Healthy lifestyle change and all-cause and cancer mortality in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Healthy lifestyles are inversely associated with the risk of noncommunicable diseases, which are leading causes of death. However, few studies have used longitudinal data to assess the impact of changing lifestyle behaviours on all-cause and cancer mortality. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, lifestyle profiles of 308,497 cancer-free adults (71% female) aged 35-70 years at recruitment across nine countries were assessed with baseline and follow-up questionnaires administered on average of 7 years apart. A healthy lifestyle index (HLI), assessed at two time points, combined information on smoking status, alcohol intake, body mass index, and physical activity, and ranged from 0 to 16 units. A change score was calculated as the difference between HLI at baseline and follow-up. Associations between HLI change and all-cause and cancer mortality were modelled with Cox regression, and the impact of changing HLI on accelerating mortality rate was estimated by rate advancement periods (RAP, in years). RESULTS: After the follow-up questionnaire, participants were followed for an average of 9.9 years, with 21,696 deaths (8407 cancer deaths) documented. Compared to participants whose HLIs remained stable (within one unit), improving HLI by more than one unit was inversely associated with all-cause and cancer mortality (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.81, 0.88; and HR: 0.87; 95% CI: 0.82, 0.92; respectively), while worsening HLI by more than one unit was associated with an increase in mortality (all-cause mortality HR: 1.26; 95% CI: 1.20, 1.33; cancer mortality HR: 1.19; 95% CI: 1.09, 1.29). Participants who worsened HLI by more than one advanced their risk of death by 1.62 (1.44, 1.96) years, while participants who improved HLI by the same amount delayed their risk of death by 1.19 (0.65, 2.32) years, compared to those with stable HLI. CONCLUSIONS: Making healthier lifestyle changes during adulthood was inversely associated with all-cause and cancer mortality and delayed risk of death. Conversely, making unhealthier lifestyle changes was positively associated with mortality and an accelerated risk of death.

Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition.

In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.

Changes in Lifestyle and Risk of Colorectal Cancer in the European Prospective Investigation Into Cancer and Nutrition.

INTRODUCTION: We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multicountry European cohort. METHODS: We used baseline and follow-up questionnaire data from the European Prospective Investigation into Cancer cohort to assess changes in lifestyle habits and their associations with CRC development. We calculated a healthy lifestyle index (HLI) score based on smoking status, alcohol consumption, body mass index, and physical activity collected at the 2 time points. HLI ranged from 0 (most unfavorable) to 16 (most favorable). We estimated the association between HLI changes and CRC risk using Cox regression models and reported hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Among 295,865 participants, 2,799 CRC cases were observed over a median of 7.8 years. The median time between questionnaires was 5.7 years. Each unit increase in HLI from the baseline to the follow-up assessment was associated with a statistically significant 3% lower CRC risk. Among participants in the top tertile at baseline (HLI > 11), those in the bottom tertile at follow-up (HLI ≤ 9) had a higher CRC risk (HR 1.34; 95% CI 1.02-1.75) than those remaining in the top tertile. Among individuals in the bottom tertile at baseline, those in the top tertile at follow-up had a lower risk (HR 0.77; 95% CI 0.59-1.00) than those remaining in the bottom tertile. DISCUSSION: Improving adherence to a healthy lifestyle was inversely associated with CRC risk, while worsening adherence was positively associated with CRC risk. These results justify and support recommendations for healthy lifestyle changes and healthy lifestyle maintenance for CRC prevention.

MRI-Pathology Agreement in Rectal Cancer: Real-World Data from a Prospective Rectal Cancer Registry.

Introduction: Magnetic Resonance Imaging (MRI) is routinely used in preoperative rectal cancer staging. The concordance of MRI staging with final pathologic exam, albeit improved, has not yet reached perfection. The aim of this study is to analyze the agreement between MRI and pathologic exam in patients operated on for mid-low rectal cancer. Material and Method: Patients undergoing neoadjuvant chemoradiation therapy (nCRT) or upfront surgery were analyzed. Between January 2019 to December 2019, 140 patients enrolled in the AIMS Academy rectal cancer registry were analyzed. Sixty-two patients received nCRT and 78 underwent upfront surgery. Results: Overall, the agreement between MRI and pathologic exam on T stage and N stage were 64.7% and 69.2%, respectively. The agreement between MRI and pathologic exam on T stage was 62.7% for patients who did not receive nCRT and 67.4% for patients who received nCRT (p = 0.62). The agreement on N stage was 76.3% for patients who did not receive nCRT and 60.0% for patients who received nCRT (p = 0.075). Conclusions: Real-world data shows MRI is still far from being able to correlate with the pathology findings which raises questions about the accuracy of the real-life decision-making process during cancer boards.

