The evolution of two transmissible cancers in Tasmanian devils.

Tasmanian devils have spawned two transmissible cancer lineages, named devil facial tumor 1 (DFT1) and devil facial tumor 2 (DFT2). We investigated the genetic diversity and evolution of these clones by analyzing 78 DFT1 and 41 DFT2 genomes relative to a newly assembled, chromosome-level reference. Time-resolved phylogenetic trees reveal that DFT1 first emerged in 1986 (1982 to 1989) and DFT2 in 2011 (2009 to 2012). Subclone analysis documents transmission of heterogeneous cell populations. DFT2 has faster mutation rates than DFT1 across all variant classes, including substitutions, indels, rearrangements, transposable element insertions, and copy number alterations, and we identify a hypermutated DFT1 lineage with defective DNA mismatch repair. Several loci show plausible evidence of positive selection in DFT1 or DFT2, including loss of chromosome Y and inactivation of MGA, but none are common to both cancers. This study reveals the parallel long-term evolution of two transmissible cancers inhabiting a common niche in Tasmanian devils.

Overview of stab injuries in Far North Queensland: A new insight into the demographics, injury patterns and management.

BACKGROUND: Cairns Hospital is the northernmost tertiary referral hospital in Far North Queensland (FNQ) and manages trauma from a large catchment area. A large burden of stab injuries occurs in at-risk patient groups, such as Indigenous and mental health patients, in this region. This research aims to present an overview of the demographics, injury patterns, management and outcomes for stabbings injuries in FNQ. METHODS: A five-year retrospective single-centre study of all patients treated for neck, torso or junctional stab wounds in Far North Queensland was performed searching for all patients with a coded diagnosis of stabbing or knife injury from 1 March 2016 to 31 March 2021. RESULTS: 214 knife injuries were identified and 50.5% of those injured identified as Aboriginal and/or Torres Strait Islander. Stabbing injury locations were most commonly the abdomen/flank/pelvis (n = 81) and the chest/thorax (n = 77). Two-thirds of injuries that breached abdominal fascia had concurrent intra-abdominal injury. Hollow viscus injury commonly involved the small bowel (n = 8), colon (n = 5) and stomach (n = 2), whilst the liver was the most frequently injured solid organ (n = 6). There were 19 vascular injuries, excluding the extremities. 89.2% received diagnostic imaging in the emergency department. FAST scan had 76% sensitivity and 100% specificity for intra-abdominal injury at operation. Overall, 35% of patients required an operation. There were only two in-hospital deaths. CONCLUSION: Stab injuries annually in FNQ are comparable to other centres in Australia. Overall injury severity was low, with excellent survival rates and outcomes for patients who reached hospital. Operative intervention rates for abdominal stab wounds were low in FNQ compared to available data and imaging again appears protective against negative laparotomy rate.

Ventral hernia repair with a hybrid laparoscopic technique.

BACKGROUND: Ventral hernias are increasingly managed with minimally invasive laparoscopic surgery. Invasive open surgery is typically used for the repair of large-sized hernias (>10 cm diameter). The two methods are often considered mutually exclusive. We report a hybrid technique for repair of medium to large-sized hernias. METHODS: Data was collected prospectively from 44 hernias repaired using the hybrid technique from 2012 to 2020. Operative data was examined and follow-up conducted by both clinical and phone review. As for surgical technique, laparoscopic access was established via a 5 mm optical port and two (or more) 5 mm ports were added under vision. Hernia contents were reduced and extraperitoneal fat excised around the defect. Hernias with diameters ranging from 5 to 10 cm were fixed using the hybrid technique. A small incision was made directly over the hernia and polyester mesh was placed intraabdominally before defect closure with a transfascial suture. Pneumoperitoneum was re-established and mesh fixation achieved using absorbable tacks and/or fixation sutures. RESULTS: Of the 44 ventral hernias repaired with the hybrid technique, 43 were secondary hernias from incisional defects. Average hernia diameter was 6.6 cm. 86% of patients were discharged within the first 48 h. Four patients (9%) had recurrences during the study period. Minor complications occurred in 8 patients (18%): 3 (7%) had post-operative wound infection, 3 patients (7%) developed post-operative seroma. Two patients (5%) had clinically significant wound haematoma. CONCLUSION: Laparoscopic hybrid ventral hernia repair can be safely performed by a combination of laparoscopic and open techniques, offering an alternative method in the management of medium-sized ventral hernias.

The impact of acute surgical unit rostering on National Emergency Access Targets during the COVID-19 pandemic: a single hospital experience.

