How the training pathways and capacity of rural physicians inform their scope of practice: A qualitative study examining the experiences of Australian and international medical graduates in South-East New South Wales, Australia.

INTRODUCTION: Current strategies to address shortages of rural doctors focus on developing a pipeline for rural generalist practice. Limited research has explored how doctors' professional journey engenders the skills required to practice rurally. OBJECTIVE: This paper analyses how rural general practitioners' clinical pathway informs their scope of practice and future retention. DESIGN: Qualitative thematic analysis using semi-structured telephone interviews. Twenty-one general practitioners appointed in their local health district of Murrumbidgee and Southern New South Wales, Australia, within the past 10 years. Participants comprised 10 Australian medical graduates (AMG) and 11 international medical graduates (IMG). FINDINGS: AMGs and IMGs contrasted how their pathway into rural practice, and capacity to work rurally, informed their scope of practice. Australian medical graduates' familiarity with rural areas was consolidated through congruous experiences, including at rural clinical schools. Paradoxically, the fluency of their training limited the amount of unsupervised experience and confidence AMGs gained. Together with a focus on work-life balance, this limited many to providing mainstream general practice, precluding extending their scope of practice. International medical graduates described disseminated experiences, often unsupervised in high-volume contexts. However, a lack of professional opportunities prevented them from extending their scope of practice. DISCUSSION: IMG and AMG motivation and pathway for working rurally differ. Respective cohorts have concerns regarding requisite skills and knowledge for rural practice, which incorporates opportunity and recognition. Entry points for training should be variable to allow consideration of life stage, prior skill development and extension of scope of practice. CONCLUSION: Doctors' scope of practice is informed by their pathways into rural practice. Australian medical graduates may not gain adequate competence during expedited training programs to confidently undertake extended clinical activities. International medical graduates, however lacked the opportunities and support, to utilise their expertise in rural practice. Complementarily utilising the expertise and commitment of both AMGs and IMGs may synergistically address workforce shortages.

A Novel Cartesian Plot Analysis for Fixed Monolayers That Relates Cell Phenotype to Transfer of Contents between Fibroblasts and Cancer Cells by Cell-Projection Pumping.

We recently described cell-projection pumping as a mechanism transferring cytoplasm between cells. The uptake of fibroblast cytoplasm by co-cultured SAOS-2 osteosarcoma cells changes SAOS-2 morphology and increases cell migration and proliferation, as seen by single-cell tracking and in FACS separated SAOS-2 from co-cultures. Morphological changes in SAOS-2 seen by single cell tracking are consistent with previous observations in fixed monolayers of SAOS-2 co-cultures. Notably, earlier studies with fixed co-cultures were limited by the absence of a quantitative method for identifying sub-populations of co-cultured cells, or for quantitating transfer relative to control populations of SAOS-2 or fibroblasts cultured alone. We now overcome that limitation by a novel Cartesian plot analysis that identifies individual co-cultured cells as belonging to one of five distinct cell populations, and also gives numerical measure of similarity to control cell populations. We verified the utility of the method by first confirming the previously established relationship between SAOS-2 morphology and uptake of fibroblast contents, and also demonstrated similar effects in other cancer cell lines including from melanomas, and cancers of the ovary and colon. The method was extended to examine global DNA methylation, and while there was no clear effect on SAOS-2 DNA methylation, co-cultured fibroblasts had greatly reduced DNA methylation, similar to cancer associated fibroblasts.

Comparability and validity of cancer registry data in the northwest of Russia.

