Publications by authors named "Andrew Barbour"

88 Publications

Radiomics Biomarkers Correlate with CD8 Expression and Predict Immune Signatures in Melanoma Patients.

Mol Cancer Res 2021 Apr 2. Epub 2021 Apr 2.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia.

Treatment for metastatic melanoma includes targeted and/or immunotherapy. Although many patients respond, only a subset has complete response. As late-stage patients often have multiple tumors in difficult access sites, non-invasive techniques are necessary for the development of predictive/prognostic biomarkers. PET/CT scans from 52 patients with stage III/IV melanoma were assessed and CT image parameters were evaluated as prognostic biomarkers. Analysis indicated patients with high standard deviation or high mean of positive pixels (MPP) had worse progression-free survival ( = 0.00047 and = 0.0014, respectively) and worse overall survival ( = 0.0223 and = 0.0465, respectively). Whole-exome sequencing showed high MPP was associated with mutation status ( = 0.0389). RNA-sequencing indicated patients with immune "cold" signatures had worse survival, which was associated with CT biomarker, MPP4 ( = 0.0284). Multiplex immunofluorescence confirmed a correlation between CD8 expression and image biomarkers ( = 0.0028). IMPLICATIONS: CT parameters have the potential to be cost-effective biomarkers of survival in melanoma, and reflect the tumor immune-microenvironment. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/00/0/000/F1.large.jpg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-20-1038DOI Listing
April 2021

Human CD141 dendritic cells (cDC1) are impaired in patients with advanced melanoma but can be targeted to enhance anti-PD-1 in a humanized mouse model.

J Immunother Cancer 2021 Mar;9(3)

Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia

Background: The conventional type 1 dendritic cell subset (cDC1) is indispensable for tumor immune responses and the efficacy of immune checkpoint inhibitor (ICI) therapies in animal models but little is known about the role of the human CD141 DC cDC1 equivalent in patients with melanoma.

Methods: We developed a flow cytometry assay to quantify and characterize human blood DC subsets in healthy donors and patients with stage 3 and stage 4 metastatic melanoma. To examine whether harnessing CD141 DCs could improve responses to ICIs in human melanoma, we developed a humanized mouse model by engrafting immunodeficient NSG-SGM3 mice with human CD34 hematopoietic stem cells (HSCs) from umbilical cord blood followed by transplantation of a human melanoma cell line and treatment with anti-programmed cell death protein-1 (anti-PD-1).

Results: Blood CD141 DC numbers were significantly reduced in patients with stage 4 melanoma compared with healthy controls. Moreover, CD141 DCs in patients with melanoma were selectively impaired in their ability to upregulate CD83 expression after stimulation with toll-like receptor 3 (TLR3) and TLR7/8 agonists ex vivo. Although DC numbers did not correlate with responses to anti-PD-1 and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ICIs, their numbers and capacity to upregulate CD83 declined further during treatment in non-responding patients. Treatment with anti-PD-1 was ineffective at controlling tumor growth in humanized mice but efficacy was enhanced by indirectly expanding and activating DCs in vivo with -like tyrosine kinase-3 ligand (Flt3L) and a TLR3 agonist. Moreover, intratumoral injections of CD141 DCs resulted in reduced tumor growth when combined with anti-PD-1 treatment.

Conclusions: These data illustrate quantitative and qualitative impairments in circulating CD141 DCs in patients with advanced melanoma and that increasing CD141 DC number and function is an attractive strategy to enhance immunogenicity and response rates to ICIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978242PMC
March 2021

Clinical pathways and outcomes of patients with Barrett's esophagus in tertiary care settings: a prospective longitudinal cohort study in Australia, 2008-2016.

Dis Esophagus 2020 Dec 12. Epub 2020 Dec 12.

Population Health Department, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.

Background: Clinical services for Barrett's esophagus have been rising worldwide including Australia, but little is known of the long-term outcomes of such patients. Retrospective studies using data at baseline are prone to both selection and misclassification bias. We investigated the clinical characteristics and outcomes of Barrett's esophagus patients in a prospective cohort.

Methods: We recruited patients diagnosed with Barrett's esophagus in tertiary settings across Australia between 2008 and 2016. We compared baseline and follow-up epidemiological and clinical data between Barrett's patients with and without dysplasia. We calculated age-adjusted incidence rates and estimated minimally and fully adjusted hazard ratios (HR) to identify those clinical factors related to disease progression.