BACKGROUND: Surgical departments have been dramatically impacted by the novel coronavirus 19 (COVID-19) pandemic, with the cancellation of elective cases and changes to the provision of emergency surgical care. The aim of this study was to determine whether structural changes made within our facility's surgical department during COVID-19 altered National Emergency Access Target (NEAT) times and impacted on patient outcomes. METHODS: Emergency surgical cases over a 4-month time period were retrospectively collected and statistically analysed, divided into pre- and mid-COVID-19 pandemic. RESULTS: Baseline characteristics between the groups were comparable. There was a significant increase in consultant presence in theatre in the COVID group. There were also statistically significant reductions in NEAT times at each timepoint, although these did not meet national guidelines. There was no change in emergency surgical workload, complication rate or mortality rates within 30 days. CONCLUSION: Any significant change to services requires a coordinated hospital-wide approach, not just from a single department, and clinicians must continue to be wary of benchmarked times as the overall feasibility and safety of NEAT times has also been highlighted again.

Appendicitis in Far North Queensland: a new take on an old story.

BACKGROUND: Appendicitis is a leading cause of surgical hospital admission. To date, there have been no published epidemiological studies describing appendicitis in tropical and remote Australia and none specifically documenting appendicitis in Indigenous Australians. This descriptive study used available state data to investigate appendicitis across Far North Queensland (FNQ). METHODS: Queensland Health hospital admission data for FNQ was analysed to explore appendicitis epidemiology and outcomes in FNQ, 2012-2018. Population data for the same time period provided rates. RESULTS: Over the study period, 3458 hospital presentations for appendicitis were available for analysis. Mean incidence was 178 per 100 000/yr. Median age was 27 years with 50.1% female patients. The annual rate of appendicitis was higher in the Indigenous population. Most patients had a laparoscopic procedure with a low rate of conversion to open surgery (2.6%). More than 80% of patients were discharged from hospital in less than 3 days. Intensive care (ICU) admission rate was low overall (1.1%) although higher for Indigenous people (2.4%). Following discharge, the hospital re-admission rate was 3.8% and all-cause mortality was 0.03%. CONCLUSION: The incidence of appendicitis in FNQ is higher than that reported in the rest of Australia in both Indigenous and non-Indigenous populations. Despite logistical challenges of health care, clinical outcomes are in line with best practice across the country. Clinicians in FNQ should maintain a high index of suspicion for diagnosing appendicitis in rural and remote settings.

Expectant management of traumatic intussusception.

Mesenteric injuries and traumatic intussusception are rare surgical presentations following blunt trauma, with potentially life-threatening complications. Diagnosis relies on high clinical suspicion and judicious use of imaging in trauma. Literature suggests that these presentations should always be managed operatively for diagnostic clarity, manual reduction of intussusception and, if indicated, resection of involvement segment. However, in the setting of a stable patient with a reassuring examination, this may not be necessary. This case presents the successful expectant management of a traumatic mesenteric haematoma acting as a pathologic lead point for small bowel intussusception.

Caravan explosions: a case series of burns patients at the Royal Brisbane and Women's Hospital.

BACKGROUND: Caravan explosions due to gas cylinder explosions or gas leaks are responsible for a small but significantly injured group of burns patients. Those involved in explosions are sometimes assumed to be at risk of primary blast wave injury; however, the likelihood of such injuries is unclear. The aim of this research was to seek evidence of primary blast injury in groups defined by clinicians as having sustained burns in explosive and non-explosive events. METHODS: This is a single-centre case series of patients with caravan-related burns from 2009 to 2019, identified using the burns data registry at the Royal Brisbane and Women's Hospital. Patients were divided into two groups based on the mechanism of injury, with injuries sustained from either a gas bottle explosion (group 1) or from gas ignition (group 2). RESULTS: Twenty-one patients were identified over the 10-year period. The explosion group suffered more extensive burns, with a median % total body surface area of 31% (23.5-43.5) and 9.5% (5-20) in group 1 and group 2, respectively (P = 0.01). There was a numerically longer median hospital and intensive care unit length of stay in group 1. In multivariable analysis, there were no statistically significant predictors of intensive care unit or hospital length of stay. None of the patients appeared to have suffered any of the expected effects of primary blast wave injury. CONCLUSION: Gas bottle explosions in caravans uncommonly, if ever, result in a blast wave of sufficient energy to cause primary blast injury.

Evolution and lineage dynamics of a transmissible cancer in Tasmanian devils.

Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 coinfection are high. DFT1 gradually accumulates copy number variants (CNVs), and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability, and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.

Tasman-PCR: a genetic diagnostic assay for Tasmanian devil facial tumour diseases.

Tasmanian devils have spawned two transmissible cancer clones, known as devil facial tumour 1 (DFT1) and devil facial tumour 2 (DFT2). DFT1 and DFT2 are transmitted between animals by the transfer of allogeneic contagious cancer cells by biting, and both cause facial tumours. DFT1 and DFT2 tumours are grossly indistinguishable, but can be differentiated using histopathology, cytogenetics or genotyping of polymorphic markers. However, standard diagnostic methods require specialist skills and equipment and entail long processing times. Here, we describe Tasman-PCR: a simple polymerase chain reaction (PCR)-based diagnostic assay that identifies and distinguishes DFT1 and DFT2 by amplification of DNA spanning tumour-specific interchromosomal translocations. We demonstrate the high sensitivity and specificity of this assay by testing DNA from 546 tumours and 804 normal devils. A temporal-spatial screen confirmed the reported geographic ranges of DFT1 and DFT2 and did not provide evidence of additional DFT clones. DFT2 affects disproportionately more males than females, and devils can be co-infected with DFT1 and DFT2. Overall, we present a PCR-based assay that delivers rapid, accurate and high-throughput diagnosis of DFT1 and DFT2. This tool provides an additional resource for devil disease management and may assist with ongoing conservation efforts.

Demonstration of immune responses against devil facial tumour disease in wild Tasmanian devils.

Devil facial tumour disease (DFTD) is a recently emerged fatal transmissible cancer decimating the wild population of Tasmanian devils (Sarcophilus harrisii). Biting transmits the cancer cells and the tumour develops in the new host as an allograft. The literature reports that immune escape mechanisms employed by DFTD inevitably result in host death. Here we present the first evidence that DFTD regression can occur and that wild devils can mount an immune response against the disease. Of the 52 devils tested, six had serum antibodies against DFTD cells and, in one case, prominent T lymphocyte infiltration in its tumour. Notably, four of the six devils with serum antibody had histories of DFTD regression. The novel demonstration of an immune response against DFTD in wild Tasmanian devils suggests that a proportion of wild devils can produce a protective immune response against naturally acquired DFTD. This has implications for tumour-host coevolution and vaccine development.

A second transmissible cancer in Tasmanian devils.

Clonally transmissible cancers are somatic cell lineages that are spread between individuals via the transfer of living cancer cells. There are only three known naturally occurring transmissible cancers, and these affect dogs, soft-shell clams, and Tasmanian devils, respectively. The Tasmanian devil transmissible facial cancer was first observed in 1996, and is threatening its host species with extinction. Until now, this disease has been consistently associated with a single aneuploid cancer cell lineage that we refer to as DFT1. Here we describe a second transmissible cancer, DFT2, in five devils located in southern Tasmania in 2014 and 2015. DFT2 causes facial tumors that are grossly indistinguishable but histologically distinct from those caused by DFT1. DFT2 bears no detectable cytogenetic similarity to DFT1 and carries a Y chromosome, which contrasts with the female origin of DFT1. DFT2 shows different alleles to both its hosts and DFT1 at microsatellite, structural variant, and major histocompatibility complex (MHC) loci, confirming that it is a second cancer that can be transmitted between devils as an allogeneic, MHC-discordant graft. These findings indicate that Tasmanian devils have spawned at least two distinct transmissible cancer lineages and suggest that transmissible cancers may arise more frequently in nature than previously considered. The discovery of DFT2 presents important challenges for the conservation of Tasmanian devils and raises the possibility that this species is particularly prone to the emergence of transmissible cancers. More generally, our findings highlight the potential for cancer cells to depart from their hosts and become dangerous transmissible pathogens.

Transmissible cancer in Tasmanian devils: localized lineage replacement and host population response.

Tasmanian devil facial tumour disease (DFTD) is a clonally transmissible cancer threatening the Tasmanian devil (Sarcophilus harrisii) with extinction. Live cancer cells are the infectious agent, transmitted to new hosts when individuals bite each other. Over the 18 years since DFTD was first observed, distinct genetic and karyotypic sublineages have evolved. In this longitudinal study, we investigate the associations between tumour karyotype, epidemic patterns and host demographic response to the disease. Reduced host population effects and low DFTD infection rates were associated with high prevalence of tetraploid tumours. Subsequent replacement by a diploid variant of DFTD coincided with a rapid increase in disease prevalence, population decline and reduced mean age of the population. Our results suggest a role for tumour genetics in DFTD transmission dynamics and epidemic outcome. Future research, for this and other highly pathogenic emerging infectious diseases, should focus on understanding the evolution of host and pathogen genotypes, their effects on susceptibility and tolerance to infection, and their implications for designing novel genetic management strategies. This study provides evidence for a rapid localized lineage replacement occurring within a transmissible cancer epidemic and highlights the possibility that distinct DFTD genetic lineages may harbour traits that influence pathogen fitness.

