Contralateral prophylactic mastectomies. Correlations between primary tumor and histological findings of controlateral breast

Backgound: In Italy in 2015 48,000 new cases of breast carcinomas were diagnosed. Women who are diagnosed with breast cancer have a significant risk of developing contralateral breast cancer during the rest of their lives and this risk is closely associated to the family history, to the onset of breast cancer at a young age and is expressed at about 0.5 to 1% of metachronous tumors per year. The purpose of this work was to evaluate which and how many neoplastic lesions were seen in the contralateral breast that underwent prophylactic mastectomy and to understand what factors predict the appearance of such lesions. Methods: 168 bilateral mastectomies were analyzed in patients with an average age of 47 years, carried out from July 2008 to April 2016, at the Breast Unit of the Sant’Andrea Hospital. We considered women of any age suffering from unilateral breast cancer without either clinical or radiological evidence of a malignant lesion in the contralateral breast and negative for mutations of the BRCA1-BRCA2 genes test. Of the 168 bilateral mastectomies 35 patients were excluded from the study because they underwent neoadjuvant chemotherapy, another 35 patients because they were suffering from a bilateral neoplasia and 7 cases because they had mutated BRCA1 or BRCA2 genes. Therefore the remaining 91 patients were included in the study. Results: Both the histological features of the primary tumor and any lesions found in the contralateral prophylactic breast were analyzed. Histological examination of the main breast showed 59 cases of Invasive Ductal Carcinoma (IDC), 17 cases of Invasive Lobular Carcinoma (ILC), 9 cases of In Situ Ductal Carcinoma (ISDC), 3 microinvasive ductal, 1 invasive tubular carcinoma, 1 in situ lobular and 1 widespread in situ. In the contralateral breast, the definitive histological examination revealed that 47 patients had an occult lesion in the prophylactic contralateral breast; in particular 2 cases of LIN 1, 7 cases of LIN2, 6 cases of lobular carcinoma in situ, 26 between DIN1A/DIN1A-B/DIN1B, 4 cases of carcinoma in situ and 2 cases of Invasive Ductal Carcinoma. The correlation obtained from the observation of the main tumor has shown that in a total of 59 invasive ductal carcinoma 32 have a controlateral occult lesions and in a total of 17 cases of invasive lobular carcinoma 9 have an occult lesion in the prophylactic breast. Of these lesions, the multicentric relationship is that 50% of invasive ductal and invasive lobular carcinoma of the main breast have a contralateral lesion. Conclusion: In conclusion we would like to remind, as demonstrated by our follow-up data and as the literature reiterates, that this surgery does not improve patient survival. Certainly patients with unilateral breast cancer have many surgical therapies to be able to deal with not only having a bilateral mastectomy. The end point of this work is try to understand the risk factors of having a contralateral breast lesion to reduce the probability of a metachronous cance

The Combination of Advanced Tools for Parameters Investigation and Tools Maintenance in Flow Forming Process

Abstract In this work, the authors present an investigation on technological parameters affecting the flow forming process of aluminum alloy 6060 tubular structures and to discuss about the tools maintenance. Flow forming tests were carried out by mounting a single roller on a lathe machine. A 3D thermo-mechanical finite element model was developed to analyze the interaction between the roller and the workpiece in terms of forces, strains and thermal distribution. The effects of friction conditions were investigated through the FE model results and comparing them with acquired thermal maps. The model was validated by comparing the geometrical characteristics of the workpieces, such as the axial elongation, the inner and outer tube diameter. Aluminum spring-back was taken into account with material model adopted in the numerical algorithm. Once collected a complete information on the process parameters, some thermal images were acquired on roller in order to find a parameters set able to reduce the stresses acting on it as far as to obtain the maximum elongation with the minimum number of passes

Hallucinations in the Child and Adolescent "Ultra-High Risk" population: A Systematic Review

Abstract Background and Hypothesis "Ultra-high risk" for psychosis young adults are assumed to be at higher risk of developing a psychotic spectrum disorder. Predominantly, the ultrahigh-risk population is aged 18–35 years, but it may also include younger children and adolescents. Individuals in this population experience psychosis prodromes in the form of attenuated or brief psychotic symptoms (particularly perceptual abnormalities). Albeit diagnosis is made via structured interviews, such measures fail to sufficiently assess the precise form and content of perceptual abnormalities, especially as they manifest in children and adolescents. Study Design The present study involved a systematic review of the literature on perceptual abnormalities (particularly hallucinations) in ultrahigh-risk children and adolescents. Results The analysis reviewed five studies and drew conclusions about the perceptual abnormalities (ie, hallucinations) experienced by the study samples, focusing on form, content, and associations with other symptoms. Of note, 2 of the investigated studies suggested a relationship between hallucinations and experiences of childhood trauma. Conclusions The transition to psychosis and experiences of childhood trauma could correspond to different types of hallucinations in ultrahigh-risk children and adolescents. This knowledge could improve the identification of prodromal states in the young, ultrahigh-risk population

