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.

Top Ten Tips Palliative Care Clinicians Should Know About Buprenorphine.

Pain management in palliative care (PC) is becoming more complex as patients survive longer with life-limiting illnesses and population-wide trends involving opioid misuse become more common in serious illness. Buprenorphine, a generally safe partial mu-opioid receptor agonist, has been shown to be effective for both pain management and opioid use disorder. It is critical that PC clinicians become comfortable with indications for its use, strategies for initiation while understanding risks and benefits. This article, written by a team of PC and addiction-trained specialists, including physicians, nurse practitioners, social workers, and a pharmacist, offers 10 tips to demystify buprenorphine use in serious illness.

Medical Metaphors: Increasing Clarity but at What Cost?

Background: Clinicians often use metaphors to explain complex ideas. Metaphors also have the potential to reinforce unhelpful thinking regarding symptoms. We surveyed musculoskeletal specialists regarding use of metaphors in their daily practice and then assessed the contexts in which they are used, the themes of metaphors, and potential for reinforcement of common misconceptions (unhelpful thinking). Two primary research questions were posed: 1- What are the common characteristics of the medical metaphors used in patient-clinician communication by musculoskeletal specialists? And, 2- What percentage of medical metaphors used in patient-clinician communication have potential to induce unhelpful thinking and what are the characteristics of those metaphors? Methods: Eighty-one orthopedic and trauma specialists provided examples of metaphors they use in daily practice. Qualitative analysis of responses was performed through open coding of the data with the use of a constant-comparative technique involving several rounds of reading and rereading the data. Results: The 157 metaphors were categorized into 15 different themes. The most common themes were mechanical, objects, and sports and leisure. We also classified metaphors as addressing the natural history of the disease, treatment, mechanism, anatomy, or other. Thirty-five metaphors (22%) were identified as having the potential to reinforce unhelpful thinking. The most common purpose of these metaphors was for explaining the mechanism or natural history of the disease. Conclusion: Metaphors can either reinforce or reorient potentially unhealthy misconceptions. They can also reinforce despair and worry, or they can improve hope and sense of control. Orthopedic surgeons can be strategic and thoughtful in their use of metaphors, planning and practicing specific metaphors for optimal mental, social, and physical health.

Locked plating of geriatric olecranon fractures leads to low fixation failure and acceptable complication rates.

HYPOTHESIS: The purpose of this study was to report the rate of major complications in patients with geriatric olecranon fractures managed operatively with a locking plate. Secondary objectives included minor complications, as well as pain and range of motion at the final follow-up. We hypothesized that these patients have a low rate of complications as well as low pain and satisfactory elbow range of motion at the final follow-up. MATERIALS AND METHODS: A retrospective review of isolated geriatric olecranon fractures presenting from 2006 to 2019 was performed at a single level I trauma center. Inclusion criteria were ≥75 years of age, operative management with a locking plate, and clinic follow-up at least until evidence of radiographic union or a major complication. Exclusion criteria included nonoperative management, insufficient follow-up, and absence of locking plate in surgical technique. Variables examined included demographic information, Charleston comorbidity index, American Society of Anesthesiologists score, living independence, gait assistance, mechanism of injury, open vs. closed fracture, Mayo radiographic classification, Arbeitsgemeinschaft für Osteosynthesefragen classification, time to surgery, implant type, presence of triceps offloading suture, length of postoperative immobilization, date of radiographic union, range of motion at the final follow-up, pain visual analog scale score at the final follow-up, major and minor complications, and return to the operative room. A major complication was defined as a return to the operative room for deep infection or loss of fixation (displacement of fracture >5 mm). A minor complication was defined as any other complication. RESULTS: A total of 65 patients ≥75 years of age with olecranon fractures were identified. Of these, 36 patients met inclusion criteria with an average follow-up of 23 weeks (range 5-207). The mean length of immobilization was 13 days (range 0-29 days). Thirty-two of 36 (88.8%) patients achieved radiographic evidence of union at an average of 8.9 weeks (range 5.3-24.1 weeks). There were 4 remaining patients who underwent secondary intervention before primary union representing an 11.1% major complication rate including 2 deep infections (5.6%) and 3 failures of fixation (8.3%). There were 7 minor complications in 5 of 36 (13.9%) patients. At the final follow-up, the average visual analog scale score was 2.6 (range 0-6), the average elbow arc of motion was 120° (range 70-147°), and mean pronation/supination was 85°/84° (range 45-90°/45-90°). CONCLUSION: Geriatric olecranon fractures are a challenging orthopedic problem with remaining controversy regarding ideal treatment. Despite advancement in geriatric fracture care, there is scant literature on the outcomes of locked plating technology in geriatric olecranon fractures. This study supports use of operative anatomic fixation with precontoured locked plates and early mobilization with an acceptable failure rate.

