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Background: Within a dramatic socio-political context, cancer represents a growing health burden in the Gaza Strip. We investigated the survival experience of people diagnosed with breast (BC) or colorectal (CRC) cancer from 2005 to 2014., Methods: Data included 1360 BC cases (median age 55.1 years) and 722 CRC cases (median age: 59.5 years; 52.5% men) recorded by the Gaza Cancer Registry according to a standard protocol. Clinical information was available for cases diagnosed in 2005-2006 only. Survival probabilities were estimated by Kaplan-Meyer method, while hazard ratios (HRs) and 95% confidence intervals (CI), adjusted for age and sex, were computed to assess factors associated with the risk of death., Results: Five-year survival was 65.1% for women with BC and 50.2% for patients with CRC. Advanced age (> 65 years), stage, and grade increased the death risk. Full access to therapies was associated with a reduced risk of death as compared with patients who had limited access (HR = 0.26, 95% CI:0.13-0.51 for BC; and HR = 0.11, 95% CI:0.04-0.31 for CRC)., Conclusion(s): The 5-year survival after BC or CRC in the Gaza Strip was in line with estimates from surrounding Arab countries, but it was much lower than in developed Mediterranean countries (e.g., in Italy or in Jewish people in Israel).

Background: Mechanisms influencing breast cancer (BC) development and recurrence include hyperglycemia, hyperinsulinemia, high insulin-like growth factor-1, high circulating estrogen, inflammation and impaired cellular differentiation/apoptosis. A lifestyle program that targets all the above mechanisms may be warranted. Low glycemic index (GI) foods produce lower post-prandial glucose and insulin responses and have been associated with lower BC risk. Moderate physical activity post-diagnosis reduces BC recurrence and mortality, partly explained by reduced insulin and estrogen levels. Vitamin D increases cell differentiation/apoptosis and high serum vitamin D levels improve BC survival. Yet no trial has evaluated the combined effect of a low GI diet, moderate physical activity and vitamin D supplementation on BC recurrence in the context of a Mediterranean lifestyle setting., Methods: Women (30-74 yr) who had undergone surgery for primary histologically confirmed BC (stages I-III) within the previous 12 months, in cancer centres in Italy, will be randomized to follow, for a maximum of 33 months, either a high intensity treatment (HIT) composed of low GI diet + exercise + vitamin D (60 ng/mL serum concentration) or a lower intensity treatment (LITE) with general advice to follow a healthy diet and exercise pattern + vitamin D to avoid insufficiency. Both interventions are on a background of a Mediterranean diet. Considering a 20% recurrence rate within 3 years for BC cases and a predicted rate of 10% in the HIT group, with power of 80% and two-sided alpha of 0.05, the subject number required will be 506 (n = 253 in each arm). Clinic visits will be scheduled every 3 months. Dietary and exercise counselling and vitamin D supplements will be given at each clinic visit when blood samples, anthropometric measures and 7-day food records will be collected., Discussion: DEDiCa study aims to reduce BC recurrence in women with BC using a lifestyle approach with additional vitamin D and to investigate possible cardio-metabolic benefits as well as epigenetic modifications according to lifestyle changes. Given the supporting evidence and safety of the components of our intervention we believe it is feasible and urgent to test it in cancer patients., Trial Registration: May 11, 2016; NCT02786875 ., Eudract Number: 2015-005147-14.

