41 results on '"Bambury RM"'
Search Results
2. Commentary on “DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma.”
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Teo, MY, primary, Bambury, RM, additional, Zabor, EC, additional, Jordan, E, additional, Al-Ahmadie, H, additional, Boyd, ME, additional, Bouvier, N, additional, Mullane, SA, additional, Cha, EK, additional, Roper, N, additional, Ostrovnaya, I, additional, Hyman, DM, additional, Bochner, BH, additional, Arcila, ME, additional, Solit, DB, additional, Berger, MF, additional, Bajorin, DF, additional, Bellmunt, J, additional, Iyer, G, additional, and Rosenberg, JE., additional
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- 2018
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3. Immune Checkpoint Inhibitors and Palliative Care at the End of Life: An Irish Multicentre Retrospective Study
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O'Sullivan, HM, Conroy, M, Power, DG, Bambury, RM, O’Mahony, D, Collins, DC, O’Leary, MJ, and O’Reilly, S
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Background and Objectives:Immune checkpoint inhibitors (ICIs) have less toxicity than standard chemotherapy and are now standard of care for many patients with advanced cancer. A manageable side effect profile and potential for durable responses may lead to aggressive care of the palliative patient. We sought to evaluate palliative care input and ICI use at the end of life at two Irish cancer centres. Methods:We identified deceased patients who received at least one dose of an ICI between first of January 2013 to 31stof December 2018. A retrospective electronic chart review was performed. Results:The electronic records of 102 patients were analysed. Fifty eight percent were male and the median age of diagnosis of advanced disease was 60 years (range 17-78). Median time from last dose of ICI to death was 57 days (range 8-574) and 20% of patients died within 30 days of last dose of ICI. Most patients, 92%, were referred to palliative care. The median time from palliative care referral to death was 64 days (range 1- 1010). In the last 30 days of life, 39% of patients attended the emergency department (ED) and 46% had at least one hospital admission. Late palliative care referrals, ≤3 months before death, were associated with hospitalisations in the last month of life (64% vs. 36%, P= .02). Timing of palliative care referral did not affect ICI prescribing at the end of life (P= 0.38). ICI use in the last 30 days of life was not associated with increased ED presentations or hospitalisations at the end of life. Patients who received ICI in the last month had a higher likelihood of in-hospital death (43% vs. 16%, P= 0.02). Conclusions:ICI within 30 days of death was associated with dying in hospital but did not lead to more hospitalisations and emergency department presentations. Early palliative care did not affect ICI use but reduced hospitalisations at the end of life.
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- 2024
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4. Abstract P3-10-23: Caveolin 1 and Patient Outcomes in Breast Cancer
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Bambury, RM, primary, Gonzalez-Angulo, A-M, additional, Carey, MS, additional, Sahin, A, additional, Brown, P, additional, Speers, C, additional, Lluch, A, additional, Mills, GB, additional, and Hennessy, BT, additional
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- 2010
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5. Intratumor heterogeneity and branched evolution.
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Bambury RM, Power DG, O'Reilly S, Bambury, Richard M, Power, Derek G, and O'Reilly, Seamus
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- 2012
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6. The impact of expanded access programs for systemic anticancer therapy in an Irish cancer centre.
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Cronin TK, Ronayne C, O'Donovan N, McGuinness E, Cooke K, Dennehy M, Dennehy C, Power DG, Cahill MR, Collins DC, Connolly RM, Bambury RM, Mykytiv V, Higgins MJ, Noonan SA, and O'Reilly S
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- Humans, Aged, Middle Aged, Male, Female, Adult, Ireland, Aged, 80 and over, Cancer Care Facilities statistics & numerical data, Neoplasms drug therapy, Health Services Accessibility statistics & numerical data, Antineoplastic Agents therapeutic use
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Background: Expanded access programs (EAPs) allow cancer patients with unmet clinical need to obtain access to pre-authorisation treatments. There is no standardised process for implementing these programs nationally, and real-world data on their impact is lacking., Aims: This study aimed to evaluate the prevalence of such EAPs and their impact in a cancer centre., Methods: Data relating to adult cancer patients treated via EAPs from 2011 to 2021 in three Cork university hospitals was collated. Descriptive statistics were employed to get an overview of the impact these programs currently have on cancer care provision., Results: We identified 193 patients who accessed EAPs during the study period, availing of 33 separate drugs for a total of 50 different cancer indications. The prevalence of EAP usage was shown to have been trending upwards in recent years with a total of 189 programs being accessed throughout the period. Drugs provided were from a number of different anti-cancer drug classes, particularly targeted therapies (n = 18) and immune checkpoint inhibitors (n = 17). Cancers from a wide range of both solid and liquid tumour types were treated with EAP drugs, and patients treated were from across a broad spectrum of ages (26-82, SD 11.99)., Conclusions: EAPs have an increasing role in accessing novel cancer therapies in our community and by extension nationally. Equity of EAP access would be facilitated by a national registry of available agents which we have established. Assessment of their benefits and toxicities would be enhanced by the requirement for a real-world database as a condition of EAP approval., (© 2024. The Author(s).)
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- 2024
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7. Risk Stratification Tools to Aid Decisions on Adjuvant Chemotherapy Usage in Resected Soft Tissue Sarcomas: A Ten-Year Review of an Irish Sarcoma Center Experience.