BACKGROUND: Despite the elaborate history of statistical reporting in the USSR, Russia established modern population-based cancer registries (PBCR) only in the 1990s. The quality of PBCRs data has not been thoroughly analyzed. This study aims at assessing the comparability and validity of cancer statistics in regions of the Northwestern Federal District (NWFD) of Russia. MATERIAL AND METHODS: Data from ten Russian regional PBCRs covering ∼13 million (∼5 million in St. Petersburg) were processed in line with IARC/IACR and ENCR recommendations. We extracted and analyzed all registered cases but focused on cases diagnosed between 2008 and 2017. For comparability and validity assessment, we applied established qualitative and quantitative methods. RESULTS: Data collection in NWFD is in line with international standards. Distributions of diagnosis dates revealed higher variation in several regions, but overall, distributions are relatively uniform. The proportion of multiple primaries between 2008 and 2017 ranged from 6.7% in Vologda Oblast to 12.4% in Saint-Petersburg. We observed substantial regional heterogeneity for most indicators of validity. In 2013-2017, proportions of morphologically verified cases ranged between 61.7 and 89%. Death certificates only (DCO) cases proportion was in the range of 1-14% for all regions, except for Saint-Petersburg (up to 23%). The proportion of cases with a primary site unknown was between 1 and 3%. Certain cancer types (e.g., pancreas, liver, hematological malignancies, and CNS tumors) and cancers in older age groups showed lower validity. CONCLUSION: While the overall level of comparability and validity of PBCRs data of four out of ten regions of NWFD of Russia meets the international standards, differences between the regions are substantial. The local instructions for cancer registration need to be updated and implemented. The data validity assessment also reflects pitfalls in the quality of diagnosis of certain cancer types and patient groups.

Geographic variation in health system performance in rural areas of New South Wales, Australia.

OBJECTIVES: (i) To quantify geographic variation in selected health system performance indicators across local government areas of rural New South Wales and (ii) to compare relationships between sociodemographic factors and health system performance indicators across the regions. DESIGN: Ecological study. SETTING: Rural New South Wales communities. PARTICIPANTS: Eighty-nine local government areas in rural areas comprising 47 inner regional, 33 outer regional, 6 remote and 3 very remote areas. MAIN OUTCOME MEASURES: Deaths from avoidable causes, public hospital admissions for potentially preventable conditions, screening program participation, immunisation coverage. RESULTS: The largest geographic variation between rural areas of New South Wales was seen for avoidable mortality and potentially preventable hospital admissions. The average annual avoidable age-standardised mortality rate (2013-2017) ranged from 78.1 per 100 000 population to 493.7 per 100 000 population and the age-standardised rate of potentially preventable hospitalisations (2016-2017) ranged from 1491 to 5797 per 100 000 population. Approximately three quarters of local government areas had bowel and breast cancer screening participation rates equivalent to or better than the overall New South Wales rate; however, only 34% of local government areas met the New South Wales rate for cervical cancer screening. The least variation was seen for immunisation coverage; Byron had the lowest immunisation coverage for all 3 ages. The most common explanations for variation between rural local government areas in New South Wales were remoteness and socioeconomic characteristics. CONCLUSIONS: The analysis of health system performance indicators reveals differences among New South Wales rural local government areas. The results highlight specific areas that might benefit from targeted intervention to improve inequities particularly for avoidable mortality and potentially preventable hospitalisations.

Why do some medical graduates lose their intention to practise rurally?