Background: Neoadjuvant Chemotherapy (NC) including trastuzumab induces a high rate of pathological Complete Responses (pCR) in patients with locally advanced HER2-overexpressing Breast Cancer (BC), but is penalized by a severe cardiotoxicity when combined with anthracyclines. A phase II study was designed to assess whether an anthracycline-free NC regimen based on the early addition of trastuzumab to paclitaxel may increase the pCR rate without inducing severe cardiotoxicity in patients with locally advanced HER2-overexpressing BC. Immunomonitoring was performed to assess the contribution of patients' immunological background to the induction of clinical responses., Methods: Stage II-III HER2-positive BC patients received 24 weeks paclitaxel and trastuzumab NC, followed by 1 year adjuvant trastuzumab ± hormonal and/or radio-therapy. Assessment of pCR rate was the primary endpoint. A group of HER2-negative BC patients treated with neoadjuvant taxanes and anthracyclines was included. Serum levels of 10 cytokines and the efficiency of trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC) were monitored in vitro every 3 months., Results: From July 2006 to February 2013, we enrolled 109 patients including 46 evaluable HER2-positive cases. A pCR rate of 50% was reached and no severe cardiotoxicity occurred. Serum cytokine profiling revealed only an IL-10 decrease (P = 0.02) in patients achieving a partial response, while HER2-negative patients disclosed marked cytokines changes. Compared to the unfavourable F/F genotype, patients carrying the V allele in the FcγRIIIa-158 polymorphism showed a higher efficacy of trastuzumab-ADCC throughout treatment (P ≤0.05)., Conclusions: In the absence of anthracyclines, trastuzumab and paclitaxel induced a high rate of pCR, exploiting the synergy between the immunomodulating properties of these drugs and the retained immunological proficiency of patients with HER2-overexpressing BC., Trial Registration: Trial registration number: NCT02307227, registered on ClinicalTrials.gov (http://www.clinicaltrials.gov, November 26, 2014).

Background: Incidence rates of various cancers are increasing in Arab countries and are expected to reach those of industrialized ones in few decades. This paper aimed to describe the incidence rates of most common cancers--and/or of those cancer preventable through modifiable behaviors--recorded in the province of Setif, Algeria from 1986 through 2010., Methods: Cancer diagnoses for the 1986-2010 period were provided by the population-based Cancer Registry of Setif, disentangled by site, morphology, age (quinquennia), sex, and calendar period. The corresponding population was obtained from the Algerian Institute of Statistics. Age-standardized rates (world population) (ASR-WR) were computed by calendar period (five quinquennias from 1986-1990 to 2006-2010), while annual percent changes (APCs) were computed for the period 1996-2010., Results: During the 2006-2010 period, ASR-WR for all cancer sites were 106.4/100,000 in men and 110.3 in women. The four leading cancers were: lung (18.0%); colon-rectum (9.6%); bladder (9.1%); and prostate (6.5%) in men; breast (36.4%); colon-rectum (8.5%); cervix uteri (6.0%); and thyroid (6.0%) in women. Between 1996-2010, overall cancer incidence increased statistically significantly (p < 0.05) in both men (APC = +2.5%) and women (APC = +3.7%). Statistically significant decreasing trends were observed for nasopharyngeal carcinoma (APC = -3.4%) in men, and for cervical (APC = -4.2%) and gallbladder (APC = -3.2%) cancers in women. Statistically significant increasing trends were observed for most common cancers both in men (lung:+1.8%, colon-rectum:+5.4%, prostate:+4.3%, liver:+8.9%, and bladder:+5.9%) and women (breast:+8.2%, colon-rectum:+4.5%, lung:+10.0%, liver:+5.4%, thyroid:+5.3%, and larynx:+13.8%)., Conclusions: International recommendations against cancer must be strongly promoted in Setif after taking into account epidemiological transition, lifestyle, and environmental changes.

Background: The aging of the Italian population will unavoidably lead to a growing number of persons diagnosed and living with cancer. A comprehensive description of the burden of cancer mortality among Italian elderly (65-84 years of age) in the last four decades has not been carried out yet. Cancer mortality rates were used to describe time trends between 1970-2008., Methods: Mortality counts, provided by the Italian National Institute of Statistics, were grouped according to data availability: in quinquennia from 1970-74 through 1995-99, and in 2000-03 and 2006-08 groups. Age-standardized rates (world population) were computed by calendar periods while annual percent changes (APCs) were computed for elderly and middle aged (35-64 years) people for the period 1995-2008., Results: The number of cancer deaths in elderly nearly doubled between 1970-74 (31,400 deaths/year in men, and 24,000 in women) and 2006-08 (63,000 deaths/year in men, and 42,000 in women). Overall cancer mortality rates peaked during the quinquennia 1985-89 and 1990-94 (about 1,500/100,000 in men and 680 in women) and declined thereafter. Throughout 1995-2008 cancer mortality rates decreased by -1.6%/year in men and -0.9%/year in women. These decreases were mainly driven by cancers of the stomach, bladder, prostate, and lung (APC = -3.3%, -2.7%, -2.5%, -2.2%, respectively) in men, and by cancers of the stomach, bladder, and breast (APC = -3.5%, -1.9%, -1.1%, respectively) in women. Conversely, increases in mortality rates between 1995 and 2008 were recorded for lung cancer (APC = +0.6%) in women, cutaneous melanoma (APC = +1.7%) in men, and pancreatic cancer (APC = +0.6% in men and +0.9% in women)., Conclusions: Overall favorable trends in cancer mortality were observed among Italian elderly between 1995 and 2008. Early diagnosis, improved efficacy of anti-cancer treatments and management of comorbidities are the most likely explanations of these positive observations. However, enduring preventive interventions against the most common risk factor (e.g. cigarette smoking), early diagnosis, and access to care should be reconsidered and extended to match the reductions of cancer mortality recorded in the elderly with those in the middle aged.

