Predictors of atrial fibrillation in ibrutinib-treated CLL patients: a prospective study

Abstract Background Ibrutinib is an oral irreversible inhibitor of Bruton’s tyrosine kinase, indicated for the treatment of chronic lymphocytic leukaemia. The drug is generally well tolerated; however, not infrequent side effects are reported, with the major two being bleeding and ibrutinib-related atrial fibrillation. Atrial fibrillation pathogenesis in this setting is not completely clear, and no prospective studies have evaluated the impact of previous cardiologic history and baseline characteristics. Methods We prospectively performed cardiologic assessment in 43 CLL patients before starting ibrutinib therapy. Cardiologic workup included comorbidity collection and electrocardiographic and echocardiographic baseline evaluation. Results After a median observation of 8 months, seven patients developed atrial fibrillation (16.3%). Cases developing atrial fibrillation were all elderly males (p = 0.04), and mostly with a history of previous arterial hypertension (p = 0.009). Atrial fibrillation occurrence also correlated with the presence of one or more pre-existent cardiologic comorbidities (p = 0.03), with a higher atrial fibrillation risk score (calculated with comorbidities and cardiologic risk factor evaluation p < 0.001), and with higher left atrial diameter (p = 0.02) and area (p = 0.03) by echocardiography. The occurrence of atrial fibrillation was managed after an integrated cardio-oncologic evaluation: anticoagulation was started in 4 (57.1%) patients and beta-blockers or amiodarone in 5 (71.4%). One patient underwent electric cardioversion and another patient pacemaker positioning to normalise heart rate in order to continue ibrutinib. Conclusion Our data show that echocardiography is a highly informative and reproducible tool that should be included in pre-treatment workup for patients who are candidates for ibrutinib therapy

Additional file 1: of Predictors of atrial fibrillation in ibrutinib-treated CLL patients: a prospective study

Supplementary material and results. (DOC 60 kb

Perioperative Chemotherapy in Poorly Differentiated Neuroendocrine Neoplasia of the Bladder: A Multicenter Analysis

There is scant evidence about optimal management of poorly differentiated neuroendocrine carcinoma of the bladder (BNEC). We performed a multicenter retrospective study on BNEC patients from 13 Italian neuroendocrine-dedicated centers to analyze strategies associated with better outcomes. Mixed adeno-neuroendocrine carcinomas (MANEC) were included. We analyzed overall survival (OS) in the overall cohort, relapse-free survival (RFS) in radically operated patients and progression-free survival (PFS) in patients who received chemotherapy for metastatic disease. Fifty-one BNEC patients were included (male: 46, median age: 70 years). Overall, median OS was 16.0 months, radical tumor resection was performed in 37 patients (72.5%) and 11 of these (29.7%) also received peri-operative platinum-etoposide chemotherapy. Median OS was longer in patients with better performance status (PS) and in those with stage I-III disease at diagnosis compared to stage IV. Among patients who underwent radical tumor resection (N = 37), RFS was longer in patients with better PS and showed a trend towards a longer RFS in those treated with peri-operative chemotherapy than with surgery alone (11 vs. 6 months; p = 0.078). Among 28 patients receiving chemotherapy for metastatic disease, PFS was 5.0 months and there was a trend towards improved PFS in patients receiving carboplatin-etoposide chemotherapy compared to other regimens. A multivariate model unmasked a significant association between carboplatin-etoposide chemotherapy and risk for disease progression or death (HR: 0.39 (95%CI: 0.16-0.96) p = 0.040). Performance status might be associated with improved RFS in radically operated patients, while type of chemotherapy might affect PFS in patients receiving chemotherapy for metastatic BNEC

Organ-on-chip model shows that ATP release through connexin hemichannels drives spontaneous Ca2+ signaling in non-sensory cells of the greater epithelial ridge in the developing cochlea

Prior work supports the hypothesis that ATP release through connexin hemichannels drives spontaneous Ca2+ signaling in non-sensory cells of the greater epithelial ridge (GER) in the developing cochlea; however, direct proof is lacking. To address this issue, we plated cochlear organotypic cultures (COCs) and whole cell-based biosensors with nM ATP sensitivity (ATP-WCBs) at the bottom and top of an ad hoc designed transparent microfluidic chamber, respectively. By performing dual multiphoton Ca2+ imaging, we monitored the propagation of intercellular Ca2+ waves in the GER of COCs and ATP-dependent Ca2+ responses in overlying ATP-WCBs. Ca2+ signals in both COCs and ATP-WCBs were inhibited by supplementing the extracellular medium with ATP diphosphohydrolase (apyrase). Spontaneous Ca2+ signals were strongly depressed in the presence of Gjb6-/- COCs, in which connexin 30 (Cx30) is absent and connexin 26 (Cx26) is strongly downregulated. In contrast, spontaneous Ca2+ signals were not affected by replacement of Panx1-/- with Panx1+/+ COCs in the microfluidic chamber. Similar results were obtained by estimating ATP release from COCs using a classical luciferin-luciferase bioluminescence assay. Therefore, connexin hemichannels and not pannexin 1 channels mediate the release of ATP that is responsible for Ca2+ wave propagation in the developing mouse cochlea. The technological advances presented here have the potential to shed light on a plethora of unrelated open issues that involve paracrine signaling in physiology and pathology and cannot be addressed with standard methods

