The impact of COVID-19 pandemic on gambling: A systematic review.

BACKGROUND AND AIMS: Since the COVID-19 outbreak, people's habits changed radically. In fact, to limit the spread of SARS-CoV-2, governments implemented restrictive measures that influenced the lives of individuals. The aim of this systematic review is to analyze the impact of COVID-19 on gambling by examining three different outcomes: frequency, expenditure, and transition among possible types of gambling. METHODS: All studies assessing the impact of restrictive measures implemented to limit the spread of SARS-CoV-2 on gambling were included. For the search, two different databases were used: Pubmed and CINAHL. Moreover, two different populations were analyzed: the general population, and subjects who used to gamble before SARS-CoV-2 pandemic. All qualitative studies, reports not based on peer-review, and papers in which the statistical unit was not the subject but the gambling or wagering operators were excluded. RESULTS: From the search, 408 reports were identified. Of these, 28 were included in the systematic review. From the studies, a strong reduction in the frequency and expenditure of land-based gambling emerged, while the results about online gambling were different among the studies. However, a reduction was observed assessing sports betting, and an increase emerged considering online casino and skill games. Finally, a significant migration from land-based gambling to online platforms was identified. The main reasons for these findings were the physical closures of land-based gambling venues and the more time spent at home, the suspension or cancelation of sporting events on which subjects used to bet, and more mental health issues during this challenging period. CONCLUSIONS: The COVID-19 pandemic greatly affected subjects' habits, including gambling, by reducing land-based gambling and sports betting, and increasing gambling on online platforms. This shift poses significant challenges, requiring a comprehensive approach to monitor and mitigate the negative consequences of this increase in online gambling caused by the pandemic.

Circulating endogenous sex steroids and risk of differentiated thyroid carcinoma in men and women.

Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow-up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri-menopausal women, 111 in post-menopausal women, and 70 in men) and 706 cancer-free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre-menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96-2.92, ptrend = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96-3.30, ptrend = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28-1.05, ptrend = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post-menopausal women and men but may suggest an involvement of altered sex steroid production in pre-menopausal women.

Pre-diagnostic circulating resistin concentrations and mortality among individuals with colorectal cancer: Results from the European Prospective Investigation into Cancer and Nutrition study.

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine-Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HRQ4vsQ1 = 0.95, 95% CI: 0.73-1.23; Ptrend = .97; and HRper doubling of resistin concentration = 1.00; 95% CI: 0.84-1.19; P = .98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression.

Ultra-processed foods, adiposity and risk of head and neck cancer and oesophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study: a mediation analysis.

PURPOSE: To investigate the role of adiposity in the associations between ultra-processed food (UPF) consumption and head and neck cancer (HNC) and oesophageal adenocarcinoma (OAC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Our study included 450,111 EPIC participants. We used Cox regressions to investigate the associations between the consumption of UPFs and HNC and OAC risk. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio (WHR) in these associations. In sensitivity analyses, we investigated accidental death as a negative control outcome. RESULTS: During a mean follow-up of 14.13 ± 3.98 years, 910 and 215 participants developed HNC and OAC, respectively. A 10% g/d higher consumption of UPFs was associated with an increased risk of HNC (hazard ratio [HR] = 1.23, 95% confidence interval [CI] 1.14-1.34) and OAC (HR = 1.24, 95% CI 1.05-1.47). WHR mediated 5% (95% CI 3-10%) of the association between the consumption of UPFs and HNC risk, while BMI and WHR, respectively, mediated 13% (95% CI 6-53%) and 15% (95% CI 8-72%) of the association between the consumption of UPFs and OAC risk. UPF consumption was positively associated with accidental death in the negative control analysis. CONCLUSIONS: We reaffirmed that higher UPF consumption is associated with greater risk of HNC and OAC in EPIC. The proportion mediated via adiposity was small. Further research is required to investigate other mechanisms that may be at play (if there is indeed any causal effect of UPF consumption on these cancers).

Multimorbidity and SARS-CoV-2-Related Outcomes: Analysis of a Cohort of Italian Patients.