INTRODUCTION: Chronic medical workforce shortage and maldistribution continue to be a significant challenge in rural Australia. The Rural Clinical Schools (RCSs) program helps to alleviate this problem with evidence of increased rural location in graduates of rural training programs. However, rural work intent may change during the years after completing a rural placement. This qualitative study investigated the factors involved in the change of career intention from rural to urban work location among the Australian National University Medical School (ANUMS) Rural Stream (RS) alumni. METHODS: A purposive sampling method was utilised to recruit ANUMS RS 2006-2016 graduates who expressed that their work plans had changed. Data collected with the use of in-depth, semi-structured interviews were transcribed verbatim. Transcripts were interpreted using thematic analysis and a modified version of I-poems, a component of Voice-Centred Relational Method or the Listening Guide. RESULTS: Thematic analysis produced three main themes. First, 'impacts of the working environment' highlighted some participants' views that career progression and sustenance, high-quality training and agreeable working conditions could not be achieved rurally. Second, 'ramifications of isolation' described the experienced or predicted feelings of social and professional isolation. Third, 'familial considerations' explained how the wishes and requirements of partners and families strongly influenced the participants' future work decisions. These findings were supplemented by the 'committed voice' and 'voice of uncertainty', heard through the use of I-poems. The 'committed voice' communicated the participants' dedication to their careers and partners. The 'voice of uncertainty' expressed confusion of intentions as participants attempted to balance the bidimensional needs of the 'committed voice'. CONCLUSION: The complex interaction between the availability of high-quality training positions, support issues and work-life balance is associated with the change of rural work intention of RCS graduates. Career and partner/family commitments are significant factors. Meanwhile, uncertainty towards future work location provides the opportunity for carefully developed and appropriate rural workforce strategies to intervene.

Potential Hydrodynamic Cytoplasmic Transfer between Mammalian Cells: Cell-Projection Pumping.

We earlier reported cytoplasmic fluorescence exchange between cultured human fibroblasts (Fibs) and malignant cells (MCs). Others report similar transfer via either tunneling nanotubes (TNTs) or shed membrane vesicles, and this changes the phenotype of recipient cells. Our time-lapse microscopy showed most exchange was from Fibs into MCs, with less in the reverse direction. Although TNTs were seen, we were surprised transfer was not via TNTs but was instead via fine and often branching cell projections that defied direct visual resolution because of their size and rapid movement. Their structure was revealed nonetheless by their organellar cargo and the grooves they formed indenting MCs, which was consistent with holotomography. Discrete, rapid, and highly localized transfer events evidenced against a role for shed vesicles. Transfer coincided with rapid retraction of the cell projections, suggesting a hydrodynamic mechanism. Increased hydrodynamic pressure in retracting cell projections normally returns cytoplasm to the cell body. We hypothesize "cell-projection pumping" (CPP), in which cytoplasm in retracting cell projections partially equilibrates into adjacent recipient cells via microfusions that form temporary intercellular cytoplasmic continuities. We tested plausibility for CPP by combined mathematical modeling, comparison of predictions from the model with experimental results, and then computer simulations based on experimental data. The mathematical model predicted preferential CPP into cells with lower cell stiffness, expected from equilibration of pressure toward least resistance. Predictions from the model were satisfied when Fibs were cocultured with MCs and fluorescence exchange was related to cell stiffness by atomic force microscopy. When transfer into 5000 simulated recipient MCs or Fibs was studied in computer simulations, inputting experimental cell stiffness and donor cell fluorescence values generated transfers to simulated recipient cells similar to those seen by experiment. We propose CPP as a potentially novel mechanism in mammalian intercellular cytoplasmic transfer and communication.

Why do doctors work in rural areas in high-income countries? A qualitative systematic review of recruitment and retention.

OBJECTIVE: To identify and assess the drivers and barriers to recruiting and retaining doctors in rural communities of high-income countries. DESIGN: A systematic review and thematic analysis. SETTING: Publications were sourced from medical and scientific databases online. PARTICIPANTS: Qualitative, mixed-methods and review studies from peer-reviewed journals published since 2000 that discussed recruitment or retention of doctors to rural areas in high-income countries. MAIN OUTCOME MEASURES: Identification and assessment of themes in the literature pertaining to recruitment and retention of rural doctors. Recurrent themes were assessed for relevance and applicability to current rural shortages. RESULTS: A thematic analysis was completed on 41 papers assessed as in scope of the review. Papers were scrutinised for relevance to established rural recruitment and retention strategies. Key themes were rural background, education and training, personal and professional circumstances, and integration with the community. CONCLUSION: While rural origin has long been promoted as the key factor for recruiting rural doctors, initiatives targeting only these individuals ignore a potentially larger cohort of future rural doctors. Rurally focused medical education and training need to encompass students and doctors from all backgrounds. The major barriers to rural recruitment are family-unit considerations for partners and children, concerns over isolation and a poor perception of rural practice. Attracting doctors to practise rurally is only half the challenge however, and strategies to retain rural doctors need a greater focus on personal and professional support networks and community integration. Additional strategies are needed to retain international and bonded doctors restricted to rural areas.