Results: The cohort comprised 268 patients with Barrett's esophagus (median follow-up 5 years). At recruitment, 224 (84%) had no dysplasia, 44 (16%) had low-grade or indefinite dysplasia (LGD/IND). The age-adjusted incidence of esophageal adenocarcinoma (EAC) was 0.5% per year in LGD/IND compared with 0.1% per year in those with no dysplasia. Risk of progression to high-grade dysplasia/EAC was associated with prior LGD/IND (fully adjusted HR 6.55, 95% confidence interval [CI] 1.96-21.8) but not long-segment disease (HR 1.03, 95%CI 0.29-3.58).

Conclusions: These prospective data suggest presence of dysplasia is a stronger predictor of progression to cancer than segment length in patients with Barrett's esophagus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/dote/doaa119DOI Listing
December 2020

Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients.

Sci Rep 2020 10 19;10(1):17687. Epub 2020 Oct 19.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.

Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (< 20 Mut/Mb; p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72-15.7). Stage IV (HR 2.5, 0.74-8.6) and low TMB (HR 2.3, 0.57-9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44-5.2).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-74956-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572377PMC
October 2020

Factors predicting toxicity and response following isolated limb infusion for melanoma: An international multi-centre study.

Eur J Surg Oncol 2020 11 13;46(11):2140-2146. Epub 2020 Jul 13.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.

Introduction: Isolated limb infusion (ILI) is a minimally-invasive procedure for delivering high-dose regional chemotherapy to treat melanoma in-transit metastases confined to a limb. The aim of this international multi-centre study was to identify predictive factors for toxicity and response.

Methods: Data of 687 patients who underwent a first ILI for melanoma in-transit metastases confined to the limb between 1992 and 2018 were collected at five Australian and four US tertiary referral centres.

Results: After ILI, predictive factors for increased limb toxicity (Wieberdink grade III/IV limb toxicity, n = 192, 27.9%) were: female gender, younger age, procedures performed before 2005, lower limb procedures, higher melphalan dose, longer drug circulation and ischemia times, and increased tissue hypoxia. No patient experienced grade V toxicity (necessitating amputation). A complete response (n = 199, 28.9%) was associated with a lower stage of disease, lower burden of disease (BOD) and thinner Breslow thickness of the primary melanoma. Additionally, an overall response (combined complete and partial response, n = 441, 64.1%) was associated with female gender, Australian centres, procedures performed before 2005, lower limb procedures and lower actinomycin-D doses. On multivariate analysis, higher melphalan dose remained a predictive factor for toxicity, while lower stage of disease and lower BOD remained predictive factors for overall response.

Conclusion: ILI is safe and effective to treat melanoma in-transit metastases. Predictive factors for toxicity and response identified in this study will allow improved patient selection and optimization of intra-operative parameters to increase response rates, while keeping toxicity low.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejso.2020.06.040DOI Listing
November 2020

Opioid-induced Somatic Activation: Prevalence in a Population of Patients With Chronic Pain.

Cureus 2020 May 1;12(5):e7911. Epub 2020 May 1.

Psychiatry, Duke University Health System, Durham, USA.

Context and objective Opioids have heterogeneous side effects including a well-known effect of sedation; however, the opposing effect of stimulation, or somatic activation, has been largely ignored or overlooked. The objective of this study is to determine the prevalence of opioid-induced somatic activation (OISA). Methods We conducted a retrospective chart review of 189 patients seen by a single clinical psychiatrist/pain specialist. During the initial encounter, the clinician took a standardized history of every opioid currently or previously taken by the patients, and enquired if the patients had experienced a somatically activating or sedating effect per opioid. Results Patients recalled an average exposure to 5.1 opioids (SD: 1.9). Ninety-one patients (48.1%; mean: 1.6) reported somatic activation, while 118 (62.4%; mean: 1.7) reported sedation from at least one opioid. Fifty-eight patients (30.7%) identified at least one opioid as activating, and another as sedating. The distribution of OISA did not significantly differ by gender, race, primary pain diagnosis, or depression. The distribution of OISA by oxycodone significantly differed compared to morphine sulfate (27.3% vs 8.9%; p: 0.005), while sedation did not (29.0% vs 24.3%; p: 0.46). Conclusions In this study, we quantified the previously unstudied phenomenon of OISA. This phenomenon appears dependent on opioid type with some opioids, such as oxycodone, appearing more likely to have this effect. Given current concerns about the risks of opioids in high-risk populations, future studies are needed to study this phenomenon to arrive at an accurate determination of the potential risks and benefits of OISA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7759/cureus.7911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263729PMC
May 2020

Effective targeting of intact and proteolysed CDCP1 for imaging and treatment of pancreatic ductal adenocarcinoma.

Theranostics 2020 4;10(9):4116-4133. Epub 2020 Mar 4.

Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.

