Still Unanswered Questions About SARS-CoV-2 Mortality and Future Directions for Occupational Medicine.

The article discusses a recent study on mortality attributable to COVID-19 in Italy and the need for further analysis. The study used a reliable methodology to estimate excess deaths due to the pandemic. However, there are still questions about the specific effects of COVID-19 compared to other factors, such as delayed or missing access to treatment for other illnesses. Analyzing the time course of excess deaths could reveal such effects. There are also open questions about how COVID-19 deaths are classified and reported, which could lead to over or under-diagnosing cases. The article notes that occupational physicians have played an important role in preventing the spread of COVID-19 among workers. A recent study found that personal protective equipment (PPE), particularly masks, effectively reduced the risk of infection among healthcare workers. However, it is still unclear whether Occupational Medicine should incorporate infectious diseases as a major concern or return to its historically agnostic attitude toward communicable diseases. More data on mortality from specific diseases will be needed for further analysis and understanding of the pandemic's effects on mortality rates in Italy.

Epidemiologic Health Impact Assessment: Estimation of Attributable Cases and Application to Decision Making.

OBJECTIVES: The epidemiologic Health Impact Assessment (eHIA) process is receiving growing attention in Italy. In the context of such an approach, the present paper has three objectives: to review the computational aspects of eHIA for stressing strengths and weaknesses of methods and formulas; to discuss which rate at baseline could be used for the estimation of attributable cases; how to use the results of eHIA to make decisions regarding the realization of industrial projects. METHODS AND RESULTS: Using a linear formulation of the relationship between exposure and disease occurrence: a) formulas have been derived to compute attributable cases (AC) using both Relative Risk (RR) and Excess Risk (ER) approaches; b) a discussion is made of the use as baseline rate of the rate that is caused by all the risk factors for a particular disease and a suggestion is made to use the rate that is caused simply by the risk factors that are under evaluation; c) under assumptions and approximations that must be validated in any specific situation, formulas are derived to compute Incremental Lifetime Cumulative Risk (ILCR), an indicator that can be used to compare the results coming from the eHIA approach with the levels of action used by USEPA and others (10-6, 10-5, 10-4). -Conclusion: In this paper, the methodology and the formulas commonly used in eHIA have been enlarged to consider the case in which the baseline rate is equal to zero, suggesting to use Excess Risk (ER) estimates instead of Relative Risk (RR) estimates. Using different baseline rates produces very different estimates of AC, and work needs to be done on this topic. Lastly, due to assumptions, approximations, and uncertainty of eHIA computations, prudence and caution should be exercised in using eHIA results in decision making, particularly if hard decisions have to be made.

Real-world data on healthcare resource consumption and costs before and after kidney transplantation.

End-stage renal disease (ESRD) is increasing worldwide as a consequence of population aging and increasing chronic illness. Treatment consists mostly of dialysis and kidney transplantation (KTx), and KTx offers advantages for life expectancy and long-term cost reductions compared with dialysis. This study uses the administrative database of the Lombardy Region to analyze the costs of a cohort of patients with ESRD receiving KTx, covering a time period of 24 months before transplant to 12 months after. During 2011, 276 patients underwent kidney transplantation (8.7% preemptive and 91.3% non-preemptive). In the period before transplantation, the main cost driver was dialysis (66.6% for the period from -24 to -12 months and 73.8% for the period from -12 to 0 months), while in the 12 months after KTx, the most relevant cost was surgery. The total cost -24 to -12 months pre-KTx was 35 049.2€; the cost -12 to 0 months was 36 745.9€; and the cost 12 months after KTx was 43 805.8€. Non-preemptive patients showed much higher costs both pre- and post-KTx than preemptive patients. This study highlights how KTx modifies the resource consumption and costs composition of patients with ESRD vs those undergoing dialysis treatment and how KTx may be economically beneficial, especially preemptive intervention.

