Cause specific mortality in an Italian pool of asbestos workers cohorts.

BACKGROUND: Asbestos is a known human carcinogen and is causally associated with malignant mesothelioma, lung, larynx and ovarian cancers. METHODS: Cancer risk was studied among a pool of formerly asbestos-exposed workers in Italy. Fifty-two Italian asbestos cohorts (asbestos-cement, rolling-stock, shipbuilding, and other) were pooled and their mortality follow-up was updated to 2018. Standardized mortality ratios (SMRs) were computed for major causes of death considering duration of exposure and time since first exposure (TSFE), using reference rates by region, age and calendar period. RESULTS: The study included 63,502 subjects (57,156 men and 6346 women): 40% who were alive, 58% who died (cause known for 92%), and 2% lost to follow-up. Mortality was increased for all causes (SMR: men = 1.04, 95% confidence interval [CI] 1.03-1.05; women = 1.15, 95% CI 1.11-1.18), all malignancies (SMR: men = 1.21, 95% CI 1.18-1.23; women = 1.29, 95% CI 1.22-1.37), pleural and peritoneal malignancies (men: SMR = 10.46, 95% CI 9.86-11.09 and 4.29, 95% CI 3.66-5.00; women: SMR = 27.13, 95% CI 23.29-31.42 and 7.51, 95% CI 5.52-9.98), lung (SMR: men = 1.28, 95% CI 1.24-1.32; women = 1.26, 95% CI 1.02-1.53), and ovarian cancer (SMR = 1.42, 95% CI 1.08-1.84). Pleural cancer mortality increased during the first 40 years of TSFE (latency), reaching a plateau thereafter. CONCLUSIONS: Analyses by time-dependent variables showed that the risk for pleural neoplasms increased with latency and no longer increases at long TSFE, consistent with with asbestos clearance from the lungs. Peritoneal neoplasm risk increased over all observation time.

Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: A Sarculator-based risk stratification analysis of the ISG-STS 1001 randomized trial.

BACKGROUND: The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic stratification based on the Sarculator nomogram for STS. METHODS: This study analyzed data from ISG-STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology-tailored (HT) chemotherapy in adult patients with STS. The 10-year predicted overall survival (pr-OS) was estimated with the Sarculator and was stratified into higher (10-year pr-OS < 60%) and lower risk subgroups (10-year pr-OS ≥ 60%). RESULTS: The median pr-OS was 0.63 (interquartile range [IQR], 0.51-0.72) for the entire study population, 0.62 (IQR, 0.51-0.70) for the AI arm, and 0.64 (IQR, 0.51-0.73) for the HT arm. Three- and 5-year overall survival (OS) were 0.86 (95% confidence interval [CI], 0.82-0.93) and 0.81 (95% CI, 0.71-0.86) in lower risk patients and 0.69 (95% CI, 0.70-0.85) and 0.59 (95% CI, 0.51-0.72) in the higher risk patients (log-rank test, P = .004). In higher risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.68 and 0.58, respectively, and 0.85 and 0.66, respectively, in the AI arm (P = .04); the corresponding figures in the HT arm were 0.69 and 0.60, respectively, and 0.69 and 0.55, respectively (P > .99). In lower risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P = .507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P = .105). CONCLUSIONS: High-risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS. LAY SUMMARY: People affected by soft tissue sarcomas of the extremities and trunk wall are at some risk of developing metastasis after surgery. Preoperative or postoperative chemotherapy has been tested in clinical trials to reduce the chances of distant metastasis. However, study findings have not been conclusive. This study stratified the risk of metastasis for people affected by sarcomas who were included in a clinical trial testing neoadjuvant chemotherapy. Exploiting the prognostic nomogram Sarculator, it found a benefit for chemotherapy when the predicted risk, based on patient and tumor characteristics, was high.

Intravenous methylprednisolone pulses in hospitalised patients with severe COVID-19 pneumonia: a double-blind, randomised, placebo-controlled trial.