: CUB domain-containing protein 1 (CDCP1) is a cell surface receptor regulating key signalling pathways in malignant cells. CDCP1 has been proposed as a molecular target to abrogate oncogenic signalling pathways and specifically deliver anti-cancer agents to tumors. However, the development of CDCP1-targeting agents has been questioned by its frequent proteolytic processing which was thought to result in shedding of the CDCP1 extracellular domain limiting its targetability. In this study, we investigated the relevance of targeting CDCP1 in the context of pancreatic ductal adenocarcinoma (PDAC) and assess the impact of CDCP1 proteolysis on the effectiveness of CDCP1 targeting agents. : The involvement of CDCP1 in PDAC progression was assessed by association analysis in several PDAC cohorts and the proteolytic processing of CDCP1 was evaluated in PDAC cell lines and patient-derived cells. The consequences of CDCP1 proteolysis on its targetability in PDAC cells was assessed using immunoprecipitation, immunostaining and biochemical assays. The involvement of CDCP1 in PDAC progression was examined by loss-of-function and experiments employing PDAC cells expressing intact or cleaved CDCP1. Finally, we generated antibody-based imaging and therapeutic agents targeting CDCP1 to demonstrate the feasibility of targeting this receptor for detection and treatment of PDAC tumors. : High CDCP1 expression in PDAC is significantly associated with poorer patient survival. In PDAC cells proteolysis of CDCP1 does not always result in the shedding of CDCP1-extracellular domain which can interact with membrane-bound CDCP1 allowing signal transduction between the different CDCP1-fragments. Targeting CDCP1 impairs PDAC cell functions and PDAC tumor growth independently of CDCP1 cleavage status. A CDCP1-targeting antibody is highly effective at delivering imaging radionuclides and cytotoxins to PDAC cells allowing specific detection of tumors by PET/CT imaging and superior anti-tumor effects compared to gemcitabine in models. : Independent of its cleavage status, CDCP1 exerts oncogenic functions in PDAC and has significant potential to be targeted for improved radiological staging and treatment of this cancer. Its elevated expression by most PDAC tumors and lack of expression by normal pancreas and other major organs, suggest that targeting CDCP1 could benefit a significant proportion of PDAC patients. These data support the further development of CDCP1-targeting agents as personalizable tools for effective imaging and treatment of PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.43589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086361PMC
March 2020

Management of early-stage gastro-esophageal cancers: expert perspectives from the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty.

Expert Rev Anticancer Ther 2020 04 12;20(4):305-324. Epub 2020 Apr 12.

Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia.

: A multimodal approach in operable early-stage oesophago-gastric (OG) cancer has evolved in the last decade, leading to improvement in overall outcomes.: A review of the published literature and conference abstracts was undertaken on the topic of optimal adjunctive chemotherapy or chemoradiotherapy in early-stage OG cancers. This review article focuses on the current evidence pertaining to neoadjuvant and perioperative strategies in curable OG cancers including the evolving landscape of immunotherapy and targeted drugs in this setting.: Adjunctive therapies in the form of preoperative chemo-radiotherapy (CRT) or chemotherapy and perioperative chemotherapy over surgery alone improve outcomes in patients with operable OG cancer. Although there are variations in practice around the world, a multi-disciplinary approach to patient care is of paramount importance. Immunotherapy and on treatment functional imaging are two examples of emerging strategies to improve the outcome for early-stage patients. A better understanding of the molecular biology of this disease may help overcome the problem of tumor heterogeneity and enable more rationally designed and targeted therapeutic interventions in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14737140.2020.1746185DOI Listing
April 2020

International Multicenter Experience of Isolated Limb Infusion for In-Transit Melanoma Metastases in Octogenarian and Nonagenarian Patients.

Ann Surg Oncol 2020 May 9;27(5):1420-1429. Epub 2020 Mar 9.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Background: Isolated limb infusion (ILI) is used to treat in-transit melanoma metastases confined to an extremity. However, little is known about its safety and efficacy in octogenarians and nonagenarians (ON).

Patients And Methods: ON patients (≥ 80 years) who underwent a first ILI for American Joint Committee on Cancer seventh edition stage IIIB/IIIC melanoma between 1992 and 2018 at nine international centers were included and compared with younger patients (< 80 years). A cytotoxic drug combination of melphalan and actinomycin-D was used.