Surface Faulting Caused by the 2016 Central Italy Seismic Sequence: Field Mapping and LiDAR/UAV Imaging

The three mainshock events (M6.1 24 August, M5.9 26 October, and M6.5 30 October 2016) in the Central Italy earthquake sequence produced surface ruptures on known segments of the Mt. Vettore-Mt. Bove normal fault system. As a result, teams from Italian national research institutions and universities, working collaboratively with the U.S. Geothechnical Extreme Events Reconnaissance Association (GEER), were mobilized to collect perishable data. Our reconnaissance approach included field mapping and advanced imaging technique, both directed towards documenting the location and extent of surface rupture on the main fault exposure and secondary features. Mapping activity occurred after each mainshock (with different levels of detail at different times), which provides data on the progression of locations and amounts of slip between events. Along the full length of the Mt. Vettore-Mt. Bove fault system, vertical offsets ranged from 0-35 cm and 70-200 cm for the 24 August and 30 October events, respectively. Comparisons between observed surface rupture displacements and available empirical models show that the three events fit within expected ranges.Published1585-16104T. Sismicità dell'ItaliaJCR Journa

Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: a phase II randomised trial

Background: New strategies to prolong disease control warrant investigation in patients with metastatic pancreatic adenocarcinoma. This open-label, randomised, multi-centre phase II trial explored the role of maintenance sunitinib after first-line chemotherapy in this setting. Methods: Patients with pathologic diagnosis of metastatic pancreatic adenocarcinoma, performance status >50%, no progression after 6 months of chemotherapy were centrally randomised by an independent contract research organisation, which was also responsible for data collection and monitoring, to observation (arm A) or sunitinib at 37.5mg daily until progression or a maximum of 6 months (arm B). The primary outcome measure was the probability of being progression-free at 6 months (PFS-6) from randomisation. Assuming P0 = 10%; P1 = 30%, α .10; β .10, the target accrual was 26 patients per arm. Results: 28 per arm were randomised. One arm B patient had kidney cancer and was excluded. Sunitinib was given for a median of 91 days (7-186). Main grade 3-4 toxicity was thrombocytopenia, neutropenia and hand-foot syndrome (12%), diarrhoea 8%. In arm A versus B, PFS-6 was 3.6% (95% confidence interval (CI): 0-10.6%) and 22.2% (95% CI: 6.2-38.2%; P<0.01); 2 y overall survival was 7.1% (95% CI: 0-16.8%) and 22.9% (95% CI: 5.8-40.0%; P = 0.11), stable disease 21.4% and 51.9% (P = 0.02). Conclusion: This is the first randomised trial on maintenance therapy in metastatic pancreatic adenocarcinoma. The primary end-point was fulfilled and 2 y overall survival was remarkably high, suggesting that maintenance sunitinib is promising and should be further explored in this patient population

Clinical and molecular epidemiology of erythropoietic protoporphyria in Italy

Background: Erythropoietic protoporphyria (EPP) is a rare inherited disease associated with heme metabolism, characterized by severe life-long photosensitivity and liver involvement. Objectives: To provide epidemiological data of EPP in Italy. Materials and Methods: Prospective/retrospective data of EPP patients were collected by an Italian network of porphyria specialist centres (Gruppo Italiano Porfiria, GrIP) over a 20-year period (1996-2017). Results: In total, 179 patients (79 females) with a clinical and biochemical diagnosis of EPP were assessed, revealing a prevalence of 3.15 cases per million persons and an incidence of 0.13 cases per million persons/year. Incidence significantly increased after 2009 (due to the availability of alfa-melanotide, which effectively limits skin photosensitivity). Mean age at diagnosis was 28 years, with only 22 patients (12.2%) diagnosed 6410 years old. Gene mutations were assessed in 173 (96.6%) patients; most (164; 91.3%) were FECH mutations on one allele in association with the hypomorphic variant, c.315-48C, on the other (classic EPP), and nine (5.2%) were ALAS2 mutations (X-linked EPP). Only one case of autosomal recessive EPP was observed. Of the 42 different FECH mutations, 15 are novel, three mutations collectively accounted for 45.9% (75/164) of the mutations (c.215dupT [27.2%], c.901_902delTG [11.5%] and c.67\u2009+\u20095G\u2009>\u2009A [7.2%]), and frameshift mutations were prevalent (33.3%). A form of light protection was used by 109/179 (60.8%) patients, and 100 (56%) had at least one \u3b1-melanotide implant. Three cases of severe acute liver involvement, requiring OLT, were observed. Conclusions: These data define, for the first time, the clinical and molecular epidemiology of EPP in Italy