BACKGROUND: Since the outbreak of the COVID-19 pandemic, identifying the main risk factors has been imperative to properly manage the public health challenges that the pandemic exposes, such as organizing effective vaccination campaigns. In addition to gender and age, multimorbidity seems to be 1 of the predisposing factors coming out of many studies investigating the possible causes of increased susceptibility to SARS-CoV-2 infection and adverse outcomes. However, only a few studies conducted have used large samples. OBJECTIVE: The objective is to evaluate the association between multimorbidity, the probability to be tested, susceptibility, and the severity of SARS-CoV-2 infection in the Piedmont population (Northern Italy, about 4 million inhabitants). For this purpose, we considered 5 main outcomes: access to the swab, positivity to SARS-CoV-2, hospitalization, intensive care unit (ICU) admission, and death within 30 days from the first positive swab. METHODS: Data were obtained from different Piedmont health administrative databases. Subjects aged from 45 to 74 years and infections diagnosed from February to May 2020 were considered. Multimorbidity was defined both with the Charlson Comorbidity Index (CCI) and by identifying patients with previous comorbidities, such as diabetes and oncological, cardiovascular, and respiratory diseases. Multivariable logistic regression models (adjusted for age and month of infection and stratified by gender) were performed for each outcome. Analyses were also conducted by separating 2 age groups (45-59 and 60-74 years). RESULTS: Of 1,918,549 subjects, 85,348 (4.4%) performed at least 1 swab, of whom 12,793 (14.9%) tested positive for SARS-CoV-2. Of these 12,793 subjects, 4644 (36.3%) were hospitalized, 1508 (11.8%) were admitted to the ICU, and 749 (5.9%) died within 30 days from the first positive swab. Individuals with a higher CCI had a higher probability of being swabbed but a lower probability of testing positive. We observed the same results when analyzing subjects with previous oncological and cardiovascular diseases. Moreover, especially in the youngest group, we identified a greater risk of being hospitalized and dying. Among comorbidities considered in the study, respiratory diseases seemed to be the most likely to increase the risk of having a positive swab and worse disease outcomes. CONCLUSIONS: Our study shows that patients with multimorbidity, although swabbed more frequently, are less likely to get infected with SARS-CoV-2, probably due to greater attention on protective methods. Moreover, a history of respiratory diseases is a risk factor for a worse prognosis of COVID-19. Nonetheless, whatever comorbidities affect the patients, a strong dose-response effect was observed between an increased CCI score and COVID-19 hospitalization, ICU admission, and death. These results are important in terms of public health because they help in identifying a group of subjects who are more prone to worse SARS-CoV-2 outcomes. This information is important for promoting targeted prevention and developing policies for the prioritization of public health interventions.

Mediating Role of Lifestyle Behaviors in the Association between Education and Cancer: Results from the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Many studies have shown that socioeconomic position (SEP) is associated with the incidence of malignant tumors at different sites. This study aims to estimate the association between educational level (as proxy for SEP) and cancer incidence and to understand whether the observed associations might be partially explained by lifestyle behaviors. METHODS: The analyses were performed on data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, globally and by sex. We used Cox proportional hazards models together with mediation analysis to disentangle the total effect (TE) of educational level [measured through the Relative Index of Inequality (RII)] on cancer incidence into pure direct (PDE) and total indirect (TIE) effect, unexplained and explained by mediators, respectively. PDE and TIE were then combined to compute the proportions mediated (PM). RESULTS: After an average of 14 years of follow-up, 52,422 malignant tumors were ascertained. Low educated participants showed higher risk of developing stomach, lung, kidney (in women), and bladder (in men) cancers, and, conversely, lower risk of melanoma and breast cancer (in post-menopausal women), when compared with more educated participants. Mediation analyses showed that portions of the TE of RII on cancer could be explained by site-specific related lifestyle behaviors for stomach, lung, and breast (in women). CONCLUSIONS: Cancer incidence in Europe is determined at least in part by a socioeconomically stratified distribution of risk factors. IMPACT: These observational findings support policies to reduce cancer occurrence by altering mediators, such as lifestyle behaviors, particularly focusing on underprivileged strata of the population.