RATIONALE: Pulse glucocorticoid therapy is used in hyperinflammation related to coronavirus disease 2019 (COVID-19). We evaluated the efficacy and safety of pulse intravenous methylprednisolone in addition to standard treatment in COVID-19 pneumonia. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, 304 hospitalised patients with COVID-19 pneumonia were randomised to receive 1 g of methylprednisolone intravenously for three consecutive days or placebo in addition to standard dexamethasone. The primary outcome was the duration of patient hospitalisation, calculated as the time interval between randomisation and hospital discharge without the need for supplementary oxygen. The key secondary outcomes were survival free from invasive ventilation with orotracheal intubation and overall survival. RESULTS: Overall, 112 (75.4%) out of 151 patients in the pulse methylprednisolone arm and 111 (75.2%) of 150 in the placebo arm were discharged from hospital without oxygen within 30 days from randomisation. Median time to discharge was similar in both groups (15 days, 95% CI 13.0-17.0 days and 16 days, 95% CI 13.8-18.2 days, respectively; hazard ratio (HR) 0.92, 95% CI 0.71-1.20; p=0.528). No significant differences between pulse methylprednisolone and placebo arms were observed in terms of admission to intensive care unit with orotracheal intubation or death (20.0% versus 16.1%; HR 1.26, 95% CI 0.74-2.16; p=0.176) or overall mortality (10.0% versus 12.2%; HR 0.83, 95% CI 0.42-1.64; p=0.584). Serious adverse events occurred with similar frequency in the two groups. CONCLUSIONS: Methylprenisolone pulse therapy added to dexamethasone was not of benefit in patients with COVID-19 pneumonia.

Gonadotropin Releasing Hormone Agonists Have an Anti-apoptotic Effect on Cumulus Cells.

BACKGROUND: Ovaries are sensitive to chemotherapy, which may lead to early depletion of primordial follicle reserve. One strategy for gonadal function preservation is temporary ovarian suppression with Gonadotropin Releasing Hormone agonists (GnRHa) during chemotherapy. To date, GnRHa protective mechanism of action remains not fully elucidated. METHODS: We collected 260 immature cumulus cell-oocyte complexes (COC) from 111 women < 38 years old, with a normal ovarian reserve. The COC were randomly assigned to the following groups: a) control; culture with the addition of b) GnRHa; c) cyclophosphamide; d) cyclophosphamide plus GnRHa. After in vitro treatments, RNA and proteins were extracted from oocytes and cumulus cells (CC), separately. Potential effects of drugs were evaluated on GnRH receptors, apoptosis pathways, ceramide pathway, and glutathione synthesis by quantitative PCR and, whenever possible, by Western blot. RESULTS: Cyclophosphamide triggered activation of the extrinsic pathway of apoptosis mediated by BAX in CC. The co-administration of GnRHa inhibited the apoptosis pathway in CC. According to our model, the GnRHa does not directly act on oocytes, which do not express GnRH receptors. Moreover, glutathione synthesis was decreased after GnRHa treatment both in CC and oocytes. CONCLUSION: Our data suggest that the protective mechanisms induced by GnRHa is mediated by an anti-apoptotic effect on CC.

Maternal diet during pregnancy and micronuclei frequency in peripheral blood T lymphocytes in mothers and newborns (Rhea cohort, Crete).

PURPOSE: The study assessed whether diet and adherence to cancer prevention guidelines during pregnancy were associated with micronucleus (MN) frequency in mothers and newborns. MN is biomarkers of early genetic effects that have been associated with cancer risk in adults. METHODS: A total of 188 mothers and 200 newborns from the Rhea cohort (Greece) were included in the study. At early-mid pregnancy, we conducted personal interviews and a validated food frequency questionnaire was completed. With this information, we constructed a score reflecting adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention guidelines on diet, physical activity and body fatness. At delivery, maternal and/or cord blood was collected to measure DNA and hemoglobin adducts of dietary origin and frequencies of MN in binucleated and mononucleated T lymphocytes (MNBN and MNMONO). RESULTS: In mothers, higher levels of red meat consumption were associated with increased MNBN frequency [2nd tertile IRR = 1.34 (1.00, 1.80), 3rd tertile IRR = 1.33 (0.96, 1.85)] and MNMONO frequency [2nd tertile IRR = 1.53 (0.84, 2.77), 3rd tertile IRR = 2.69 (1.44, 5.05)]. The opposite trend was observed for MNBN in newborns [2nd tertile IRR = 0.64 (0.44, 0.94), 3rd tertile IRR = 0.68 (0.46, 1.01)], and no association was observed with MNMONO. Increased MN frequency in pregnant women with high red meat consumption is consistent with previous knowledge. CONCLUSIONS: Our results also suggest exposure to genotoxics during pregnancy might affect differently mothers and newborns. The predictive value of MN as biomarker for childhood cancer, rather than adulthood, remains unclear. With few exceptions, the association between maternal carcinogenic exposures during pregnancy and childhood cancer or early biologic effect biomarkers remains poorly understood.

