Publications by authors named "Malcolm Moore"

440 Publications

Impact of Screening on Breast Cancer Incidence in Kazakhstan: Results of Component Analysis.

Asian Pac J Cancer Prev 2021 Sep 1;22(9):2807-2817. Epub 2021 Sep 1.

Central Asian Cancer Institute, Nur-Sultan, Kazakhstan.

Objective: The study is to conduct a component analysis of the dynamics of the incidence of BC (BC) in Kazakhstan, taking into account regions.

Methods: Primary data were for registered patients with BC (ICD 10 - C50) in the whole country during the period of 2009-2018. Evaluation of changes in BC incidence in the population of Kazakhstan was performed using component analysis according to the methodological recommendations.

Results: The study period, 40,199 new cases of BC were recorded. The incidence rate increased from 39.5 (2009) to 49.6 in 2018 and the overall growth was 2.8 per 100,000 population of female, including due to the age structure - ∑ΔA=+2.99, due to the risk of acquiring illness - ∑ΔR=+6.82 and their combined effect - ∑ΔRA=+0.31. The component analysis revealed that the increase in the number of patients with BC was mainly due to the growth of the population (ΔP=+31.1%), changes in its age structure (ΔA=+18.0%) and changes associated with the risk of acquiring illness (ΔR=+41.0%). The increase in the number of patients in the regions of the republic is associated with the influence of demographic factors and with risk factors for getting sick, including mammographic screening.

Conclusion: Thus, as a result of the component analysis, the role of the influence of demographic factors and the risk of acquiring illness on the formation of the number of patients and the incidence of BC was evaluated, while geographical variability was established. This research was the first epidemiological study of the dynamics of BC in the regional context by the method of component analysis in the population of Kazakhstan. The implementation of the results of this study is recommended in management of anticancer activities for BC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.31557/APJCP.2021.22.9.2807DOI Listing
September 2021

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

Acta Oncol 2021 Oct 23;60(10):1264-1271. Epub 2021 Aug 23.

Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/0284186X.2021.1967443DOI Listing
October 2021

CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment.

Mol Cancer Ther 2021 08 4;20(8):1388-1399. Epub 2021 Jun 4.

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York.

Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF1 receptor (CSF1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow-derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3 regulatory T cells and, surprisingly, enhanced infiltration of CD8 T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T-cell-modulating effects that may translate into cancer immunotherapy for bone and soft-tissue sarcomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-20-0591DOI Listing
August 2021

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

Rural Remote Health 2021 06 4;21(2):5747. Epub 2021 Jun 4.

Rural Clinical School, College of Health and Medicine, Australian National University, Acton, ACT 2601, Australia

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22605/RRH5747DOI Listing
June 2021

Extracellular vesicles from human airway basal cells respond to cigarette smoke extract and affect vascular endothelial cells.

Sci Rep 2021 03 17;11(1):6104. Epub 2021 Mar 17.

Department of Cell Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The human airway epithelium lining the bronchial tree contains basal cells that proliferate, differentiate, and communicate with other components of their microenvironment. One method that cells use for intercellular communication involves the secretion of exosomes and other extracellular vesicles (EVs). We isolated exosome-enriched EVs that were produced from an immortalized human airway basal cell line (BCi-NS1.1) and found that their secretion is increased by exposure to cigarette smoke extract, suggesting that this stress stimulates release of EVs which could affect signaling to other cells. We have previously shown that primary human airway basal cells secrete vascular endothelial growth factor A (VEGFA) which can activate MAPK signaling cascades in endothelial cells via VEGF receptor-2 (VEGFR2). Here, we show that exposure of endothelial cells to exosome-enriched airway basal cell EVs promotes the survival of these cells and that this effect also involves VEGFR2 activation and is, at least in part, mediated by VEGFA present in the EVs. These observations demonstrate that EVs are involved in the intercellular signaling between airway basal cells and the endothelium which we previously reported. The downstream signaling pathways involved may be distinct and specific to the EVs, however, as increased phosphorylation of Akt, STAT3, p44/42 MAPK, and p38 MAPK was not seen following exposure of endothelial cells to airway basal cell EVs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-85534-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969738PMC
March 2021

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

Aust J Rural Health 2021 Feb 10;29(1):41-51. Epub 2021 Feb 10.