Exome-Wide Association Study of Pancreatic Cancer Risk.

We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10-6; exome-wide statistical significance threshold P < 2.5x10-6). Cases had more rare inactivating variants in DNA repair genes than controls, even after excluding 13 genes known to predispose to pancreatic cancer (adjusted odds ratio, 1.35; P = .045). At the suggestive threshold (P < .001), 6 genes were enriched for rare damaging variants (UHMK1, AP1G2, DNTA, CHST6, FGFR3, and EPHA1) and 7 genes had associations with pancreatic cancer risk, based on the sequence-kernel association test. We confirmed variants in BRCA2 as the most common high-penetrant genetic factor associated with pancreatic cancer and we also identified candidate pancreatic cancer genes. Large collaborations and novel approaches are needed to overcome the genetic heterogeneity of pancreatic cancer predisposition.

Perioperative Gemcitabine + Erlotinib Plus Pancreaticoduodenectomy for Resectable Pancreatic Adenocarcinoma: ACOSOG Z5041 (Alliance) Phase II Trial.

BACKGROUND: There is considerable interest in a neoadjuvant approach for resectable pancreatic ductal adenocarcinoma (PDAC). This study evaluated perioperative gemcitabine + erlotinib (G+E) for resectable PDAC. METHODS: A multicenter, cooperative group, single-arm, phase II trial was conducted between April 2009 and November 2013 (ACOSOG Z5041). Patients with biopsy-confirmed PDAC in the pancreatic head without evidence of involvement of major mesenteric vessels (resectable) were eligible. Patients (n = 123) received an 8-week cycle of G+E before and after surgery. The primary endpoint was 2-year overall survival (OS), and secondary endpoints included toxicity, response, resection rate, and time to progression. Resectability was assessed retrospectively by central review. The study closed early due to slow accrual, and no formal hypothesis testing was performed. RESULTS: Overall, 114 patients were eligible, consented, and initiated protocol treatment. By central radiologic review, 97 (85%) of the 114 patients met the protocol-defined resectability criteria. Grade 3+ toxicity was reported in 60% and 79% of patients during the neoadjuvant phase and overall, respectively. Twenty-two of 114 (19%) patients did not proceed to surgery; 83 patients (73%) were successfully resected. R0 and R1 margins were obtained in 67 (81%) and 16 (19%) resected patients, respectively, and 54 patients completed postoperative G+E (65%). The 2-year OS rate for the entire cohort (n = 114) was 40% (95% confidence interval [CI] 31-50), with a median OS of 21.3 months (95% CI 17.2-25.9). The 2-year OS rate for resected patients (n = 83) was 52% (95% CI 41-63), with a median OS of 25.4 months (95% CI 21.8-29.6). CONCLUSIONS: For resectable PDAC, perioperative G+E is feasible. Further evaluation of neoadjuvant strategies in resectable PDAC is warranted with more active systemic regimens.

Fate Decision Between Group 3 Innate Lymphoid and Conventional NK Cell Lineages by Notch Signaling in Human Circulating Hematopoietic Progenitors.