Mortality among workers exposed to asbestos at the shipyard of Genoa, Italy: a 55 years follow-up.

BACKGROUND: Exposure to asbestos remains a global issue due to its massive use in the twentieth century and its long environmental persistence. Exposure to asbestos still occurs during dismantling of ships and vessels, buildings renovation, mining operations, and is reported in developing countries. Current estimate report exposure of hundreds of million people in occupational settings in countries where its use remains unregulated. METHODS: We conducted a historical prospective cohort mortality study aimed at estimating mortality from specific causes, the temporal changes of pleural and lung cancer mortality, and the attributable fraction (AF) of lung cancer deaths following asbestos exposure. The study included 3984 shipyard workers employed at the shipyard of Genoa, Italy, between 1960 and 1981 and followed up to December 2014. Standardized Mortality Ratios (SMR) and their 95% confidence intervals (95%CI) were computed. RESULTS: Overall deaths recorded were 3331 (83.6%). Excess mortality was observed for all cancers (SMR = 127, 95%CI:120-134), pleural mesothelioma (575, 469-697), cancers of the larynx (183, 134-244) and of the lung (154, 139-170), and for respiratory tract diseases (127, 114-141), including asbestosis (2277, 1525-3270). Ninety out of 399 deaths (22.6%) from lung cancer were attributed to asbestos exposure. The estimated lung cancer AF was 49.3% in workers with the highest SMR for pleural cancer. Median latency times for pleural and lung cancer were 42.8 years (minimum latency: 9.3 years) and 38.7 years (minimum latency: 6 years). The peak of mesothelioma incidence, expected in Italy in the period 2015-2024, was confirmed. CONCLUSIONS: The long follow-up period of our study allowed the detection of a substantial disease burden following asbestos exposure. These findings support the urgent need for the prevention of asbestos related diseases through the implementation of asbestos ban worldwide, including those countries where asbestos is still mined, manufactured and used.

Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial.

BACKGROUND: Previous trials from our group suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of the extremities or trunk wall, and no difference in overall survival benefit between three cycles versus five cycles of the same neoadjuvant regimen. We aimed to show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy. METHODS: For this international, open-label, randomised, controlled, phase 3, multicentre trial, patients were enrolled from 32 hospitals in Italy, Spain, France, and Poland. Eligible patients were aged 18 years or older with localised, high-risk (high malignancy grade, 5 cm or longer in diameter, and deeply located according to the investing fascia), soft-tissue sarcoma of the extremities or trunk wall and belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Patients were randomly assigned (1:1) to receive three cycles of full-dose standard chemotherapy (epirubicin 60 mg/m2 per day [short infusion, days 1 and 2] plus ifosfamide 3 g/m2 per day [days 1, 2, and 3], repeated every 21 days) or histotype-tailored chemotherapy: for high-grade myxoid liposarcoma, trabectedin 1·3 mg/m2 via 24-h continuous infusion, repeated every 21 days; for leiomyosarcoma, gemcitabine 1800 mg/m2 on day 1 intravenously over 180 min plus dacarbazine 500 mg/m2 on day 1 intravenously over 20 min, repeated every 14 days; for synovial sarcoma, high-dose ifosfamide 14 g/m2, given over 14 days via an external infusion pump, every 28 days; for malignant peripheral nerve sheath tumour, intravenous etoposide 150 mg/m2 per day (days 1, 2, and 3) plus intravenous ifosfamide 3 g/m2 per day (days 1, 2, and 3), repeated every 21 days; and for undifferentiated pleomorphic sarcoma, gemcitabine 900 mg/m2 on days 1 and 8 intravenously over 90 min plus docetaxel 75 mg/m2 on day 8 intravenously over 1 h, repeated every 21 days. Randomisation was stratified by administration of preoperative radiotherapy and by country of enrolment. Computer-generated random lists were prepared by use of permuted balanced blocks of size 4 and 6 in random sequence. An internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered into the system. No masking of treatment assignments was done. The primary endpoint was disease-free survival. The primary and safety analyses were planned in the intention-to-treat population. We did yearly futility analyses on an intention-to-treat basis. The study was registered with ClinicalTrials.gov, number NCT01710176, and with the European Union Drug Regulating Authorities Clinical Trials, number EUDRACT 2010-023484-17, and is closed to patient entry. FINDINGS: Between May 19, 2011, and May 13, 2016, 287 patients were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy), all of whom, except one patient assigned to standard chemotherapy, were included in the efficacy analysis (97 [34%] with undifferentiated pleomorphic sarcoma; 64 [22%] with high-grade myxoid liposarcoma; 70 [24%] with synovial sarcoma; 27 [9%] with malignant peripheral nerve sheath tumour; and 28 [10%] with leiomyosarcoma). At the third futility analysis, with a median follow-up of 12·3 months (IQR 2·75-28·20), the projected disease-free survival at 46 months was 62% (95% CI 48-77) in the standard chemotherapy group and 38% (22-55) in the histotype-tailored chemotherapy group (stratified log-rank p=0·004; hazard ratio 2·00, 95% CI 1·22-3·26; p=0·006). The most common grade 3 or higher adverse events in the standard chemotherapy group (n=125) were neutropenia (107 [86%]), anaemia (24 [19%]), and thrombocytopenia (21 [17%]); the most common grade 3 or higher adverse event in the histotype-tailored chemotherapy group (n=114) was neutropenia (30 [26%]). No treatment-related deaths were reported in both groups. In agreement with the Independent Data Monitoring Committee, the study was closed to patient entry after the third futility analysis. INTERPRETATION: In a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma. FUNDING: European Union grant (Eurosarc FP7 278472).