Results: Of the 687 patients undergoing a first ILI, 160 were ON patients (median age 84 years; range 80-100 years). Compared with the younger cohort (n = 527; median age 67 years; range 29-79 years), ON patients were more frequently female (70.0% vs. 56.9%; p = 0.003), had more stage IIIB disease (63.8 vs. 53.3%; p = 0.02), and underwent more upper limb ILIs (16.9% vs. 9.5%; p = 0.009). ON patients experienced similar Wieberdink limb toxicity grades III/IV (25.0% vs. 29.2%; p = 0.45). No toxicity-related limb amputations were performed. Overall response for ON patients was 67.3%, versus 64.6% for younger patients (p = 0.53). Median in-field progression-free survival was 9 months for both groups (p = 0.88). Median distant progression-free survival was 36 versus 23 months (p = 0.16), overall survival was 29 versus 40 months (p < 0.0001), and melanoma-specific survival was 46 versus 78 months (p = 0.0007) for ON patients compared with younger patients, respectively.

Conclusions: ILI in ON patients is safe and effective with similar response and regional control rates compared with younger patients. However, overall and melanoma-specific survival are shorter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-08312-0DOI Listing
May 2020

Artificial Intelligence in Health Care: Insights From an Educational Forum.

J Med Educ Curric Dev 2019 Jan-Dec;6:2382120519889348. Epub 2020 Jan 28.

School of Medicine, Duke University, Durham, NC, USA.

Discussions surrounding the future of artificial intelligenc (AI) in healthcare often cause consternation among healthcare professionals. These feelings may stem from a lack of formal education on AI and how to be a leader of AI implementation in medical systems. To address this, our academic medical center hosted an educational summit exploring how to become a leader of AI in healthcare. This article presents three lessons learned from hosting this summit, thus providing guidance for developing medical curriculum on the topic of AI in healthcare.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2382120519889348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993147PMC
January 2020

Radiation Therapy Practice Patterns for Brain Metastases in the United States in the Stereotactic Radiosurgery Era.

Adv Radiat Oncol 2020 Jan-Feb;5(1):43-52. Epub 2019 Jul 26.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Purpose: Utilization of stereotactic radiosurgery (SRS) for brain metastases (BM) has increased, prompting reassessment of whole brain radiation therapy (WBRT). A pattern of care analysis of SRS and WBRT dose-fractionations was performed in patients presenting with BM at the time of cancer diagnosis.

Methods And Materials: Adults with BM at cancer diagnosis between 2010 to 2015 and no prior malignancy were identified in the National Cancer Database. SRS was defined using published thresholds. Short (ShWBRT), standard (StWBRT), and extended (ExWBRT) dose-fractionations were defined as 4 to 9, 10 to 15, and >15 fractions. Radioresistant histology was defined as melanoma, renal cell carcinoma, sarcoma or spindle cell, or gastrointestinal primary.

Results: Of 4,087,967 adults with their first lifetime cancer, 90,388 (2.2%) had BM at initial diagnosis. Of these, 11,486 (12.7%) received SRS and 24,262 (26.8%) WBRT as first-course radiation therapy. The proportion of annual WBRT use decreased from 27.8% to 23.5% of newly diagnosed patients, and SRS increased from 8.7% to 17.9%. Common dose-fractionations were 30 Gy in 10 fractions (56.8%) for WBRT and 20 Gy in 1 fraction (13.0%) for SRS. On multivariate analysis, factors significantly associated with SRS versus WBRT included later year of diagnosis (2015 vs 2010, adjusted odds ratio [aOR] = 2.4), radioresistance (aOR = 2.0), academic facility (aOR = 1.9), highest income quartile (aOR = 1.6), chemotherapy administration (aOR = 1.4), and longer travel distance (>15 vs < 5 miles, aOR = 1.4). Linear regression revealed significant ExWBRT reductions (-22.4%/y, R = 0.97,  < .001) and no significant change for ShWBRT or StWBRT. Patients were significantly more likely to receive ShWBRT than StWBRT if not treated with chemotherapy (aOR = 3.5).

Conclusions: Utilization of WBRT, particularly ExWBRT, decreased while SRS utilization doubled as the first radiation therapy course in patients with BM at diagnosis. Patients with radioresistant histologies were more likely to receive SRS. Those not receiving chemotherapy, potentially owing to poor performance status, were less likely to receive SRS and more likely to receive ShWBRT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.adro.2019.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004940PMC
July 2019

CAR T cells and checkpoint inhibition for the treatment of glioblastoma.

