Associations between environmental exposures in the Middle East Area of Operations and pregnancy outcomes in Australian Defence Force veterans.

Military personnel deployed on operations may encounter a variety of hazards with the capacity to adversely affect reproductive health. This paper investigates the association between self-reported exposure to reproductive toxicants and adverse pregnancy outcomes in Australian Defence Force veterans who deployed to Iraq and Afghanistan during the period 2001-2009. Utilising the Middle East Area of Operations (MEAO) Census Study data set, descriptive analyses of participants' self-reported exposure were compared with the occupational environmental monitoring data taken at their reported deployment location. Univariate analyses assessed the significance of unadjusted associations between self-reported exposures and reproductive outcomes. There is no systematic or consistent relationship between deployment to the MEAO and adverse pregnancy outcomes. Overall, self-reported adverse reproductive outcomes were significantly increased in veterans who deployed to both Afghanistan and Iraq (p = 0.04) compared to those who only deployed to only one of those locations; particularly in women (p = 0.009). Miscarriage was the most likely of these (p = 0.008). These figures would benefit from being confirmed against medical records but are worthy of further study. In this historical cohort study, causal inference cannot be made due to absence of control groups to exclude sources of potential bias. Imprecision in the assessment of environmental hazards in the MEAO and other methodological constraints make it impossible to calculate precise estimates of risk. The results warrant continued investigation, especially when combined with previous findings related to pregnancy outcomes in this population, the importance of reproductive outcomes, and the potential emergence of new hazards.

A population-based study of soft tissue sarcoma incidence and survival in Australia: An analysis of 26,970 cases.

BACKGROUND: Soft tissue sarcomas (STS) are rare, often fatal tumors, but little is known of the epidemiology and survival in the Australian population. This study aims to provide the first epidemiological analysis of incidence and survival rates of STS in the Australian population. METHODS: A retrospective population-based observational study was conducted between 1982 and 2009 of all patients with a diagnosis of STS using the Australian Institute of Health and Welfare (AIHW) Australian Cancer Database. Incidence rates per 100,000; incidence rate ratios, age-standardized incidence rates, prevalence and incidence rates of subtypes of STS, median, one-year and 5-year survival rates were examined. RESULTS: A total of 26,970 patients were identified. Between 1982 and 2009 STS incidence rates significantly increased from 3.99 [95% CI 3.68-4.32] to 6.12 [95% CI 5.80-6.46] per 100,000 Australian population, with a peak incident rate ratio (IRR) of 1.59 [95% CI 1.51-1.69] (p < 0.0001) in 2001. Median age at diagnosis increased from 58 to 63 years. Incidence rates were stable across all 10-year age cohorts, except for people aged over 70 where it increased. Overall, age-standardized incidence rates increased from 4.70 [95% CI 4.42-5.00] in 1982 to 5.87 [95% CI 5.63-6.11] per 100 000 Australians in 2009. Leiomyosarcoma (20.43%), malignant fibrous histiocytoma (16.14%), and soft tissue tumors/sarcomas, not otherwise specified (10.18%) were the most common STS subtypes. Median survival from diagnosis increased from 5.80 years [95% CI 5.06-6.54] in 1985-1989 cohort to 8.18 years [95% CI 7.54-8.81] in the 2000-2004 cohort (log-rank test p < 0.0001). CONCLUSION: The incidence of STS is increasing in Australia, most noticeably in those aged over 70 years, with a small but statistically significant increase in overall survival rates.

The ties that bind: what's in a title?

BACKGROUND: Many Australian and New Zealand surgeons use the title 'Mister' rather than 'Doctor', a practice dating back to traditions established over 600 years ago. The Royal Australasian College of Surgeons is currently undergoing a period of critical self-reflection, embodied by its 'Respect' campaign. Active measures to embrace diversity and encourage women into surgery are underway. METHODS: This paper reviews the historical basis to the use of gendered titles and their current use amongst fellows. De-identified demographic data from the college register of active fellows was searched by self-identified title, country or state, and gender. Data were further reviewed by surgical sub-specialty and year of fellowship. RESULTS: The college dataset suggests that there is significant variance in the preference for gendered titles, determined predominantly by geography rather than specialty. The highest use of gendered titles (by male and female surgeons) was in Victoria/Tasmania (58% male, 22% female) and New Zealand (81% male, 17% female). By contrast, only 2% of female surgeons in other states elected a gendered title (Miss/Mrs/Ms). CONCLUSION: Surgery is the only profession that continues to use gendered titles. As the College of Surgeons moves towards greater equity and diversity, consideration should be given to phasing out the use of gendered titles, which serve to divide rather than unite our profession.

Intravenous lobular capillary haemangioma (pyogenic granuloma): A case report and a review of imaging findings as reported in the literature.