PUREAIR protocol: randomized controlled trial of intensive pulmonary rehabilitation versus standard care in patients undergoing surgical resection for lung cancer.

BACKGROUND: Non-small cell lung cancer is the most common type of lung cancer. Surgery is proven to be the most effective treatment in early stages, despite its potential impact on quality of life. Pulmonary rehabilitation, either before or after surgery, is associated with reduced morbidity related symptoms and improved exercise capacity, lung function and quality of life. METHODS: We describe the study protocol for the open-label randomized controlled trial we are conducting on patients affected by primary lung cancer (stages I-II) eligible for surgical treatment. The control group receives standard care consisting in one educational session before surgery and early inpatient postoperative physiotherapy. The treatment group receives, in addition to standard care, intensive rehabilitation involving 14 preoperative sessions (6 outpatient and 8 home-based) and 39 postoperative sessions (15 outpatient and 24 home-based) with aerobic, resistance and respiratory training, as well as scar massage and group bodyweight exercise training. Assessments are performed at baseline, the day before surgery and one month and six months after surgery. The main outcome is the long-term exercise capacity measured with the Six-Minute Walk Test; short-term exercise capacity, lung function, postoperative morbidity, length of hospital stay, quality of life (Short Form 12), mood disturbances (Hospital Anxiety and Depression Scale) and pain (Numeric Rating Scale) are also recorded and analysed. Patient compliance and treatment-related side effects are also collected. Statistical analyses will be performed according to the intention-to-treat approach. T-test for independent samples will be used for continuous variables after assessment of normality of distribution. Chi-square test will be used for categorical variables. Expecting a 10% dropout rate, assuming α of 5% and power of 80%, we planned to enrol 140 patients to demonstrate a statistically significant difference of 25 m at Six-Minute Walk Test. DISCUSSION: Pulmonary Resection and Intensive Rehabilitation study (PuReAIR) will contribute significantly in investigating the effects of perioperative rehabilitation on exercise capacity, symptoms, lung function and long-term outcomes in surgically treated lung cancer patients. This study protocol will facilitate interpretation of future results and wide application of evidence-based practice. TRIAL REGISTRATION: ClinicalTrials.gov Registry n. NCT02405273 [31.03.2015].

CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor.