Position Paper on Asbestos of the Italian Society of Occupational Medicine.

The Position Paper (PP) on asbestos of the Italian Society of Occupational Medicine (SIML) aims at providing a tool to the occupational physician to address current diagnostic criteria and results of epidemiological studies, and their consequences in terms of preventive and evaluation actions for insurance, compensation and litigation. The PP was based on an extensive review of the scientific literature and was compiled by a Working Group comprising researchers who have contributed to the international literature on asbestos-related diseases, as well as occupational physicians with extensive experience in the evaluation of risks and the medical surveillance of workers currently and formerly exposed to asbestos. The PP was drafted and reviewed between 2017 and 2018; its final version was prepared according to the guidelines of AGREE Reporting Checklist. All the members of the Working Group subscribed to the document, which was eventually approved by SIML's Executive Committee. The first section addresses industrial hygiene issues, such as methods for environmental monitoring, advantages and limitations of different microscopy techniques, the potential role of microfibers and approaches for retrospective assessment of exposure, in particular in epidemiological studies. The second section reviews the biological effects of asbestos with particular attention to the diagnostic aspects of asbestosis, pleural changes, mesothelioma and lung cancer. In the following section the criteria of causal attribution are discussed, together with different hypotheses on the form of the risk functions, with a comparison of the opinions prevalent in the literature. In particular, the models of the risk function for mesothelioma were examined, in the light of the hypothesis of an acceleration or anticipation of the events in relation to the dose. The last section discusses topics of immediate relevance for the occupational physician, such as health surveillance of former exposed and of workers currently exposed in remediation activities.

Management and Survival of Pleural Mesothelioma: A Record Linkage Study.

BACKGROUND: Pleural mesothelioma (PM) is a rare, highly lethal tumor. A definite consensus on its management has yet to be established. OBJECTIVES: To assess management, overall survival (OS), and their predictors in a cohort of patients from Lombardy, the largest Italian region (about 10 million inhabitants). METHODS: Through a record linkage between Lombardy health care administrative databases, we identified patients diagnosed with PM in 2006-2011 without history of cancer, evaluating their management. OS from PM diagnosis was estimated using the Kaplan-Meier method. Predictors of OS and of treatment were assessed using Cox regression models with time-dependent covariates when appropriate. RESULTS: Out of 1,326 patients, 754 (56.9%) received treatment for PM: 205 (15.5%) underwent surgery, and 696 (52.5%) used chemotherapy. Surgery was spread across several hospitals, and most patients diagnosed in nonspecialized centers (70%) underwent surgery in the same centers. Age at diagnosis was a strong inverse determinant of surgery. Determinants of receiving chemotherapy were younger age, a more recent first diagnosis, and first diagnosis in a specialized center. OS was 45.4% at 1 year, 24.8% at 2 years, and 9.6% at 5 years (median 11 months). OS decreased with age, and was higher for those who underwent surgery, but not for those treated with chemotherapy. CONCLUSIONS: Management of PM varied widely in clinical practice, and significant predictors of treatment were younger age and recent diagnosis, though a high proportion of patients were not treated. Patients were treated in various hospitals, indicating the importance of concentrating serious rare neoplasms in Comprehensive Cancer Centers (as recognized by the Italian Health Ministry).

Increase of exposure and event acceleration. / Aumento dell'esposizione e anticipazione degli eventi.