Authors' response: Mezei et al's "Comments on a recent case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis"

: Mezei et al's letter (1) is an opportunity to provide more details about our study on pericardial and tunica vaginalis testis (TVT) mesothelioma (2), which is based on the Italian national mesothelioma registry (ReNaM): a surveillance system on mesothelioma, with individual asbestos exposure assessment. Incidence of pericardial mesothelioma has been estimated around 0.5 and 0.2 cases per 10 million person-years in men and women, respectively, and around 1 case for TVT mesothelioma. ReNaM collected 138 cases thanks to its long period of observation (1993-2015) and national coverage. Conducting a population-based case-control study with incidence-density sampling of controls across Italy and over a 23 year time-span should have been planned in 1993 and would have been beyond feasibility and ReNaM scope. We rather exploited two existing series of controls (3). The resulting incomplete time- and spatial matching of cases and controls is a limitation of our study and has been acknowledged in our article. The analysis of case-control studies can nevertheless be accomplished in logistic models accounting for the variables of interest, in both individually and frequency matched studies (4). Furthermore, analyses restricted to (i) regions with enrolled controls, (ii) cases with definite diagnosis, (iii) incidence period 2000-2015, and (iv) subjects born before 1950 have been provided in the manuscript, confirming the strength of the association with asbestos exposure (supplemental material tables S4-7). Following Mezei et al's suggestion, we performed further sensitivity analyses by restriction to regions with controls and fitting conditional regression models using risk-sets made of combinations of age and year of birth categories (5-year classes for both). We confirmed positive associations with occupational exposure to asbestos of pericardial mesothelioma, with odds ratios (OR) (adjusted for region) of 9.16 among women [95% confidence interval (CI) 0.56-150] and 5.63 (95% CI 1.02-31.0) among men; for TVT mesothelioma the OR was 7.70 (95% CI 2.89-20.5). Using risk sets of age categories and introducing year of birth (5-year categories) as a covariate (dummy variables) the OR were similar: OR (adjusted for region) of 9.17 among women (95% CI 0.56-150) and 5.76 (95% CI 1.07-31.0) among men; for TVT the OR was 9.86 (95% CI 3.46-28.1). Possible bias from incomplete geographical overlap between cases and controls has been addressed in the paper (table S4) and above. In spatially restricted analyses, OR were larger than in those including cases from the whole country, indicating that bias was towards the null. Mezei et al further noted that "the regional distribution of controls is different from that of person-time observed". This objection is not relevant because the above analyses were adjusted by region. Our controls were provided by a population-based study on pleural mesothelioma (called MISEM) and a hospital-based study on cholangiocarcinoma (called CARA). In MISEM, the response rate was 48.4%, a low but not unexpected rate as participation among population controls is usually lower and has been declining over time (5). It is important to underline that ReNaM applied the same questionnaire that was used for interviews and carried out the same exposure assessment as both MISEM and CARA. As repeatedly stated in ReNaM papers (6-7), each regional operating center assesses asbestos exposure based on the individual questionnaire, other available information, and knowledge of local industries. Occupational exposure to asbestos is classified as definite, probable or possible. Occupational exposure is (i) definite when the subject`s work was reported or otherwise known to have involved the use of asbestos or asbestos-containing materials (MCA); (ii) probable when subjects worked in factories where asbestos or MCA were used, but their personal exposure could not be documented; and (iii) possible when they were employed in industrial activities known to entail the use of asbestos or MCA. Hence, the definite and probable categories are closer to one another and were combined in our analyses. In any case, restricting analyses to subjects with definite occupational exposure and using each set of controls separately, as suggested by Mezei et al, yielded elevated OR for TVT and pericardial mesothelioma among men using both the above described modelling strategies; the OR could not be calculated for women. There were 70 (25 pericardial and 45 TVT) occupationally exposed mesothelioma cases. In population-based studies, analyses by occupation are limited by the low prevalence of most specific jobs. As briefly reported in our paper, for purely descriptive purposes, the industrial activity of exposure (cases may have multiple exposures), were