CTLA-4 function as a negative regulator of T cell-mediated immune response is well established, whereas much less is known about the immunoregulatory role of its soluble isoform (sCTLA-4). No data are available on CTLA-4 expression and prognostic impact in malignant pleural mesothelioma (MPM). We investigated, by immunohistochemistry, CTLA-4 expression in tumor tissues and, by ELISA, sCTLA-4 levels in sera and matched pleural effusions from 45 MPM patients. Prognostic effect of CTLA-4 expression on overall survival (OS) was assessed through Cox regression and prognostic significance expressed as death rate ratio (HR). We found that 56.0 % of MPM tissues expressed CTLA-4 with variable intensity and percentage of positive cells estimated by the immunoreactive score. sCTLA-4 levels were significantly higher in sera (S-sCTLA-4) than in pleural effusions (PE-sCTLA-4) (geometric mean ratio = 2.70, P value = 0.020). CTLA-4 expression at the tissue level was higher in the epithelioid histological subtype than in the sarcomatoid, whereas at the serum level, it was higher in the sarcomatoid subtype. A homogeneous favorable prognostic effect was found for CTLA-4 overexpression in tissue, serum and pleural effusion. Interestingly, only the PE-sCTLA-4 was found to be a statistically significant positive prognostic factor (HR = 0.37, 95 % CI = 0.18-0.77, P value = 0.007). Indeed, PE-sCTLA-4 correlated with CTLA-4 expression in tissues, whereas this latter expression showed a weak association with OS. To confirm our findings, further experimental evidences obtained from a larger cohort of MPM patients are required. However, our results would indicate a positive correlation of PE-sCTLA-4 levels and OS in MPM patients.

Outdoor air pollution exposures and micronuclei frequencies in lymphocytes from pregnant women and newborns in Crete, Greece (Rhea cohort).

BACKGROUND: Micronuclei (MN) are biomarkers of early genetic effects that have been used to investigate the association between environmental exposures and cancer. However, few studies have examined the association between environmental exposures during pregnancy and MN in mothers and newborns. OBJECTIVES: We examined MN frequency in maternal blood and in cord blood, in relation to maternal air pollution exposure, and the potential interaction with maternal vitamin C intake and maternal smoking. METHODS: We used the cytokinesis-block micronucleus assay to assess MN frequency per 1000 bi-nucleated T-lymphocytes from 181 mothers and 183 newborns born in 2007-2008 in Heraklion (Crete, Greece). The ESCAPE land-use regression methods were used to estimate annual mean exposure to outdoor air pollution [particulate matter (PM), black carbon, nitrogen dioxide (NO2) and nitrogen oxides (NOx)] at maternal home addresses. Food frequency questionnaires were used to estimate maternal dietary vitamin C intake during pregnancy. Smoking habits were self-reported using questionnaires which were checked by measuring maternal urinary cotinine levels. RESULTS: Exposure to PM2.5 was associated with increased MN frequencies in pregnant women [rate ratio [RR (95%CI)] per 5 µg/m(3)=1.53 (1.02, 2.29)]. This increase was considerably higher among women who did not fulfill the recommended vitamin C dietary allowances [RR=9.35 (2.77, 31.61); n=20]. Exposure to PM2.5-10, PM10, NO2 and NOx were also associated with a higher incidence of MN frequencies in smoker women (n=56). No associations were found for newborns. CONCLUSIONS: We found an association between air pollution, particularly PM2.5, and MN frequency in mothers but not in newborns. This association was more pronounced among women with a lower dietary intake of vitamin C during pregnancy and among women who smoked during pregnancy. While results are clear in mothers, the association between maternal carcinogenic exposures during pregnancy and biomarkers of early biologic effect in the newborn remains poorly understood.

Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments.