INTRODUCTION: In a previous paper on acceleration of failure time we highlighted the difficulties of the application to the case of mesothelioma of the methodology proposed by Berry. In this contribution we elaborate further on the concept of anticipation/acceleration, taking into account the content of the III Italian Consensus Document. METHODS: We analyzed the ways in which the concept of anticipation/acceleration has been proposed and interpreted in the III Consensus Document. RESULTS: We show that the concept of anticipation of the III Consensus Document has to do with incidence (frequency) in a population (and not with acceleration of the pathological process in an individual case), and is a measure which is alternative to other measures of frequency effects. In addition, we show that the same epidemiological result is compatible with causal models where no cases, all the cases, or some of the cases are anticipated. DISCUSSION: This paper suggests that the concept of anticipation measurable through epidemiologic data has to do exclusively with the anticipation of a frequency indicator (more occurrencies and anticipated occurrencies are indistinguishable and alternative concepts) but not with the acceleration of the biological process in individual cases. In causal terms, without a biological support it is not possible to infer from the epidemiologic results if a causal model is in action with no, all, or some of cases anticipated.

Effectiveness of trastuzumab in first-line HER2+ metastatic breast cancer after failure in adjuvant setting: a controlled cohort study.

BACKGROUND: The evidence supporting the use of trastuzumab (T) in a metastatic setting comes from studies that included (almost) only patients who never received prior T. We investigated the effectiveness of T as first-line therapy for metastatic breast cancer (mBC) in women previously treated with T in the adjuvant setting. MATERIALS AND METHODS: By using record linkage of five administrative health care databases of Lombardy, Italy, we identified 2,046 women treated with T for early breast cancer (eBC) in 2006-2009, 96 of whom developed a metastasis and were retreated with T in first-line treatment for mBC (treatment group). We compared the overall survival (OS) of these women with that of 197 women treated with T in first-line treatment for mBC, who were treated with therapies other than T for early disease (control group). We computed Kaplan-Meier 2-year OS and used a proportional hazard model to estimate the multivariate hazard ratio (HR) of death in the intervention group compared with the control group, adjusted by age, use of endocrine therapy, and site of metastasis. RESULTS: Two-year OS was 60.0% in the treatment group and 59.5% in the control group. The adjusted HR of death in the treatment group compared with the control group was 0.79 (95% confidence interval, 0.50-1.26). CONCLUSION: Our data provide convincing evidence that the outcome of women receiving first-line T treatment for mBC after T failure in the adjuvant setting is comparable to that of women not receiving T for eBC. These data are of specific interest, given the unavailability of data from randomized clinical trials.

[A set of indicators to monitor the adherence to the guidelines for the diagnosis and treatment of breast cancer]. / Indicatori per il monitoraggio dei percorsi diagnostico-terapeutici del tumore della mammella.

OBJECTIVES: to present a set of indicators developed from six Local Health Authorities of the Lombardy Region to monitor the diagnostic and therapeutic pathway of breast cancer patients, applied to 2007-2009 incident cases. DESIGN: retrospective cohort study. SETTING AND PARTICIPANTS: all subjects with primary breast cancer, incident in the period 2007-2009, and collected by cancer registries of Milano 1, Bergamo, Cremona, Milano, Milano 2 and Monza-Brianza (5,320,272 inhabitants) were included. MAIN OUTCOME MEASURES: through the use of combined current health databases (health registry, hospitalizations, outpatient, pharmaceutical prescription and specific database for anticancer drugs), for each incident case 34 different indicators have been developed to measure the appropriateness of the procedures provided for diagnosis, treatment (surgical and medical) and follow-up. For each indicator, we analyzed the relationship with age, stage, deprivation index, type of treatment, volume of the specific procedure of the hospital where primary surgery was performed. Estimates were adjusted using multilevel regression models. RESULTS: 12,988 incident cases, without metastatic diseases and other cancers, were included in the cohort: 62% were localized to the breast, 33% to the axillary lymph-nodes, 3% metastatic ab initio, and 2% with unknown stage. Deviations from the expected value of different magnitude depending on the type of indicator were observed: the most important differences were detected for the follow-up indicators. There was, in fact, an excess of several procedures in the first year of follow-up: 75% of the cases performed a dosage of a tumor marker, 67% an ecography or a CT scan or an MR, and 37% a bone scan. On the other hand, the access to neoadjuvant and adjuvant treatments in older women was far below the expected values. CONCLUSIONS: the study presents data derived from a large cohort of population cases; the set of indicators was validated by a board of oncologists. The use of indicators calculated by linking the cancer registries (that provide staging) and administrative databases allows the assessment of compliance to the guidelines for diagnosis and treatment of tumours. This experience shows that it is possible to develop a methodology, shared with clinicians, to define indicators that measure the distance between guidelines and current clinical practice in order to decrease variability, to limit inappropriateness, and to reduce unnecessary diagnostic tests for patients (and, consequently, hospitals organizational overload). In order to be sustainable and equitable, a health care system must be able to ensure implementation of protocols/procedures based exclusively on the best available scientific evidences.

