 43 and 14 females from groups 1 and 2, respectively. RESULTS: On first evaluation, AMH levels were similar in groups 1 and 2, but lower than in group 3. In all groups, AMH was negatively related with chronological age and FSH levels. When subjects were stratified according to age, AMH levels were not different between groups. When AMH was evaluated up to 2 years after the baseline evaluation, no changes emerged in either group of women with DTC. In the prospective study, the incidence of abnormal menstrual cycles and the onset of menopause were observed in similar percentages of women with a history of RAI-treated DTC and of those treated with surgery alone. CONCLUSIONS: AMH can be considered a reliable index of ovarian reserve in women with DTC. Chronological age is the main factor influencing AMH levels in both DTC patients and controls. After age-related stratification, AMH levels are similar in women with DTC treated with RAI and those treated with surgery alone.

Emerging Therapies in Pheochromocytoma and Paraganglioma: Immune Checkpoint Inhibitors in the Starting Blocks.

Pheochromocytoma and paraganglioma are neuroendocrine neoplasms, originating in the adrenal medulla and in parasympathetic and sympathetic autonomic nervous system ganglia, respectively. They usually present as localized tumours curable with surgery. However, these tumours may exhibit heterogeneous clinical course, ranging from no/minimal progression to aggressive (progressive/metastatic) behavior. For this setting of patients, current therapies are unsatisfactory. Immune checkpoint inhibitors have shown outstanding results for several types of solid cancers. We therefore aimed to summarize and discuss available data on efficacy and safety of current FDA-approved immune checkpoint inhibitors in patients with pheochromocytoma and paraganglioma. After an extensive search, we found 15 useful data sources (four full-published articles, four supplements of scientific journals, seven ongoing registered clinical trials). The data we detected, even with the limit of the small number of patients treated, make a great expectation on the therapeutic use of immune checkpoint inhibitors. Besides, the newly detected predictors of response will (hopefully) be of great helps in selecting the subset of patients that might benefit the most from this class of drugs. Finally, new trials are in the starting blocks, and they are expected to shed in the next future new light on a therapy, which is considered a milestone in oncology.

Epidemiology of pancreatic neuroendocrine neoplasms: a gender perspective.

PURPOSE: Pancreatic neuroendocrine neoplasms (PNENs) are a group of clinically rare and heterogeneous tumors of the pancreas. Currently there are no studies investigating the gender difference in PNEN susceptibility. Thus, the purpose of this study was aimed at examining how gender shapes risk factors, clinicopathological features, and comorbidities in PNENs. METHODS: The study design consisted of an Italian multicenter, retrospective study. The study included all consecutive patients with PNENs followed at the participating centers. Two hundred and twenty-nine patients (105 males,124 females, age 54 ± 0.98 years) with PNENs were enrolled at the participating centers. The clinicopathological features (age, gender, BMI, histology, tumor size, tumor grade, distant metastasis, hormonal function, and diagnostic circumstances), comorbidities (cardiovascular diseases (CVD), pancreatitis, type 2 diabetes (T2DM), and potential risk factors (smoking and drinking) were included in the analysis. RESULTS: Females were slightly prevalent (54.15%). PNENs were diagnosed at younger age in females compared to males (p = 0.04). The prevalence of CVD was significantly higher in males than in females (p = 0.006). In the female group, the presence of T2DM was significantly associated with higher tumor grade (p = 0.04) and metastatic disease (p = 0.02). The proportion of smokers and alcohol drinkers was significantly higher in the male group (p < 0.001). No significant gender differences were detected regarding the other parameters included in the analysis. CONCLUSIONS: This study has identified gender differences of PNENs in terms of age at diagnosis, associated comorbidities, and potential risk factors. A gender-tailored approach could become a potential strategy to better understand the natural history of PNENs and improve the effectiveness of PNENs clinical management.