INTRODUCTION: Intravenous lobular capillary haemangioma (IVLCH) is a rare benign lesion with minimal published reports containing a description of its appearance at medical imaging. We present the ultrasound and MRI images of a histologically proven IVLCH and provide the first review of the imaging findings reported in the literature. METHODS: The imaging findings of a case of IVLCH are presented. A PubMed search of English language articles was performed from 1966 to October 2016, and all relevant papers were reviewed. Imaging findings from those papers are summarised. RESULTS: Key features on ultrasound are of a well-defined, usually hypoechoic, mass which is highly vascular. The host vein is usually apparent. MRI imaging usually shows T1 signal isointense to muscle and variable T2 signal, either isointense or of high signal relative to the vein. The lesions enhance with gadolinium. CONCLUSION: Intravenous lobular capillary haemangioma has distinctive ultrasound but less consistent MRI features although radiological diagnosis should usually be possible. Review of reported cases shows that a previously described gender bias is incorrect.

Patterns of head and neck sarcoma in Australia.

BACKGROUND: Sarcomas affecting the head and neck often require complex management due to the combination of anatomic, aesthetic and oncological considerations. The incidence and patterns of presentation are poorly understood and have not been reviewed in the Australian population. METHOD: This study sourced incidence and demographic data from the National Cancer Registry at the Australian Institute of Health and Welfare for the years 1982-2009 (corresponding to 97.3% of the Australian population). All cases of sarcoma, according to ICD-O-3 classification ((International Classification of Diseases for Oncology, 3rd edition), were assessed. RESULTS: A total of 3911 new cases of sarcoma affecting the head and neck were recorded during the period 1982-2009, including 1383, 2106 and 442 cases arising from skin, soft tissue and bone, respectively. The annual incidence rate of sarcomas affecting the head and neck was 1.59 per 100 000 population. The incidence of head and neck sarcoma rose substantially in older age groups (age 65 years and above) and was most common in male patients (69%). Malignant fibrous histiocytoma (MFH) was the most common pathology. There was an increase in incidence in skin-origin sarcoma in the head and neck, particularly affecting elderly males. CONCLUSION: The incidence of head and neck sarcoma in Australia is higher than that reported for an equivalent European population. The increase in MFH arising from the skin in elderly male patients mirrors the patterns of common cutaneous malignancy, particularly melanoma, suggesting that ultraviolet radiation is an epidemiological factor. Management of head and neck sarcoma is complex and best managed in a specialist multidisciplinary environment.

Desmoid Fibromatosis Presenting as Deep Venous Thrombosis: A Case Report and Discussion.

BACKGROUND Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common, serious cardiovascular event. Predisposing factors include genetic disorders, immobility, and underlying malignancy. Soft tissue tumors are by contrast rare, but should be included in the differential etiology of DVT, especially when the patient is young and has few thrombotic risk factors. CASE REPORT We present a 40-year-old patient whose initial diagnosis was spontaneous DVT of the lower leg, treated conventionally. Subsequently, he developed progressive calf swelling, which was diagnosed as multifocal desmoid fibromatosis, a rare and complex soft tissue tumor. CONCLUSIONS DVT is common but soft tissue tumors are rare. The disparity in incidence of these very distinct pathologies may contribute to late diagnosis of occult soft tissue pathology. We discuss the incidence, etiology, pathology, diagnosis, and best management of both desmoid fibromatosis and DVT, which may co-exist in a causative way.

Making cancer visible--Dyes in surgical oncology.

Dyes share an intricate relationship with oncology. Dyes can cause cancer as chemical carcinogens, but can also be harnessed against cancer when used as diagnostic and therapeutic agents. Histopathology, imaging, and newer molecular diagnostics all rely on dyes, and their use in sentinel lymph node biopsies and intra-operative imaging has helped drive a paradigm shift in cancer surgery towards minimally-invasive and organ sparing approaches with enhanced resection accuracy. As therapeutic agents, the cytotoxicity of specific dyes can be employed in direct chemo-ablation or in photodynamic therapy. The same agent can have dual functionalities in cancer detection and treatment, in a novel field known as theranostics. This is facilitated by newer generation dyes conjugated with tumour-targeting probes such as antibodies, and these bio-conjugate agents can also incorporate nanotechnology or radio-isotopes. Further advances will be closely aligned with our increasing understanding of molecular oncology, and will form a new generation of cancer detection and treatment agents that promote precision medicine for cancer. Dyes and their roles have evolved and been reinvented, but they remain relevant as ever. This review explores the fascinating history of dyes, and their place in the state-of-the-art of oncology.

Surgery: no profession for a lady.

