Nature and management of melanoma recurrences following adjuvant anti-PD-1 based therapy.

INTRODUCTION: Approximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking. METHODS: This was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected. RESULTS: 711 patients from 17 sites were included. Median age was 60 [range 16-92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0-68.5) and median follow up time from recurrence was 19.8 months (range 0.2-73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with "second adjuvant" anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %. CONCLUSION: Most recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment.

Domestic and Family Violence Screening and Response: A Prospective, Cross-Sectional, Mixed Methods Survey in Private Mental Health Clients.

Most domestic and family violence (DFV) research has focused on establishing prevalence and screening rates in public health and community samples. This study sought to address a gap in the literature by evaluating DFV screening and response practices in a private mental healthcare inpatient service and determining if clients of the service had unmet DFV needs. A prospective, convenience sample, mixed methods, cross-sectional survey of adult inpatient mental health consumers was employed. Sixty-two participants completed the Royal Melbourne Hospital Patient Family Violence Survey. Quantitative Likert-type and categorical responses were collated and analysed descriptively (count and percentage). Free-text responses were analysed using qualitative description within a content analysis framework. Sixty-five percent of participants had been screened for at least one DFV issue, on at least one occasion, with 35% not being screened, to their recall. Twenty-three percent reported disclosing DFV concerns, 82% felt very supported by the clinician's response to their disclosure, and 86% were provided with information they found helpful. Unmet needs were identified in 13% of participants, who had wanted to disclose DFV concerns but not feel comfortable to do so. No unscreened respondents disclosed DFV concerns, highlighting the need to uphold best practice guidelines for direct enquiry. Most disclosing clients were positive about the support they received. Indicated areas for improvement were screening rates, active follow-up, increasing psychology support levels and safety planning.

Metastatic Non-Myofibroblastic Sarcoma Harbouring EML4-ALK Fusion-Dramatic Response to ALK Tyrosine Kinase Inhibitors and Development of Resistance Mutations.

BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangements are rare in non-myofibroblastic sarcoma and there is limited data on the efficacy of ALK tyrosine kinase inhibitors (TKIs) and mechanisms of resistance in these patients. CASE: A 58 year-old man with metastatic non-myofibroblastic sarcoma was found to have an EML4-ALK fusion on molecular sequencing. After progression on first line systemic therapy with doxorubicin, the patient received alectinib, a second generation ALK inhibitor, and had a marked clinical and radiological response. He progressed after 5 months of treatment. Repeat lung biopsy identified the emergence of an ALK I1171N resistance mutation. He was then treated with lorlatinib, again with rapid clinical improvement and significant partial radiological response. He progressed after 4 months, at which time a repeat lung biopsy identified a new ALK kinase domain mutation G1202R. The patient was subsequently treated with chemotherapy, though unfortunately died shortly after due to rapidly progressive disease. CONCLUSION: This case report adds to a body of evidence demonstrating the potential transformative response to targeted therapy in non-lung solid organ tumours harbouring ALK fusions. This is the first description tracking the development of resistance mutations in a patient with non-myofibroblastic sarcoma and questions the utility of the presence of G1202R mutation as a marker of lorlatinib sensitivity in non-lung ALK rearranged tumours, contrary to experience in lung cancer.

Canine detection of chronic wasting disease (CWD) in laboratory and field settings.

Chronic wasting disease (CWD) is a fatal transmissible spongiform encephalopathy that affects both free-ranging and farmed cervid species, including mule deer, white-tailed deer, and elk (Odocoileus hemionus, Odocoileus virginianus, and Cervus canadensis). Due to the long incubation period and variability of clinical signs, CWD can expand and spread to new areas before they reach diagnostically detectable levels. Antemortem testing methods currently available can be difficult to obtain and to be applied to the large numbers required for adequate surveillance. However, key volatile biomarkers could be harnessed for non-invasive antemortem surveillance. Detection dogs are the most effective tool currently available for volatile detection; dogs can effectively complete wildlife surveys at rates surpassing that of humans. This study is the first to demonstrate that trained detection dogs can be used as an antemortem test for CWD. First, we trained three dogs to differentiate between CWD-positive and CWD-negative white-tailed deer faeces in a laboratory setting. Dogs spent significantly more time at the positive sample than the negative samples, suggesting that they differentiated between the positive and negative volatile signatures. We then trained the same dogs to search for CWD-positive faecal samples in a more naturalistic field setting. In the field, dogs found 8/11 CWD-positive samples and had an average false detection rate of 13%. These results suggest that dogs can be trained to differentiate CWD-positive faeces from CWD-negative faeces in both laboratory and field settings. Future studies will compare canine accuracy to other antemortem methods, as well as improved canine training methods.

The Potential of Honey as a Prebiotic Food to Re-engineer the Gut Microbiome Toward a Healthy State.