Trastuzumab-related cardiotoxicity in early breast cancer: a cohort study.

BACKGROUND: Concerns have been raised about the cardiac safety profile of trastuzumab for the adjuvant treatment of early stage breast cancer in clinical practice. We assessed trastuzumab-related cardiotoxicity and its predictors in a large cohort of Italian women. METHODS: Through a record linkage between four regional health care databases, we identified the rate of severe cardiac adverse events among women treated with trastuzumab for early breast cancer in Lombardy. The cumulative risk of cardiotoxicity was estimated using the Kaplan-Meier method, and independent predictors were assessed using the Cox model. RESULTS: Of 2,046 trastuzumab users, 53 (2.6%) experienced at least one hospitalization for a cardiac event, and there were two cardiac deaths. The cumulative risk of cardiotoxicity increased up to 2 years after starting treatment, reaching a plateau at 2.8%. The risk was low (0.2%) among young women, whereas the incidence was approximately 10% in women aged ≥70 years, irrespective of cardiovascular risk factors. Age and history of cardiac disease were strong predictors of cardiotoxicity, with a hazard ratio of 11.3 (95% confidence interval [CI]: 3.5-36.6) for women aged ≥70 years as compared with those <50 years of age. Hazard ratio was 4.4 (95% CI: 2.1-9.5) for women with a history of cardiac disease compared with those without a history of cardiac disease. CONCLUSIONS: Cardiotoxicity of trastuzumab varies considerably across subgroups of patients. The long-term safety profile was less favorable than in the largest clinical trial. Strategies to reduce cardiotoxicity in high-risk women should be investigated.

Hospitalization rates and cost in severe or complicated obesity: an Italian cohort study.

BACKGROUND: The economic and social costs of obesity are estimated to be considerable, particularly for inpatient care. The aim of this study was to compare the hospitalization rates of individuals with severe (body mass index [BMI] ≥40 kg/m2) or complicated (BMI ≥30 kg/m2) obesity with those of the general population in two regions of Northwest Italy, and to describe absolute costs of hospitalization and their determinants. METHODS: Between 1996 and 2002, 6,516 patients who were admitted for the first time to a hospital offering a nutritional rehabilitation programme for obesity were enrolled and followed-up (mean follow-up time: 7.3 years). Standardized hospitalization rates (SHRs) were computed by sex for all-cause and cause-specific hospitalization. The general population of the two regions was used as the reference population. The annual cost of hospitalization was estimated for the study cohort only at the individual level, and its association with different determinants was assessed using a multivariable linear model for longitudinal data. RESULTS: SHRs of the study cohort versus the general population increased for all-cause hospitalization (males: 3.53, 95% CI 3.45-3.61; females: 3.22, 95% CI 3.18-3.26) as well as for most obesity-related conditions. The absolute median annual cost of hospitalization was 2,436 euros for males and 2,293 euros for females. Older age at cohort enrolment, BMI ≥40 kg/m2, waist circumference above the median (males: 1.26 metres; females: 1.13 metres), and the presence of co-morbidities, such as cardiovascular diseases, respiratory diseases, cancer, diseases of the musculoskeletal system and connective tissue, and mental disorders, significantly increased the absolute median annual costs of hospitalization. CONCLUSIONS: The economic consequences of high hospitalization rates in obese individuals are relevant. Reducing the occurrence of co-morbidities among obese persons may be one important goal, not only for clinical reasons, but also from a public health point of view.

