For many tumor types chemotherapy still represents the therapy of choice and many standard treatments are based on the use of platinum (PT) drugs. However, de novo or acquired resistance to platinum ...is frequent and leads to disease progression. In Epithelial Ovarian Cancer (EOC) patients, PT-resistant recurrences are very common and improving the response to treatment still represents an unmet clinical need. To identify new modulators of PT-sensitivity, we performed a loss-of-function screening targeting 680 genes potentially involved in the response of EOC cells to platinum. We found that SGK2 (Serum-and Glucocorticoid-inducible kinase 2) plays a key role in PT-response. We show here that EOC cells relay on the induction of autophagy to escape PT-induced death and that SGK2 inhibition increases PT sensitivity inducing a block in the autophagy cascade due to the impairment of lysosomal acidification. Mechanistically we demonstrate that SGK2 controls autophagy in a kinase-dependent manner by binding and inhibiting the V-ATPase proton pump. Accordingly, SGK2 phosphorylates the subunit V1H (ATP6V1H) of V-ATPase and silencing or chemical inhibition of SGK2, affects the normal autophagic flux and sensitizes EOC cells to platinum. Hence, we identified a new pathway that links autophagy to the survival of cancer cells under platinum treatment in which the druggable kinase SGK2 plays a central role. Our data suggest that blocking autophagy via SGK2 inhibition could represent a novel therapeutic strategy to improve patients' response to platinum.
A study was conducted to assess the fraction of female breast cancer (BC) deaths attributable to alcohol consumption in Italy. National mortality data for the period 2015–2019 were used along with ...national estimates of women from the general population exposed to moderate (11–20 gr/day) or heavy (>20 gr/day) alcohol consumption. From 2015 to 2019, 2918 (4.6%) out of 63,428 BC| deaths were attributable to alcohol consumption, including 1269 deaths (2.0%) caused by moderate consumption. Study findings could help stakeholders to prioritize programs aimed at reducing alcohol consumption, and to improve ways to effectively communicate alcohol-related health risks, including moderate consumption.
•Alcohol is a well-established risk factor for seven cancers, but its impact on breast cancer mortality is poorly known;•The aim of this study was to estimate, in Italy for the period 2015–2019, the fraction of female breast cancer deaths attributable to moderate or heavy alcohol consumption.•Out of 63,428 of breast cancer deaths, 2.0% (i.e., 1269) were attributable to moderate alcohol consumption and 2.6% (i.e., 1649) to heavy consumption.
The relation between inflammation deriving from diet and endometrial cancer risk has not yet been investigated. In this study, we explored the association between the dietary inflammatory index (DII) ...and endometrial cancer risk in an Italian case-control study. Cases comprised 454 patients with incident, histologically confirmed carcinoma of the endometrium, and controls comprised 908 subjects admitted to the same network of hospitals as cases for a wide spectrum of acute, non-neoplastic conditions. DII scores were computed on the basis of dietary intake assessed using a reproducible and valid seventy-eight-item FFQ. OR were calculated through logistic regression models conditioned on age and study centre and adjusted for recognised confounding factors, including total energy intake. Women with the most pro-inflammatory diet had a higher risk for endometrial cancer compared with women with the most anti-inflammatory diet (OR(Quartile) 4 v. 1 1·46; 95% CI 1·02, 2·11; P(trend)=0·04). A pro-inflammatory diet may increase the risk for endometrial cancer.
Abstract To assess incidence and risk factors for de novo cancers (DNCs) after kidney transplant (KT), we carried out a cohort investigation in 15 Italian KT centres. Seven thousand two-hundred ...seventeen KT recipients (64.2% men), transplanted between 1997 and 2007 and followed-up until 2009, represented the study group. Person years (PY) were computed from 30 days after transplant to cancer diagnosis, death, return to dialysis or to study closure. The number of observed DNCs was compared to that expected in the general population of Italy through standardised incidence ratios (SIR) and 95% confidence intervals (CI). To identify risk factors, incidence rate ratios (IRR) were computed. Three-hundred ninety five DNCs were diagnosed during 39.598 PYs, with Kaposi’s sarcoma (KS), post-transplant lymphoproliferative disorders (PTLD), particularly non-Hodgkin’ lymphoma (NHL), lung, kidney and prostate as the most common types. The overall IR was 9.98/1.000 PY, with a 1.7-fold augmented SIR (95% CI: 1.6-1.9). SIRs were particularly elevated for KS (135), lip (9.4), kidney carcinoma (4.9), NHL (4.5) and mesothelioma (4.2). KT recipients born in Southern Italy were at reduced risk of kidney cancer and solid tumors, though at a higher KS risk, than those born in Northern Italy. Use of mTOR inhibitors (mTORi) exerted, for all cancers combined, a 46% significantly reduced risk (95% CI: 0.4–0.7). Our study findings confirmed, in Italy, the increased risks for cancer following KT, and they also suggested a possible protective effect of mTORi in reducing the frequency of post transplant cancers.