construction (22 exposures, 7 and 15 for pericardial and TVT mesotheliomas, respectively), steel mills and other metal working industries (4 and 11), textile industries (2 and 3), and agriculture (2 and 5); other sectors had lower exposure frequencies. The absence of industries like asbestos-cement production, shipbuilding and railway carriages production/repair should not be surprising and had already been observed (7). In the Italian multicenter cohort study of asbestos workers (8), given the person-years of observation accrued by workers employed in these industries and gender- and site-specific crude incidence rates, approximately 0.1 case of pericardial and 0.2 of TVT mesothelioma would have been expected from 1970 to 2010. Even increasing ten-fold such figures to account for higher occupational risks among these workers would not change much. Asbestos exposure in agriculture has been repeatedly discussed in ReNaM reports (9: pages 70, 73, 128, 164 and 205). Exposure opportunities included the presence of asbestos in wine production, reuse of hessian bags previously containing asbestos, or construction and maintenance of rural buildings. Similarly, mesothelioma cases and agricultural workers exposed to asbestos have been noted in France (10). In conclusion, the additional analyses we performed according to Mezei et al's suggestions confirm the association between asbestos exposure and pericardial and TVT mesothelioma, supporting the causal role of asbestos for all mesotheliomas. ReNaM`s continuing surveillance system with national coverage is a precious platform for launching analytical studies on pleural and extra pleural mesothelioma. References 1. Mezei G, Chang ET, Mowat FS, Moolgavkar SH. Comments on a recent case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis Scand J Work Environ Health. 2021;47(1):85-86. https://doi.org/10.5271/3909 2. Marinaccio A, Consonni D, Mensi C, Mirabelli D, Migliore E, Magnani C et al.; ReNaM Working Group. Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks. Scand J Work Environ Health. 2020;46(6):609-617. https://doi.org/10.5271/sjweh.3895. 3. Greenland S. Control-initiated case-control studies. Int J Epidemiol 1985 Mar;14(1):130-4. https://doi.org/10.1093/ije/14.1.130. 4. Pearce N. Analysis of matched case-control studies. BMJ 2016 Feb;352:i969. https://doi.org/10.1136/bmj.i969. 5. Bigert C, Gustavsson P, Straif K, Pesch B, Brüning T, Kendzia B et al. Lung cancer risk among cooks when accounting for tobacco smoking: a pooled analysis of case-control studies from Europe, Canada, New Zealand, and China. J Occup Environ Med 2015 Feb;57(2):202-9. https://doi.org/10.1097/JOM.0000000000000337. 6. Marinaccio A, Binazzi A, Marzio DD, Scarselli A, Verardo M, Mirabelli D et al.; ReNaM Working Group. Pleural malignant mesothelioma epidemic: incidence, modalities of asbestos exposure and occupations involved from the Italian National Register. Int J Cancer 2012 May;130(9):2146-54. https://doi.org/10.1002/ijc.26229. 7. Marinaccio A, Binazzi A, Di Marzio D, Scarselli A, Verardo M, Mirabelli D et al. Incidence of extrapleural malignant mesothelioma and asbestos exposure, from the Italian national register. Occup Environ Med 2010 Nov;67(11):760-5. https://doi.org/10.1136/oem.2009.051466. 8. Ferrante D, Chellini E, Merler E, Pavone V, Silvestri S, Miligi L et al.; the working group. Italian pool of asbestos workers cohorts: mortality trends of asbestos-related neoplasms after long time since first exposure. Occup Environ Med 2017 Dec;74(12):887-98. https://doi.org/10.1136/oemed-2016-104100. 9. ReNaM VI Report. Available from: https://www.inail.it/cs/internet/docs/alg-pubbl-registro-nazionale-mesoteliomi-6-rapporto.pdf. Italian 10. Marant Micallef C, Shield KD, Vignat J, Baldi I, Charbotel B, Fervers B et al. Cancers in France in 2015 attributable to occupational exposures. Int J Hyg Environ Health 2019 Jan;222(1):22-9. https://doi.org/10.1016/j.ijheh.2018.07.015

Malignant mesothelioma due to non-occupational asbestos exposure from the Italian national surveillance system (ReNaM): epidemiology and public health issues

Italy produced and imported a large amount of raw asbestos, up to the ban in 1992, with a peak in the period between 1976 and 1980 at about 160\u2005000 tons/year. The National Register of Mesotheliomas (ReNaM, "Registro Nazionale dei Mesoteliomi" in Italian), a surveillance system of mesothelioma incidence, has been active since 2002, operating through a regional structure

Epidemiological patterns of asbestos exposure and spatial clusters of incident cases of malignant mesothelioma from the Italian national registry.

BACKGROUND: Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM). METHODS: In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster. RESULTS: Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters. CONCLUSIONS: Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs