Assessment of Occupational Carcinogenic Risk by Comparing Data from the Italian Register of Occupational Exposures to Carcinogens (SIREP) with the International Agency for Research on Cancer (IARC) Evidence.

In Italy, the National Register on Occupational Exposure to Carcinogens (SIREP) is established pursuant to article 243 of Legislative Decree 81/2008 and is aimed to collect information on the exposure of workers to carcinogens transmitted by employers. The aim of this study is to assess its level of implementation comparing prevailing carcinogens reported in SIREP with the monitoring of risks in the workplace evidenced by the International Agency for Research on Cancer (IARC). The data reported in the SIREP have been integrated with IARC and the database on carcinogenic risk in the workplace named MATline in order to build a matrix containing the carcinogens classified according to the IARC (Group 1 and 2A agents) and to a semi-quantitative indicator of risk level (High or Low) calculated upon the number of exposures reported in SIREP. The matrix contains the following data: carcinogens, economic sector (NACE Rev2 coding) and cancer sites. The comparison between SIREP and IARC evidence allowed us to highlight situations with a high risk of carcinogenicity and to address appropriate actions of prevention to contain the risks of exposure to carcinogenic substances.

Occupational Mortality Matrix: A Tool for Epidemiological Assessment of Work-Related Risk Based on Current Data Sources.

Mortality from occupational diseases significantly afflicts society, in terms of both economic costs and human suffering. The International Labour Organization (ILO) estimated that 2.4 million workers die from work-related diseases every year. In Europe, around 80,000 workers die from cancer attributed to occupational exposure to carcinogens. This study developed the Occupational Mortality Matrix (OMM) aimed to identify significant associations between causes of death and occupational sectors through an individual record linkage between mortality data and the administrative archive of occupational histories. The study population consisted of 6,433,492 deceased subjects in Italy (in the period 2005-2015), of which 2,723,152 records of work histories were retrieved (42%). The proportional mortality ratio (PMR) was estimated to investigate the excess of mortality for specific causes associated with occupational sectors. Higher PMRs were reported for traditionally risky occupations such as shipbuilding for mesothelioma cases (PMR: 8.15; 95% CI: 7.28-9.13) and leather production for sino-nasal cancer (PMR: 5.04; 95% CI: 3.54-7.19), as well as for unexpected risks such as male breast cancer in the pharmaceutical industry (PMR: 2.56; 95% CI: 1.33-4.93) and brain cancer in railways (PMR: 1.43; 95% CI: 1.24-1.66). The OMM proved to be a valid tool for research studies to generate hypotheses about the occupational etiology of diseases, and to monitor and support priority actions for risk reduction in workplaces.

Real-life use of ramucirumab in gastric cancer in Spain: the RAMIS study.

Aims: To obtain real-world data on ramucirumab use and effectiveness for the treatment of advanced gastric cancer (AGC) or gastroesophageal junction adenocarcinoma (GEJ). Methods: Observational, retrospective study carried out in 20 Spanish hospitals, in patients who started ramucirumab treatment between December 2015 and December 2018. Descriptive analysis was conducted for patient characteristics, treatment patterns and effectiveness outcomes. Results: Three hundred seventeen patients were included (93.7% treated with ramucirumab-paclitaxel and 6.3% with ramucirumab); age 62.5 (11.3) years; 66.9% male. Median progression-free survival and overall survival were 3.9 months (95% CI: 3.4-4.3) and 7.4 (95% CI: 6.4-8.9) in combination regimen and 2.0 (1.1-2.8) and 4.3 (95% CI: 1.9-7.3) in monotherapy, respectively. Conclusion: The study findings were consistent with available real-world studies and randomized clinical trials.

Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1⁺/⁻ mice after paternal irradiation.

The hypothesis of transgenerational induction of increased cancer susceptibility after paternal radiation exposure has long been controversial because of inconsistent results and the lack of a mechanistic interpretation. Here, exploiting Ptch1 heterozygous knockout mice, susceptible to spontaneous and radiation-induced medulloblastoma, we show that exposure of paternal germ cells to 1 Gy X-rays, at the spermatogonial stage, increased by a considerable 1.4-fold the offspring susceptibility to medulloblastoma induced by neonatal irradiation. This effect gained further biological significance thanks to a number of supporting data on the immunohistochemical characterization of the target tissue and preneoplastic lesions (PNLs). These results altogether pointed to increased proliferation of cerebellar granule cell precursors and PNLs cells, which favoured the development of frank tumours. The LOH analysis of tumor DNA showed Ptch1 biallelic loss in all tumor samples, suggesting that mechanisms other than interstitial deletions, typical of radiation-induced medulloblastoma, did not account for the observed increased cancer risk. This data was supported by comet analysis showing no differences in DNA damage induction and repair in cerebellar cells as a function of paternal irradiation. Finally, we provide biological plausibility to our results offering evidence of a possible epigenetic mechanism of inheritance based on radiation-induced changes of the microRNA profile of paternal sperm.