Expert Opin Biol Ther 2020 06 17;20(6):579-591. Epub 2020 Feb 17.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

: Glioblastoma (GBM) is a highly aggressive brain tumor and is one of the most lethal human cancers. Chimeric antigen receptor (CAR) T cell therapy has markedly improved survival in previously incurable disease; however, this vanguard treatment still faces challenges in GBM. Likewise, checkpoint blockade therapies have not enjoyed the same victories against GBM. As it becomes increasingly evident that a mono-therapeutic approach is unlikely to provide anti-tumor efficacy, there evolves a critical need for combined treatment strategies.: This review highlights the clinical successes observed with CAR T cell therapy as well the current efforts to overcome its perceived limitations. The review also explores employed combinations of CAR T cell approaches with immune checkpoint blockade strategies, which aim to potentiate immunotherapeutic benefits while restricting the impact of tumor heterogeneity and T cell exhaustion.: Barriers such as tumor heterogeneity and T cell exhaustion have exposed the weaknesses of various mono-immunotherapeutic approaches to GBM, including CAR T cell and checkpoint blockade strategies. Combining these potentially complementary strategies, however, may proffer a rational means of mitigating these barriers and advancing therapeutic successes against GBM and other solid tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14712598.2020.1727436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202971PMC
June 2020

The AGITG GAP Study: A Phase II Study of Perioperative Gemcitabine and Nab-Paclitaxel for Resectable Pancreas Cancer.

Ann Surg Oncol 2020 Jul 29;27(7):2506-2515. Epub 2020 Jan 29.

Prince of Wales Hospital, Sydney, NSW, Australia.

Background: While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy.

Methods: Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/m and gemcitabine 1000 mg/m on days 1, 8, and 15 (28-day cycle) presurgery, and four cycles postoperatively. Early response to chemotherapy was measured with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans on day 15.

Results: Preoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (≥ 1 mm) resections, 14 (48%) had R1 (< 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months.

Conclusions: The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a > 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-08205-2DOI Listing
July 2020

Australasian Gastrointestinal Trials Group (AGITG) and Trans-Tasman Radiation Oncology Group (TROG) Guidelines for Pancreatic Stereotactic Body Radiation Therapy (SBRT).

Pract Radiat Oncol 2020 May - Jun;10(3):e136-e146. Epub 2019 Nov 21.

Royal North Shore Hospital, Sydney, Australia; University of Sydney, Sydney, Australia.

Purpose: Nonrandomized data exploring pancreas stereotactic body radiation therapy (SBRT) has demonstrated excellent local control rates and low toxicity. Before commencing a randomized trial investigating pancreas SBRT, standardization of prescription dose, dose constraints, simulation technique, and clinical target volume delineation are required.

Methods And Materials: Specialists in radiation oncology, medical oncology, hepatobiliary surgery, and gastroenterology attended 2 consecutive Australasian Gastrointestinal Trials Group workshops in 2017 and 2018. Sample cases were discussed during workshop contact with specifically invited international speakers highly experienced in pancreas SBRT. Furthermore, sample cases were contoured and planned between workshop contact to finalize dose constraints and clinical target volume delineation.

Results: Over 2 separate workshops, consensus was reached on dose and simulation technique. The working group recommended a dose prescription of 40 Gy in 5 fractions. Treatment delivery during end-expiratory breath hold with triple-phase contrast enhanced computed tomography was recommended. In addition, dose constraints, stepwise contouring guidelines, and an anatomic atlas for pancreatic SBRT were developed.

Conclusions: Pancreas SBRT is emerging as a promising treatment modality requiring prospective evaluation in randomized studies. This work attempts to standardize dose, simulation technique, and volume delineation to support the delivery of high quality SBRT in a multicenter study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prro.2019.07.018DOI Listing
December 2020

The Impact of Signet Ring Cell Differentiation on Outcome in Patients with Esophageal and Gastroesophageal Junction Adenocarcinoma.

Ann Surg Oncol 2019 Aug 2;26(8):2375-2384. Epub 2019 Apr 2.

Upper Gastrointestinal/Soft Tissue Unit, Princess Alexandra Hospital, Brisbane, QLD, Australia.

Background: Little is known about the association between signet ring cell (SRC) differentiation and response to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal and junctional adenocarcinoma (EAC). We aimed to assess if SRC differentiation is associated with survival and response to nCT or nCRT in patients with EAC.

Methods: Patients who underwent nCT and nCRT followed by surgery for EAC from 2000 until 2016 were identified from two institutional prospectively maintained databases. The pretreatment biopsy report or surgical resection specimen was used to differentiate patients into an SRC or non-SRC group.

Results: Overall, 129 (19%) of 689 patients included had SRCs (nCT: n = 64; nCRT: n = 65). The SRC group had a more advanced ypT stage (p = 0.003), a higher number of positive lymph nodes in the resection specimen {median (interquartile range [IQR]) 2 [0-5] vs. 1 [0-3]; p = 0.002} and a higher rate of R1/R2 resections (19.4% vs. 12%; p = 0.026). SRC differentiation was not an independent prognostic factor for overall survival (OS) or disease-free survival (DFS). Following nCT, the SRC group had significantly shorter DFS (median [IQR] 12 [5-50] vs. 23 [8-164]; p = 0.013), but not OS, compared with the non-SRC group. In contrast, no differences according to SRC status for OS or DFS were found in patients who underwent nCRT.

