Jodie Leditschke

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.

Reduction in choline acetyltransferase immunoreactivity but not muscarinic-M2 receptor immunoreactivity in the brainstem of SIDS infants

The cholinergic neurotransmitter system is vital for several brainstem functions including cardiorespiratory control and central chemosensitivity. This study has examined aspects of the cholinergic neurotransmitter system in the brainstem of sudden infant death syndrome (SIDS) and control infants. The cellular localisation and the optical density of the immunoreactivity of the cholinergic enzyme choline acetyltransferase (CHAT-IR) and the muscarinic acetylcholine receptor m2 (m2-IR) in the medulla was described in 14 SIDS and 9 control cases. There was a reduction in the number of CHAT-IR neurons in the hypoglossal nucleus (control: 71.2+/-8.3% vs SIDS: 46.1+/-5.3%) and the dorsal motor nucleus of the vagus (DMV) (control: 77.2+/-5.0% vs SIDS: 52.5+/-7.4%) and reduced optical density of CHAT-IR in the hypoglossal nucleus (control: 0.20+/-0.01 vs SIDS; 0.14+/-0.02) in SIDS infants. In contrast there were no changes in the optical density of m2-IR in the hypoglossal nucleus, the DMV, or the arcuate nucleus. Hypoplasia of the arcuate nucleus was observed in one SIDS infant. These results suggest that there is a specific defect in some cholinergic motor neurons in the medulla of SIDS infants. This could lead to abnormal control of cardiovascular and respiratory function and airway patency and may be one of the contributing factors in the etiology of SIDS.

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.

A community-based model of rapid autopsy in end-stage cancer patients

To the Editor: Systematic genomic studies, including the Cancer Genome Atlas (TCGA)1 and the International Cancer Genome Consortium (ICGC)2, have provided an unprecedented catalog of driver mutations in human cancer. However, these studies use mainly primary, pre-treatment tumor material obtained at surgery with curative intent. There is an urgent need to identify and characterize resistance mechanisms to understand how cancers can evade even the best medical efforts and kill patients; therefore, access to end-stage disease is important. Solid cancers show considerable spatial3, temporal4,5 and genomic heterogeneity at diagnosis. Selective pressure and mutagenic impact of treatment6 drives intra-patient evolution of cancer cell populations4,7. Understanding acquired resistance requires access to paired preand post-treatment samples4,7; however, curative surgery is typically confined to patients with locoregional disease, and opportunities for tumor sampling in advanced disseminated disease are limited. Here, we describe Cancer Tissue Collection After Death (CASCADE), an autopsy program that overcomes logistical challenges to enable collection of samples at end stage for research in melanoma and breast, ovarian and prostate cancers. For the CASCADE study, we aimed to recruit cancer patients close to the end of life, including those outside the minority of patients who die in hospitals. To preserve tissue integrity, autopsies must commence within a few hours of death, requiring access to around-the-clock services. Intervention in the emotionally charged end-of-life environment must be managed in an ethical manner and to a high standard. Finally, we aimed for the study to be highly cost-effective. We believe our approach to meeting these challenges is applicable to researchers in other large urban centers. Here we summarize the main steps in CASCADE’s operating protocol and our experiences from the initial 3 years and 30 autopsies performed (Fig. 1). Information about institutional review board approvals (including a detailed patient informationand-consent form), the autopsy procedure and certain laboratory processes is given in Supplementary Methods and Supplementary Figure 1. Recruitment of participants was led by the clinicians. Such discussions require careful consideration, in timing and in language, and were initiated only if there was a perception that tissue donation would be acceptable to the patients and their families. Factors suggesting acceptability include the emotional stability of the participant and family members and their clarity about and acceptance of the terminal nature of the disease. On occasion, participants prompted discussion by asking about organ or body donation. Consent discussions typically involved oncologists and/or palliative care physicians employed at recruiting hospitals who had established a care relationship with the participant and their family during the patient’s cancer journey. Frequently, the study was introduced at one meeting and discussed over several subsequent clinic visits, allowing patients and their families time to consider participation. We view the involvement of family members in the consent process as essential to support the participant and facilitate decisionmaking. Involvement of family members also ensures that they are fully aware of the autopsy process and helps to clarify funeral arrangements for the study team. After obtaining consent, study investigators collated clinical information, including that related to past and current treatment and diagnostic procedures such as imaging, on an ongoing basis. Between September 2012 and August 2015, 40 patients were approached, and 37 (92.5%) expressed interest in participating. Of those 32 patients (80%) consented; the other 5 had rapid clinical deterioration precluding

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.

Corrigendum: Whole–genome characterization of chemoresistant ovarian cancer

This corrects the article DOI: 10.1038/nature14410

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.

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.

Overview of the heat and fire crisis: organising the mortuary and other services: melbourne

The black Saturday bushfires struck Victoria on 7 th February 2009, claiming the lives of 173 people, injuring many others, and destroying countless homes and properties. When considering the mortuary response to the bushfires, it should be placed in the context of the late January heatwave, when 3–4 days of 40 degree temperatures resulted in some 150 additional deaths amongst susceptible groups. It was during the course of managing these extra deaths, that the bushfires struck. Victorian Institute of Forensic Medicine (VIFM) staff and volunteers from interstate and international forensic centres were involved in multiple aspects of the operation: • responding to deaths from the heatwave; • at the bushfire scenes; • in the performance of post-mortem and specialist examinations; • in the scientific laboratories; • in the collection and reconciliation of ante-mortem data; • in presentations to the Identification Board. The task was difficult, complex and stressful, although careful planning enabled the response to be calm and coordinated for much of the active post-mortem phase. Staff across the Institute took up additional roles to fill gaps and to support the internal leadership of those in the thick of the operation. This discussion will be centered around the management of the mortuary during this disaster response.