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.

The ecology and evolution of wildlife cancers: Applications for management and conservation.

Ecological and evolutionary concepts have been widely adopted to understand host-pathogen dynamics, and more recently, integrated into wildlife disease management. Cancer is a ubiquitous disease that affects most metazoan species; however, the role of oncogenic phenomena in eco-evolutionary processes and its implications for wildlife management and conservation remains undeveloped. Despite the pervasive nature of cancer across taxa, our ability to detect its occurrence, progression and prevalence in wildlife populations is constrained due to logistic and diagnostic limitations, which suggests that most cancers in the wild are unreported and understudied. Nevertheless, an increasing number of virus-associated and directly transmissible cancers in terrestrial and aquatic environments have been detected. Furthermore, anthropogenic activities and sudden environmental changes are increasingly associated with cancer incidence in wildlife. This highlights the need to upscale surveillance efforts, collection of critical data and developing novel approaches for studying the emergence and evolution of cancers in the wild. Here, we discuss the relevance of malignant cells as important agents of selection and offer a holistic framework to understand the interplay of ecological, epidemiological and evolutionary dynamics of cancer in wildlife. We use a directly transmissible cancer (devil facial tumour disease) as a model system to reveal the potential evolutionary dynamics and broader ecological effects of cancer epidemics in wildlife. We provide further examples of tumour-host interactions and trade-offs that may lead to changes in life histories, and epidemiological and population dynamics. Within this framework, we explore immunological strategies at the individual level as well as transgenerational adaptations at the population level. Then, we highlight the need to integrate multiple disciplines to undertake comparative cancer research at the human-domestic-wildlife interface and their environments. Finally, we suggest strategies for screening cancer incidence in wildlife and discuss how to integrate ecological and evolutionary concepts in the management of current and future cancer epizootics.

Geriatric Femoral Neck Fractures: Hemiarthroplasty Implant Trends Across a Health System From 2006 to 2018.

INTRODUCTION: Hemiarthroplasty is increasingly used for the treatment of geriatric femoral neck fractures in an effort to optimize value-based care. The current American Association of Orthopaedic Surgeons (AAOS) guidelines released in 2014 for the treatment of geriatric hip fractures recommend the utilization of monopolar cemented constructs. The purpose of this study was to evaluate hip hemiarthroplasty implant cost variability and implant selection trends from 2006 to 2018. MATERIALS AND METHODS: A retrospective review of 940 geriatric hip fractures treated with hemiarthroplasty was conducted across 3 institutions from 2006 to 2018. Variables examined were construct type, surgeon, operative time, patient mortality, and implant cost. Statistical analysis consisted of multigroup comparative tests and multiple linear regression analyses to evaluate correlative measures. RESULTS: The study population was 85.0 ± 7.9 years of age with a body mass index of 24.0 ± 5.5. A total of 33 (3.5%) patients were deceased at the 90-day postoperative mark and 45 (4.8%) patients at the 1-year mark. There was no statistical difference in terms of mortality between the 4 implant cohorts at the 90-day mark (P = .56) and 1-year mark (P = .24). The bipolar press-fit construct was the most expensive, US$3900.61 ± US$2607.54, and the monopolar cemented construct was the least expensive, US$2618.68 ± US$1834.16. The mean operative time was 6 minutes greater for press-fit implants, 93.6 ± 32.0, than cemented implants, 87.1 ± 33.6 (P = .02). The use of monopolar cemented implants increased from 12.1% to 83.3%, while bipolar press-fit decreased from 57.6% to 4.6% from 2013 to 2018. DISCUSSION: The use of a bipolar and/or press-fit implant significantly increases construct cost despite little evidence in the literature of improved outcomes. Contrary to previous research, cemented implants do not increase the operative time. CONCLUSIONS: Encouragingly, selection of the most cost-conscience implant, monopolar cemented, has been increasing since 2014, which may reflect the influence of current AAOS guidelines. LEVEL OF EVIDENCE: Diagnostic Level III.

Proactive Identification of Palliative Care Needs Among Patients With COVID-19 in the ICU.

In the setting of the coronavirus disease 2019 (COVID-19) pandemic, new strategies are needed to address the unique and significant palliative care (PC) needs of patients with COVID-19 and their families, particularly when health systems are stressed by patient surges. Many PC teams rely on referral-based consultation methods that can result in needs going unidentified and/or unmet. Here, we describe a novel system to proactively identify and meet the PC needs of all patients with COVID-19 being cared for in our hospital's intensive care units. Patients were screened through a combination of chart review and brief provider interview, and PC consultations were provided via telemedicine for those with unmet needs identified. In the first six weeks of operation, our pilot program of proactive screening and outreach resulted in PC consultation for 12 of the 29 (41%) adult patients admitted to the intensive care unit with COVID-19 at our institution. Consultations were most commonly for patient and family support as well as for goals of care and advance care planning, consistent with identified PC needs within this unique patient population.

COVID-19 Lessons: The Alignment of Palliative Medicine and Trauma-Informed Care.

As the COVID-19 pandemic wears on, its psychological, emotional, and existential toll continues to grow and indeed may now rival the physical suffering caused by the illness. Patients, caregivers, and health-care workers are particularly at risk for trauma responses and would be well served by trauma-informed care practices to minimize both immediate and long-term psychological distress. Given the significant overlap between the core tenets of trauma-informed care and accepted guidelines for the provision of quality palliative care (PC), PC teams are particularly well poised to both incorporate such practices into routine care and to argue for their integration across health systems. We outline this intersection to highlight the uniquely powerful role PC teams can play to reduce the long-term psychological impact of the COVID-19 pandemic.

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.

Molecular characterization of Cryptosporidium and Giardia from the Tasmanian devil (Sarcophilus harrisii).

The Tasmanian devil (Sarcophilus harrisii) is a carnivorous marsupial found only in the wild in Tasmania, Australia. Tasmanian devils are classified as endangered and are currently threatened by devil facial tumour disease, a lethal transmissible cancer that has decimated the wild population in Tasmania. To prevent extinction of Tasmanian devils, conservation management was implemented in 2003 under the Save the Tasmanian Devil Program. This study aimed to assess if conservation management was altering the interactions between Tasmanian devils and their parasites. Molecular tools were used to investigate the prevalence and diversity of two protozoan parasites, Cryptosporidium and Giardia, in Tasmanian devils. A comparison of parasite prevalence between wild and captive Tasmanian devils showed that both Cryptosporidium and Giardia were significantly more prevalent in wild devils (p < 0.05); Cryptosporidium was identified in 37.9% of wild devils but only 10.7% of captive devils, while Giardia was identified in 24.1% of wild devils but only 0.82% of captive devils. Molecular analysis identified the presence of novel genotypes of both Cryptosporidium and Giardia. The novel Cryptosporidium genotype was 98.1% similar at the 18S rDNA to Cryptosporidium varanii (syn. C. saurophilum) with additional samples identified as C. fayeri, C. muris, and C. galli. Two novel Giardia genotypes, TD genotype 1 and TD genotype 2, were similar to G. duodenalis from dogs (94.4%) and a Giardia assemblage A isolate from humans (86.9%). Giardia duodenalis BIV, a zoonotic genotype of Giardia, was also identified in a single captive Tasmanian devil. These findings suggest that conservation management may be altering host-parasite interactions in the Tasmanian devil, and the presence of G. duodenalis BIV in a captive devil points to possible human-devil parasite transmission.

Significant decline in anticancer immune capacity during puberty in the Tasmanian devil.

Tasmanian devils (Sarcophilus harrisii) are at risk of extinction in the wild due to Devil Facial Tumour Disease (DFTD), a rare contagious cancer. The prevalence of DFTD differs by age class: higher disease prevalence is seen in adults (2-3 years) versus younger devils (<2 years). Here we propose that immunological changes during puberty may play a role in susceptibility to DFTD. We show that the second year of life is a key developmental period for Tasmanian devils, during which they undergo puberty and pronounced changes in the immune system. Puberty coincides with a significant decrease in lymphocyte abundance resulting in a much higher neutrophil:lymphocyte ratio in adults than subadults. Quantitative PCR analysis of gene expression of transcription factors T-bet and GATA-3 and cytokines interferon gamma (IFN-γ) and interleukin 4 (IL-4) revealed a drastic increase in GATA-3 and IL-4 expression during puberty. These changes led to a significantly lower IFN-γ:IL-4 ratio in 2-year-olds than <1 year olds (on average 1.3-fold difference in males and 4.0-fold in females), which reflects a major shift of the immune system towards Th2 responses. These results all indicate that adult devils are expected to have a lower anticancer immune capacity than subadults, which may explain the observed pattern of disease prevalence of DFTD in the wild.

Hematologic and serum biochemical changes associated with Devil Facial Tumor Disease in Tasmanian Devils.

BACKGROUND: Devil Facial Tumor Disease (DFTD) is an infectious tumor causing significant population declines in wild Tasmanian Devils. While clinical assessment and pathology have been well reported for DFTD, there is a lack of information on hematologic and biochemical alterations associated with DFTD. OBJECTIVES: The purpose of the study was to determine hematologic and serum biochemical variation in healthy, wounded, and DFTD-affected Tasmanian Devils. METHODS: Blood samples were collected from wild Tasmanian Devils at 5 sites in Tasmania. Hematology and clinical biochemistry variables were compared between clinically healthy, wounded, and DFTD-affected devils. Differences were also analyzed among stages of DFTD, including individuals pre- and postclinical signs developing, and between ulcerated and nonulcerated DFTD tumors. RESULTS: Statistically significantly increased counts in WBC, neutrophils, and platelets, and concentration of fibrinogen, as well as decreased counts in lymphocytes, erythrocytes, and HGB concentration were observed in DFTD-affected devils compared to healthy devils. Activities of ALP, ALT, and GLDH, concentrations of sodium, potassium and albumin, and sodium-to-potassium ratio and albumin-to-globulin ratio were significantly lower, and AST activity was significantly higher in animals with DFTD when compared to clinically healthy animals. No significant differences were found among stages of DFTD or ulcerated and nonulcerated tumors. CONCLUSIONS: The differences in hematology and clinical chemistry variables in devils with DFTD compared to healthy devils are nonspecific and reflective of acute phase response and inflammation, and anemia of chronic disease. Similar changes are observed with wounds but to a lesser extent.

HEMATOLOGICAL AND SERUM BIOCHEMICAL VALUES IN ANESTHETIZED CAPTIVE TASMANIAN DEVILS (SARCOPHILUS HARRISII).

The Tasmanian devil (Sarcophilus harrisii) population has decreased by estimates of 80% in the past 20 yr due to the effects of devil facial tumor disease (DFTD). In the process of creating a DFTD-free insurance population, the captive population and the number of institutions housing devils worldwide has increased tremendously. In order to provide the best husbandry and veterinary care for these captive animals, it is essential to know normal hematology and biochemistry values for the species. Baseline reference intervals (RIs) were determined for hematology and biochemistry variables for 170 healthy anesthetized captive Tasmanian devils and significant sex and age differences were determined. Higher relative neutrophil counts, hemoglobin, mean corpuscular hemoglobin (MCH), creatinine, creatine phosphokinase, and cholesterol were seen in males compared to females, whereas higher white cell counts (WBC) and lymphocyte counts (absolute and relative) were seen in females. Subadults have higher red blood cell counts, WBC, lymphocytes (absolute and relative), calcium and phosphorus, alkaline phosphatase, glutamate dehydrogenase, glucose, and albumin than adults; whereas, adults have higher relative neutrophils, relative eosinophils, mean corpuscular volume, MCH, platelets, total solids, total plasma proteins, globulins, and chloride than subadults. This study provides a comprehensive report of hematology and serum biochemistry RIs for healthy captive anesthetized Tasmanian devils and offers invaluable diagnostic information to care for the growing captive population of this endangered marsupial.