Honey has a long history of use for the treatment of digestive ailments. Certain honey types have well-established bioactive properties including antibacterial and anti-inflammatory activities. In addition, honey contains non-digestible carbohydrates in the form of oligosaccharides, and there is increasing evidence from in vitro, animal, and pilot human studies that some kinds of honey have prebiotic activity. Prebiotics are foods or compounds, such as non-digestible carbohydrates, that are used to promote specific, favorable changes in the composition and function of the gut microbiota. The gut microbiota plays a critical role in human health and well-being, with disturbances to the balance of these organisms linked to gut inflammation and the development and progression of numerous conditions, such as colon cancer, irritable bowel syndrome, obesity, and mental health issues. Consequently, there is increasing interest in manipulating the gut microbiota to a more favorable balance as a way of improving health by dietary means. Current research suggests that certain kinds of honey can reduce the presence of infection-causing bacteria in the gut including Salmonella, Escherichia coli, and Clostridiodes difficile, while simultaneously stimulating the growth of potentially beneficial species, such as Lactobacillus and Bifidobacteria. In this paper, we review the current and growing evidence that shows the prebiotic potential of honey to promote healthy gut function, regulate the microbial communities in the gut, and reduce infection and inflammation. We outline gaps in knowledge and explore the potential of honey as a viable option to promote or re-engineer a healthy gut microbiome.

Characterising the Gut Microbiomes in Wild and Captive Short-Beaked Echidnas Reveals Diet-Associated Changes.

The gut microbiome plays a vital role in health and wellbeing of animals, and an increasing number of studies are investigating microbiome changes in wild and managed populations to improve conservation and welfare. The short-beaked echidna (Tachyglossus aculeatus) is an iconic Australian species, the most widespread native mammal, and commonly held in zoos. Echidnas are cryptic animals, and much is still unknown about many aspects of their biology. Furthermore, some wild echidna populations are under threat, while echidnas held in captivity can have severe gastric health problems. Here, we used citizen science and zoos to collect echidna scats from across Australia to perform the largest gut microbiome study on any native Australian animal. Using 16S rRNA gene metabarcoding of scat samples, we characterised and compared the gut microbiomes of echidnas in wild (n = 159) and managed (n = 44) populations, which were fed four different diets. Wild echidna samples were highly variable, yet commonly dominated by soil and plant-fermenting bacteria, while echidnas in captivity were dominated by gut commensals and plant-fermenting bacteria, suggesting plant matter may play a significant role in echidna diet. This work demonstrates significant differences between zoo held and wild echidnas, as well as managed animals on different diets, revealing that diet is important in shaping the gut microbiomes in echidnas. This first analysis of echidna gut microbiome highlights extensive microbial diversity in wild echidnas and changes in microbiome composition in managed populations. This is a first step towards using microbiome analysis to better understand diet, gastrointestinal biology, and improve management in these iconic animals.

EchidnaCSI: Engaging the public in research and conservation of the short-beaked echidna.

The short-beaked echidna is an iconic Australian animal and the most-widespread native mammal, inhabiting diverse environments. The cryptic nature of echidnas has limited research into their ecology in most areas; however, from the well-researched and endangered Kangaroo Island echidna population, we understand that the threats include habitat loss, roads, and invasive species. To obtain more information about echidnas Australia-wide, we established the Echidna Conservation Science Initiative (EchidnaCSI) citizen science project. EchidnaCSI calls on members of the public to submit photographs of wild echidnas and learn to identify and collect echidna scats for molecular analysis. To facilitate participation, we developed a smartphone application as well as ongoing social and traditional media activities and community events. In 3 y, more than 9,000 members of the public have downloaded the EchidnaCSI app, collecting 400 scats and submitting over 8,000 sightings of echidnas from across Australia. A subset of submitted scat samples were subjected to DNA extraction and PCR, which validated the approach of using citizen science for scat collection and viability for molecular analysis. To assess the impact of the project through public participation, we surveyed our participants (n = 944) to understand their demographics and motivations for engagement. Survey results also revealed that EchidnaCSI served as a gateway into citizen science more generally for many participants. EchidnaCSI demonstrates the potential for using citizen science approaches to collect high-quality data and material from a cryptic species over a very large geographic area and the considerable engagement value of citizen science research.

Case Report: Paclitaxel-Induced Pneumonitis in Early Breast Cancer: A Single Institution Experience and Review.

Taxane-based chemotherapy regimens are in widespread use as standard of care treatment for patients with early breast cancer, though rarely its use can be complicated by taxane-induced pneumonitis (TIP). While breast cancer is the most diagnosed cancer in women worldwide, TIP remains under-described in this setting. Key questions relate to its incidence, diagnosis and management, potential predictive biomarkers, and the balance between this life-threatening toxicity and curatively intended treatment. At a single Australian institution, 6 cases of TIP are identified among 132 patients treated with a paclitaxel-containing regimen for early breast cancer (4.55%, 95% confidence interval 1.69-9.63%). This review first outlines the presentation, management, and outcomes for these cases, then answers these questions and proposes an approach to suspected TIP in patients with breast cancer.