The role of Notch signaling in human innate lymphoid cell (ILC) differentiation is unclear, although IL-7 and IL-15 promote differentiation of natural cytotoxicity receptor (NCR) NKp44+ group 3 ILCs (NCR+ILC3s) and conventional NK (cNK) cells from CD34+ hematopoietic progenitor cells (HPCs) ex vivo. In this study, we analyzed the functions of Notch in the differentiation of NCR+ILC3s and cNK cells from human HPC subpopulations circulating in peripheral blood by limiting dilution and clonal assays using high-throughput flow cytometry. We demonstrated that Notch signaling in combination with IL-7 induced NCR+ILC3 differentiation, but conversely suppressed IL-15-dependent cNK cell generation in CD45RA+Flt-3-c-Kitlow, a novel innate lymphocyte-committed HPC subpopulation. In contrast, Notch signaling induced CD45RA-Flt-3+c-Kithigh multipotent HPCs to generate CD34+CD7+CD62Lhigh, the earliest thymic progenitor-like cells, which preserved high cNK/T cell potential, but lost NCR+ILC3 potential. These findings implicate the countervailing functions of Notch signaling in the fate decision between NCR+ILC3 and cNK cell lineages at different maturational stages of human HPCs. Inhibition of Notch functions by Abs specific for either the Notch1 or Notch2 negative regulatory region suggested that both Notch1 and Notch2 signals were involved in the fate decision of innate lymphocyte-committed HPCs and in the generation of earliest thymic progenitor-like cells from multipotent HPCs. Furthermore, the synergistic interaction between Notch and IL-7 in NCR+ILC3 commitment was primarily explicable by the induction of IL-7 receptor expression in the innate lymphocyte-committed HPCs by Notch stimulation, suggesting the pivotal role of Notch in the transcriptional control required for human NCR+ILC3 commitment.

Sublethal Total Body Irradiation Causes Long-Term Deficits in Thymus Function by Reducing Lymphoid Progenitors.

Total body irradiation (TBI) damages hematopoietic cells in the bone marrow and thymus; however, the long-term effects of irradiation with aging remain unclear. In this study, we found that the impact of radiation on thymopoiesis in mice varied by sex and dose but, overall, thymopoiesis remained suppressed for ≥12 mo after a single exposure. Male and female mice showed a long-term dose-dependent reduction in thymic cKit+ lymphoid progenitors that was maintained throughout life. Damage to hematopoietic stem cells (HSCs) in the bone marrow was dose dependent, with as little as 0.5 Gy causing a significant long-term reduction. In addition, the potential for T lineage commitment was radiation sensitive with aging. Overall, the impact of irradiation on the hematopoietic lineage was more severe in females. In contrast, the rate of decline in thymic epithelial cell numbers with age was radiation-sensitive only in males, and other characteristics including Ccl25 transcription were unaffected. Taken together, these data suggest that long-term suppression of thymopoiesis after sublethal irradiation was primarily due to fewer progenitors in the BM combined with reduced potential for T lineage commitment. A single irradiation dose also caused synchronization of thymopoiesis, with a periodic thymocyte differentiation profile persisting for at least 12 mo postirradiation. This study suggests that the number and capability of HSCs for T cell production can be dramatically and permanently damaged after a single relatively low TBI dose, accelerating aging-associated thymic involution. Our findings may impact evaluation and therapeutic intervention of human TBI events.

Productivity losses associated with premature mortality due to cancer in Russia: A population-wide study covering 2001-2030.

Aims: Productivity losses related to premature cancer mortality have been assessed for most developed countries but results for Russia are limited to cross-sectional reports. The aim of this study was to quantify productivity costs due to cancer mortality in Russia between 2001 and 2015 and project this to 2030. Methods: Cancer mortality data (2001-2015) were acquired from the State Cancer Registry, whereas population data, labour force participation rates and annual earnings were retrieved from the Federal State Statistics Service. Cancer mortality was projected to 2030 and the human capital approach was applied to estimate productivity losses. Results: The total annual losses increased from US6.5b in 2001-2005 to US$8.1b in 2011-2015, corresponding to 0.24% of the annual gross domestic product. The value is expected to remain high in 2030 (US$7.5b, 0.14% of gross domestic product). Productivity losses per cancer death are predicted to grow faster in women (from US$18,622 to US$22,386) than in men (from US$25,064 to US$28,459). Total losses were found to be highest for breast cancer in women (US$0.6b, 20% of overall losses in women) and lung cancer in men (US$1.2b, 24%). The absolute predicted change of annual losses between 2011-2015 and 2026-2030 was greatest for cervix uteri (+US$214m) in women and for lip, oral and pharyngeal cancers in men (+US$182m). Conclusions: In Russia, productivity losses due to premature cancer mortality are substantial. Given the expected importance especially for potentially preventable cancers, steps to implement effective evidence-based national cancer control policies are urgently required.