Rural Clinical School, ANU Medical School, The Australian National University, Canberra, ACT, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajr.12688DOI Listing
February 2021

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

Aust J Rural Health 2020 Dec 16;28(6):543-554. Epub 2020 Nov 16.

Rural Clinical School, Australian National University (ANU) Medical School, ANU College of Health and Medicine, Canberra, ACT, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajr.12675DOI Listing
December 2020

Expanded Low Allele Frequency and V600E Testing in Metastatic Colorectal Cancer as Predictive Biomarkers for Cetuximab in the Randomized CO.17 Trial.

Clin Cancer Res 2021 01 21;27(1):52-59. Epub 2020 Oct 21.

University of Texas, MD Anderson Cancer Center, Houston, Texas.

Purpose: Expanded mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC), and low mutant allele frequency (MAF) mutations are of unclear significance. We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive beads, emulsion, amplification, and magnetics (BEAMing) analysis, capable of detecting alterations below standard clinical assays.

Patients And Methods: CO.17 trial compared cetuximab versus best supportive care (BSC) in -unselected mCRC. We performed analysis on microdissected tissue of 242 patients in CO.17 trial using BEAMing for (codons 12/13/59/61/117/146) and V600E. Patients without BEAMing but with previous Sanger sequencing-detected mutations were included.

Results: , and mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival [OS; HR, 0.51; 95% confidence interval (CI), 0.32-0.81; = 0.004] and progression-free survival (PFS; HR, 0.25; 95% CI, 0.15-0.41; < 0.0001) compared with BSC in wild-type patients. Cetuximab did not improve OS/PFS for , or mutated tumors, and tests of interaction confirmed expanded ( = 0.0002) and ( = 0.006) as predictive, while mutations were not ( = 0.089). BEAMing identified 14% more tumors as mutant than Sanger sequencing, and cetuximab lacked activity in these patients. Mutations at MAF < 5% were noted in 6 of 242 patients (2%). One patient with a A59T mutation (MAF = 2%) responded to cetuximab. More than mutations were low MAF (OR, 20.50; 95% CI, 3.88-96.85; = 0.0038).

Conclusions: We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal alterations are uncommon and remain of indeterminate significance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-2710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785657PMC
January 2021

Spatial inequities of mental health nurses in rural and remote Australia.

Int J Ment Health Nurs 2021 Feb 17;30(1):167-176. Epub 2020 Aug 17.

Rural Clinical School, Medical School, College of Health and Medicine, The Australian National University, Acton, Australian Capital Territory, Australia.

Despite an increased burden from chronic mental health conditions, access to effective mental health services in rural and remote areas is limited, and these services remain spatially undefined. We examine the spatial availability of mental health nurses across local government areas in Australia and identify gaps in mental health service delivery capacity in a finer-grained level than the state/territory data. A spatial distribution of mental health nurses was conducted. We utilized the 2017 National Health Workforce Dataset which was aggregated to LGA level based on the 2018 Australian Bureau Statistics (ABS) Data. The availability of mental health nurses was measured using the full time equivalent (FTE) rates per 100 000 population. We calculated the proportion of LGAs with zero total FTE rates based on remoteness categories. We also compared the mean of total FTE rates based on remoteness categories using analysis of variance. A spatial distribution of mental health nurses was visualized using GIS software for total FTE rates. Our analysis included 544 LGA across Australia, with 24.8% being defined as remote and very remote. The mean total FTE for mental health nurses per 100 000 populations is 56.6 (±132.2) with a median of 17.4 (IQR: 61.8). A wide standard deviation reflects unequal distribution of mental health nurses across LGAs. The availability of total FTE rates for mental health nurses per 100 000 populations is significantly lower in remote and very remote LGAs in comparison with major cities. As many as 35.1% of LGAs across Australia have no FTE for mental health nurses with 46% are remote and very remote. Our study reflects the existing unequal distribution of mental health nurses between metropolitan/urban setting and rural and remote areas. We suggest three broad strategies to address these spatial inequities: improving supply and data information systems; revisiting task-shifting strategies, retraining the existing health workforce to develop skills necessary for mental health care to rural and remote communities; and incorporating the provision of mental health services within expanding innovative delivery models including consumer-led, telemedicine and community-based groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/inm.12769DOI Listing
February 2021

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

Biophys J 2020 03 31;118(6):1248-1260. Epub 2020 Jan 31.

