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•PARPi can work as powerful anti-inflammatory molecules.•SARS-CoV-2 triggers pro-inflammatory and prothrombotic cascades.•PARPi could be successfully used as antithrombotic drugs in ...severe or moderate forms of COVID-19.•PARPi have shown potential anti-viral replication activities
In the last three months, the whole scientific community has shifted its focus to the fight against the COVI-2 infection (COVID-19) trying to use different medications to save the patients' life. In some studies, the results were completely inconclusive, as in the case of chloroquine. However, the recent discovery on benefits deriving from use of such anticoagulants for Covid-19 patients, has increased the success of patients’ treatment. Among lots of old and new drugs, PARP-inhibitors were not considered as possible option in the treatment of Covi-2 infection, being the latter able to induce the inflammatory and thrombotic cascades. Since PARP-inhibitors are able to reduce and block mechanisms leading to thrombosis and inflammation, they could be used as antithrombotic medications. Therefore, the present brief report is aimed to open the discussion on the potentials of PARP-inhibitors in non-oncological settings, like Covid-19.
Summary Background & aims Sarcopenia has been indicated as a reliable marker of frailty and poor prognosis among the oldest individuals. We evaluated the relationship between sarcopenia and 2-year ...risk of falls in a population of persons aged 80 years or older. Methods Data are from the baseline and follow-up evaluations of the Aging and Longevity Study in the Sirente Geographic Area (ilSIRENTE Study) ( n = 260). According to the European Working Group on Sarcopenia in Older People (EWGSOP), sarcopenia was diagnosed in presence of low muscle mass (mid-arm muscle circumference) plus either low muscle strength (hand grip) or low physical performance (4-m walking speed). The primary outcome measure was the incident falls during the follow-up period of 2 years. The relationship between sarcopenia and incident falls was estimated by deriving hazard ratios (HRs) from multiple logistic regression models considering the dependent variable of interest at least one fall during the follow-up period. Results Sixty-six participants (25.4%) were identified as affected by sarcopenia. Eighteen out of 66 (27.3%) participants with sarcopenia and 19 out of 194 (9.8%) without sarcopenia reported incident falls during the two-year follow-up of the study ( p < 0.001). After adjusting for age, gender, cognitive impairment, ADL impairment, sensory impairments, BMI, depression, physical activity, cholesterol, stroke, diabetes, number of medications, and C-reactive protein, participants with sarcopenia had a higher risk of incident falls compared with non sarcopenic subjects (adjusted hazard ratio HR, 3.23; 95% confidence interval CI, 1.25–8.29). Conclusions The present study suggests that sarcopenia – assessed using the EWGSOP algorithm – is highly prevalent among elderly persons without gender differences (25%). Sarcopenic participants were over three times more likely to fall during a follow-up period of 2 years relative to non sarcopenic individuals, regardless of age, gender and other confounding factors.
Abstract Background In the last decades, several efforts have been done to clarify the role of BRCA mutational status in women with advanced ovarian cancer demonstrating its role in cancer ...development, as well as the prognostic significance of BRCA genotype. Objctive Our aim is to evaluate the correlation between BRCA mutational status and disease presentation in a large series of advanced high-grade serous ovarian cancer patients. Study Design this is a retrospective multicenter study including a consecutive series of newly diagnosed high-grade serous ovarian cancer patients with FIGO Stage IIIC-IV disease, at least 18 months of follow-up time, tested for BRCA 1/2 germline mutation status. Disease presentation was analyzed using the following variables: laparoscopic predictive-index value, incidence of bulky lymph nodes and ovarian masses. Progression-free survival was defined as the months elapsed from initial diagnosis (staging laparoscopy) and recurrent disease or last follow-up. Results 324 high-grade serous ovarian cancer patients received BRCA testing, and 273 fulfilled inclusion criteria. BRCA1/2 germline mutations were observed in 107 women (39.2%). No differences were documented according to BRCA mutation status in terms of FIGO Stage, CA125 levels, and presence of ascites. In patients with BRCA1/2 mutations we observed a higher incidence of peritoneal spread without ovarian mass (25.2% versus 13.9%; p-value=0.018), and of bulky lymph nodes (30.8% versus 17.5%, p-value=0.010) compared with women showing BRCA1/2 wild type genotype. Furthermore, women with BRCA1/2 mutations showed high peritoneal tumor load (laparoscopic predictive-index value≥8; 42.1% versus 27.1%; p-value=0.016) more frequently. Focusing on survival, no differences in term of median progression-free survival were observed among women treated with primary debulking surgery and neoadjuvant chemotherapy in the group of patients with BRCA1/2 mutations (p-value=0.268). On the other hand, in women showing BRCA wild type genotype, median progression-free survival after primary debulking surgery was 8 months longer compared with patients treated with neoadjuvant chemotherapy approach (26 months versus 18 months; p-value=0.003). Conclusions women with BRCA1/2 mutations show at diagnosis higher peritoneal tumor load, and increased frequency of bulky lymph nodes compared to patients without germline BRCA mutations. Primary debulking surgery seems to ensure a longer progression-free survival in women with BRCA wild type genotype compared to neoadjuvant chemotherapy. BRCA testing might be a reliable tool to personalize treatment in patients with high-grade serous ovarian cancer, thus giving novel points of discussion to the ongoing debate regarding the best initial treatment approach.