Leptospirosis in Tasmanian Devils ( Sarcophilus harrisii ) in Tasmania, 2008-12.

In 2014, we performed a diagnostic study of leptospirosis in Tasmanian devil ( Sarcophilus harrisii ) samples collected between 2008 and 2012 from wild and captive animals. Tasmanian devil populations have been declining because of a facial tumor disease since the 1990s, with ongoing investigations examining potential causative agents. Identifying other causative pathogens that may contribute additively to their decline is important to preserve current and future populations. We tested 81 Tasmanian devil serum samples and two tissue samples using PCR, microscopic agglutination test (MAT), and microsphere immunoassay (MIA). We found evidence of leptospirosis in Tasmanian devil populations across a wide geographic range of Tasmania. Antibodies to serovars in the serogroup Javanica, which are not considered endemic to Australia, were identified in 10 Tasmanian devils using MAT. We also identified serovar Celledoni serologically using the immunoglobulin G MIA and detected Leptospira in one sample using PCR.

Immunoglubolin dynamics and cancer prevalence in Tasmanian devils (Sarcophilus harrisii).

Immunoglobulins such as IgG and IgM have been shown to induce anti-tumour cytotoxic activity. In the present study we therefore explore total serum IgG and IgM expression dynamics in 23 known-aged Tasmanian devils (Sarcophilus harrisii) of which 9 where affected by Devil Facial Tumour Disease (DFTD). DFTD is clonally transmissible cancer that has caused massive declines in devil numbers. Our analyses revealed that IgM and IgG expression levels as well as IgM/IgG ratios decreased with increasing devil age. Neither age, sex, IgM nor IgG expression levels affected devil DFTD status in our analyses. However, devils with increased IgM relative to IgG expression levels had significantly lower DFTD prevalence. Our results therefore suggest that IgM/IgG ratios may play an important role in determining devil susceptibility to DFTD. We consequently propose that our findings warrant further studies to elucidate the underpinning(s) of devil IgM/IgG ratios and DFTD status.

Doxorubicin and carboplatin trials in Tasmanian devils (Sarcophilus harrisii) with Tasmanian devil facial tumor disease.

The devil facial tumor disease (DFTD) is having a devastating impact on Tasmanian devils (Sarcophilus harrisii) (devils) in the wild. Only a single study has been published regarding treatment of DFTD, where vincristine was not found to be an effective chemotherapeutic agent. In the current study, devils were treated with escalating dosages of carboplatin (8-26 mg/kg) (n = 13) and doxorubicin (0.75-1.0 mg/kg) (n = 5). Dosages for carboplatin (20 mg/kg) and doxorubicin (1.0 mg/kg) were identified as maximally tolerated dosages. Limiting toxicities for carboplatin were anorexia and weight loss (gastrointestinal signs) and azotemia. Limiting toxicities for doxorubicin were neutropenia, anorexia and weight loss. None of the treated devils responded to either drug, suggesting that, based on the clonality of this tumour, it is unlikely that either drug individually or in combination would be effective treatments for DFTD. These results, however, provide valuable information for practitioners who may choose to treat other neoplastic diseases in the devil or other marsupials. In addition, these results show that even drugs that are metabolized and excreted in the same manner can be tolerated to different degrees by the same species.

Hematologic and serum biochemical reference intervals for wild Tasmanian devils (Sarcophilus harrisii).