Cell Biology, The Memorial Sloan Kettering Cancer Center, New York, New York.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpj.2020.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091489PMC
March 2020

Latency and interval therapy affect the evolution in metastatic colorectal cancer.

Sci Rep 2020 01 17;10(1):581. Epub 2020 Jan 17.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g., those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of latency in the evolutionary path of metastatic CRC and may have implications for future treatment options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-57476-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969060PMC
January 2020

Increased cell size, structural complexity and migration of cancer cells acquiring fibroblast organelles by cell-projection pumping.

PLoS One 2019 7;14(11):e0224800. Epub 2019 Nov 7.

Cell Biology, The Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.

We recently described a hydrodynamic mechanism for cytoplasmic transfer between cells, termed cell-projection pumping (CPP). Earlier image analysis related altered SAOS-2 osteosarcoma cell morphology, to what we now recognize as CPP uptake of fibroblast cytoplasm. We here examine SAOS-2 phenotype following co-culture with human dermal fibroblasts (HDF) in which organelles were pre-labelled with a fluorescent lipophilic marker. Fluorescence activated cell sorting (FACS) analysis was performed of HDF and SAOS-2, cultured either alone or together. FACS forward scatter is proportionate to cell size, and increased for SAOS-2 with high levels of HDF fluorescence uptake (p < 0.004). FACS side scatter is proportionate to internal cell complexity, and increased in SAOS-2 with increasing uptake of HDF fluorescence (p < 0.004), consistent with uptake of HDF organelles. Scratch migration assays revealed that HDF migrated more quickly than SAOS-2 in both isolated cell culture, and following co-culture (p < 0.004). Notably, SAOS-2 with high levels of HDF labelling migrated faster compared with SAOS-2 with low HDF labelling (p < 0.008). A slight and unconvincing reduction in SAOS-2 proliferation was seen (p < 0.02). Similar results were obtained in single additional experiments with A673 and H312 cancer cells. Forward and side scatter results suggest organellar transfer by CPP increases cancer cell morphological diversity. This may contribute to histological pleomorphism relevant to cancer diagnosis and prognosis. Also, increased migration of sub-populations of cancer cells with high CPP organellar uptake, may contribute to invasion and metastasis in-vivo. We thus suggest relevance of CPP to cancer diagnosis and progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224800PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837525PMC
March 2020

Altered Gene Expression along the Glycolysis-Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer.

Clin Cancer Res 2020 01 3;26(1):135-146. Epub 2019 Sep 3.

Pancreas Centre BC, Vancouver, British Columbia, Canada.

Purpose: Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis.

Experimental Design: We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG).

Results: On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test = 0.018) and metastatic settings (log-rank test = 0.027). Patients with cholesterogenic tumors had the longest median survival. and -amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers and . Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes.

Conclusions: Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-1543DOI Listing
January 2020

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

Rural Remote Health 2019 08 30;19(3):5328. Epub 2019 Aug 30.

Rural Clinical School and ANU Medical School, ANU College of Health & Medicine, The Australian National University, Building #54, Mills Road, Canberra, ACT 0200, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22605/RRH5328DOI Listing
August 2019

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

Ann Surg Oncol 2019 Dec 15;26(13):4489-4497. Epub 2019 Aug 15.

University of Chicago Comprehensive Cancer Center, Chicago, IL, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-019-07685-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868305PMC
December 2019

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

Med Teach 2019 10 17;41(10):1184-1191. Epub 2019 Jul 17.

Rural Clinical School, Australia National University , Canberra , Australia.

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. 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 (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 and . We then analyzed future course performance using multiple regression. 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. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/0142159X.2019.1626978DOI Listing
October 2019

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

Scand J Public Health 2019 Jul;47(5):482-491

6 Section of Cancer Surveillance, International Agency for Research on Cancer, France.

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. : 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. : 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).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1403494819845565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651608PMC
July 2019

Detection of Relapse by Low-dose Computed Tomography During Surveillance in Stage I Testicular Germ Cell Tumours.

Eur Urol Oncol 2019 07 2;2(4):437-442. Epub 2018 Oct 2.

Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; University of Toronto, Toronto, Canada.

Background: Standard-dose computed tomography (SDCT) scans are associated with radiation exposure during stage I testicular cancer surveillance.

Objective: To evaluate low-dose CT (LDCT) for clinical use.

Design, Setting, And Participants: In this single-arm prospective study, patients on surveillance for stage I testicular germ cell tumour underwent SDCT and LDCT scans on their first visit after enrolment. The adequacy of LDCT image quality was assessed for subsequent use. Patients were followed with LDCT only and suspected relapse was confirmed by SDCT.

Outcome Measures And Statistical Analysis: We assessed whether initial LDCT scans were of sufficient quality for routine clinical use. We compared mean differences in nodal size at relapse between LDCT and SDCT using a one-sample paired t test. The relapse free-rate was calculated using the Kaplan-Meier method.

Results And Limitations: Of 257 patients, one was excluded because of inadequate image quality. At median follow-up of 5.25 yr, 35 patients had relapsed, 33 with retroperitoneal lymphadenopathy. The 2- and 5-yr relapse-free rates were 89.5% and 85.3%, respectively. The mean size of retroperitoneal nodal relapse was 17.3 and 17.5mm on the short axis, 23.2 and 22.7mm on the long axis, and 26.1 and 26.7mm on craniocaudal length for LDCT and SDCT, respectively. The mean difference between LDCT and SDCT was 0.14mm (p=0.55) short axis, -0.54mm (p=0.092) long axis, and -0.51mm (p=0.086) length. A limitation was the lack of a control arm.

Conclusions: LDCT image quality was adequate for clinical use, and retroperitoneal nodal relapse was detected with minimal differences seen between LD and SDCT. LDCT can be safely adopted and will decrease overall radiation exposure in stage I germ cell tumour surveillance.

Patient Summary: We studied the use of low-dose computed tomography scans for detecting testicular cancer recurrence in lymph nodes of the abdomen and pelvis and found that they were safe, effective and would potentially reduce overall X-ray exposure. This trial is registered at ClinicalTrials.gov as NCT03142802.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euo.2018.08.031DOI Listing
July 2019

Rural clinical school students do come back: But it may take time

Aust J Gen Pract 2018 11;47(11):812-814

BSocSc, MCHAM, Research Assistant, ANU Medical School Rural Clinical School, ACT

Background And Objectives: Rural clinical schools (RCSs) help address Australia’s rural workforce shortfall, but they require an investment by rural clinicians and communities. Our objective was to determine the location of RCS graduates as one measure of the effectiveness of RCSs.

Method: This cross-sectional study obtained work location data for Australian National University Medical School (ANUMS) graduates and analysed both RCS and non-RCS data.

Results: The percentage of graduates working in rural areas after their fifth postgraduate year (PGY6–11: 34.7%) was significantly greater than that of graduates in PGY1–5 (15.2%, P <0.001).

Discussion: Many graduates who trained in rural sites spend time in cities before returning to work in rural areas. This is encouraging for rural clinicians and communities, but it can take time for graduates to return.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.31128/AJGP-02-18-4505DOI Listing
November 2018

Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in Wild-Type Pancreatic Ductal Adenocarcinoma.

Clin Cancer Res 2019 Aug 8;25(15):4674-4681. Epub 2019 May 8.

Pancreas Centre British Columbia, Vancouver, Canada.

Purpose: Gene fusions involving neuregulin 1 () have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of fusion-positive pancreatic ductal adenocarcinoma is not fully understood.

Experimental Design: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging.

Results: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as wild type by whole-genome sequencing. All wild-type tumors were positive for gene fusions involving the ERBB3 ligand . Two of 3 patients with fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy.

Conclusions: This work adds to a growing body of evidence that gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with wild-type tumors harboring gene fusions may benefit from treatment with afatinib..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-0191DOI Listing
August 2019

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

HPB (Oxford) 2019 06 22;21(6):643-652. Epub 2018 Nov 22.

Department of Surgery, University Health Network, University of Toronto, Toronto, Canada; University of Toronto, Toronto, Canada. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hpb.2018.10.004DOI Listing
June 2019

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

Aust J Rural Health 2018 Dec 19;26(6):400-407. Epub 2018 Nov 19.

Rural Clinical School, Australian National University, Canberra, Australian Capital Territory, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajr.12427DOI Listing
December 2018

Handover training in the workplace: having a CHAT.

Clin Teach 2019 06 28;16(3):248-252. Epub 2018 Sep 28.

Office of Education, The University of Sydney School of Medicine, Sydney, New South Wales, Australia.

Background: Clinical handover is a core skill that needs to be learned by students and junior clinical staff to improve patient safety. Despite this, training is frequently lacking and of poor quality. A user-friendly assessment tool can assist clinicians to provide training and feedback.

Context: This tool was developed in the context of medical students on short placements in remote health services, supervised by registered nurses, in outback Australia. Students make telephone handover calls to the Royal Flying Doctor Service (RFDS), which provides generalist and aeromedical retrieval services to its communities.

Methods: Doctors in the RFDS at Broken Hill used a clinical handover assessment tool (CHAT), based on the introduction, situation, background, assessment and recommendation (ISBAR) handover mnemonic, for assessment and training on telephone handovers given by medical students in this remote setting. Medical students were invited to complete surveys and doctors completed interviews about their experience of giving or receiving handovers. Students highly valued the experience of learning handovers in a clinical setting. Doctors in the RFDS found the tool helpful for assessment and for giving feedback in their routine work. We identified no concerns about the safety of patients or students. …we explored the acceptability and educational impact of doctors giving immediate feedback on medical students' handover skills using CHAT CONCLUSIONS: We suggest that work-based handover assessment and feedback provided by clinicians are feasible and should be developed further. Students can learn to give handovers safely even in a remote setting. Clinicians may find CHAT helpful in the learning and teaching of structured handovers in other clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tct.12931DOI Listing
June 2019

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

BJU Int 2018 11 31;122(5):814-822. Epub 2018 May 31.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bju.14372DOI Listing
November 2018

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

Cancer 2018 04 16;124(7):1374-1382. Epub 2018 Jan 16.

Memorial Sloan Kettering Cancer Center, New York, New York.

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/m , 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.31218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867226PMC
April 2018

Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury.

Nat Med 2018 02 8;24(2):239-246. Epub 2018 Jan 8.

Program in Immunology, Clinical Research Division and Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

There is a substantial unmet clinical need for new strategies to protect the hematopoietic stem cell (HSC) pool and regenerate hematopoiesis after radiation injury from either cancer therapy or accidental exposure. Increasing evidence suggests that sex hormones, beyond their role in promoting sexual dimorphism, regulate HSC self-renewal, differentiation, and proliferation. We and others have previously reported that sex-steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice. Here we found that a luteinizing hormone (LH)-releasing hormone antagonist (LHRH-Ant), currently in wide clinical use for sex-steroid inhibition, promoted hematopoietic recovery and mouse survival when administered 24 h after an otherwise-lethal dose of total-body irradiation (L-TBI). Unexpectedly, this protective effect was independent of sex steroids and instead relied on suppression of LH levels. Human and mouse long-term self-renewing HSCs (LT-HSCs) expressed high levels of the LH/choriogonadotropin receptor (LHCGR) and expanded ex vivo when stimulated with LH. In contrast, the suppression of LH after L-TBI inhibited entry of HSCs into the cell cycle, thus promoting HSC quiescence and protecting the cells from exhaustion. These findings reveal a role of LH in regulating HSC function and offer a new therapeutic approach for hematopoietic regeneration after hematopoietic injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nm.4470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803436PMC
February 2018

Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial.

Clin Cancer Res 2018 03 29;24(6):1344-1354. Epub 2017 Dec 29.

PanCuRx Translational Research Initiative, Ontario, Institute for Cancer Research, Toronto, Ontario, Canada.

To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection. Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype ( = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. expression in tumor measured by RNA hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-17-2994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968824PMC
March 2018
-->