Inflammation and diet have been suggested to be important risk factors for hepatocellular cancer (HCC). This Italian multicentre hospital-based case-control study conducted between 1999 and 2002 and ...including 185 cases with incident, histologically confirmed HCC, and 404 controls hospitalised for acute non-neoplastic diseases provided an opportunity to investigate the association between HCC and the dietary inflammatory index (DII). The DII was computed on the basis of dietary intake assessed 2 years before the date of interview by a validated sixty-three-item FFQ. Logistic regression models were used to estimate OR adjusted for age, sex, study centre, education, BMI, smoking, physical activity, serum markers of hepatitis B and C infection and energy intake. Energy adjustment for DII was performed using the residual method. Participants in the highest tertile of DII scores (i.e. with a more pro-inflammatory diet) had a higher risk for HCC (ORtertile 3 v, 1 2·43; 95 % CI 1·27, 4·68; P trend=0·03). When stratified by the presence or absence of hepatitis B/C infection and sex, DII was strongly associated with HCC in hepatitis B- and C-negative participants (ORtertile 3 v. 1 4·18; 95 % CI 1·53, 11·39; P trend=0·02) and among males (ORtertile 3 v. 1 3·60; 95 % CI 1·65, 7·87; P trend=0·001). These results indicate that a pro-inflammatory diet is associated with increased risk for HCC, in those without a history of hepatitis B/C infection and among males.
Head and neck cancer (HNC) is a preventable malignancy that continues to cause substantial morbidity and mortality worldwide. Using data from the ARCAGE and Rome studies, we investigated the main ...predictors of survival after larynx, hypopharynx and oral cavity (OC) cancers. We used the Kaplan–Meier method to estimate overall survival, and Cox proportional models to examine the relationship between survival and sociodemographic and clinical characteristics. 604 larynx, 146 hypopharynx and 460 OC cancer cases were included in this study. Over a median follow‐up time of 4.6 years, nearly 50% (n = 586) of patients died. Five‐year survival was 65% for larynx, 55% for OC and 35% for hypopharynx cancers. In a multivariable analysis, we observed an increased mortality risk among older (≥71 years) versus younger (≤50 years) patients with larynx/hypopharynx combined (LH) and OC cancers HR = 1.61, 95% CI 1.09–2.38 (LH) and HR = 2.12, 95% CI 1.35–3.33 (OC), current versus never smokers HR = 2.67, 95% CI 1.40–5.08 (LH) and HR = 2.16, 95% CI 1.32–3.54 (OC) and advanced versus early stage disease at diagnosis IV versus I, HR = 2.60, 95% CI 1.78–3.79 (LH) and HR = 3.17, 95% CI 2.05–4.89 (OC). Survival was not associated with sex, alcohol consumption, education, oral health, p16 expression, presence of HPV infection or body mass index 2 years before cancer diagnosis. Despite advances in diagnosis and therapeutic modalities, survival after HNC remains low in Europe. In addition to the recognized prognostic effect of stage at diagnosis, smoking history and older age at diagnosis are important prognostic indicators for HNC.
What's new?
Most people diagnosed with head and neck cancer do not survive to the 8‐year mark. These authors examined which factors correlate with survival after cancer of the larynx, hypopharynx or oral cavity. They found increased mortality among patients over age 70 years, current smokers, and those with advanced disease. Stage at diagnosis is one of the strongest predictors of survival, but even with modern detection methods, most patients in Europe are still diagnosed with advanced disease.
Head and neck squamous cell carcinomas (HNSCCs) cause more than 300,000 deaths worldwide each year. Locoregional and distant recurrences represent worse prognostic events and accepted surrogate ...markers of patients' overall survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected miRNAs could be used as biomarkers of recurrence in HNSCC.
A NanoString array was used to identify miRNAs associated with locoregional recurrence in 44 patients with HNSCC. Bioinformatic approaches validated the signature and identified potential miRNA targets. Validation experiments were performed using an independent cohort of primary HNSCC samples and a panel of HNSCC cell lines.
experiments validated the
results.
Our data identified a four-miRNA signature that classified HNSCC patients at high- or low-risk of recurrence. These miRNAs collectively impinge on the epithelial-mesenchymal transition process.
and wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets SASH1 and KRT13, whereas miR-1, miR-133, and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGFβ pathways. A six-gene signature comprising these targets identified patients at high risk of recurrences, as well. Combined pharmacological inhibition of SP1 and TGFβ pathways induced HNSCC cell death and, when timely administered, prevented recurrence formation in a preclinical model of HNSCC recurrence.
By integrating different experimental approaches and competences, we identified critical mediators of recurrence formation in HNSCC that may merit to be considered for future clinical development.
.
