Gender-related differences in patients with carcinoid syndrome: new insights from an Italian multicenter cohort study.

BACKGROUND: The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking. PURPOSE: To evaluate gender differences in clinical presentation and outcome of CaS. METHODS: Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender. RESULTS: Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p = 0.002, and 3.7%, p = 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p = 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p = 0.044; 6.7% vs 31.5%, p = 0.001; 50.9% vs. 26.7%, p = 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p = 0.04), but no differences in terms of PFS (p = 0.51) and OS (p = 0.64) were found between gender. CONCLUSIONS: In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable.

Expected and paradoxical effects of obesity on cancer treatment response.

Obesity, whose prevalence is pandemic and continuing to increase, is a major preventable and modifiable risk factor for diabetes and cardiovascular diseases, as well as for cancer. Furthermore, epidemiological studies have shown that obesity is a negative independent prognostic factor for several oncological outcomes, including overall and cancer-specific survival, for several site-specific cancers as well as for all cancers combined. Yet, a recently growing body of evidence suggests that sometimes overweight and obesity may associate with better outcomes, and that immunotherapy may show improved response among obese patients compared with patients with a normal weight. The so-called 'obesity paradox' has been reported in several advanced cancer as well as in other diseases, albeit the mechanisms behind this unexpected relationship are still not clear. Aim of this review is to explore the expected as well as the paradoxical relationship between obesity and cancer prognosis, with a particular emphasis on the effects of cancer therapies in obese people.

Clinico-pathological features, treatments and survival of malignant insulinomas: a multicenter study.

INTRODUCTION: Management of malignant insulinomas is challenging due to the need to control both hypoglycaemic syndrome and tumor growth. Literature data is limited to small series. AIM OF THE STUDY: To analyze clinico-pathological characteristics, treatments and prognosis of patients with malignant insulinoma. MATERIALS AND METHODS: Multicenter retrospective study on 31 patients (male: 61.3%) diagnosed between 1988 and 2017. RESULTS: The mean age at diagnosis was 48 years. The mean NET diameter was 41 ± 31 mm, and 70.8% of NETs were G2. Metastases were widespread in 38.7%, hepatic in 41.9% and only lymph nodal in 19.4%. In 16.1% of the cases, the hypoglycaemic syndrome occurred after 46 ± 35 months from the diagnosis of originally non-functioning NET, whereas in 83.9% of the cases it led to the diagnosis of NET, of which 42.3% with a mean diagnostic delay of 32.7 ± 39.8 months. Surgical treatment was performed in 67.7% of the cases. The 5-year survival rate was 62%. Overall survival was significantly higher in patients with Ki-67 ≤10% (P = 0.03), insulin level <60 µU/mL (P = 0.015) and in patients who underwent surgery (P = 0.006). Peptide Receptor Radionuclide Therapy (PRRT) was performed in 45.1%, with syndrome control in 93% of patients. CONCLUSIONS: Our study includes the largest series of patients with malignant insulinoma reported to date. The hypoglycaemic syndrome may occur after years in initially non-functioning NETs or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 ≤10% are prognostic factors associated with better survival. PPRT proved to be effective in the control of hypoglycaemia in majority of cases.

Survival prognostic factors of gastro-enteric-pancreatic neuroendocrine tumors after primary tumor resection in a single tertiary center: Comparison of gastro-enteric and pancreatic locations.