Summary Background & aims Lean body mass loss has been indicated as a reliable marker of frailty and poor physical performance among older individuals. We evaluated the relationship between calf ...circumference and frailty, physical performance, muscle strength, and functional status in persons aged 80 years or older. Methods Data are from the baseline evaluation of the Aging and Longevity Study in the Sirente geographic area (ilSIRENTE Study) ( n = 357). The calf circumference was measured at the point of greatest circumference. Frailty was categorized according to the present of slow gait speed, weakness, weight loss, energy expenditure and exhaustion. Physical performance was assessed using the physical performance battery score, which is based on three timed tests: 4-m walking speed test, the balance test and the chair stand test. Analyses of covariance were performed to evaluate the relationship between different calf circumference and physical function. Results After adjustment for potential confounders, which included age, gender, education, body mass index, sensory impairments, cerebrovascular diseases, albumin, reactive C protein, interleukine-6, and cholesterol, physical performance (SPPB score: 7.27 versus 6.18, p = 0.02) and muscle strength (Hand Grip: 32 kg versus 28 kg, p = 0.03) measures significantly improved as calf circumference increased. The frailty index score was significantly lower among subjects with higher calf circumference (1.66 versus 2.17, p = 0.01). Conclusions The present study suggests that among community-dwelling older people, calf circumference may be positively related to lower frailty index and higher functional performance. As such, calf circumference is a valuable tool for guiding public health policy and clinical decisions.
Early detection is essential for treatment plans before onset of metastatic disease. Our purpose was to demonstrate feasibility to detect and monitor estrogen receptor 1 (
) gene mutations at the ...single circulating tumor cell (CTC) level in metastatic breast cancer (MBC).
We used a CTC molecular characterization approach to investigate heterogeneity of 14 hotspot mutations in
and their correlation with endocrine resistance. Combining the CellSearch and DEPArray technologies allowed recovery of 71 single CTCs and 12 WBC from 3 ER-positive MBC patients. Forty CTCs and 12 WBC were subjected to whole genome amplification by MALBAC and Sanger sequencing.
Among 3 selected patients, 2 had an
mutation (Y537). One showed two different
variants in a single CTC and another showed loss of heterozygosity. All mutations were detected in matched cell-free DNA (cfDNA). Furthermore, one had 2 serial blood samples analyzed and showed changes in both cfDNA and CTCs with emergence of mutations in
(Y537S and T570I), which has not been reported previously.
CTCs are easily accessible biomarkers to monitor and better personalize management of patients with previously demonstrated ER-MBC who are progressing on endocrine therapy. We showed that single CTC analysis can yield important information on clonal heterogeneity and can be a source of discovery of novel and potential driver mutations. Finally, we also validate a workflow for liquid biopsy that will facilitate early detection of
mutations, the emergence of endocrine resistance and the choice of further target therapy.
.