Background: The prognosis of cutaneous melanoma (CM) differs for patients with identical clinico-pathological stage, and no molecular markers discriminating the prognosis of stage III individuals have been established. Genome-wide alterations in DNA methylation are a common event in cancer. This study aimed to define the prognostic value of genomic DNA methylation levels in stage III CM patients., Methods: Overall level of genomic DNA methylation was measured using bisulfite pyrosequencing at three CpG sites (CpG1, CpG2, CpG3) of the Long Interspersed Nucleotide Element-1 (LINE-1) sequences in short-term CM cultures from 42 stage IIIC patients. The impact of LINE-1 methylation on overall survival (OS) was assessed using Cox regression and Kaplan-Meier analysis., Results: Hypomethylation (i.e., methylation below median) at CpG2 and CpG3 sites significantly associated with improved prognosis of CM, CpG3 showing the strongest association. Patients with hypomethylated CpG3 had increased OS (P = 0.01, log-rank = 6.39) by Kaplan-Meyer analysis. Median OS of patients with hypomethylated or hypermethylated CpG3 were 31.9 and 11.5 months, respectively. The 5 year OS for patients with hypomethylated CpG3 was 48% compared to 7% for patients with hypermethylated sequences. Among the variables examined by Cox regression analysis, LINE-1 methylation at CpG2 and CpG3 was the only predictor of OS (Hazard Ratio = 2.63, for hypermethylated CpG3; 95% Confidence Interval: 1.21-5.69; P = 0.01)., Conclusion: LINE-1 methylation is identified as a molecular marker of prognosis for CM patients in stage IIIC. Evaluation of LINE-1 promises to represent a key tool for driving the most appropriate clinical management of stage III CM patients.

Background: A population of breast cancer patients exists who, for various reasons, never received adjuvant post-operative tamoxifen (TAM). This study was aimed to evaluate the role of late TAM in these patients., Methods: From 1997 to 2003, patients aged 35 to 75 years, operated more than 2 years previously for monolateral breast cancer without adjuvant TAM, with no signs of metastases and no contraindication to TAM were randomized to TAM 20 mg/day orally for 2 years or follow-up alone. Events were categorized as locoregional relapse, distant metastases, metachronous breast cancer, tumours other than breast cancer and death from any causes, whichever occurred first. The sample size (197 patients per arm, plus 10% allowance) was based on the assumption of a 30% decrease in the number of events occurring at a rate of 5% annually in the 10 years following randomization. Four hundred and thirty-three patients were randomized in the study (TAM 217, follow-up 216). Patients characteristics (TAM/follow-up) included: median age 55/55 years, median time from surgery 25/25 months (range, 25-288/25-294), in situ carcinoma 18/24, oestrogen receptor (ER) positive in 75/68, negative in 70/57, unknown in 72/91 patients. Previous adjuvant treatment included chemotherapy in 131/120 and an LHRH analogue in 11/13 patients., Results: Thirty-six patients prematurely discontinued TAM after a median of 1 month, mostly because of subjective intolerance. Eighty-three events (TAM 39, follow-up 44) occurred: locoregional relapse in 10/8, distant metastases in 14/16, metachronous breast cancer in 4/10, other tumours in 11/10 patients. Less ER-positive secondary breast cancers occurred in the TAM treated patients than in follow-up patients (1 vs 10, p = 0.005). Event-free survival was similar in both groups of patients., Conclusions: This 5-year analysis revealed significantly less metachronous ER-positive breast cancers in the TAM treated patients. No other statistically significant differences have emerged thus far.