AIM: This study aimed to evaluated prognostic factors of patients with GEP-NETs after primary tumor resection comparing pancreatic and gastro-enteric locations. METHODS: Patients undergone surgery for primary GEP-NETs between 01/2000 and 03/2012 were considered. All specimens were reclassified according to the WHO 2010 scheme. RESULTS: A total of 83 patients were considered: 37 pancreatic NETs (pNET) and 46 gastroenteric NETs (GE-NET). The two groups were similar in terms of age, sex and tumors size. A higher rate of patients with pNETs had Ki67 score ≥3 (64.8% vs. 39%, p = 0.027) while the rates of Mitotic Index ≥2x10HPF (62% pNET vs. 50% GE-NET, p = 0.374) and diagnosis of neuroendocrine carcinoma NEC (16.2% pNET vs. 17.3% GE-NET, p = 0.100) were similar. The rates of distant metastases (GE-NETs 30.4% vs. p-NETs 29.7%, p = 0.944) and liver metastases (19.5% GE-NET vs. 27% pNET, p = 0.421) were comparable. Radical resection was achieved in a similar proportion in both groups [33 patients (89.1%) pNET vs. 36 (78.2%) GE-NET, p = 0.393]. After a median follow-up of 47.1 months overall 3, 5 and 10-years survival rates of whole patients were 88.1%, 81.2% and 76.7%. There was not difference on 5-years overall survival between pNET (81.4%) and GE-NET (81%, p = 0.901). At multivariate analysis age ≥70 [OR 4.177 (CI 95% 1.26-13.8), p = 0.019] and NEC [OR 5.932 (CI 95% 1.81-19.40), p < 0.001] were negative prognostic factors of survival. CONCLUSION: Overall survival of GEP-NET after resection of primary tumors seems to be correlated to patient's age and WHO 2010 staging system but not to primary tumor site.

A rare case of adulthood-onset growth hormone deficiency presenting as sporadic, symptomatic hypoglycemia.

Symptomatic hypoglycemia is described in children with severe GH deficiency (GHD), but is rare in adults with GHD. We describe the case of a 62- yr-old man, referred for recurrent hypoglycemic events. He reported a previous head trauma at the age of 20 yr and a diagnosis of reactive hypoglycemia at the age of 50 yr. In the last months, during a period of job-related stress, the hypoglycemic episodes became more frequent and severe (glucose <2.2 mmol/l), finally requiring hospitalization. On admission, the patient was in good general health, with normal renal and hepatic function. During hospitalization, no hypoglycemic episodes were recorded, also during a 72-h fasting test. Biochemical data and abdominal computed tomography (CT) excluded insulinoma. A tumor-induced hypoglycemia was ruled out. The 4-h oral glucose tolerance test (OGTT) showed an impaired glucose tolerance with a tendency toward asymptomatic hypoglycemia. Hormonal study disclosed low levels of GH (0.2 ng/ml) and IGF-I (51 ng/ml); the response of GH to GHRH plus arginine confirmed a severe GHD (GH peak 2.7 ng/ml). Other pituitary and counterregulation hormones were within the normal range and magnetic resonance imaging (MRI) of the pituitary gland was normal. Replacement therapy with a low dose of rhGH induced an increase of IGF-I up to low-normal values, accompanied by lasting regression of hypoglycemic events. In conclusion, hypoglycemia was the main clinical symptom of isolated adult onset GHD, in the present case. The possible pathogenesis of isolated adult onset GHD and the association of GHD with conditions predisposing to hypoglycemia are considered and discussed.

Three-hour spontaneous GH secretion profile is as reliable as oral glucose tolerance test for the diagnosis of acromegaly.

The diagnosis of acromegaly, in an appropriate clinical context, usually relies on lack of GH suppression below 1 microg/l during OGTT coupled with elevated IGF-I levels. On the other hand, in normal subjects glucose-induced inhibition of GH secretory bursts without any further decrease of interpulse GH levels had already been shown. Based on the foregoing, we aimed to compare the diagnostic reliability of OGTT-induced GH nadir with that recorded during 3-h spontaneous GH secretion. In 59 acromegalic patients (17 male and 42 female, age, mean +/- SE 51.5 +/- 1.9, range 21-76 yr) and in 82 normal subjects (43 male and 39 female, age, mean +/- SE 35.7 +/- 1.5, range 15-72 yr) GH secretion was evaluated every 30 min from 0 to 180 min during slow saline infusion or OGTT (75 g at 0 min). A nadir GH concentration below 1 microg/l was recorded in all normal subjects either during OGTT or saline infusion if GH secretion was evaluated over 180 min. In contrast in acromegalic patients a nadir GH concentration below 1 microg/l never occurred in both conditions. This study shows that a 3-h spontaneous GH profile is as reliable as OGTT in the diagnosis of active acromegaly.