Psychometric validation of the Italian version of the Emotional Style Questionnaire.

Emotional styles concern the ways in which individuals adapt and respond to the world and can be defined using six dimensions: outlook, resilience, social intuition, self-awareness, sensitivity to context and attention. The Emotional Style Questionnaire (ESQ) assesses how people vary across the dimensions and gauges an individual's overall level of emotional health. An Italian version of the ESQ (ESQ-ITA) could favour the understanding of cultural characteristics concerning emotions and personality within the Italian population, with both clinical and social implications. The aim of the present study is to validate the ESQ in the Italian language and to assess its psychometric properties. Two studies were conducted. Study 1 examined construct validity, internal consistency, and test-retest reliability, through Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA), Cronbach's alpha estimates, and by estimating the Spearman's rank correlation Study 2 examined construct validity and internal consistency through the CFA and Cronbach's alpha estimates and investigated criterion validity by correlating the ESQ-ITA dimensions with the corresponding scales or subscales used for the validation estimating, again, the Spearman's rank correlation coefficient Study 2 also examined the criterion validity of the validated scales and the ESQ-ITA overall score to assess its suitability as an indicator of emotional health. ESQ-ITA was confirmed to be reliable and stable. The correlation between the ESQ-ITA overall score and the other scales and questionnaires supports the use of ESQ-ITA to measure emotional health. The Italian version of the ESQ opens up the possibility to enrich the research landscape with new knowledge that will be useful for advancing the pathogenetic and therapeutic aspects of psychological distress and emotional dysregulation.

Mycotoxin Exposure and Renal Cell Carcinoma Risk: An Association Study in the EPIC European Cohort.

BACKGROUND: Mycotoxins have been suggested to contribute to a spectrum of adverse health effects in humans, including at low concentrations. The recognition of these food contaminants being carcinogenic, as co-occurring rather than as singularly present, has emerged from recent research. The aim of this study was to assess the potential associations of single and multiple mycotoxin exposures with renal cell carcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Food questionnaire data from the EPIC cohort were matched to mycotoxin food occurrence data compiled by the European Food Safety Authority (EFSA) from European Member States to assess long-term dietary mycotoxin exposures, and to associate these with the risk of renal cell carcinoma (RCC, n = 911 cases) in 450,112 EPIC participants. Potential confounding factors were taken into account. Analyses were conducted using Cox's proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) with mycotoxin exposures expressed as µg/kg body weight/day. RESULTS: Demographic characteristics differed between the RCC cases and non-cases for body mass index, age, alcohol intake at recruitment, and other dietary factors. In addition, the mycotoxin exposure distributions showed that a large proportion of the EPIC population was exposed to some of the main mycotoxins present in European foods such as deoxynivalenol (DON) and derivatives, fumonisins, Fusarium toxins, Alternaria toxins, and total mycotoxins. Nevertheless, no statistically significant associations were observed between the studied mycotoxins and mycotoxin groups, and the risk of RCC development. CONCLUSIONS: These results show an absence of statistically significant associations between long-term dietary mycotoxin exposures and RCC risk. However, these results need to be validated in other cohorts and preferably using repeated dietary exposure measurements. In addition, more occurrence data of, e.g., citrinin and fumonisins in different food commodities and countries in the EFSA database are a prerequisite to establish a greater degree of certainty.

Improvements throughout the Three Waves of COVID-19 Pandemic: Results from 4 Million Inhabitants of North-West Italy.