Predicting future performance in medical students. A longitudinal study examining the effects of resilience on low and higher performing students.

Introduction: Medical students have high rates of distress and burnout, exacerbated by a high academic workload. Resilience is stated to mitigate such stress, and even allow positive adaptations in the face of such challenges. Despite this, no research has examined the relationship of resilience on the academic performance of medical students. Methods: The goal of our study was to investigate the association between resilience on academic performance. We surveyed all year 2, 3, and 4 medical students (n = 160), and combined this with data on past and future course performance. We conducted an analysis of the internal consistency and validity of the RS-14, suggesting two factors: which we represent as self-assuredness and drive. We then analyzed future course performance using multiple regression. Results: Models utilizing the combined RS-14 score suggested past-performance as the only significant predictor of future course performance. Considering self-assuredness and drive as separate predictors demonstrated self-assuredness to be a predictor of improved performance in lower-than-average students, whilst drive was a predictor of improvement in higher-than-average students. Conclusions: We suggest that the conceptualization of resilience needs greater nuance, and consideration in tandem with broader psychosocial concepts, as it may exert different effects for different students.

Neoadjuvant therapy and major arterial resection for potentially reconstructable arterial involvement by stage 3 adenocarcinoma of the pancreas.

BACKGROUND: Stage 3 pancreatic ductal adenocarcinoma (PDAC) is defined by arterial involvement. This study objective was to evaluate outcomes for patients with stage 3 PDAC with potentially reconstructable arterial involvement, considered for neoadjuvant therapy (NAT) and pancreatic resection, and to compare outcomes following arterial (AR) and non-arterial resection (NAR). METHODS: This study included patients from 2009 to 2016 with biopsy-proven stage 3 PDAC who were offered NAT before surgical exploration. AR was performed if required to achieve R0 resection. Time to event outcomes were analysed from diagnosis date. RESULTS: 87/89 patients (97.8%) received NAT (chemotherapy 41.6%, chemotherapy/radiotherapy 56.2%). 46/89 (51.7%) underwent exploration; 31 underwent resection (AR n = 20, NAR n = 11). AR patients had longer operative time (681 vs. 563 min, p = 0.006) and more blood loss (1600 vs. 575 mL, p = 0.0004), with no difference for blood transfusion, pancreatic fistula, length of stay, reoperation, or mortality. R0 rate was 30/31. Post-resection 90-day mortality was 3.2%. Median overall survival was statistically comparable between the AR and NAR groups (19.7 vs. 28.4 months, p = 0.41). CONCLUSIONS: AR had comparable clinical and oncologic outcomes to NAR. Following careful selection and non-progression after NAT, major AR may cautiously be considered if required to obtain a negative resection margin.

Social and community networks influence dietary attitudes in regional New South Wales, Australia.