Conclusions: SRC differentiation was not independently associated with worse OS in patients with EAC who underwent neoadjuvant therapy and surgery. However, nCRT was associated with greater tumor downstaging and better DFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-019-07322-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611740PMC
August 2019

Evaluation of the efficacy and toxicity of upper extremity isolated limb infusion chemotherapy for melanoma: An Australian multi-center study.

Eur J Surg Oncol 2019 05 27;45(5):832-837. Epub 2019 Feb 27.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Discipline of Surgery, The University of Sydney, Sydney, NSW, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. Electronic address:

Background: Isolated limb infusion (ILI) is a minimally invasive treatment for patients with locally advanced extremity melanoma. Most studies combine results of upper-limb ILI (UL-ILI) and lower-limb ILI (LL-ILI), leaving UL-ILIs relatively underreported as LL-ILIs comprise the vast majority in these reports. However, differences between the two procedures may be clinically important. The aim of this study was to evaluate the efficacy and toxicity of UL-ILI in an Australian multi-center setting.

Patients And Methods: 316 ILI procedures for melanoma performed between 1992 and 2008 in five Australian institutions were analyzed. In all institutions melphalan (±actinomycin D) was circulated in the isolated limb for 20-30 min.

Results: Baseline patient characteristics for UL-ILI (n = 27) and LL-ILI (n = 289) were similar, except that more men underwent UL-ILI (66% vs. 38%; p = 0.007) and disease in LL-ILI was mostly located on the distal limb (p = 0.02). Median tourniquet times were shorter for UL-ILI (38 vs. 48 min; p = 0.04) and UL-ILI patients experienced less limb toxicity (Grade III/IV in 24% vs. 31%; p = 0.01). Complete response (CR) rates were similar: 33% after LL-ILI (p = 0.70), 30% after UL-ILI, while overall response (OR) rates were higher after LL-ILI: (76%) than UL-ILI (59%; p = 0.05). No difference in survival was seen.

Conclusions: UL-ILI is safe to perform and effective, resulting in low limb toxicity. CR rates were similar to those for LL-ILI, but OR rates were lower for UL-ILI. It may be possible to improve OR rates achieved by UL-ILI by optimizing perioperative factors, while maintaining low toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejso.2019.02.026DOI Listing
May 2019

The relative distribution of oral cancer in the United States by subsite.

Oral Oncol 2019 02 18;89:56-58. Epub 2018 Dec 18.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oraloncology.2018.12.017DOI Listing
February 2019

Complex structural rearrangements are present in high-grade dysplastic Barrett's oesophagus samples.

BMC Med Genomics 2019 02 4;12(1):31. Epub 2019 Feb 4.

Surgical Oncology Group, Diamantina Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.

Background: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett's oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals.

Methods: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples.

Results: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples.

Conclusions: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-019-0476-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360790PMC
February 2019

Patients with in-transit melanoma metastases have comparable survival outcomes following isolated limb infusion or intralesional PV-10-A propensity score matched, single center study.

J Surg Oncol 2019 May 15;119(6):717-727. Epub 2019 Jan 15.

Queensland Melanoma Project, Princess Alexandra Hospital, Queensland Health, Brisbane, Queensland, Australia.

Background And Objective: Isolated limb infusion (ILI) and intralesional PV-10 are well described locoregional therapies for in-transit melanoma. The objective of this study was to assess the effect of these treatments on survival outcomes within a cohort matched for key characteristics.

Methods: Patients were treated using ILI or intralesional PV-10 at a single institution and the data prospectively recorded. Propensity score matching was performed using key covariates within a logistic regression model. The primary outcome was the melanoma-specific survival.

Results: Seventy-two patients nonrandomized were successfully matched. Both treatments produced similar best overall responses. The median melanoma-specific survival (MSS) was 74.4 months from ILI and 36.4 months from PV-10 treatments (P = 0.164). Within the ILI subgroup, the 12-, 24-, 36- and 60-month MSS rates were 85.3%, 75.3%, 60.1%, and 60.1%, respectively. From the time of PV-10 the corresponding 12-, 24-, 36-, and 60-month MSS rates were 82.6%, 70.0%, 53.9%, and 35.9%. On multivariate analysis, there was a significant difference in survival comparing completely with noncomplete responders ( P = 0.031).

Conclusions: These findings demonstrate that ILI and PV-10 treatments for in-transit disease produce comparable long-term survival. Both therapies have reproducible response rates and predominantly localized and tolerable side-effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.25373DOI Listing
May 2019

Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus.