At the very beginning of the European spread of SARS-CoV-2, Piedmont was one of the most affected regions in Italy, with a strong impact on healthcare organizations. In this study, we evaluated the characteristics and outcomes of the COVID-19 patients in an entire region during the first three pandemic waves, identifying similarities and differences in the SARS-CoV-2 epidemic's timeline. We collected the health-administrative data of all the Piedmont COVID-19 patients infected during the first three pandemic waves (1 March 2020-15 April 2020; 15 October 2020-15 December 2020; 1 March 2021-15 April 2021, respectively). We compared differences among the waves in subjects positive for SARS-CoV-2 and in patients admitted to ICU. Overall, 18.621 subjects tested positive during the first wave (405 patients/day), 144.350 (2366.4 patients/day) in the second, and 81.823 (1778.8 patients/day) in the third. In the second and third waves, we observed a reduction in median age, comorbidity burden, mortality in outpatients, inpatients, and patients admitted to ICU, in intubation, invasive ventilation and tracheostomy, and a parallel increase in the use of CPAP. Our study confirmed a trend towards younger and healthier patients over time but also showed an independent effect of the period on mortality and ICU admission. The appearance of new viral variants, the starting of vaccination, and organizational improvements in tracking, outpatients and inpatients management could have influenced these trends.

Health status assessment of a population of asylum seekers in Northern Italy.

BACKGROUND: Since 2011 Italy has faced an extraordinary increase in migrants arrivals, mainly from the Mediterranean route, one of the world's most dangerous journeys. The purpose of the present article is to provide a comprehensive picture of the migrants' health status in the "T. Fenoglio" centre, Settimo Torinese (Turin, Italy). METHODS: A retrospective cross-sectional study was conducted using data collected from June 2016 to May 2018 on adult migrants (over 18 years old) from Africa, Middle East and South East Asia (Bangladesh, Cambodia, India, Nepal). Data was collected through the migrants' medical records. Descriptive statistics were performed on socio-demographic variables. The diagnosed diseases were anonymously registered and classified according to the International Classification of Primary Care (ICPC-2). Conditional Inference Trees were used to perform a descriptive analysis of the sample and to detect the covariates with the strongest association with the variables Disease on arrival, Disease after arrival, ICPC on arrival and ICPC after arrival. RESULTS: Analyzed observations were 9 857. 81.8% were men, median age was 23 (Interquartile range: 20.0-27.4). 70.3% of the sample came from Sub-Saharan Africa. 2 365 individuals (24%) arrived at the centre with at least one disease. On arrival, skin (27.71%), respiratory (14.46%), digestive (14.73%) and generic diseases (20.88%) were the most frequent. During the stay respiratory diseases were the most common (25.70%). The highest probability of arriving with a disease occurred in 2018 and during the period September-November 2016, in particular for people from the Horn of Africa. During this period and also in the first half of 2017, skin diseases were the most reported. In seasons with lower prevalence of diseases on arrival the most common disease code was generic for both men and women (usually fever or trauma). CONCLUSIONS: This study provides information on the diverse diseases that affect the asylum seekers population. In our sample, the Horn of Africa was the most troubled area of arrival, with severe conditions frequently reported regarding skin diseases, in particular scabies. 2018 was the most critical year, especially for migrants from the Horn of Africa and Sub-Saharan Africa. During the stay at the camp, the prevalence of respiratory diseases increased. However, skin diseases remained the main issue for people from the Horn of Africa. Overall, the most reported diseases in the sample were dermatological, respiratory, digestive and generic diseases, both on arrival and during the stay. A better understanding of the health status of asylum seekers is an important factor to determine a more efficient reception and integration process and a better allocation of economic resources in the context of migrants' health care.

Soft Drink and Juice Consumption and Renal Cell Carcinoma Incidence and Mortality in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991-2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks. RESULTS: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97-1.09), total soft drinks (HR = 1.01; 95% CI, 0.98-1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94-1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96-1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97-1.16; 1.03, 0.98-1.09; 0.97, 0.89-1.07; and 1.06, 0.99-1.14, respectively). CONCLUSIONS: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity. IMPACT: Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.

Characteristics of patients affecting the duration of positivity at SARS-CoV-2: a cohort analysis of the first wave of epidemic in Italy.