Anthropogenic selection enhances cancer evolution in Tasmanian devil tumours.

The Tasmanian Devil Facial Tumour Disease (DFTD) provides a unique opportunity to elucidate the long-term effects of natural and anthropogenic selection on cancer evolution. Since first observed in 1996, this transmissible cancer has caused local population declines by >90%. So far, four chromosomal DFTD variants (strains) have been described and karyotypic analyses of 253 tumours showed higher levels of tetraploidy in the oldest strain. We propose that increased ploidy in the oldest strain may have evolved in response to effects of genomic decay observed in asexually reproducing organisms. In this study, we focus on the evolutionary response of DFTD to a disease suppression trial. Tumours collected from devils subjected to the removal programme showed accelerated temporal evolution of tetraploidy compared with tumours from other populations where no increase in tetraploid tumours were observed. As ploidy significantly reduces tumour growth rate, we suggest that the disease suppression trial resulted in selection favouring slower growing tumours mediated by an increased level of tetraploidy. Our study reveals that DFTD has the capacity to rapidly respond to novel selective regimes and that disease eradication may result in novel tumour adaptations, which may further imperil the long-term survival of the world's largest carnivorous marsupial.

Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer.

Contagious cancers that pass between individuals as an infectious cell line are highly unusual pathogens. Devil facial tumor disease (DFTD) is one such contagious cancer that emerged 16 y ago and is driving the Tasmanian devil to extinction. As both a pathogen and an allograft, DFTD cells should be rejected by the host-immune response, yet DFTD causes 100% mortality among infected devils with no apparent rejection of tumor cells. Why DFTD cells are not rejected has been a question of considerable confusion. Here, we show that DFTD cells do not express cell surface MHC molecules in vitro or in vivo, due to down-regulation of genes essential to the antigen-processing pathway, such as ß2-microglobulin and transporters associated with antigen processing. Loss of gene expression is not due to structural mutations, but to regulatory changes including epigenetic deacetylation of histones. Consequently, MHC class I molecules can be restored to the surface of DFTD cells in vitro by using recombinant devil IFN-γ, which is associated with up-regulation of the MHC class II transactivator, a key transcription factor with deacetylase activity. Further, expression of MHC class I molecules by DFTD cells can occur in vivo during lymphocyte infiltration. These results explain why T cells do not target DFTD cells. We propose that MHC-positive or epigenetically modified DFTD cells may provide a vaccine to DFTD. In addition, we suggest that down-regulation of MHC molecules using regulatory mechanisms allows evolvability of transmissible cancers and could affect the evolutionary trajectory of DFTD.

Evolution in a transmissible cancer: a study of the chromosomal changes in devil facial tumor (DFT) as it spreads through the wild Tasmanian devil population.

Tasmanian devils (Sarcophilus harrisii) are the largest extant marsupial carnivores. This species, now confined to Tasmania, is endangered from the emergence of a transmissible cancer, devil facial tumor disease (DFTD). In the present study, we use cytogenetic and molecular techniques to examine the stability of devil facial tumor (DFT) cell lines across time and space. This article describes disease progression from February 2004 to June 2011. We demonstrate evolutionary changes in the disease, which affects devils in different sites across Tasmania and over a period of several years, producing several chromosomal variants (strains) that are capable of transmission between devils. We describe the evolution of DFTs in the field and speculate on the possible impacts on the disease, including (1) development of less aggressive forms of the disease; (2) development of more aggressive forms of the disease; (3) development of forms capable of affecting closely related species of dasyurids (e.g., quolls); (4) extinction of the disease as it acquires additional deleterious mutations that affect either cell viability or transmissibility; and (5) co-evolution of the disease and the host. We also speculate about the future of the Tasmanian devil in the wild. We note that although DFTs are regarded as unstable by comparison with another much older transmissible cancer, canine transmissible venereal tumor (CTVT), the potential for development of less aggressive forms of DFTs or for development of resistance in devils is limited by devils' small numbers, low genetic diversity, and restricted geographical distribution.