INTRODUCTION: Rural populations in Australia have a higher prevalence of obesity, cardiovascular disease, type II diabetes and some cancers. The purpose of the present study was to determine associations between socioeconomic characteristics (socioeconomic position, income, wealth, debt, occupation, social network diversity), dietary attitudes, and fruit and vegetable intake for people living rurally in Australia. METHOD: A community based cross-sectional survey between February and July 2018 of 326 adults (median age 57 years, range 20-90 years, 64.4% female) who attended rural shows in four rural towns in south-eastern New South Wales, supplemented with data from patients attending general practices in two additional towns. Participants completed a questionnaire that recorded self-reported daily consumption of fruit and vegetables, a dietary attitude score, and items measuring social and economic circumstances. RESULTS: Using multivariable regression analysis, the odds of meeting Australian fruit intake guidelines was 13% higher for each unit increase in dietary attitude score (odds ratio (OR)=1.13, 95% confidence interval (CI)=1.03-1.23). The odds of meeting vegetable intake guidelines were 19% higher for each unit increase in score (OR=1.19, 95%CI=1.09-1.31). Social and economic factors were not independently associated with fruit or vegetable intake. Dietary attitude score, in turn, increased on average by 0.07 points (95%CI=0.01-0.12) for each additional occupation type among the participants' social networks. For women who socialised regularly in small towns the score was 1.97 points higher (95%CI=0.93-3.00). Men in outer regional areas were more likely to meet vegetable intake guidelines than men in inner regional areas, whereas women in outer regional areas were more likely to meet fruit intake guidelines than women in inner regional areas. CONCLUSIONS: Greater fruit and vegetable intake was predicted by healthier dietary attitudes which in turn were related to social and community connections, rather than economic factors.

Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma.

BACKGROUND: A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. METHODS: Gemcitabine and cisplatin were dosed at 600 and 25 mg/m2 , respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]). RESULTS: Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months). CONCLUSIONS: The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society.

Gene expression signatures prognostic for relapse in stage I testicular germ cell tumours.

OBJECTIVES: To identify differentially expressed genes between relapsed and non-relapsed clinical stage I testicular germ cell tumours (TGCTs). MATERIALS AND METHODS: We reviewed patients with clinical stage I non-seminoma and seminoma from an institutional database (2000-2012) who were managed by active surveillance. Patients with non-relapsed non-seminoma and non-relapsed seminoma were defined as being relapse-free after 2 and 3 years of surveillance, respectively. RNA extraction and gene expression analysis was performed on archival primary tumour samples and gene-set enrichment analysis (GSEA) was conducted in order to identify differentiating biological pathways. RESULTS: A total of 57 patients (relapsed non-seminoma, n = 12; relapsed seminoma, n =15; non-relapsed non-seminoma, n = 15; non-relapsed seminoma, n = 15) were identified, with a median (range) relapse time of 5.6 (2.5-18.1) and 19.3 (4.7-65.3) months in the relapsed non-seminoma and relapsed seminoma cohorts, respectively. A total of 1 039 differentially expressed genes were identified that separated relapsed and non-relapsed groups. In patients with relapse, GSEA revealed enrichment in pathways associated with differentiation, such as skeletal development (i.e. FGFR1, BMP4, GLI2, SPARC, COL2A1), tissue (i.e. BMP4, SPARC, COL13A1) and bone remodelling (i.e. CARTPT, GLI2, MGP). A discriminative gene expression profile between relapsed and non-relapsed cases was discovered when combining non-seminoma and seminoma samples using 10- and 30-probe signatures; however, this profile was not observed in the seminoma and non-seminoma cohorts individually. CONCLUSION: A discriminating signature for relapsed disease was identified for clinical stage I TGCT that we were not able to identify by histology alone. Further validation is required to determine if this signature provides independent prognostic information to standard pathological risk factors.

Age-Related Patterns in Cancer Pain and Its Psychosocial Impact: Investigating the Role of Variability in Physical and Mental Health Quality of Life.

Objective: Age-related patterns in cancer pain remain equivocal. Most studies ignore heterogeneity across multiple domains of well-being, and the potential role of physical (PH) and mental health (MH) quality of life (QOL) in these age-related patterns is unknown. We investigated the relationships between age and cancer pain intensity, qualities, and interference, and physical and psychosocial adaptation and the interaction between age and PH and MH QOL on pain and adaptation to cancer pain. Design: In this cross-sectional study, 244 patients with advanced cancer and pain completed measures of pain, QOL, physical function, and psychosocial well-being. Pearson's correlations and ANOVAs assessed relationships between age and demographic and clinical factors, pain, and physical and psychosocial measures. Regression models tested the role of age and its interaction with PH and MH QOL on pain and physical and psychosocial adaptation. Results: Older age was associated with a lower likelihood of receiving an opioid prescription, greater likelihood of having comorbidities, and worse functional status. When we did not account for these factors, age was not associated with pain and most adaptation indices. When we did account for these factors and PH QOL, older age was associated with lower non-neuropathic and neuropathic pain and several indices of psychosocial adaptation. Most interestingly, older age was associated with lower non-neuropathic pain among those with high, but not low, MH QOL. Conclusions: This study addresses knowledge gaps about factors underlying age-related patterns in cancer pain. Impaired MH QOL may be a proxy for age-related patterns in cancer pain. Summary: This study investigated age-related patterns in the experience of cancer pain and the role of quality of life in resilience and vulnerability to pain and adaptation to pain. Older age is associated with lower non-neuropathic pain among those with high, but not low, mental health quality of life, suggesting that impaired mental health quality of life is an important indicator of vulnerability to multidimensional pain outcomes.

How does studying rurally affect peer networks and resilience? A social network analysis of rural- and urban-based students.

OBJECTIVE: To examine differences in peer networks between urban-based students and rural-stream students in an Australian medical school and to examine how characteristics of networks relate to resilience. DESIGN: Cross-sectional survey asking students to signify social, academic and support relationships with students in the same year and to complete a survey on their resilience. SETTING AND PARTICIPANTS: All second-, third- and fourth-year students at the Australian National University Medical School. MAIN OUTCOME MEASURES: Social network analysis comparing peer networks, t-test comparing mean resilience of urban and rural students. RESULTS: A visual analysis of the peer networks of year 2, 3 and 4 medical students suggests greater integration of rural-stream students within the year 2 and 4 urban cohorts. Resilience is similar between year 2 and 3 students in both urban and rural streams, but is significantly higher in year 4 rural-stream students, compared to their urban-based peers. Networks of rural-stream students suggest key differences between their period spent rurally and on their return and integration within the larger student cohort. Furthermore, rural students, once reintegrated, had larger and stronger social networks than their urban counterparts. CONCLUSION: The results of the study suggest that the rural experience can instruct support systems in urban settings. However, whether the rural placement creates a more resilient student or resilient students are selected for rural placement is unclear.

The challenge of generalist care in remote Australia: Beyond aeromedical retrieval.

OBJECTIVE: To examine clinical service activity amongst patients of the Royal Flying Doctor Service South Eastern Section in Far West New South Wales and to evaluate the management of chronic disease among frequent users of evacuation services. DESIGN: A retrospective audit of the Royal Flying Doctor Service South Eastern Section patient database inclusive of patients within the geographical study area who accessed a clinical or remote consultation, or evacuation service at least once between 1 July 2008 and 30 June 2013. Frequent users of evacuation services (≥3 evacuations per year) were investigated through RFDS patient files for determinants of chronic disease management. MAIN OUTCOME MEASURES: Category of service accessed, clinical consultation amongst frequent evacuees, determinants of chronic disease management. RESULTS: Total number of evacuees increased by 5.4%; number of remote and clinical consultation patients increased by 5.4%. Of the 47 frequent users of evacuation services, 19 (40%) were infrequent or non-users of clinics (≤3 attendances per year) and 32 (70%) did not have a general practice management plan. Frequent evacuees averaged 2.7 chronic conditions per patient and had seen an average of 16.8 primary care physicians over the 5-year evaluation. CONCLUSION: Most frequent evacuees had several chronic conditions, multiple primary care providers, did not have a general practice management plan and had infrequent clinic reviews. This evidence highlights the challenge of remote primary care and the need to improve systems of chronic disease management. It underlines the importance of current local efforts to improve electronic records, follow-up and team care and to explore further telehealth implementation.