OBJECTIVES: to investigate the characteristics of patients affecting the duration of positivity test by RT-PCR in the population of Piedmont, a Region of North-West of Italy. DESIGN: observational cohort study. SETTING AND PARTICIPANTS: from the administrative database of the regional SARS-CoV-2 surveillance system, a cohort of all patients who tested positive by a RT-PCR assay to SARS-CoV-2 occurring from 22.02.2020 to 30.09.2020 in the Piedmont Region (N. 29,292) was obtained. The cohort has been linked to the hospital discharge database and to the vital statistics database. MAIN OUTCOMES MEASURES: outcome of the study was the risk of non negativization, estimated by fitting Generalizing Estimating Equation model (GEE), a longitudinal model which consider for each subject several records collected on fixed time intervals 15, 30, 45 or 60+ days from the first positive test. Negativization was defined as the condition in which two consecutive samples taken from the patient at least 24 hours apart were negative for the presence of SARS-CoV-2. RESULTS: the median duration of positive RT-PCR was 27 days. A higher median of days until positive persistence was observed in people over 80 (34 days, IQR 25-49), female (28 days, IQR 18-40), symptomatic patients (28 days, IQR 19-40), hospitalized people (32 days, IQR 21-44), patients with Charlson's index >0 (34 days, IQR 23-49), patients host of elderly nursing homes (37 days, IQR 25-51). In the GEE multivariable model, the variables associated to the non negativization at all times intervals were: older age (at 15th day: class 65+, OR 2.56, 95%CI 2.39-2.74), female gender (at 15th day: OR 1.12, 95%CI 1.06-1.18), and to be hospitalized for COVID-19 (at 15th day: OR 1.38, 95%CI 1.29-1.48). The presence of comorbidities and of symptoms were associate with the non negativization at 15th day (respectively, class 4+: OR 1.29, 95%CI 1.08-1.56 and symptoms: OR 1.20, 95%CI 1.13-1.27), but not at 45th day. CONCLUSIONS: older age, female gender, presence of comorbidities and severity of disease (proxy hospitalization for COVID-19) were risk factors for non negativization at all times intervals. The presence of symptoms was a risk factors for the non negativization after 2 weeks from the first diagnosis and not at 45th day. Using a longitudinal model for the analysis of the dataset, it is possible to compare the weight of the variables included in the model at different times and correct an overestimation of the attributable risk after the first considered time interval.

Emergency management in patients with haemophilia A and inhibitors on prophylaxis with emicizumab: AICE practical guidance in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET.

Emicizumab has been approved in several countries for regular prophylaxis in patients with congenital haemophilia A and FVIII inhibitors because it substantially reduces their bleeding risk and improves quality of life. However, although significantly less frequent, some breakthrough bleeds may still occur while on emicizumab, requiring treatment with bypassing or other haemostatic agents. Thrombotic complications have been reported with the associated use of activated prothrombin complex concentrates. In addition, when surgery/invasive procedures are needed while on emicizumab, their management requires multidisciplinary competences and direct supervision by experts in the use of this agent. Given this, and in order to expand the current knowledge on the use of emicizumab and concomitant haemostatic agents, and reduce the risk of complications in this setting, the Italian Association of Haemophilia Centres (AICE) here provides guidance on the management of breakthrough bleeds and surgery in emergency situations in patients with haemophilia A and inhibitors on emicizumab prophylaxis. This paper has been shared with other National Scientific Societies involved in the field.

Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial.

BACKGROUND: Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy. METHODS: Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0·15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639. FINDINGS: 124 patients were enrolled between Nov 10, 2004, and Sept 23, 2009, with data cutoff of March 15, 2012. Four (3%) patients died early. After a median follow-up of 4·2 years (IQR, 3·2-5·2), the 5 year freedom from relapse was 95% (95% CI 89-98), disease-free survival was 95% (89-98), event-free survival was 90% (83-94), and overall survival was 94% (89-97). The comparison with APML3 data showed that hazard ratios were 0·23 (95% CI 0·08-0·64, p=0·002) for freedom from relapse, 0·21 (0·07-0·59, p=0·001) for disease-free survival, 0·34 (0·16-0·69, p=0·002) for event-free survival, and 0·35 (0·14-0·91, p=0·02) for overall survival. INTERPRETATION: Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse when compared with historical controls. This improvement, together with a non-significant reduction in early deaths and absence of deaths in remission, translated into better event-free and overall survival. FUNDING: Phebra.

All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4).

The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.