Rate advancement measurement for lung cancer and pleural mesothelioma in asbestos-exposed workers

IntroductionExposure to asbestos increases the risk of lung cancer and mesothelioma. Few studies quantified the premature occurrence of these diseases in asbestos-exposed workers. Focus on premature disease onset (rate advancement or acceleration) can be useful in risk communication and for the evaluation of exposure impact. We estimated rate advancement for total mortality, lung cancer and pleural mesothelioma deaths, by classes of cumulative asbestos exposure in a pooled cohort of asbestos cement (AC) workers in Italy. MethodThe cohort study included 12 578 workers from 21 cohorts, with 6626 deaths in total, 858 deaths from lung cancer and 394 from pleural malignant neoplasm (MN). Rate advancement was estimated by fitting a competitive mortality Weibull model to the hazard of death over time since first exposure (TSFE). ResultAcceleration time (AT) was estimated at different TSFE values. The highest level of cumulative exposure compared with the lowest, for pleural MN AT was 16.9 (95% CI 14.9 to 19.2) and 33.8 (95% CI 29.8 to 38.4) years at TSFE of 20 and 40 years, respectively. For lung cancer, it was 13.3 (95% CI 12.0 to 14.7) and 26.6 (95% CI 23.9 to 29.4) years, respectively. As for total mortality, AT was 3.35 (95% CI 2.98 to 3.71) years at 20 years TSFE, and 6.70 (95% CI 5.95 to 7.41) at 40 years TSFE. ConclusionThe current study observed marked rate advancement after asbestos exposure for lung cancer and pleural mesothelioma, as well as for total mortality

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

Rate advancement measurement for lung cancer and pleural mesothelioma in asbestos-exposed workers

Introduction: Exposure to asbestos increases the risk of lung cancer and mesothelioma. Few studies quantified the premature occurrence of these diseases in asbestos-exposed workers. Focus on premature disease onset (rate advancement or acceleration) can be useful in risk communication and for the evaluation of exposure impact. We estimated rate advancement for total mortality, lung cancer and pleural mesothelioma deaths, by classes of cumulative asbestos exposure in a pooled cohort of asbestos cement (AC) workers in Italy. Method: The cohort study included 12 578 workers from 21 cohorts, with 6626 deaths in total, 858 deaths from lung cancer and 394 from pleural malignant neoplasm (MN). Rate advancement was estimated by fitting a competitive mortality Weibull model to the hazard of death over time since first exposure (TSFE). Result: Acceleration time (AT) was estimated at different TSFE values. The highest level of cumulative exposure compared with the lowest, for pleural MN AT was 16.9 (95% CI 14.9 to 19.2) and 33.8 (95% CI 29.8 to 38.4) years at TSFE of 20 and 40 years, respectively. For lung cancer, it was 13.3 (95% CI 12.0 to 14.7) and 26.6 (95% CI 23.9 to 29.4) years, respectively. As for total mortality, AT was 3.35 (95% CI 2.98 to 3.71) years at 20 years TSFE, and 6.70 (95% CI 5.95 to 7.41) at 40 years TSFE. Conclusion: The current study observed marked rate advancement after asbestos exposure for lung cancer and pleural mesothelioma, as well as for total mortality

Rate advancement measurement for lung cancer and pleural mesothelioma in asbestos-exposed workers

Introduction: Exposure to asbestos increases the risk of lung cancer and mesothelioma. Few studies quantified the premature occurrence of these diseases in asbestos-exposed workers. Focus on premature disease onset (rate advancement or acceleration) can be useful in risk communication and for the evaluation of exposure impact. We estimated rate advancement for total mortality, lung cancer and pleural mesothelioma deaths, by classes of cumulative asbestos exposure in a pooled cohort of asbestos cement (AC) workers in Italy. Method: The cohort study included 12 578 workers from 21 cohorts, with 6626 deaths in total, 858 deaths from lung cancer and 394 from pleural malignant neoplasm (MN). Rate advancement was estimated by fitting a competitive mortality Weibull model to the hazard of death over time since first exposure (TSFE). Result: Acceleration time (AT) was estimated at different TSFE values. The highest level of cumulative exposure compared with the lowest, for pleural MN AT was 16.9 (95% CI 14.9 to 19.2) and 33.8 (95% CI 29.8 to 38.4) years at TSFE of 20 and 40 years, respectively. For lung cancer, it was 13.3 (95% CI 12.0 to 14.7) and 26.6 (95% CI 23.9 to 29.4) years, respectively. As for total mortality, AT was 3.35 (95% CI 2.98 to 3.71) years at 20 years TSFE, and 6.70 (95% CI 5.95 to 7.41) at 40 years TSFE. Conclusion: The current study observed marked rate advancement after asbestos exposure for lung cancer and pleural mesothelioma, as well as for total mortality