Should we consider gallbladder cancer a new smoking-related cancer? A comprehensive meta-analysis focused on dose-response relationships.

The few studies on the association of smoking with gallbladder cancer risk have given conflicting results. Here, we provide the most accurate and up-to-date quantification of the effect of cigarette smoking on gallbladder cancer risk, and investigate for the first time the dose-response relationships. Using an innovative approach for the identification of publications, we conducted a systematic review and meta-analysis of epidemiological studies published until March 2019 on the association of smoking with gallbladder cancer risk. Pooled relative risks (RRs) for smoking were estimated using random-effects models; one-stage random-effects log-linear models were used for dose-response relationships. Out of 22 eligible articles, 20 (11 case-control and 9 cohort studies) were included in the meta-analysis, for a total of 4,676 gallbladder cancer cases. Compared to never smokers, the pooled RR was 1.33 (95% confidence interval [CI]: 1.17-1.51) for current and 1.07 (95% CI: 0.94-1.23) for former smokers. The risk of gallbladder cancer increased linearly with smoking intensity and duration, the RR being 1.60 (95% CI: 1.21-2.11) for 30 cigarettes/day and 1.25 (95% CI: 1.01-1.56) for 30 years of smoking. There was a nonsignificant linear decrease in gallbladder cancer risk with increasing time since quitting, compared to current smokers. Former smokers reached the risk of those who had never smoked 20 years after quitting. This comprehensive meta-analysis suggests a moderately but significantly higher risk of gallbladder cancer for current but not former smokers. We also provide the first report of a linear increase in gallbladder cancer risk according to smoking intensity and duration.

Smoking and Colorectal Cancer Risk, Overall and by Molecular Subtypes: A Meta-Analysis.

INTRODUCTION: The aim of this study was to provide the most comprehensive and up-to-date evidence on the association between cigarette smoking and colorectal cancer (CRC) risk. METHODS: We conducted a systematic review and meta-analysis of epidemiological studies on the association between cigarette smoking and CRC risk published up to September 2018. We calculated relative risk (RR) of CRC according to smoking status, intensity, duration, pack-years, and time since quitting, with a focus on molecular subtypes of CRC. RESULTS: The meta-analysis summarizes the evidence from 188 original studies. Compared with never smokers, the pooled RR for CRC was 1.14 (95% confidence interval [CI] 1.10-1.18) for current smokers and 1.17 (95% CI 1.15-1.20) for former smokers. CRC risk increased linearly with smoking intensity and duration. Former smokers who had quit smoking for more than 25 years had significantly decreased risk of CRC compared with current smokers. Smoking was strongly associated with the risk of CRC, characterized by high CpG island methylator phenotype (RR 1.42; 95% CI 1.20-1.67; number of studies [n] = 4), BRAF mutation (RR 1.63; 95% CI 1.23-2.16; n = 4), or high microsatellite instability (RR 1.56; 95% CI 1.32-1.85; n = 8), but not characterized by KRAS (RR 1.04; 95% CI 0.90-1.20; n = 5) or TP53 (RR 1.13; 95% CI 0.99-1.29; n = 5) mutations. DISCUSSION: Cigarette smoking increases the risk of CRC in a dose-dependent manner with intensity and duration, and quitting smoking reduces CRC risk. Smoking greatly increases the risk of CRC that develops through the microsatellite instability pathway, characterized by microsatellite instability-high, CpG island methylator phenotype positive, and BRAF mutation.

A novel nomogram to identify candidates for active surveillance amongst patients with International Society of Urological Pathology (ISUP) Grade Group (GG) 1 or ISUP GG2 prostate cancer, according to multiparametric magnetic resonance imaging findings.