BACKGROUND: This open-label study compared docetaxel/gemcitabine vs. paclitaxel/gemcitabine and a weekly (W) vs. 3-weekly (3 W) schedule in metastatic breast cancer (MBC). METHODS: Patients relapsed after adjuvant/neoadjuvant anthracycline-containing chemotherapy were randomized to: A) gemcitabine 1000 mg/m2 Day 1,8 + docetaxel 75 mg/m2 Day 1 q3W; B) gemcitabine 1250 mg/m2 Day 1,8 + paclitaxel 175 mg/m2 Day 1 q3W; C) gemcitabine 800 mg/m2 Day 1,8,15 + docetaxel 30 mg/m2 Day 1,8,15 q4W; D) gemcitabine 800 mg/m2 Day 1,15 + paclitaxel 80 mg/m2 Day 1,8,15 q4W. Primary endpoint was time-to-progression (TTP). Secondary endpoints were overall survival (OS) and overall response rate (ORR). RESULTS: Interim analysis led to accrual interruption (241 patients enrolled of 360 planned). Median TTP (months) was 8.33 (95% CI: 6.19-10.16) with W and 7.51 (95% CI: 5.93-8.33) with 3 W (p=0.319). No differences were observed in median TTP between docetaxel and paclitaxel, with 85.6% and 87.0% of patients progressing, respectively. OS did not differ between regimens/schedules. ORR was comparable between regimens (HR: 0.882; 95% CI: 0.523-1.488; p=0.639), while it was significantly higher in W than in the 3 W (HR: 0.504; 95% CI: 0.299-0.850; p=0.010) schedule. Grade 3/4 toxicities occurred in 69.2% and 71.9% of patients on docetaxel and paclitaxel, and in 65.8% and 75.2% in W and 3 W. CONCLUSIONS: Both treatment regimens showed similar TTP. W might be associated with a better tumour response compared with 3 W. TRIAL REGISTRATION: Clinicaltrial.gov ID NCT00236899.

Risk of childhood leukaemia and non-Hodgkin's lymphoma after parental occupational exposure to solvents and other agents: the SETIL Study.

AIM: In the context of the Italian Multicentric Epidemiological Study on Risk Factors for Childhood Leukaemia and Non-Hodgkin's Lymphoma (SETIL), the risk of childhood cancer was investigated in relation to parental occupational exposures. METHODS: All cases of childhood leukaemia and non-Hodgkin's lymphoma (NHL) in children aged 0-10 years were identified. Controls were chosen at random from the local population in each region. Parents were interviewed using a structured questionnaire. The collected data were blindly reviewed by expert industrial hygienists in order to estimate exposure to a list of agents. Statistical analyses were performed for each agent using unconditional multivariable logistic regression models, taking into account timing of exposure. RESULTS: 683 cases of acute childhood leukaemia, 97 cases of NHL and 1044 controls were identified. Increased risk of childhood leukaemia was found for maternal exposure to aliphatic (OR 4.3) or aromatic hydrocarbons (OR 3.8) in the preconception period, and for paternal exposure to diesel exhaust (OR 1.4), lead exposure (OR 1.7) and mineral oils (OR 1.4)[corrected]. Risk of NHL appeared to be related to paternal exposure to oxygenated solvents (OR 2.5) and petrol exhaust (OR 2.2). CONCLUSIONS: We found increased risk for childhood leukaemia associated with maternal occupational exposure to aromatic and aliphatic hydrocarbons, particularly in the preconception period; increased risks were also observed for paternal exposure to diesel exhaust fumes, mineral oils and lead. The risk of NHL appeared to be related to paternal exposure to oxygenated solvent and petrol exhausts.

Evaluation of CTLA-4 expression and relevance as a novel prognostic factor in patients with non-small cell lung cancer.

The role of CTLA-4 in negative regulation of T-cell mediated immune response is particularly well established. Much less is known about its expression and function in tumour cells, and to our knowledge, no data are available on its possible impact on prognosis of NSCLC patients. We investigated CTLA-4 expression and prognostic role in 81 patients with radically resected stage I-III NSCLC. The analysis was performed by tissue microarray immunohistochemistry, and the median H-score of 20 was used as a threshold to define CTLA-4 overexpressing tumours. Correlation with standard prognostic factors was performed by using absolute and relative fold change indexes. Hazard ratios (HR) and corresponding 95% confidence limits (95% CL) were computed through the Cox model. A higher frequency of CTLA-4 overexpression (>20) was found in non-squamous than in squamous NSCLC (52.8 vs. 35.7%) and in Ki67 ≤ 15 expressing tumours, as compared to those with Ki67 > 15 (51.5 vs. 38.7%). A reduced death rate was found in CTLA-4 overexpressing tumours (HR = 0.60, 95% CL = 0.28/1.23), and a further decrease was observed when considering tumours with CTLA-4 > 20 and Ki67 ≤ 15, in comparison with tumours with CTLA-4 ≤ 20 and Ki67 > 15 (HR = 0.41; 95% CL = 0.15/1.13). Our observational and exploratory study provides a first and promising indication for an independent prognostic effect of CTLA-4 overexpression in radically resected NSCLC. We presume that this effect relies on modulation of the interaction of microscopic disease with CTLA-4-ligands expressing cells leading to NSCLC cell death.