Mol Cell Proteomics 2018 12 10;17(12):2324-2334. Epub 2018 Aug 10.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia. Electronic address:

Esophageal adenocarcinoma (EAC) is thought to develop from asymptomatic Barrett's esophagus (BE) with a low annual rate of conversion. Current endoscopy surveillance of BE patients is probably not cost-effective. Previously, we discovered serum glycoprotein biomarker candidates which could discriminate BE patients from EAC. Here, we aimed to validate candidate serum glycoprotein biomarkers in independent cohorts, and to develop a biomarker candidate panel for BE surveillance. Serum glycoprotein biomarker candidates were measured in 301 serum samples collected from Australia (4 states) and the United States (1 clinic) using previously established lectin magnetic bead array (LeMBA) coupled multiple reaction monitoring mass spectrometry (MRM-MS) tier 3 assay. The area under receiver operating characteristic curve (AUROC) was calculated as a measure of discrimination, and multivariate recursive partitioning was used to formulate a multi-marker panel for BE surveillance. Complement C9 (C9), gelsolin (GSN), serum paraoxonase/arylesterase 1 (PON1) and serum paraoxonase/lactonase 3 (PON3) were validated as diagnostic glycoprotein biomarkers in lectin pull-down samples for EAC across both cohorts. A panel of 10 serum glycoprotein biomarker candidates discriminated BE patients not requiring intervention (BE± low grade dysplasia) from those requiring intervention (BE with high grade dysplasia (BE-HGD) or EAC) with an AUROC value of 0.93. Tissue expression of C9 was found to be induced in BE, dysplastic BE and EAC. In longitudinal samples from subjects that have progressed toward EAC, levels of serum C9 were significantly ( < 0.05) increased with disease progression in EPHA (erythroagglutinin from ) and NPL ( lectin) pull-down samples. The results confirm alteration of complement pathway glycoproteins during BE-EAC pathogenesis. Further prospective clinical validation of the confirmed biomarker candidates in a large cohort is warranted, prior to development of a first-line BE surveillance blood test.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/mcp.RA118.000734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283291PMC
December 2018

Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus.

J Surg Oncol 2018 Jun 28;117(8):1687-1696. Epub 2018 May 28.

Upper Gastrointestinal/Soft Tissue Unit, Discipline of Surgery, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.

Background: The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC.

Methods: Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared.

Results: Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P = 0.802) or in-hospital mortality (2% vs 0%, P = 0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P = 0.013), and higher pathological complete response rates (15% vs 5%, P < 0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P = 0.645) were found.

Conclusion: In this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.25089DOI Listing
June 2018

Neoadjuvant therapy reduces cardiopulmunary function in patients undegoing oesophagectomy.

Int J Surg 2018 May 16;53:86-92. Epub 2018 Mar 16.

Upper GastrointestinaI and Soft Tissue Unit, Princess Alexandra Hospital, Queensland, Australia; Discipline of Surgery, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Queensland, Australia.

Neoadjuvant therapy (NAT) for oesophageal cancer may reduce cardiopulmonary function, assessed by cardiopulmonary exercise testing (CPEX). Impaired cardiopulmonary function is associated with mortality following esophagectomy. We sought to assess the impact of NAT on cardiopulmonary function using CPEX and assessing the clinical relevance of any change in particular if changes were associated with post-operative morbidity. This was a prospective, cohort study of 40 patients in whom CPEX was performed before and after NAT. Thirty-eight patients underwent surgery and follow-up with perioperative outcomes measured. The primary variables derived from CPEX were the anaerobic threshold (AT) and peak oxygen uptake (V˙Opeak). There were significant reductions in the AT (pre-NAT: 12.4 ± 3.0 vs. post-NAT 10.6 ± 2.0 mL kg.min; p = 0.001). This reduction was also evident for V˙Opeak (pre-NAT: 16.6 ± 3.6 vs. post-NAT 14.9 ± 3.7 mL kg.min; p = 0.004). The relative reduction in V˙Opeak was greater in chemotherapy patients who developed any peri-operative morbidity (p = 0.04). For patients who underwent chemoradiotherapy, there was a significantly greater relative reduction in AT (p = 0.03) for those who encountered a respiratory complication. Cardiopulmonary function significantly declined as a result of NAT prior to oesophagectomy. The reduction in AT and V˙Opeak was similar in both the chemotherapy and chemoradiotherapy groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijsu.2018.03.030DOI Listing
May 2018

Intralesional PV-10 for the treatment of in-transit melanoma metastases-Results of a prospective, non-randomized, single center study.

J Surg Oncol 2018 Mar 12;117(4):579-587. Epub 2018 Mar 12.

Queensland Melanoma Project, Princess Alexandra Hospital, Brisbane, Australia.