OBJECTIVES: To develop a novel nomogram to identify candidates for active surveillance (AS) that combines clinical, biopsy and multiparametric magnetic resonance imaging (mpMRI) findings; and to compare its predictive accuracy to, respectively: (i) Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, (ii) Johns Hopkins (JH) criteria, (iii) European Association of Urology (EAU) low-risk classification, and (iv) EAU low-risk or low-volume with International Society of Urological Pathology (ISUP) Grade Group (GG) 2 classification. PATIENTS AND METHODS: We selected 1837 patients with ISUP GG1 or GG2 prostate cancer (PCa), treated with radical prostatectomy (RP) between 2012 and 2018. The outcome of interest was the presence of unfavourable disease (i.e., clinically significant PCa [csPCa]) at RP, defined as: ISUP GG ≥ 3 and/or pathological T stage (pT) ≥3a and/or pathological N stage (pN) 1. First, logistic regression models including PRIAS, JH, EAU low-risk, and EAU low-risk or low-volume ISUP GG2 binary classifications (not eligible vs eligible) were used. Second, a multivariable logistic regression model including age, prostate-specific antigen density (PSA-D), ISUP GG, and the percentage of positive cores (Model 1) was fitted. Third, Prostate Imaging-Reporting and Data System (PI-RADS) score (Model 2), extracapsular extension (ECE) score (Model 3) and PI-RADS + ECE score (Model 4) were added to Model 1. Only variables associated with higher csPCa rates in Model 4 were retained in the final simplified Model 5. The area under the receiver operating characteristic curve (AUC), calibration plots and decision curve analyses were used. RESULTS: Of the 1837 patients, 775 (42.2%) had csPCa at RP. Overall, 837 (47.5%), 986 (53.7%), 348 (18.9%), and 209 (11.4%) patients were eligible for AS according to, respectively, the EAU low-risk, EAU low-risk or low-volume ISUP GG2, PRIAS, and JH criteria. The proportion of csPCa amongst the EAU low-risk, EAU low-risk or low-volume ISUP GG2, PRIAS and JH candidates was, respectively 28.5%, 29.3%, 25.6% and 17.2%. Model 4 and Model 5 (in which only PSA-D, ISUP GG, PI-RADS and ECE score were retained) had a greater AUC (0.84), compared to the four proposed AS criteria (all P < 0.001). The adoption of a 25% nomogram threshold increased the proportion of AS-eligible patients from 18.9% (PRIAS) and 11.4% (JH) to 44.4%. Moreover, the same 25% nomogram threshold resulted in significantly lower estimated risks of csPCa (11.3%), compared to PRIAS (Δ: -14.3%), JH (Δ: -5.9%), EAU low-risk (Δ: -17.2%), and EAU low-risk or low-volume ISUP GG2 classifications (Δ: -18.0%). CONCLUSION: The novel nomogram combining clinical, biopsy and mpMRI findings was able to increase by ~25% and 35% the absolute frequency of patients suitable for AS, compared to, respectively, the PRIAS or JH criteria. Moreover, this nomogram significantly reduced the estimated frequency of csPCa that would be recommended for AS compared to, respectively, the PRIAS, JH, EAU low-risk, and EAU low-risk or low-volume ISUP GG2 classifications.

Dose-risk relationships between cigarette smoking and ovarian cancer histotypes: a comprehensive meta-analysis.

PURPOSE: Although smoking has not been associated with overall ovarian cancer risk, a different impact on various histotypes has been reported. Our aim is to provide an accurate, up-to-date estimate of the dose-risk relationships between cigarette smoking and epithelial ovarian cancer, overall and by histotypes. METHODS: Using an innovative approach for the identification of original study publications, we conducted a systematic review and meta-analysis of epidemiological studies published on the topic until September 2018. Summary relative risks (RR) for cigarette smoking were estimated using random-effects models; dose-risk relationships were evaluated using one-stage random-effects models with restricted cubic splines. RESULTS: Thirty-seven studies were considered in the meta-analysis. The summary RRs for current versus never smokers were 1.05 (95% confidence interval CI 0.95-1.16) for overall ovarian cancer, 1.78 (95% CI 1.52-2.07) for mucinous, 0.77 (95% CI 0.65-0.93) for clear cell, 0.81 (95% CI 0.73-0.91) for endometrioid, and 1.05 (95% CI 0.94; 1.17) for serous cancer. The risk of borderline mucinous (RR 2.09) and serous (RR 1.16) tumors was higher than for invasive cancers (RR 1.44 and 0.95, respectively). For mucinous cancer, risk was noticeably higher with smoking intensity and duration (RR 2.35 for 20 cigarettes/day, and 2.11 for 20 years of smoking). A non-significant linear relation was found with smoking intensity, duration, and time since quitting for overall ovarian cancer and other histotypes. CONCLUSIONS: This uniquely large and comprehensive meta-analysis confirms that although cigarette smoking does not appear to be a risk factor for ovarian cancer, and it is even slightly protective for some rare histotypes, there is a strong dose-risk relationship with mucinous ovarian cancer.