Chronic disease prevalence from Italian administrative databases in the VALORE project: a validation through comparison of population estimates with general practice databases and national survey.

BACKGROUND: Administrative databases are widely available and have been extensively used to provide estimates of chronic disease prevalence for the purpose of surveillance of both geographical and temporal trends. There are, however, other sources of data available, such as medical records from primary care and national surveys. In this paper we compare disease prevalence estimates obtained from these three different data sources. METHODS: Data from general practitioners (GP) and administrative transactions for health services were collected from five Italian regions (Veneto, Emilia Romagna, Tuscany, Marche and Sicily) belonging to all the three macroareas of the country (North, Center, South). Crude prevalence estimates were calculated by data source and region for diabetes, ischaemic heart disease, heart failure and chronic obstructive pulmonary disease (COPD). For diabetes and COPD, prevalence estimates were also obtained from a national health survey. When necessary, estimates were adjusted for completeness of data ascertainment. RESULTS: Crude prevalence estimates of diabetes in administrative databases (range: from 4.8% to 7.1%) were lower than corresponding GP (6.2%-8.5%) and survey-based estimates (5.1%-7.5%). Geographical trends were similar in the three sources and estimates based on treatment were the same, while estimates adjusted for completeness of ascertainment (6.1%-8.8%) were slightly higher. For ischaemic heart disease administrative and GP data sources were fairly consistent, with prevalence ranging from 3.7% to 4.7% and from 3.3% to 4.9%, respectively. In the case of heart failure administrative estimates were consistently higher than GPs' estimates in all five regions, the highest difference being 1.4% vs 1.1%. For COPD the estimates from administrative data, ranging from 3.1% to 5.2%, fell into the confidence interval of the Survey estimates in four regions, but failed to detect the higher prevalence in the most Southern region (4.0% in administrative data vs 6.8% in survey data). The prevalence estimates for COPD from GP data were consistently higher than the corresponding estimates from the other two sources. CONCLUSION: This study supports the use of data from Italian administrative databases to estimate geographic differences in population prevalence of ischaemic heart disease, treated diabetes, diabetes mellitus and heart failure. The algorithm for COPD used in this study requires further refinement.

Bevacizumab in clinical practice: prescribing appropriateness relative to national indications and safety.

The aim of this study was to describe the clinical use of bevacizumab in Lombardy (9.5 million inhabitants), Italy, during 2006-2007 in patients with metastatic colorectal cancer (mCRC) to evaluate compliance with the Italian Medicine Agency (AIFA) indications, the incidence of adverse events, and the survival rate. We performed computerized record linkage among three different Lombardy health care databases: File F registry, Regional discharge database, and Registry Office records. Patients were classified into approved and off-label uses according to the AIFA indications. Treatment with bevacizumab was administered to 780 patients, of whom 81.7% (n = 637) had mCRC. Among these, 37.8% (n = 241) of patients received the drug in observance of AIFA indications. Overall, ∼10% of patients had serious treatment-related toxicities (fistula, 3.5%; venous thromboembolism, 2.8%; hemorrhage, 1.9%; intestinal perforation and arterial thromboembolism, <1%). The 1-year survival rate was 74.3% and the 2-year survival rate was 39.2%. The median survival time was 20.5 months, and there were no meaningful differences between gender and age groups. There was a gap between the bevacizumab approved indication and clinical practice pattern: overall, less than one half of the patients received bevacizumab in observance with the regulatory indication. The main reason for nonadherence to the indication was use as a second-line or advanced line of therapy. The incidence of serious adverse events and the survival rates of mCRC patients were similar to those reported in clinical trials.