Background: Patients with in-transit melanoma metastases frequently experience high rates of recurrence, limited overall survival and reduced quality of life. After promising results within a Phase II, multi-center study, PV-10 treatment was continued at our institution for patients with in-transit disease.

Methodology: An open-label, non-randomized, prospective study was performed at the Princess Alexandra Hospital, Queensland, Australia. Patients were treated with PV-10 in accordance with the treatment protocol established during a previous Phase II study. The primary outcome was the complete response of treated lesions.

Results: Forty-five patients were enrolled over a total of 82 treatment episodes from July 2008 to December 2015. With sequential PV-10 treatments the complete response rate was 42% and overall response rate 87% on an intention to treat analysis. The median follow-up duration was 22 months and the median overall survival was 25 months from first PV-10 treatment. Having fewer than 15 metastases at the time of treatment was associated with a complete response (P = 0.03).

Conclusions: Intralesional PV-10 provided rapid lesion-specific ablation of melanoma metastases with well-tolerated local effects and minimal systemic adverse events. This therapy should be considered for patients with multiple accessible deposits within the spectrum of low to moderate disease volume.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.24921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668008PMC
March 2018

Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma.

Hepatology 2018 09 12;68(3):949-963. Epub 2018 Jun 12.

Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Intrahepatic cholangiocarcinoma remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole-exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, "undetermined"). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, comutation profiles, and enriched pathways. High-throughput drug repositioning in seven patient-matched cell lines, chosen to reflect the genetic alterations specific for each patient group, confirmed in silico predictions of subgroup-specific vulnerabilities linked to enriched pathways. Intriguingly, patients lacking all three mutations ("undetermined") harbored the most extensive structural alterations, while isocitrate dehydrogenase mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings.

Conclusion: Stratification of intrahepatic cholangiocarcinoma patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epimutational) that influence pharmacologic response in drug repositioning protocols; this genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity and could facilitate advancement of therapeutic response in this dismal disease. (Hepatology 2018).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.29764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599967PMC
September 2018

Safety and Efficacy of Isolated Limb Infusion Chemotherapy for Advanced Locoregional Melanoma in Elderly Patients: An Australian Multicenter Study.

Ann Surg Oncol 2017 Oct 10;24(11):3245-3251. Epub 2017 Aug 10.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Background: Isolated limb infusion (ILI) offers a minimally invasive treatment option for locally advanced extremity melanoma.

Objective: The aim of the current study was to evaluate the safety and efficacy of ILI in elderly patients in an Australian multicenter setting.

Methods: The results of 316 first ILI procedures, performed between 1992 and 2008 in five Australian institutions, were identified and analyzed, with the main focus on elderly patients (≥75 years of age). All institutions used the same protocol: melphalan was circulated in the isolated limb for 20-30 min (±actinomycin D), and toxicity, responses, and survival were recorded.

Results: Characteristics of patients aged ≥75 years (n = 148) were similar to those aged <75 years (n = 168), except that older patients had more melanoma deposits (median 4 vs. 5; p = 0.035) and lower limb volumes (5.4 vs. 6.5 L; p = 0.001). Median drug circulation times were lower in the older group (21 vs. 24 min; p = 0.04), and older patients experienced less limb toxicity (grade III/IV in 22 and 37% of patients, respectively; p = 0.003). A complete response (CR) was seen in 27% of patients aged ≥75 years and in 38% of patients aged <75 years (p = 0.06), while overall response rates were 72 and 77%, respectively (p = 0.30). No difference in survival was seen (p = 0.69).

Conclusions: The ILI technique proved safe and effective in elderly patients. When present, toxicity was localized, and lower compared with younger patients, possibly due to shorter drug circulation times. CR rates were higher in younger patients, although not significantly, while overall response and survival were equal. Optimization of perioperative factors in elderly patients may allow response rates to be raised further, while maintaining low toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-017-6046-5DOI Listing
October 2017

When is a sentinel node biopsy indicated for patients with primary melanoma? An update of the 'Australian guidelines for the management of cutaneous melanoma'.

Australas J Dermatol 2017 Nov 17;58(4):274-277. Epub 2017 Jul 17.

Melanoma Institute Australia, Poche Centre, Sydney, New South Wales, Australia.

A sentinel lymph node biopsy is a surgical staging procedure performed for patients with primary cutaneous melanoma who are clinically lymph-node negative to determine whether there is low volume nodal metastasis in the draining lymph node field. A systematic review was recently performed to update the Australian clinical practice guidelines for the diagnosis and management of melanoma, addressing the question, 'When is a sentinel lymph node biopsy indicated?' This article discusses the findings of the systematic review and the evidence base for the updated guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajd.12662DOI Listing
November 2017

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017