Effectiveness of a Smartphone App to Promote Physical Activity Among Persons With Type 2 Diabetes: Randomized Controlled Trial.

BACKGROUND: Physical activity is well known to have beneficial effects on glycemic control and to reduce risk factors for cardiovascular disease in persons with type 2 diabetes. Yet, successful implementation of lifestyle interventions targeting physical activity in primary care has shown to be difficult. Smartphone apps may provide useful tools to support physical activity. The DiaCert app was specifically designed for integration into primary care and is an automated mobile health (mHealth) solution promoting daily walking. OBJECTIVE: This study aimed to investigate the effect of a 3-month-long intervention promoting physical activity through the use of the DiaCert app among persons with type 2 diabetes in Sweden. Our primary objective was to assess the effect on moderate to vigorous physical activity (MVPA) at 3 months of follow-up. Our secondary objective was to assess the effect on MVPA at 6 months of follow-up and on BMI, waist circumference, hemoglobin A1c, blood lipids, and blood pressure at 3 and 6 months of follow-up. METHODS: We recruited men and women with type 2 diabetes from 5 primary health care centers and 1 specialized center. Participants were randomized 1:1 to the intervention or control group. The intervention group was administered standard care and access to the DiaCert app at baseline and 3 months onward. The control group received standard care only. Outcomes of objectively measured physical activity using accelerometers, BMI, waist circumference, biomarkers, and blood pressure were assessed at baseline and follow-ups. Linear mixed models were used to assess differences in outcomes between the groups. RESULTS: A total of 181 study participants, 65.7% (119/181) men and 34.3% (62/181) women, were recruited into the study and randomized to the intervention (n=93) or control group (n=88). The participants' mean age and BMI were 60.0 (SD 11.4) years and 30.4 (SD 5.3) kg/m2, respectively. We found no significant effect of the intervention (group by time interaction) on MVPA at either the 3-month (ß=1.51, 95% CI -5.53 to 8.55) or the 6-month (ß=-3.53, 95% CI -10.97 to 3.92) follow-up. We found no effect on any of the secondary outcomes at follow-ups, except for a significant effect on BMI at 6 months (ß=0.52, 95% CI 0.20 to 0.84). However, mean BMI did not differ between the groups at the 6-month follow-up. CONCLUSIONS: We found no evidence that persons with type 2 diabetes being randomized to use an app promoting daily walking increased their levels of MVPA at 3 or 6 months' follow-up compared with controls receiving standard care. The effect of the app on BMI was unclear, and we found nothing to support an effect on secondary outcomes. Further research is needed to determine what type of mHealth intervention could be effective to increase physical activity among persons with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03053336; https://clinicaltrials.gov/study/NCT03053336.

Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience.

Cervico-vaginal (CV) localization of extra-mammary Paget's disease (EMPD) of the vulva is extremely rare. In order to investigate the incidence risk and the pathognomonic clinical and pathological features of this condition, a retrospective analysis was conducted including 94 women treated for vulvar EMPD at the European Institute of Oncology, Milan, Italy, from October 1997 to May 2020. Overall nine patients developed CV involvement from EMPD, with a cumulative incidence of 2.5% (95% CI: 0.5-8.0%) at 5 years, 6.5% (95% CI: 1.9-15.1%) at 10 years and 14.0% (95% CI: 4.8-27.8%) at 15 years, respectively. All cases except one were firstly detected by abnormal glandular cytology. None reported vaginal bleeding or other suspicious symptoms. The colposcopic findings were heterogeneous and could sometimes be misdiagnosed. Cervical and/or vaginal biopsies were always performed for histopathological diagnosis by identification of Paget cells in the epithelium or stroma. Most patients developed invasive EMPD (5/9) of the cervix and/or vagina and underwent hysterectomy with partial or total colpectomy. CV involvement from EMPD should not be underestimated in women with a long-standing history of vulvar Paget's disease. Liquid-based cytology with immunocytochemistry represents a valuable tool for early diagnosis and should be routinely performed during the required lifelong follow-up.

Prognostic significance of serum potassium in patients hospitalized for acute heart failure.