Background: Breast cancer in men is an infrequent occurrence, accounting for approximately 1% of all breast tumors with an incidence of about 1:100,000. The relative rarity of male breast cancer (MBC) limits our understanding of the epidemiologic, genetic and clinical features of this tumor., Methods: From 1997 to 2003, 10 MBC patients were referred to our Institute for genetic counselling and BRCA1/2 testing. Here we report on the genetic and phenotypic characterization of 10 families with MBC from the North East of Italy. In particular, we wished to assess the occurrence of specific cancer types in relatives of MBC probands in families with and without BRCA2 predisposing mutations. Moreover, families with recurrent BRCA2 mutations were also characterized by haplotype analysis using 5 BRCA2-linked dinucleotide repeat markers and 8 intragenic BRCA2 polymorphisms., Results: Two pathogenic mutations in the BRCA2 gene were observed: the 9106C>T (Q2960X) and the IVS16-2A>G (splicing) mutations, each in 2 cases. A BRCA1 mutation of uncertain significance 4590C>G (P1491A) was also observed. In families with BRCA2 mutations, female breast cancer was more frequent in the first and second-degree relatives compared to the families with wild type BRCA1/2 (31.9% vs. 8.0% p = 0.001). Reconstruction of the chromosome phasing in three families and the analysis of three isolated cases with the IVS16-2A>G BRCA2 mutation identified the same haplotype associated with MBC, supporting the possibility that this founder mutation previously detected in Slovenian families is also present in the North East of our Country. Moreover, analysis of one family with the 9106C>T BRCA2 mutation allowed the identification of common haplotypes for both microsatellite and intragenic polymorphisms segregating with the mutation. Three isolated cases with the same mutation shared the same intragenic polymorphisms and three 5' microsatellite markers, but showed a different haplotype for 3' markers, which were common to all three cases., Conclusion: The 9106C>T and the IVS16-2A>G mutations constitute recurrent BRCA2 mutations in MBC cases from the North-East of Italy and may be associated with a founder effect. Knowledge of these two recurrent BRCA2 mutations predisposing to MBC may facilitate the analyses aimed at the identification of mutation carriers in our geographic area.

Background: The clinical and pathological characteristics and the clinical course of patients with breast cancer and BRCA 1-2 mutation are poorly known., Methods: From 1997, patients with breast cancer and a family history of breast or ovarian cancer were offered BRCA testing. The clinical and pathological features of patients with known BRCA status were retrospectively assessed and comparisons were made between cancers arising in BRCA positive and BRCA wild type (WT) patients respectively. Type of treatment, pattern of relapse, event (local relapse, contralateral breast cancer, metastases) free and overall survival were also compared in the two groups. Out of the 210 patients tested, 125 had been treated and followed-up at our Institution and were evaluated in this study., Results: BRCA positive patients tended to be more often premenopausal (79% vs 65%) and to have positive lymphnodes (63% vs 49%), poorly differentiated tumours (76% vs 40%--p = 0.002 at univariate analysis, not significant at multivariate analysis) and negative estrogen receptors (43% vs 29%). Treatment was not different in the two groups. In the 86 BRCA-WT patients, the first event was a local relapse in 3 (3%), metachronous contralateral breast cancer in 7 (8%) and distant metastases in 16 (19%). In the 39 BRCA positive patients, the corresponding figures were 3 (8%), 8 (21%) and 3 (8%). There was no difference in event free survival, with a median of 180 months in both groups of patients. At 20 years, projected survival was 85% for BRCA positive patients and 55% for BRCA-WT, but this difference was not statistically significant., Conclusion: Although BRCA positive patients have more frequently negative prognostic factors, their prognosis appears to be equal to or better than in patients with BRCA-WT.