BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

AIM: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. METHODS AND RESULTS: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1-3) compared with non-carriers (median n = 9, range = 1-7) (P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3-8) than non-carriers (median n = 5, range = 3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. CONCLUSION: Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.

Whole-genome characterization of chemoresistant ovarian cancer.

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Mortuary operations following mass fatality natural disasters: a review.

This is a critical review to discuss the best practice approaches to mortuary operations in preparation for and the response to natural, mass fatality, disaster events, as identified by a review of published articles. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) Statement guided the identification of potential articles to use in this critical review. Subsequent searches were also conducted to identify articles relating to heat wave, and flood mortality. All identified peer-reviewed studies published in English which discussed the preparation and response of mortuaries to mass fatality natural disasters occurring in developed countries were included. Using the PRISMA-P method of identifying articles, 18 articles were selected for inclusion in this review. Although there are numerous articles which describe the mortuary response to mass fatality incidents, few articles analyzed the response, or discussed the roles which supported and enabled the organization to undertake the task of identifying disaster victims. It is thus difficult to determine objectively if the actions and activities outlined in the articles represent best-practice.

The development of a protocol for post-mortem management of Ebola virus disease in the setting of developed countries.

The management of the recent Ebola virus disease (EVD) epidemic continues to pose currently insuperable challenges to health care providers in the resource-deprived countries of West Africa. In an age where air travel facilitates rapid movement of people between countries and continents, there is an urgent requirement for health systems around the globe to develop management strategies and protocols in the event that EVD cases are suspected or confirmed. Departments of forensic pathology play an important, and underestimated, role in public health service delivery, particularly at times of novel infectious disease emergence. This role can include disease identification, characterization, and notification, as well as close engagement with agencies responsible for disease surveillance and treatment provision. A mass outbreak of EVD in the Western world is considered highly unlikely; however, there is clear responsibility on departments of forensic pathology to develop protocols for rapid assessment of sporadic or suspected cases while ensuring the health and safety of mortuary and pathology personnel. The Ontario Forensic Pathology Service and the Victorian Institute of Forensic Medicine have collaborated on the development of a protocol for management of EVD cases presenting at a scene or in the mortuary. It is hoped that this trans-national, inter-departmental exercise will serve as a model for future co-operative endeavors. The protocol has been distributed to forensic pathology departments around Australia and may be modified to accommodate local resource capabilities.

Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling.

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.

Post mortem sampling of the bladder for the identification of victims of fire related deaths.

In a coronial setting a deceased person must be formally identified. It is difficult to identify a deceased person when their physical features are disrupted and identification by visual means cannot occur. In the absence of visual identification, the confirmation of identity of a deceased person relies on the scientific comparison of information obtained post mortem with ante mortem information. The ante mortem information may include dental and medical records, fingerprints, and DNA profiling. For cases involving incinerated remains, this traditionally requires the collection of blood, muscle or bone samples from the deceased (depending on the severity of the burns) for DNA analysis and subsequent comparison to a reference sample for kinship determination. Following on from work conducted during the DVI response to a plane crash in Papua New Guinea in 2011, a study has been performed examining the viability of utilising material obtained from bladder swabs in deaths associated with fires. Twenty-eight cases were analysed during 2012 with deaths occurring in motor vehicle and aviation accidents, as well as house fires, homicides and from self-immolation. Bladder and conventional (blood, muscle or bone) samples were subjected to DNA analysis and compared. Our findings demonstrate that the bladder samples all gave DNA of sufficient quality for DNA profiling. This easily obtained sample (when available) can be now recommended in the scientific identification process of fire affected deceased persons.

Forensic medical lessons learned from the Victorian Bushfire Disaster: recommendations from the Phase 5 debrief.

The February 7th 2009 bushfires in Victoria, Australia, resulted in the deaths of 173 individuals, of whom 164 were included in the subsequent DVI operation. The final stage of the International DVI protocol is a debrief, referred to as Phase 5. The Phase 5 operational debrief process conducted in the wake of this disaster was designed for the purpose of developing new strategies in light of this experience. The agencies involved included the Coroners Court of Victoria, the Victorian Institute of Forensic Medicine, the Department of Justice, and Victoria Police. During the course of this debriefing process strategies and protocols were developed which aim to improve the capacity of all agencies to respond and resolve future incidents. This paper outlines the Phase 5 debrief carried out in the 6 months following the final coronial identification board, and details the findings and recommendations made by the agencies involved.

Mortuary operations in the aftermath of the 2009 Victorian bushfires.

On the day of the 2009 Victorian bushfires the Victorian Institute of Forensic Medicine activated its emergency plan. Within 48 h a temporary body storage facility was constructed adjacent to the existing mortuary. This temporary facility had the capacity to store up to 300 deceased persons. Pathologists, anthropologists, odontologists, police and mortuary assistants responded from all around Australia, New Zealand and Indonesia. The existing forensic mortuary and staff were divided into two areas: DVI (disaster victim identification) and "routine operations". A high priority for the mortuary was to ensure the casework of the "routine" deceased persons (those cases which were not related to the bushfires) was handled concurrently and in a timely manner. On admission each set of victim remains was given both a Coroner's case number in addition to the DVI number allocated at the scene. The case was CT scanned, examined by a pathologist, an anthropologist, and odontologist and in some instances a fingerprint expert. Where possible a DNA sample was taken. All processes, samples, labels and paperwork underwent a quality assurance check prior to the case completion. Regular audits were conducted. All of post mortem examinations were completed within 20 days of admission. Occupational health and safety issues of the staff were a high priority; this included correct manual handling, infection control and psychological debriefings. During the operation it was found that some remains were contaminated with asbestos. Procedures were set in place to manage these cases individually and each was isolated to reduce the risk of exposure by staff to asbestos. This overall mortuary operation identified a number of significant challenges, in particular the management of multiple parts of human remains for one individual. A new procedure was developed to ensure that all human remains, where possible, were reconciled with identified deceased persons prior to the release to the funeral director. It also highlighted the need to have well documented plans in place including plans for temporary mortuary facilities.