AIM: We investigated the prognostic significance of serum potassium abnormalities at discharge in patients hospitalized for acute heart failure (AHF). METHODS AND RESULTS: In a retrospective analysis, we included 926 patients hospitalized for AHF, stratified by serum potassium levels at discharge as hypokalaemia (<3.5 mEq/L), normokalaemia (3.5-5.0 mEq/L), and hyperkalaemia (>5.0 mEq/L). The primary endpoint was all-cause death at 1 year since hospital discharge. At discharge, 40 patients had hypokalaemia (4.3%), 840 normokalaemia (90.7%), and 46 hyperkalaemia (5.0%). Patients with hyperkalaemia at discharge were more frequently men, had more signs of congestion, and lower LVEF while patients with hypokalaemia were more likely to be women with HFpEF. Treatment with ACEi/ARBs and MRAs ≥50% of target dose at discharge was similar across groups. One year all-cause death occurred in 10% of the patients with hypokalaemia, 13.9% of those with normokalaemia, and 30.4% of those with hyperkalaemia (P = 0.006). After adjustment for covariates, including renal function, background treatment, and baseline potassium level, hyperkalaemia resulted an independent predictor of the primary endpoint (HR 1.96, 95% IC [1.01-3.82]; P = 0.048). CONCLUSIONS: In patients with AHF, the presence of hyperkalaemia at discharge is an independent predictor of 1 year all-cause death.

Combined Role of Troponin and Natriuretic Peptides Measurements in Patients With Covid-19 (from the Cardio-COVID-Italy Multicenter Study).

Data concerning the combined prognostic role of natriuretic peptide (NP) and troponin in patients with COVID-19 are lacking. The aim of the study is to evaluate the combined prognostic value of NPs and troponin in hospitalized COVID-19 patients. From March 1, 2020 to April 9, 2020, consecutive patients with COVID-19 and available data on cardiac biomarkers at admission were recruited. Patients admitted for acute coronary syndrome were excluded. Troponin levels were defined as elevated when greater than the 99th percentile of normal values. NPs were considered elevated if above the limit for ruling in acute heart failure (HF). A total of 341 patients were included in this study, mean age 68 ± 13 years, 72% were men. During a median follow-up period of 14 days, 81 patients (24%) died. In the Cox regression analysis, patients with elevated both NPs and troponin levels had higher risk of death compared with those with normal levels of both (hazard ratio 2.94; 95% confidence interval 1.31 to 6.64; p = 0.009), and this remained significant after adjustment for age, gender, oxygen saturation, HF history, and chronic kidney disease. Interestingly, NPs provided risk stratification also in patients with normal troponin values (hazard ratio 2.86; 95% confidence interval 1.21 to 6.72; p = 0.016 with high NPs levels). These data show the combined prognostic role of troponin and NPs in COVID-19 patients. NPs value may be helpful in identifying patients with a worse prognosis among those with normal troponin values. Further, NPs' cut-point used for diagnosis of acute HF has a predictive role in patients with COVID-19.

Sex-related differences in patients with coronavirus disease 2019: results of the Cardio-COVID-Italy multicentre study.

INTRODUCTION: The role of sex compared to comorbidities and other prognostic variables in patients with coronavirus disease (COVID-19) is unclear. METHODS: This is a retrospective observational study on patients with COVID-19 infection, referred to 13 cardiology units. The primary objective was to assess the difference in risk of death between the sexes. The secondary objective was to explore sex-based heterogeneity in the association between demographic, clinical and laboratory variables, and patients' risk of death. RESULTS: Seven hundred and one patients were included: 214 (30.5%) women and 487 (69.5%) men. During a median follow-up of 15 days, deaths occurred in 39 (18.2%) women and 126 (25.9%) men. In a multivariable Cox regression model, men had a nonsignificantly higher risk of death vs. women (P = 0.07).The risk of death was more than double in men with a low lymphocytes count as compared with men with a high lymphocytes count [overall survival hazard ratio (OS-HR) 2.56, 95% confidence interval (CI) 1.72-3.81]. In contrast, lymphocytes count was not related to death in women (P = 0.03).Platelets count was associated with better outcome in men (OS-HR for increase of 50 × 103 units: 0.88 95% CI 0.78-1.00) but not in women. The strength of association between higher PaO2/FiO2 ratio and lower risk of death was larger in women (OS-HR for increase of 50 mmHg/%: 0.72, 95% CI 0.59-0.89) vs. men (OS-HR: 0.88, 95% CI 0.80-0.98; P = 0.05). CONCLUSIONS: Patients' sex is a relevant variable that should be taken into account when evaluating risk of death from COVID-19. There is a sex-based heterogeneity in the association between baseline variables and patients' risk of death.

Satisfaction with online teaching of medical statistics during the COVID-19 pandemic: A survey by the Education Committee of the Italian Society of Medical Statistics and Clinical Epidemiology.

On May 2020, after 2 months of online teaching with no face-to-face lectures, the Education Committee of the Italian scientific Society of Medical Statistics and Clinical Epidemiology conceived an online survey to assess satisfaction of Italian academics of medical statistics with online teaching and remote exams. This survey highlighted teachers' perceptions as well as opportunities and limitations of online teaching of medical statistics, biostatistics, and epidemiology. Although 61% of Italian academics of medical statistics declared to be favorable to provide online teaching of medical statistics, biostatistics, and epidemiology in the future, we recognize that distance education cannot substitute the unique value of teaching and knowledge exchange that could only be transmitted through a personal interaction between students and teachers. These indications may be useful to improve the quality of the teaching process in the future.

Adherence and optimization of angiotensin converting enzyme inhibitor/angiotensin II receptors blockers and beta-blockers in patients hospitalized for acute heart failure.

AIMS: Treatment with angiotensin converting enzyme inhibitor (ACEi)/angiotensin II receptors blockers (ARBs) and beta-blockers is frequently suboptimal at discharge in patients hospitalized for acute heart failure (AHF). We investigated the prognostic significance of medical treatment at discharge and its changes during hospitalization. METHODS AND RESULTS: In a retrospective analysis, we included 623 patients hospitalized for AHF with reduced left ventricular ejection fraction (<40%). The primary endpoint was all-cause mortality and heart failure rehospitalization to Day 180 since hospital discharge. A total of 249 (42.4%) of patients received no ACEi/ARBs/BB or <50% target dose (TD) of these drugs, 249 (42.4%) had either ACEi/ARBs or BB ≥ 50% of TD, and 89 (15.2%) ACEi/ARBs and BB ≥ 50% of TD at discharge. The primary endpoint was significantly lower in patients receiving at least one drug ≥50% of TD compared with no or low-dose treatment (ACEi/ARBs or BB ≥ 50% TD: adjusted hazard ratio (HR) 0.69, 95% confidence interval (CI) [0.49-0.98], P = 0.04; ACEi/ARBs and BB ≥ 50% TD: adjusted HR 0.54, 95% CI [0.30-0.96], P = 0.03). With regard to treatment changes from admission to discharge, therapy was decreased in 258 (44.6%) patients, stable in 194 (33.6%), and increased in 126 (21.8%). Compared with patients with stable therapy, treatment intensification was associated with a lower rate of the primary endpoint (adjusted HR 0.49, 95% CI [0.29-0.83]; P = 0.01). CONCLUSIONS: In patients with AHF, prescription of ACEi/ARBs/BB ≥ 50% TD at the time of discharge, whether achieved or not through treatment intensification during the hospitalization, is associated with better post-discharge outcomes.

The prognostic value of serial troponin measurements in patients admitted for COVID-19.

AIMS: Myocardial injury (MI) in coronavirus disease-19 (COVID-19) is quite prevalent at admission and affects prognosis. Little is known about troponin trajectories and their prognostic role. We aimed to describe the early in-hospital evolution of MI and its prognostic impact. METHODS AND RESULTS: We performed an analysis from an Italian multicentre study enrolling COVID-19 patients, hospitalized from 1 March to 9 April 2020. MI was defined as increased troponin level. The first troponin was tested within 24 h from admission, the second one between 24 and 48 h. Elevated troponin was defined as values above the 99th percentile of normal values. Patients were divided in four groups: normal, normal then elevated, elevated then normal, and elevated. The outcome was in-hospital death. The study population included 197 patients; 41% had normal troponin at both evaluations, 44% had elevated troponin at both assessments, 8% had normal then elevated troponin, and 7% had elevated then normal troponin. During hospitalization, 49 (25%) patients died. Patients with incident MI, with persistent MI, and with MI only at admission had a higher risk of death compared with those with normal troponin at both evaluations (P < 0.001). At multivariable analysis, patients with normal troponin at admission and MI injury on Day 2 had the highest mortality risk (hazard ratio 3.78, 95% confidence interval 1.10-13.09, P = 0.035). CONCLUSIONS: In patients admitted for COVID-19, re-test MI on Day 2 provides a prognostic value. A non-negligible proportion of patients with incident MI on Day 2 is identified at high risk of death only by the second measurement.

Cisplatin plus capecitabine concomitant with intensity-modulated radiation therapy in non-metastatic anal squamous cell carcinoma: the experience of a single research cancer center.

BACKGROUND AND AIMS: The standard treatment of non-metastatic anal squamous cell carcinoma (ASCC) consists of chemotherapy with mitomycin (MMC) plus 5-fluorouracil (5FU) for 1-2 cycles concomitant with pelvic radiotherapy. Subsequent studies introduced cisplatin (CDDP) combined with 5FU, with unclear results. We evaluated the doublet capecitabine (C) and CDDP as a possible alternative to MMC-5FU regimen concomitant with intensity-modulated radiation therapy (IMRT). PATIENTS AND METHODS: We carried out a retrospective study on 67 patients affected by stage I-III ASCC, treated with CDDP (60-70 mg/m2 every 21 days for two courses) plus C (825 mg/m2 twice daily for 5 days/week) chemotherapy concomitant with IMRT for curative intent. RESULTS: At a median follow up of 41 months, the clinical complete response calculated at the 6-month time-point (6-moCR), the 6-month objective response rate and the 6-month disease control rate were 93%, 94%, and 99%, respectively.Disease-free survival rates at 1, 2, and 3 years were 89%, 87%, and 85%, while the overall survival rates at 1 and 2 years were 100% and 95%. The colostomy-free survival rates were 90% at 1 year and 88% at 2 years. Grade 3-4 acute adverse events were reported in 61% of patients; predominantly skin toxicity (46%) and limited hematological toxicity (12%). CONCLUSION: In this retrospective study, chemotherapy with C plus CDDP concomitant with IMRT proved safe and effective, and may represent a possible alternative option to standard MMC-containing regimen for curative intent.

Utility of Restricted Mean Survival Time Analysis for Heart Failure Clinical Trial Evaluation and Interpretation.

OBJECTIVES: This study sought to demonstrate the statistical and utilitarian properties of restricted mean survival time (RMST) and restricted mean time lost (RMTL) for assessing treatments for heart failure (HF) with reduced ejection fraction. BACKGROUND: Although the hazard ratio (HR) is the most commonly used measure to quantify treatment effects in HF clinical trials, HRs may be difficult to interpret and require the proportional hazards assumption to be valid. RMST and RMTL are intuitive summaries of groupwise survival that measure treatment effects without model assumptions. METHODS: Patient time-to-event data were reconstructed from published landmark HF clinical trial Kaplan-Meier curves. We estimated RMST differences (ΔRMSTs) and RMTL ratios between treatment groups for primary and secondary outcomes, and compared test statistics and effect sizes with proportional hazards models. We fit Weibull estimations to extrapolate trial data to 5 years of treatment. RESULTS: Using RMSTs and RMTLs yielded similar statistical conclusions as HR analysis for a compendium of 16 HF clinical trials including 48,581 patients. RMTL ratios approximated HRs for each trial, but ΔRMSTs provided absolute effect sizes unavailable with HRs. For instance, spironolactone added 2.2 months of life over 34 months of treatment, and dapagliflozin added 0.3 months of life over 24 months of treatment. When normalized to 5-years follow-up with Weibull estimation, spironolactone and dapagliflozin added 6.0 months and 1.8 months of life for patients, respectively. CONCLUSIONS: Statistically, RMST and RMTL perform similarly to proportional hazards modeling but may help patients by providing clinically relevant intuitive estimates of treatment effects without prohibitive assumptions.

In-hospital and long-term mortality for acute heart failure: analysis at the time of admission to the emergency department.