The postoperative analgesic efficacy of preperitoneal continuous wound infusion compared to epidural continuous infusion with local anesthetics after colorectal cancer surgery: a randomized controlled multicenter study.

BACKGROUND: Open colorectal cancer (CRC) surgery induces severe and prolonged postoperative pain. The optimal method of postoperative analgesia in CRC surgery has not been established. We evaluated the efficacy of preperitoneal continuous wound infusion (CWI) of ropivacaine for postoperative analgesia after open CRC surgery in a multicenter randomized controlled trial. METHODS: Candidates for open CRC surgery randomly received preperitoneal CWI analgesia or continuous epidural infusion (CEI) analgesia with ropivacaine 0.2% 10 mL/h for 48 hours after surgery. Fifty-three patients were allocated to each group. All patients received patient-controlled IV morphine analgesia. RESULTS: Over the 72-hour period after the end of surgery, CWI analgesia was not inferior to CEI analgesia. The difference of the mean visual analog scale score between CEI and CWI patients was 1.89 (97.5% confidence interval = -0.42, 4.19) at rest and 2.76 (97.5% confidence interval = -2.28, 7.80) after coughing. Secondary end points, morphine consumption and rescue analgesia, did not differ between groups. Time to first flatus was 3.06 ± 0.77 days in the CWI group and 3.61 ± 1.41 days in the CEI group (P = 0.002). Time to first stool was shorter in the CWI than the CEI group (4.49 ± 0.99 vs 5.29 ± 1.62 days; P = 0.001). Mean time to hospital discharge was shorter in the CWI group than in the CEI group (7.4 ± 0.41 and 8.0 ± 0.38 days, respectively). More patients in the CWI group reported excellent quality of postoperative pain control (45.3% vs 7.6%). Quality of night sleep was better with CWI analgesia, particularly at the postoperative 72-hour evaluation (P = 0.009). Postoperative nausea and vomiting was significantly less frequent with CWI analgesia at 24 hours (P = 0.02), 48 hours (P = 0.01), and 72 hours (P = 0.007) after surgery evaluations. CONCLUSIONS: Preperitoneal CWI analgesia with ropivacaine 0.2% continuous infusion at 10 mL/h during 48 hours after open CRC surgery provided effective postoperative pain relief not inferior to CEI analgesia.

Micronuclei in neonates and children: effects of environmental, genetic, demographic and disease variables.

Children may be more susceptible to the effects of the environmental exposure and medical treatments than adults; however, limited information is available about the differences in genotoxic effects in children by age, sex and health status. Micronucleus (MN) assay is a well established method of monitoring genotoxicity, and this approach is thoroughly validated for adult lymphocytes by the Human Micronucleus Biomonitoring project (HUMN.org). Similar international undertaking is in progress for exfoliated buccal cells. Most of the MN studies in children are focused on analyses of lymphocytes but in the recent years, more investigators are interested in using exfoliated cells from the oral cavity and other cell types that can be collected non-invasively, which is particularly important in paediatric cohorts. The baseline MN frequency is relatively low in newborns and its assessment requires large cohorts and cell sample counts. Available results are mostly consistent in conclusion that environmental pollutants and radiation exposures lead to the increase in the MN frequency in children. Effects of medical treatments are less clear, and more studies are needed to optimise the doses and minimise genotoxicity without compromising therapy outcomes. Despite the recent progress in MN assay in children, more studies are warranted to establish the relationship between MN in lymphocytes and exfoliated cells, to clarify sex, age and genotype differences in baseline MN levels and the changes in response to genotoxicants. One of the most important types of MN studies in children are prospective cohorts that will help to clarify the predictive value of MN and other cytome end points for cancer and other chronic diseases of childhood and adulthood. Emerging 'omic' and other novel molecular technologies may shed light on the molecular mechanisms and biological pathways associated with the MN levels in children.

Factors affecting symmetrization of the contralateral breast: a 7-year unilateral postmastectomy breast reconstruction experience.