Objective To determine the diagnostic accuracy of the surfactant adsorption test (SAT) as a predictor for the need for surfactant replacement therapy in neonates with respiratory distress syndrome ...(RDS). Study design Amniotic fluid samples were collected from 41 preterm neonates with RDS treated with continuous positive airway pressure (CPAP) and 15 healthy control term neonates. Purified porcine surfactant served as a further control. Lamellar bodies and lung ultrasound score were also measured in a subset of the neonates treated with CPAP. Surfactant was administered according to the European guidelines, and clinical data were collected prospectively. Surfactant activity was measured as adsorption at the air/liquid interface and given in relative fluorescent units (RFU). Results Surfactant activity differed among native porcine surfactant (median, 4863 RFU; IQR, 4405-5081 RFU), healthy term neonates (median, 2680 RFU; IQR, 2069-3050 RFU), and preterm neonates with RDS (median, 442 RFU; IQR, 92-920 RFU; P < .0001). The neonates who failed CPAP had lower surfactant activity compared with those who did not fail CPAP (median, 92 RFU; IQR, 0-315 RFU vs 749 RFU; IQR, 360-974 RFU; P = .0002). Differences between groups were more evident beyond 20-30 minutes of fluorescence; the 30-minute time point showed the highest area under the curve (0.84; P < .001) and the best cutoff level (170 RFU; specificity, 72%; sensitivity, 96%) for the prediction of CPAP failure. Surfactant activity at 30 minutes was significantly correlated with lamellar bodies ( r = 0.51, P = .006) and lung ultrasound score ( r = -0.39, P = .013). Conclusion This technique has the potential to be developed into a fast, simple-to-interpret clinical test. The SAT can reliably identify preterm infants with subsequent CPAP failure and shows promise as a screening test for surfactant replacement in preterm neonates.
BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. ...Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed.
The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis.
An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer.
These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.
•Provide update clinical recommendations for BRCA testing for preventive purpose.•Offer testing clinical guidelines for personalised management of early and metatstatic breast cancer.•Actualize germline and tumor testing indications for PARPi-approved therapies.•Address the issues of rapid process and tumor analysis.
High-grade serous ovarian cancer (HGSOC) patients carrying the
mutation or deficient in the homologous recombination repair system (HRD) generally benefit from treatment with PARP inhibitors. Some ...international recommendations suggest that
genetic testing should be offered for all newly diagnosed epithelial ovarian cancer, along with HRD assessment. Academic tests (ATs) are continuously under development, in order to break down the barriers patients encounter in accessing HRD testing. Two different methods for shallow whole-genome sequencing (sWGS) were compared to the reference assay, Myriad. All these three assays were performed on 20 retrospective HGSOC samples. Moreover, HRD results were correlated with the progression-free survival rate (PFS). Both sWGS chemistries showed good correlation with each other and a complete agreement, even when compared to the Myriad score. Our academic HRD assay categorized patients as HRD-Deficient, HRM-Mild and HRN-Negative. These three groups were matched with PFS, providing interesting findings in terms of HRD scoring and months of survival. Both our sWGS assays and the Myriad test correlated with the patient's response to treatments. Finally, our AT confirms its capability of determining HRD status, with the advantage of being faster, cheaper, and easier to carry out. Our results showed a prognostic value for the HRD score.
Abstract Objective In this study, we evaluate the impact of disability and multimorbidity on the risk of all-cause death in a population of frail older persons living in community. Study Design and ...Setting We analyzed data from the Aging and Longevity Study in the Sirente geographic area, a prospective cohort study that collected data on all subjects aged 80 years and older ( n = 364). The main outcome measure was all-cause mortality over 4-year follow-up. Results A total of 150 deaths occurred. Sixty-seven subjects (44.6%) died in the nondisabled group compared with 83 subjects (55.3%) in the disabled group ( P < 0.01). Thirty-nine subjects (31.7%) died among subjects without multimorbidity compared with 111 subjects (46.0%) with two or more diseases ( P < 0.01). When examining the combined effect of multimorbidity and disability, the effect of disability on the risk of death was higher than that of multimorbidity. After adjusting for potential confounders, relative to those without disability and multimorbidity, disabled subjects showed an increased risk of death when multimorbidity was associated (hazard ratio HR = 3.91; 95% confidence interval CI = 1.53–10.00) and in absence of multimorbidity (HR = 2.36; 95% CI = 0.63–8.83). Conclusion Our results show that disability exerts an important influence on mortality, independently of age and other clinical and functional variables.
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