AIMS: Acute heart failure (AHF) leads to a drastic increase in mortality and rehospitalization. The aim of the study was to identify prognostic variables in a real-life population of AHF patients admitted to the emergency department with acute shortness of breath. METHODS AND RESULTS: We evaluated potential predictors of mortality in 728 consecutive patients admitted to the emergency department with AHF. Possible predictors of all-cause and cardiovascular (CV) mortality were investigated by Cox and Fine and Gray models at multivariable analysis. Among the 728 patients, 256 died during the entire follow-up, 142 of these due to CV cause. The 1 year mortality rate was 20%, with the highest risk of death during the index hospitalization (with 8% estimate in-hospital mortality at 30 days). A higher risk of events during the index hospitalization was more evident for the CV deaths, for which we found a cumulative 1 year incidence of 12% with a cumulative incidence in the first 30 days of hospitalization of about 5%. At multivariable analysis, age (P < 0.001), New York Heart Association (NYHA) class IV vs. I-II-III (P = 0.001), systolic blood pressure (P < 0.001), non-cardiac co-morbidities (≥3 vs. 0, P = 0.05), oxygen saturation (P = 0.03), serum creatinine (P < 0.001), and left ventricular ejection fraction (LVEF) (40-49% vs. <40%, P = 0.004; ≥50% vs. <40%, P = 0.003) were independent predictors of all-cause mortality during the entire follow-up. Age (P = 0.03), systolic blood pressure (P = 0.01), oxygen saturation (P = 0.03), serum creatinine (P = 0.02), and LVEF (40-49% vs. <40%, P = 0.03; ≥50% vs. <40%, P = 0.004) were independent predictors of CV mortality during the entire follow-up. NYHA class IV vs. I-II-III (P < 0.001), serum creatinine (P = 0.01), and LVEF (40-49% vs. <40%, P = 0.02; ≥50% vs. <40%, P < 0.001) remained independent predictors for in-hospital death, while only serum creatinine (P = 0.04), LVEF (40-49% vs. <40%: 0.32, P = 0.04; ≥50% vs. <40%, P < 0.001), and NYHA class vs. I-II-III (P = 0.02) remained predictors for in-hospital CV mortality. CONCLUSIONS: In this real-life cohort of patients with AHF, the results showed a similar mortality rate comparing with other analysis and with the most important registries. Age, NYHA class IV, systolic blood pressure, creatinine levels, sodium levels, and ejection fraction were independent predictors of 1 year mortality, while LVEF <40% was the only predictor of both all-cause mortality and CV mortality.

Association of Troponin Levels With Mortality in Italian Patients Hospitalized With Coronavirus Disease 2019: Results of a Multicenter Study.

IMPORTANCE: Myocardial injury, detected by elevated plasma troponin levels, has been associated with mortality in patients hospitalized with coronavirus disease 2019 (COVID-19). However, the initial data were reported from single-center or 2-center studies in Chinese populations. Compared with these patients, European and US patients are older, with more comorbidities and higher mortality rates. OBJECTIVE: To evaluate the prevalence and prognostic value of myocardial injury, detected by elevated plasma troponin levels, in a large population of White Italian patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter, cross-sectional study enrolling consecutive patients with laboratory-confirmed COVID-19 who were hospitalized in 13 Italian cardiology units from March 1 to April 9, 2020. Patients admitted for acute coronary syndrome were excluded. Elevated troponin levels were defined as values greater than the 99th percentile of normal values. MAIN OUTCOMES AND MEASURES: Clinical characteristics and outcomes stratified as elevated or normal cardiac troponin levels at admission, defined as troponin T or troponin I at a level greater than the 99th percentile of normal values. RESULTS: A total of 614 patients with COVID-19 were included in this study (mean age [SD], 67 [13] years; 70.8% male), of whom 148 patients (24.1%) died during the hospitalization. Elevated troponin levels were found in 278 patients (45.3%). These patients were older (mean [SD] age, 64.0 [13.6] years vs 71.3 [12.0] years; P < .001) and had higher prevalence of hypertension (168 patients [50.5%] vs 182 patients [65.9%]; P < .001), heart failure (24 [7.2%]; 63 [22.8%]; P < .001), coronary artery disease (50 [15.0%] vs 87 [31.5%]; P < .001), and atrial fibrillation (33 [9.9%] vs 67 [24.3%]; P < .001). Elevated troponin levels were associated with an increased in-hospital mortality (37% vs 13%; HR, 1.71 [95% CI, 1.13-2.59]; P = .01 via multivariable Cox regression analysis), and this was independent from concomitant cardiac disease. Elevated troponin levels were also associated with a higher risk of in-hospital complications: heart failure (44 patients [19.2%] vs 7 patients [2.9%]; P < .001), sepsis (31 [11.7%] vs 21 [6.4%]; P = .03), acute kidney failure (41 [20.8%] vs 13 [6.2%]; P < .001), multiorgan failure (21 [10.9%] vs 6 [2.9%]; P = .003), pulmonary embolism (27 [9.9%] vs 17 [5.2%]; P = .04), delirium (13 [6.8%] vs 3 [1.5%]; P = .02), and major bleeding (16 [7.0%] vs 4 [1.6%]; P = .008). CONCLUSIONS AND RELEVANCE: In this multicenter, cross-sectional study of Italian patients with COVID-19, elevated troponin was an independent variable associated with in-hospital mortality and a greater risk of cardiovascular and noncardiovascular complications during a hospitalization for COVID-19.