Cinacalcet adherence in dialysis patients with secondary hyperparathyroidism in Lombardy Region: clinical implications and costs.

BACKGROUND: Patients on dialysis often have secondary hyperparathyroidism (SHPT), a disorder associated with renal osteodystrophy, progressive vascular calcification, cardiovascular disease, and death. The objective of this retrospective observational study was to evaluate, in dialysis patients with SHPT, the impact of different levels of adherence to cinacalcet therapy on hospitalisations and direct healthcare costs charged to the Lombardy Regional Health Service (Italy). METHODS: Data recorded in the administrative databases on all citizens undergoing dialysis between 1 January 2011 and 31 December 2011 were selected. For the aim of this study, patients with SHPT already on dialysis in the first 6 months of 2009 who had been treated with cinacalcet for at least 365 days were selected and retrospectively analysed through to end of 2012. Healthcare resource utilisation, cinacalcet adherence, and costs for medication, hospitalisations, and diagnostic/therapeutic procedures were estimated. RESULTS: A total of 994 patients were identified (mean age 63.0 years, females 43.5%). The first patient tertile had an adherence to cinacalcet of <64.1%, whereas the third had an adherence of over 91.5%. Patients in the third adherence tertile experienced fewer all-causes hospitalisations than those in the first tertile (-19.2%; p=0.01423), fractures (-37.1%; p=0.59422), cardiovascular disease (-23.8%; p=0.04025), and sepsis (-32.3%; p=0.01386). The increase in costs for cinacalcet-adherent patients is almost completely offset by the reduction in costs for hospitalisations. CONCLUSIONS: The results of the analysis suggest that there may be some correlation between a high level of cinacalcet adherence and a decrease in hospitalisations.

Mortality in a population exposed to dioxin after the Seveso, Italy, accident in 1976: 25 years of follow-up.

The Seveso accident in 1976 caused a large, populated area north of Milan, Italy, to be contaminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study, the authors followed up the exposed population for chronic effects; this paper reports the results of the mortality follow-up extension for 1997-2001. The study cohort includes 278,108 subjects resident at the time of the accident or immigrating/born in the 10 years thereafter in three contaminated zones with decreasing TCDD soil levels (zone A, very high; zone B, high; zone R, low) and in a reference territory comprising surrounding, noncontaminated municipalities. Vital status and cause-of-death ascertainment were 99% complete. Adjusted rate ratios and 95% confidence intervals were calculated by using Poisson regression. Results confirmed previous findings of excesses of lymphatic and hematopoietic tissue neoplasms in zones A (six deaths; rate ratio = 2.23, 95% confidence interval: 1.00, 4.97) and B (28 deaths; rate ratio = 1.59, 95% confidence interval: 1.09, 2.33). These zones also showed increased mortality from circulatory diseases in the first years after the accident, from chronic obstructive pulmonary disease, and from diabetes mellitus among females. A toxic and carcinogenic risk to humans after high TCDD exposure is supported by the results of this study.

Occupational exposure to vinyl chloride and risk of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common form of cancer that arises from hepatocytes and whose risk may be affected by several known factors, including viruses, alcohol, cigarette smoking, and several genetic conditions. Liver angiosarcoma is a rare cancer that develops from endothelial cells and whose most relevant known risk factor is occupational exposure to vinyl chloride (VC). Since occupational exposure to high levels of VC may still occur, we reviewed the epidemiological and experimental evidence supporting the notion that inhalation exposure to VC is a risk factor for HCC. We find that available epidemiological evidence is based on a dose-risk study with 10 HCC cases and on a partially overlapping study reporting similar results: neither study provided controls for known non-occupational confounders for HCC. Carcinogenesis bioassays of VC inhalation in rodents indicate that angiosarcomas account for nearly all liver tumors induced. Thus, the role of inhalation exposure to VC in HCC risk remains unclear, awaiting further studies and the integration of results from epidemiological studies and animal models.