Choriocarcinoma syndrome.

OBJECTIVE: To explore the possibility of choriocarcinoma syndrome developing as a potentially fatal complication in patients with this pathology. METHOD: Choriocarcinoma syndrome consists of hemorrhagic manifestations of metastases in advanced germ cell cancer containing large elements of choriocarcinoma. It should be suspected in patients with high tumor mass, multiple metastases and elevated tumor markers characteristic of germ cell tumors. It usually occurs before and during the onset of systemic treatment with chemotherapy. Failure to diagnose it can lead to fatal consequences and may require aggressive diagnostic and therapeutic measures such as surgery. It can also be prevented by developing a good therapeutic strategy that includes an interdisciplinary team, raising the possibility of deferring testicular surgery and beginning chemotherapy beforehand. RESULTS: We report two cases of men with the diagnosis of choriocarcinoma syndrome on liver metastases. We provide ultrasound and CT images of the two cases of hemorrhage on liver metastases and radiological characteristics peculiar to each case that have never been published before. CONCLUSIONS: There should be a high index of suspicion of life-threatening complications in patients with germ cell tumors with a choriocarcinoma component, including the development of life-threatening choriocarcinoma syndrome.

Síndrome del coriocarcinoma / Choriocarcinoma syndrome

OBJETIVO: Conocer la posibilidad de desarrollo de síndrome de coriocarcinoma como una complicación potencialmente mortal en pacientes con dicha patología. MÉTODO: El Síndrome del Coriocarcinoma consiste en manifestaciones hemorrágicas de las metástasis en el cáncer avanzado de células germinales que contienen elementos de gran volumen de coriocarcinoma. Debe sospecharse en pacientes con alta masa tumoral, metástasis múltiples y marcadores tumorales elevados propios de los tumores de células germinales. Suelen aparecer antes y durante el inicio del tratamiento sistémico con quimioterapia. La falta de diagnóstico puede conllevar consecuencias fatales y pueden requerir medidas agresivas de diagnóstico y terapéuticas como la cirugía. Además debe prevenirse realizando una buena estrategia terapéutica que incluya un equipo interdisciplinar, pudiéndose plantear diferir la cirugía testicular e iniciar previamente el tratamiento con quimioterapia. RESULTADO: Presentamos dos casos de dos hombres con el diagnóstico síndrome de coriocarcinoma sobre metástasis hepáticas. Aportamos imágenes ecográfica y por TAC de los dos casos de hemorragia sobre las metástasis hepáticas y las características radiológicas peculiares de ambos casos, nunca antes publicadas. CONCLUSIONES: Debe existir un alto índice de sospecha de complicaciones potencialmente mortales en pacientes que presentan tumores de células germinales con componente de coriocarcinoma, entre ellas el desarrollo del Síndrome de Coriocarcinoma potencialmente mortal

OBJECTIVE: To explore the possibility of choriocarcinoma syndrome developing as a potentially fatal complication in patients with this pathology. METHOD: Choriocarcinoma syndrome consists of hemorrhagic manifestations of metastases in advanced germ cell cancer containing large elements of choriocarcinoma. It should be suspected in patients with high tumor mass, multiple metastases and elevated tumor markers characteristic of germ cell tumors. It usually occurs before and during the onset of systemic treatment with chemotherapy. Failure to diagnose it can lead to fatal consequences and may require aggressive diagnostic and therapeutic measures such as surgery. It can also be prevented by developing a good therapeutic strategy that includes an interdisciplinary team, raising the possibility of deferring testicular surgery and beginning chemotherapy beforehand. RESULTS: We report two cases of men with the diagnosis of choriocarcinoma syndrome on liver metastases. We provide ultrasound and CT images of the two cases of hemorrhage on liver metastases and radiological characteristics peculiar to each case that have never been published before. CONCLUSIONS: There should be a high index of suspicion of life-threatening complications in patients with germ cell tumors with a choriocarcinoma component, including the development of life-threatening choriocarcinoma syndrome

X-ray induced DNA damage and repair in germ cells of PARP1(-/-) male mice.