There are currently over 700 active female Fellows of the Royal Australasian College of Surgeons, accounting for just less than 10% of the surgical workforce. The first female Fellow of the College was Lillian Violet Cooper, of Queensland, who was admitted to Fellowship on 17 June 1927. Over the following half century, 32 women obtained Fellowships, initially awarded on the basis of experience and clinical practice and then, from 1947, by passing the Fellowship examination. This paper will examine the contribution of some of these early pioneer women, not just as surgeons, but as role models, advocates of women in professional life and champions of equality.

Primary pericardial mesothelioma presenting as multiple pericardial masses on CT.

We present the case of a 67-year-old male who was found to have multiple enhancing pericardial masses on CT imaging for investigation of weight loss and was subsequently diagnosed with primary pericardial mesothelioma. Although rare, pericardial mesothelioma is the most common primary malignancy of the pericardium and should be considered in the differential diagnosis of pericardial effusion, pericardial thickening or discreet pericardial mass. It is important for radiologists to be aware of pericardial mesothelioma as its clinical presentation is non-specific and it may be incidentally noted on radiological studies for investigation of apparently non-related symptoms. The prognosis of primary pericardial mesothelioma is universally poor.

XI-006 induces potent p53-independent apoptosis in Ewing sarcoma.

There is an imperious need for the development of novel therapeutics for the treatment of Ewing sarcoma, the second most prevalent solid bone tumour observed in children and young adolescents. Recently, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895) was shown to diminish MDM4 promoter activity in breast cancer cell lines. As amplification of MDM4 is frequently observed in sarcomas, this study examined the therapeutic potential of XI-006 for the treatment of Ewing and osteosarcoma. XI-006 treatment of Ewing and osteosarcoma cell lines (n = 11) resulted in rapid and potent apoptosis at low micro-molar concentrations specifically in Ewing sarcoma cell lines (48 hr IC50 0.099-1.61 µM). Unexpectedly, apoptotic response was not dependent on MDM4 mRNA/protein levels or TP53 status. Alkaline/neutral comet and γH2AX immunofluorescence assays revealed that the cytotoxic effects of XI-006 could not be attributed to the induction of DNA damage. RNA expression analysis revealed that the mechanism of action of XI-006 could be accredited to the inhibition of cell division and cycle regulators such as KIF20A and GPSM2. Finally, potent synergy between XI-006 and olaparib (PARP inhibitor) were observed due to the down-regulation of Mre11. Our findings suggest that XI-006 represents a novel therapeutic intervention for the treatment of Ewing sarcoma.

The Well-Being of Australian Service Mothers.

In recent years servicewomen with dependent children have for the first time in history been deployed into conflict zones in support of Australian Defence Force operations. This represents a significant social change, and the implications of deployment on the health of these service mothers are not fully understood. Data from women who participated in the Middle East Area of Operations Census study were analyzed to compare the psychological and physical symptoms reported by service mothers with service women who had no dependent children at the time of deploying to Afghanistan and/or Iraq. Of the 921 women who were included in this analysis, 235 had dependent children and 686 had no dependent children (comparison group). Service mothers were significantly older and were more likely to have served in the Air Force than women in the comparison group. Findings demonstrate that serving mothers were not at any significantly higher risk of psychological distress, post-traumatic stress symptoms, alcohol misuse, or reporting of somatic symptoms, than women who had no dependent children. A number of possible explanations for these findings are discussed, including the healthy soldier/mother effect, support from partners and extended family members, and collegial networks.

Seroprevalence of Strongyloides stercoralis in a South Australian Vietnam veteran cohort.

OBJECTIVES: Strongyloides stercoralis is a parasitic roundworm causing chronic infection that is endemic in Southeast Asia. Vietnam veterans are considered to be at high risk of Strongyloides infection. The prevalence of persistent infection in this group is unknown. This study aimed to establish the seropositivity rate of Strongyloides antibodies in South Australian Vietnam veterans and to identify the most reported symptoms within the seropositive group. METHOD: This cross-sectional study recruited 309 veterans who had served in Vietnamese territory between 1962 and 1975 and were currently resident in South Australia. Participants completed a self-administered questionnaire examining demographics, deployment, somatic symptoms and depression. Venous blood was collected for Strongyloides serology and eosinophil count. Participants who demonstrated positive Strongyloides serology underwent faecal microscopy for parasites. RESULTS: A total of 309 participants were recruited and 256 completed the questionnaire. Strongyloides seropositivity was demonstrated in 29 of 249 participants (11.6%). No participant had Strongyloides larvae detected by faecal microscopy. On multivariate analysis, only dermatological symptoms were associated with positive serology (OR 4.84, 95%CI 1.31-17.92, p-value 0.01). CONCLUSIONS: This study found a high seroprevalence (11.6%) of Strongyloides antibodies within the Vietnam veteran community in South Australia. Seropositivity was associated with increased likelihood of dermatological symptoms. IMPLICATIONS: Post-deployment screening and eradication therapy for Strongyloides should be offered to ADF staff after service in Strongyloides-endemic areas. This should include those veterans who left the service many years ago.

Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma.

PURPOSE: This international, multicenter, single-arm trial assessed efficacy and safety of intralesional rose bengal (PV-10) in 80 patients with refractory cutaneous or subcutaneous metastatic melanoma. METHODS: Sixty-two stage III and 18 stage IV melanoma patients with disease refractory to a median of six prior interventions received intralesional PV-10 into up to 20 cutaneous and subcutaneous lesions up to four times over a 16-week period and were followed for 52 weeks. Objectives were to determine best overall response rate in injected target lesions and uninjected bystander lesions, assess durability of response, and characterize adverse events. RESULTS: For target lesions, the best overall response rate was 51 %, and the complete response rate was 26 %. Median time to response was 1.9 months, and median duration of response was 4.0 months, with 8 % of patients having no evidence of disease after 52 weeks. Response was dependent on untreated disease burden, with complete response achieved in 50 % of patients receiving PV-10 to all of their disease. Response of target lesions correlated with bystander lesion regression and the occurrence of locoregional blistering. Adverse events were predominantly mild to moderate and locoregional to the treatment site, with no treatment-associated grade 4 or 5 adverse events. CONCLUSIONS: Intralesional PV-10 yielded durable local control with high rates of complete response. Toxicity was confined predominantly to the injection site. Cutaneous bystander tumor regression is consistent with an immunologic response secondary to ablation. This intralesional approach for local disease control could be complementary to current and investigational treatments for melanoma.

Can cancer registries show whether treatment is contributing to survival increases for melanoma of the skin at a population level?

RATIONALE, AIMS AND OBJECTIVES: It is uncertain whether survival increases from melanoma recorded by some population registries include a treatment effect. The US Surveillance, Epidemiology and End Results (SEER) programme has good data quality control, large numbers of cases enabling high statistical precision and summary stage plus thickness, which we consider to be a best-case population registry scenario to investigate potential for a treatment effect. We have investigated SEER data to indicate whether survivals increases are fully attributable to earlier diagnosis and other non-treatment factors. METHODS: Through relative survival regression, the effects of diagnostic period on 5-year excess mortality were investigated, adjusting for socio-demographic factors, lesion sub-site, histology, thickness and stage at diagnosis in 1990-2009 (n = 99 690 cases). RESULTS: The reduction in excess mortality (95% confidence interval) between 1990-1999 and 2000-2009 was 31 (20-41)% for localised melanoma, 18 (12-22)% for regional melanoma and 3 (-5-10)% for melanomas with distant spread. Younger age was predictive of a greater percentage reduction. Treatment benefits are inferred from the higher survivals in 2000-2009 but uncertainty remains due to incomplete data to adjust for non-treatment factors and a lack of treatment data. CONCLUSIONS: Registries should use new information systems to collect more complete data on stage, other prognostic indicators, co-morbidities and treatment, to provide more definitive and detailed information on population effects of cancer control.

Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling.

Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic amplification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 amplification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists.

Australia's female military surgeons of World War I.

The war service of Lilian Violet Cooper, the first female surgeon of the Royal Australasian College of Surgeons, is well recognized. Not so well known however, are the other pioneering female doctors who also undertook work as military surgeons during World War I. At least four of the 14 Australian female doctors that undertook overseas war service during World War I were engaged as surgeons and treated Australian, British and Allied casualties. These women operated in London, in Egypt and on the frontlines of the Macedonian campaign. While none of these other women became Fellows of the Royal Australasian College of Surgeons, their war efforts deserve recognition.

Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy.

The present study evaluated the efficacy of drozitumab, a human monoclonal agonistic antibody directed against death receptor 5 (DR5), as a new therapeutic avenue for the targeted treatment of bone and soft-tissue sarcomas. The antitumour activity of drozitumab as a monotherapy or in combination with Nutlin-3a was evaluated in a panel of sarcoma cell lines in vitro and human sarcoma patient samples ex vivo. Knockdown experiments were used to investigate the central role of p53 as a regulator of drozitumab cytotoxicity. Pre-activation of the p53 pathway through Nutlin-3a upregulated DR5, subsequently sensitising sarcoma cell lines and human sarcoma specimens to the pro-apoptotic effects of drozitumab. Silencing of p53 strongly decreased DR5 mRNA expression resulting in abrogation of drozitumab-induced apoptosis. Our study provides the first pre-clinical evaluation of combination therapy using p53-activating agents with drozitumab to further sensitise sarcomas to the cytotoxic effects of DR5 antibody therapy.