Background
Besides tobacco and alcohol, diet and inflammation have been suggested to be important risk factors for laryngeal cancer. In this study, we examined the role of diet-associated ...inflammation, as estimated by dietary inflammatory index (DII) scores, in laryngeal cancer in a multicentre case–control study conducted between 1992 and 2000 in Italy.
Methods
This study included 460 cases with incident, histologically confirmed laryngeal cancer, and 1,088 controls hospitalized for acute non-neoplastic diseases unrelated to tobacco and alcohol consumption. DII scores were computed from a reproducible and valid 78-item food-frequency questionnaire. Logistic regression models controlling for age, sex, study center, education, body mass index, tobacco smoking, alcohol drinking, and non-alcohol energy intake were used to estimate odds ratios (ORs) and the corresponding 95 % confidence intervals (CIs).
Results
Subjects with higher DII scores (i.e., with a more pro-inflammatory diet) had a higher risk of laryngeal cancer. The OR was 3.30 (95 % CI 2.06, 5.28;
p
for trend <0.0001) for the highest versus the lowest DII quartile. When DII was considered as a continuous variable, the OR was 1.27 (95 % CI 1.15, 1.40) for a one-unit (9 % of the DII range) increase. Stratified analyses produced slightly stronger associations between DII and laryngeal cancer risk among Subjects <60 years old (OR
quartile4vs1
= 4.68), overweight subjects (OR
Quartile4vs1
= 3.62), and among those with higher education (OR
Quartile4vs1
= 3.92). We also observed a strong combined effect of higher DII and tobacco smoking or alcohol consumption on risk of laryngeal cancer. Compared with non-smokers having low DII scores, the OR was 6.64 for smokers with high DII scores. Likewise, compared with non/moderate drinkers with low DII, the OR was 5.82 for heavy drinkers with high DII.
Conclusion
These results indicate that a pro-inflammatory diet is associated with increased risk of laryngeal cancer.
Non-AIDS-defining cancers (non-ADCs) have become the leading non-AIDS-related cause of death among people with HIV/AIDS. We aimed to quantify the excess risk of cancer-related deaths among Italian ...people with AIDS (PWA), as compared with people without AIDS (non-PWA).
A nationwide, population-based, retrospective cohort study was carried out among 5285 Italian PWA, aged 15-74 years, diagnosed between 2006 and 2011. Date of death and multiple-cause-of-death data were retrieved up to December 2011. Excess mortality, as compared with non-PWA, was estimated using sex- and age-standardized mortality ratios (SMRs) and the corresponding 95% confidence intervals (CIs).
Among 1229 deceased PWA, 10.3% reported non-ADCs in the death certificate, including lung (3.1%), and liver (1.4%), cancers. A 7.3-fold (95% CI: 6.1 to 8.7) excess mortality was observed for all non-ADCs combined. Statistically significant SMRs emerged for specific non-ADCs, ie, anus (5 deaths, SMR = 227.6, 95% CI: 73.9 to 531.0), Hodgkin lymphoma (12 deaths, SMR = 122.0, 95% CI: 63.0 to 213.0), unspecified uterus (4 deaths, SMR = 52.5, 95% CI: 14.3 to 134.5), liver (17 deaths, SMR = 13.2, 95% CI: 7.7 to 21.1), skin melanoma (4 deaths, SMR = 10.9, 95% CI: 3.0 to 27.8), lung (38 deaths, SMR = 8.0, 95% CI: 5.7 to 11.0), head and neck (9 deaths, SMR = 7.8, 95% CI: 3.6 to 14.9), leukemia (5 deaths, SMR = 7.6, 95% CI: 2.4 to 17.7), and colon-rectum (10 deaths, SMR = 5.4, 95% CI: 2.6 to 10.0). SMRs for non-ADCs were particularly elevated among PWA infected through injecting drug use.
This population-based study documented extremely elevated risks of death for non-ADCs among PWA. These findings stress the need of preventive interventions for both virus-related and non-virus-related cancers among HIV-infected individuals.
Background The linear association between median age at cancer onset and median age of the underlying population has been described only for breast cancer. We quantified the shape and strength of ...such association for 20 cancer types using data from all population-based cancer registries (CRs) worldwide. Methods The patients’ median age at cancer onset and of the underlying population were extracted from all CRs listed in volumes VI (1983–1987 years) and XI (2008–2012 years) of Cancer Incidence in Five Continents. The association was assessed at cross-sectional level by linear regression models and longitudinally considering only the long-standing CRs active throughout the study period (i.e., 25-year span). Results During 2008–2012, each one-year increase in median population ageing was associated in men with a nearly half year increase of median age at onset of all cancers, but skin; and a 2/3 year increase in women. Variance explained by linear model was around 60%. In long-standing CRs a decrease in median age at cancer onset was observed for prostate and cervical cancers throughout the 25-year span. Conclusions Population ageing reflected 60% of the median age at cancer onset. Misinterpretation of peaks of cancer incidence in specific age groups may be avoided by examining population pyramids.
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