Although a number of studies compare different techniques of breast reconstruction, information documenting the factors that affect breast symmetry after unilateral mastectomy and reconstruction seems to be scarce. A statistical analysis of 606 patients undergoing unilateral mastectomy and breast reconstruction performed during a 7 year period was undertaken in an endeavor to identify these factors. Patients were classified according to time of reconstruction, method of reconstruction, type of implant, and mastectomy type. Contralateral procedures included mastopexy, augmentation, and reduction mammaplasty. Delayed reconstruction more frequently required a symmetrization than an immediate reconstruction. The percentage of contralateral procedures was higher for implant reconstructions than for autologous reconstructions, and the type of mastectomy was significantly associated with the symmetrization procedure. The findings showed that non-skin-sparing mastectomy (non-SSM) needed symmetrization surgery more frequently than did SSM procedures. The data suggest a preoperative collaboration and case study between oncologic and plastic surgeons to apply, when possible, SSM with immediate implant breast reconstruction, resulting in fewer symmetrization procedures and the best aesthetic follow-up result. These factors need to be considered when mastectomy and reconstruction are planned in order to optimize the aesthetic result together with the development of breast surgery specialty units.

Predictive Value of MRP-1 in Localized High-Risk Soft Tissue Sarcomas: A Translational Research Associated to ISG-STS 1001 Randomized Phase III Trial.

MRP-1 is implicated in multidrug resistance and was described as prognostic in high-risk patients with soft-tissue sarcoma (STS) in a previous study. The current research aimed to validate MRP-1 prognostic/predictive value in localized sarcomas treated with anthracyclines plus ifosfamide within the ISG-1001 phase III study. In addition, the inhibitory activity on MRP-1 was investigated in preclinical studies to identify new combinations able to increase the efficacy of standard chemotherapy in STS. MRP-1 expression was assessed by IHC in tissue microarrays from patients with STS and tested for correlation with disease-free survival (DFS) and overall survival (OS). In vitro studies tested the efficacy of MRP-1 inhibitors (nilotinib, ripretinib, selumetinib, and avapritinib) in sarcoma cell lines. The effect of combinations of the most active MRP-1 inhibitors and chemotherapy was measured on the basis of apoptosis. MRP-1 was evaluable in 231 of 264 cases who entered the study. MRP-1 expression (strong intensity) was independently associated with worse DFS [HR, 1.78; 95% confidence interval (CI), 1.11-2.83; P = 0.016], in the multivariate analysis, with a trend for a worse OS (HR, 1.78; 95% CI, 0.97-3.25; P = 0.062). In vitro studies showed that the addition of MRP-1 inhibitors (nilotinib or avapritinib) to doxorubicin plus palifosfamide, significantly increased cell death in SK-UT-1 and CP0024 cell lines. MRP-1 is an adverse predictive factor in localized high-risk patients with STS treated with neoadjuvant anthracyclines plus ifosfamide followed by surgery. In vitro findings support the clinical assessment of the combination of chemotherapy and MRP-1 inhibitors as a promising strategy to overcome the drug ceiling effect for chemotherapy.

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. Objective: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. Design, Setting, and Participants: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. Interventions: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. Main Outcome and Measures: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao2/Fio2 ratio less than 150 mm Hg, whichever came first. Results: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. Conclusions and Relevance: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao2/Fio2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease. Trial Registration: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37.

Duration of exposure to environmental carcinogens affects DNA-adduct level in human lymphocytes.

BACKGROUND AND OBJECTIVE: An important issue in human biomonitoring is determining how exposure duration affects the kinetics of molecular biomarkers. In this study we compare the influence of exposure variables on DNA adducts. METHODS: DNA adducts were analysed by 32P-postlabelling in lympho/monocytes of 677 Caucasian subjects. RESULTS: After correction for other variables, DNA adducts increased depending on the length of occupational and smoke exposures. Higher DNA adducts were detected in workers with more than 14 years of exposure than in workers with shorter exposures (RR = 1.19, p = 0.049) and in smokers with more than 10 years of exposure than in smokers with shorter exposure (RR = 1.21, p <0.001). CONCLUSIONS: Exposure length is the primary factor affecting DNA-adduct level in lympho/monocytes both in smokers and in occupationally exposed subjects.