Audit of immediate outcomes for MCDA twins following laser therapy for twin-twin transfusion syndrome at the NSW Fetal Therapy Centre.

OBJECTIVE: To audit immediate pregnancy and neonatal outcomes of selective laser photocoagulation of communicating vessels (SLPCV) for twin-twin transfusion syndrome (TTTS) at the New South Wales Fetal Therapy Centre. METHODS: Retrospective cohort study of 151 TTTS cases undergoing SLPCV between July 2003 and May 2013, evaluating procedural details, delivery and perinatal outcomes. RESULTS: The majority of cases were Stage III at SLPCV (56.9%), although proportion of Stage II SLPCV increased over time (P = 0.03). Survival to hospital discharge of at least one baby was 85.6% and dual survival was 52.5%. Median gestational age at delivery was 32.6 weeks (IQR 29.0-35.0 weeks) with a median of 11.4 weeks (IQR 8.3-14.7) from laser to delivery. Median birthweight was 1792 g (IQR 1288-2233 g), with 75% of babies admitted to the nursery, predominantly secondary to prematurity. Immediate SLPCV complications were in utero fetal demise <1 week postprocedure in 27 fetuses (19.6%) and/or ruptured membranes <1 week postprocedure in 9 fetuses (6.6%). CONCLUSIONS: This Australian series shows that local outcomes after SLPCV for stages II-IV TTTS remain equal to the international published literature and have remained stable after an initial learning curve. Women were more likely to be Stage II rather than III in the more recent years. However, this does not appear to be attributable to altered referral patterns.

Outcomes of stage I TTTS or liquor discordant twins: a single-centre review.

OBJECTIVES: To investigate rates of progression, regression and stabilisation and outcomes for stage I twin-twin transfusion syndrome (TTTS) and significant liquor discordant (LD) monochorionic diamniotic (MCDA) twins referred to the New South Wales Fetal Therapy Centre between June 2007 and May 2013. METHODS: Retrospective cohort study of 329 monochorionic referrals, of whom 47 had LD and 28 had stage I TTTS at presentation; 43 were stage I or higher at any time during surveillance. Clinical progression, rates of therapy, survival and associated complications were evaluated. RESULTS: Of stage I cases, 64% (18/28) remained stable or regressed, with 60% (6/10) of those progressing becoming at least stage II within 2 weeks. Of LD cases, 7/47 (15%) progressed to stage I TTTS, 8/47 (17%) to stage II or higher and 3/47 (6%) to selective intrauterine growth restriction (38% total). CONCLUSION: While a stable clinical picture was the most common outcome in stage I/LD presentations, progression to stage ≥ II TTTS occurred in 36 and 17% respectively, indicating that LD is not a benign finding. Rapid progression in the majority of progressive cases and modest overall survival rates support close surveillance of these pregnancies and investigation of laser therapy as a first-line treatment of stage I TTTS. © 2016 John Wiley & Sons, Ltd.

Uncommon complications of monochorionic twin pregnancies: Twin anaemia-polycythaemia sequence.

INTRODUCTION: Twin anaemia-polycythaemia sequence (TAPS) occurs when significant haemoglobin discordance exists between monochorionic fetuses. Most reported cases occur iatrogenically after twin-to-twin transfusion syndrome (TTTS) laser therapy; spontaneous TAPS is also reported. The purpose of this study was to investigate pregnancy management and immediate neonatal outcomes for monochorionic multiple pregnancies complicated by TAPS referred to the NSW Fetal Therapy Centre (FTC). METHODS: Retrospective cohort study of multiple pregnancies referred to NSW FTC between April 2006 and April 2014. Fourteen TAPS cases [discordant middle cerebral artery peak systolic volume (MCA-PSV) or clinician diagnosis antenatally, or Hb >20 g/dL vs. <12 g/dL post-natally] were compared to an existing TTTS database (n = 142) and uncomplicated monochorionic diamniotic (MCDA) twin pregnancies (n = 45). Outcomes measured were maternal demographics; ultrasound findings at referral; management, including whether in utero fetal therapy was performed; and pregnancy outcome, including gestation at birth, mode of birth, birthweight, fetal/neonatal complications and neonatal survival to discharge. RESULTS: The majority of TAPS cases were spontaneous (9/14) and occurred later in pregnancy than TTTS (median gestation at diagnosis 26.0 ± 4.9 vs. 20.4 ± 2.6 weeks, P < 0.001). However, TAPS perinatal outcome was similar to TTTS (survival of both twins 62% vs. 53%, survival of at least one twin 85% vs. 87%, overall survival 73% vs. 70%) and overall survival significantly lower than for uncomplicated MCDA pregnancies (73% vs. 98%, P < 0.001). CONCLUSION: Overall mortality for TAPS was similar to that of TTTS but significantly higher compared to uncomplicated MCDA pregnancies, underscoring the potential severity of TAPS despite its later gestational onset.