Poly(ADP-ribose)polymerase-1 (PARP1) is a nuclear protein implicated in DNA repair, recombination, replication, and chromatin remodeling. The aim of this study was to evaluate possible differences between PARP1(-/-) and wild-type mice regarding induction and repair of DNA lesions in irradiated male germ cells. Comet assay was applied to detect DNA damage in testicular cells immediately, and two hours after 4 Gy X-ray irradiation. A similar level of spontaneous and radiation-induced DNA damage was observed in PARP1(-/-) and wild-type mice. Conversely, two hours after irradiation, a significant level of residual damage was observed in PARP1(-/-) cells only. This finding was particularly evident in round spermatids. To evaluate if PARP1 had also a role in the dynamics of H2AX phosphorylation in round spermatids, in which γ-H2AX foci had been shown to persist after completion of DNA repair, we carried out a parallel analysis of γ-H2AX foci at 0.5, 2, and 48 h after irradiation in wild-type and PARP1(-/-) mice. No evidence was obtained of an effect of PARP1 depletion on H2AX phosphorylation induction and removal. Our results suggest that, in round spermatids, under the tested experimental conditions, PARP1 has a role in radiation-induced DNA damage repair rather than in long-term chromatin modifications signaled by phosphorylated H2AX.

γ-H2AX detection in somatic and germ cells of mice.

The phosphorylation of histone H2AX at serine 139 (γ-H2AX) is one of the first steps of DNA damage response and its detection is widely used as a sensitive marker for DNA double-strand breaks induced by ionizing radiation or other genotoxic agents. Immuno-stained phosphorylated histone can be measured in single cells by flow cytometry or single γ-H2AX foci can be visualized and counted microscopically in histological or cytological preparations. Animal studies are well recognized as important tools to study mechanisms of in vivo response to genotoxic stress. Tissues are composed by many cell types differing for function, differentiation, and proliferative capacity. In particular, due to the complexity of spermatogenesis and the heterogeneity of testicular cell subpopulations, an accurate characterization of damage in this tissue is difficult and requires an approach which allows the identification of damage in the different cellular compartments. This chapter presents techniques for γ-H2AX detection in mouse bone marrow and testicular cells. Furthermore, advantages and weaknesses of flow cytometric and microscopic methods are described.

Kinetics of gamma-H2AX induction and removal in bone marrow and testicular cells of mice after X-ray irradiation.

Male germ cells have been shown to differ in their DNA damage response (DDR) with respect to somatic cells. In addition, DDR pathways are modulated along spermatogenesis, accompanying profound chromatin modifications. Histone H2AX phosphorylation is a fundamental step of DDR. Few data are available on the long-term kinetics of phosphorylated H2AX (γ-H2AX) after in vivo irradiation. We have investigated, by microscopic and flow cytometric immunochemistry, γ-H2AX induction and removal in testicular cells of irradiated mice, in comparison with bone marrow cells. In unirradiated testicular cells, much higher levels of γ-H2AX were measured by flow cytometry with respect to bone marrow cells. Irradiation induced a redistribution of γ-H2AX into discrete foci detectable by microscopy. In irradiated bone marrow, the percentage of labelled cells peaked at 1 h and rapidly declined, in agreement with data on in vitro cell lines. In contrast, spermatocytes and round spermatids showed persistent labelling until 48 h. During this time, in spermatids, topological changes were observed in γ-H2AX foci from a pattern of many uncountable dots to a pattern of few large spots. Observations of testicular sections confirmed this trend in the reduction of foci number in spite of substantially invariable percentages of labelled cells in the analysed timeframe. To assess whether γ-H2AX persistence in testicular cells was due to unrepaired DNA breaks, we performed comet assay and immunofluorescence analysis of Mdc1, a marker of DDR different from γ-H2AX. Comet assay showed that most breaks were repaired within 2 h. Forty-eight hours after irradiation, contrary to γ-H2AX foci that remained detectable in 80% of initially labelled cells, Mdc1 foci were observed in only 20-30% of cells. These data suggest that, at long times after irradiation, mechanisms additional to impairment of DNA break repair may account for the long persistence of γ-H2AX foci in male germ cells.