BACKGROUND: The Tasmanian devil (Sarcophilus harrisii) is a carnivorous marsupial threatened with extinction by a fatally infectious cancer known as devil facial tumor disease (DFTD). Conservation efforts including captive breeding and island translocations are underway to address this threat. OBJECTIVES: The objectives of this study were to determine hematologic and serum biochemical reference intervals (RI) to aid in health assessment of Tasmanian devils, and to examine seasonal, sex, reproductive status and age variations. METHODS: We collected jugular blood samples from individual wild Tasmanian devils at 2 different locations over a 2-year period to determine hematologic and serum biochemical RI by nonparametric methods using the central 0.95 fraction. RESULTS: A total of 307 blood samples were collected from 187 devils. Significant age differences were found for ALP, CK, cholesterol, calcium, phosphate, albumin, globulins, albumin: globulin ratio, and glucose. Significant differences between sexes were observed for AST, creatinine, and potassium. Significant seasonal or reproductive status variation in adult males or breeding females were observed for PCV, HGB, RBC, MCHC, MCH, MCV, neutrophils and lymphocytes, fibrinogen, total plasma protein, AST, ALP, ALT, GLDH, bilirubin, urea, calcium, chloride, total protein, albumin, A:G, and glucose. CONCLUSIONS: Many of the differences observed between subgroups can be explained by growth requirements, reproductive demands, and seasonal effects on activity. This study has determined comprehensive RI for the Tasmanian devil, which will be used to assess animals targeted for captive breeding and translocations, or affected by DFTD.

Vincristine chemotherapy trials and pharmacokinetics in tasmanian devils with tasmanian devil facial tumor disease.

Tasmanian Devil Facial Tumor Disease (DFTD) is a transmissible cancer threatening to cause the extinction of Tasmanian Devils in the wild. The aim of this study was to determine the susceptibility of the DFTD to vincristine. Escalating dosage rates of vincristine (0.05 to 0.136 mg/kg) were given to Tasmanian devils in the early stages of DFTD (n = 8). None of these dosage rates impacted the outcome of the disease. A dosage rate of 0.105 mg/kg, a rate significantly higher than that given in humans or domestic animals, was found to the highest dosage rate that could be administered safely. Signs of toxicity included anorexia, vomiting, diarrhea and neutropenia. Pharmacokinetic studies showed that, as with other species, there was a rapid drop in blood concentration following a rapid intravenous infusion with a high volume of distribution (1.96 L/kg) and a relatively long elimination half life (11 h). Plasma clearance (1.8 ml/min/kg) was slower in the Tasmanian devil than in humans, suggesting that pharmacodynamics and not pharmacokinetics explain the Tasmanian devil's ability to tolerate high dosage rates of vincristine. While providing base-line data for the use of vincristine in Tasmanian devils and possibly other marsupials with vincristine susceptible cancers, these findings strongly suggest that vincristine will not be effective in the treatment of DFTD.

Evolution of a contagious cancer: epigenetic variation in Devil Facial Tumour Disease.

The emergence of Devil Facial Tumour Disease (DFTD), a highly contagious cancer, is driving Tasmanian devils (Sarcophilus harrisii) to extinction. The cancer is a genetically and chromosomally stable clonal cell line which is transmitted by biting during social interactions. In the present study, we explore the Devil Facial Tumour (DFT) epigenome and the genes involved in DNA methylation homeostasis. We show that tumour cells have similar levels of methylation to peripheral nerves, the tissue from which DFTD originated. We did not observe any strain or region-specific epimutations. However, we revealed a significant increase in hypomethylation in DFT samples over time (p < 0.0001). We propose that loss of methylation is not because of a maintenance deficiency, as an upregulation of DNA methyltransferase 1 gene was observed in tumours compared with nerves (p < 0.005). Instead, we believe that loss of methylation is owing to active demethylation, supported by the temporal increase in MBD2 and MBD4 (p < 0.001). The implications of these changes on disease phenotypes need to be explored. Our work shows that DFTD should not be treated as a static entity, but rather as an evolving parasite with epigenetic plasticity. Understanding the role of epimutations in the evolution of this parasitic cancer will provide unique insights into the role of epigenetic plasticity in cancer evolution and progression in traditional cancers that arise and die with their hosts.