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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.

Single-nucleotide polymorphisms (SNPs) related to hereditary thrombophilia were investigated as risk factors for thromboembolism in cancer patients. Their effect in metastatic colorectal cancer (mCRC) has never been explored so far. Our aim was to analyse the effect of coagulation factor V (FVLG1691A), prothrombin (PTG20210A), methylenetetrahydrofolate reductase (MTHFRC677T and A1298C) and plasminogen activator inhibitor type 1 (PAI-15G/4G) allelic variants in this setting. Fifty-two patients treated with first-line chemotherapy plus bevacizumab who developed a thromboembolic event in their lifetime were initially genotyped. A contemporary cohort of 127 patients who did not experience any thromboembolic event was also analysed. DNA was extracted from peripheral blood and genotypes were determined by real-time PCR, using LightSNiP (TIB MOLBIOL) on LightCcler 480 (Roche). The association between thromboembolism and SNPs was investigated by univariable and multivariable analyses. All SNPs were in Hardy–Weinberg equilibrium (χ2test P>0.20). FVLG1691A and PTG20210A were present only in heterozygosis in 4 (2.2%) and 7 (3.9%) patients, respectively; MTHFRC677T in homozygosis in 29 (16.2%), MTHFRA1298C in homozygosis in 13 (7.3%); PAI-15G/4G in 98 (54.7%) and 4G/4G in 41 (23%) patients. At univariable analysis, treatment duration was significantly associated with thromboembolism (P<0.001), whereas gender, age, obesity, platelets count and chemotherapy backbone were not. Similarly, FVLG1691A and PTG20210A as well as MTHFRC677T and PAI-14G allele were significantly associated, whereas MTHFRA1298C was not. At multivariable model including PTG20210A, MTHFRC677T and PAI-14G (age, obesity, treatment duration and chemotherapy backbone were included as adjustment factors), the three SNPs were significantlty associated with higher risk of thromboembolism (P=0.025, <0.0001 and P=0.033, respectively). Further validation studies are warranted in order to design a prospective trial of thromboprophylaxis in mCRC patients with high-risk genotypes.

BackgroundGene variants, such as single nucleotide polymorphisms, have a clinical relevance in the oncological field, when they affect genes encoding enzymes involved in drug metabolism, influencing drug toxicity, treatment compliance and efficacy.PurposeThe purpose of this work is to obtain data to choose a personalised therapy based on individual gene variations, minimise adverse events (AE) and avoid the discontinuation of therapy resulting in tumour progression.Material and methodsA retrospective study was conducted on 57 males and females, age ≥18, with colorectal cancer, in therapy with five protocols using different combinations of 5-fluorouracil, irinotecan and oxaliplatin.The study evaluated the number of cases where therapy was temporarily discontinued or suspended due to AE that concerned haematological, neurological and gastrointestinal toxicity according to the CTCAE system, which provides a numerical grading scale for AE description.The prevalence of polymorphisms and association between toxicity and polymorphisms were evaluated calculating odds ratios (OR) with 95% confidence interval.The Chi-square statistical significance test was applied.Results10 polymorphisms were analysed. In order of prevalence they are:UGT1A1*28 (38.6%, n=22)GSTPi (26.32%, n=15)ABCC2rs818 (17.54%, n=10)DPYDc496A>G (15.79%, n=9)SLC31A1 (12.28%, n=7)ABCC2rs717 (10.53%, n=6)DPYDc. 1129–5923C>G (3.51%, n=2)DPYD*2Ac. 1905+1 G>A and DPYD*13 c. 1679T>G (1.75%, n=1)DPYDc. 2846A>T (0%).OR values found the association between toxicity above 2nd grade and the presence of polymorphisms. The association is:Strong positive for DPYD*2Ac. 1905+1 G>A (OR=10.68) and UGT1A1*28 (OR=7.43)Moderate positive for DPYDc. 1129–5923C>G (OR=3.58) and SLC31A1 (OR=2.13)Moderate negative for ABCC2rs818 (OR=0.33).Absent for DPYD*13 c. 1679T>G, DPYDc496A>G, ABCC2rs717 and GSTPi.ConclusionOften patients express different polymorphisms at the same time, developing a toxicity related to the total effects of all the polymorphic variants. This problem is particularly important for chemotherapeutics that are administered at very high doses, close to toxic doses, and takes on a clinical and economic relevance. The study of genes, involved in the metabolism and transport of many drugs, permits the prediction of drug toxicity and efficacy and, based on individual variations, establishing a personalised and safe therapy before the onset of the treatment.References and/or Acknowledgements1. Common Terminology Criteria for Adverse Events(CTCAE). U S department of health and human services, national institutes of health, national cancer instituteJune 14, 2010.2. Sheskin DJ. Handbook of parametric and non parametric statistical procedures2004. IIIed Boca Raton:Chapman & Hall/CRC.3. Panczyk M. Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20years. World J Gastroenterol2014August 7;20(29):9775–9827.No conflict of interest