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Weadick CS, Goggin C, Keogh RJ, Murphy JF, Feeley L, Bennett MW, O'Reilly S, Redmond HP, Kelly J, O'Mahony D, Noonan S, Clover AJP, and Bambury RM
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Background: Soft tissue sarcoma (STS) is comprised of approximately 80 subtypes, with an incidence of 4 - 5 per 100,000 annually in Europe. The National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of neoadjuvant/adjuvant chemotherapy in tumors at high risk of recurrence based on the American Joint Committee on Cancer (AJCC) staging. Alternatively, the Sarculator is a risk prediction tool that has identified a threshold of risk, above which chemotherapy may provide an overall survival (OS) benefit. Using this nomogram, patients with a 10-year predicted OS < 60% are classified as high risk and should be considered for chemotherapy. The aim of this study was to assess the prognostic accuracy of these two risk prediction methods in an Irish population., Methods: All newly diagnosed patients with resected STS discussed in the STS tumor board in Cork University Hospital between January 2012 and December 2021 were identified. Clinicopathological data were collected. Risk assessment using AJCC and Sarculator nomogram was performed on all patients with an extremity/trunk sarcoma. The OS was calculated including Kaplan-Meier method for time to event analysis., Results: In total, 200 STS patients were reviewed, of whom 134 had truncal or extremity tumors. Sarculator score was calculated for 60 of these (well differentiated liposarcomas, desmoid tumors and dermatofibrosarcoma protuberans were excluded). Using the Sarculator nomogram to calculate 10-year predicted OS, 19 patients were categorized as high risk and 41 were categorized as low risk. Using AJCC staging, 25 patients were categorized as high risk and 35 as low risk. The 5-year OS rate in the Sarculator high-risk group was 60.2%, compared with 87.1% in the low-risk group (P = 0.009). The 5-year OS rate in the AJCC high-risk group was 67.6%, compared with 86.3% in the low-risk group (P = 0.083)., Conclusions: Our cohort is representative of the broad histological subtypes expected. In our population, Sarculator score results correlate with international outcomes and higher scores were associated with increased mortality. The Sarculator was more predictive of clinical outcome than AJCC staging, and its use would lower the proportion of patients being considered for adjuvant chemotherapy thereby sparing toxicity, which is important in the setting of uncertain clinical benefit., Competing Interests: The authors declare no conflict of interest., (Copyright 2024, Weadick et al.)
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- 2024
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8. Anaplastic Lymphoma Kinase (ALK)-Rearranged Renal Cell Carcinoma: A Case Report Highlighting Diagnostic Challenges and Therapeutic Opportunities.
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Elhassan E, Girleanu C, Kelly P, Power DG, Sweeney P, Mayer N, and Bambury RM
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A 57-year-old male underwent an open right radical nephrectomy in 2015 for a 3-cm kidney tumor which was classified at the time as a combined tubulocystic and collecting duct carcinoma. One of six nodes was positive for metastatic carcinoma and the patient received adjuvant carboplatin/gemcitabine chemotherapy. In 2020, he developed enlarging retroperitoneal adenopathy and underwent a retroperitoneal lymph node dissection with 11 of 13 nodes in the resected specimen positive for the previously described renal carcinoma, followed by adjuvant radiotherapy. In November 2022, he again underwent surgery for further locoregional recurrence with resection of a right psoas mass lesion and right hemicolectomy. Pathology on this occasion was reclassified as anaplastic lymphoma kinase-rearranged renal cell carcinoma (ALK-RCC). Shortly afterward, a restaging CT revealed multiple liver metastases and evidence of further disease recurrence in the right renal bed. He commenced alectinib with a complete radiological response and has continued on it for 12 months at the time of writing this report. To our knowledge, there are only five prior reports of ALK-RCC treated with targeted ALK inhibitor therapy in the literature. We report this case to highlight the importance of recognizing and diagnosing this rare RCC subtype since it has significant therapeutic implications. Furthermore, to our knowledge, this patient has had the longest follow-up reported to date in the literature so far. A concerted effort by the histopathology and oncology community is needed to gather more data on the incidence and treatment outcomes of these tumors so that progress can be made in optimizing their management. It is important to consider novel and emerging entities from the most recent WHO 2022 classification, many of which are defined by molecular characteristics with associated therapeutic implications., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Elhassan et al.)
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- 2024
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9. An evaluation of the utilisation of biosimilar monoclonal antibody drugs in Ireland and barriers to their usage.
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Coakley KE, Bambury RM, McGuinness E, Dennehy M, Ronayne C, Cahill M, and O'Reilly S
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- Humans, Ireland, Cross-Sectional Studies, Female, Male, Retrospective Studies, Surveys and Questionnaires, Prospective Studies, Adult, Middle Aged, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal economics, Biosimilar Pharmaceuticals therapeutic use, Rituximab therapeutic use, Trastuzumab therapeutic use
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Background: While biologic drugs have demonstrated efficacy across a range of indications, patient access to these drugs is constrained due to their high cost. Biosimilars provide a means to increase patient access while reducing the financial burden., Aims: The primary objective was to determine the current usage of biosimilar and reference trastuzumab and rituximab in four Irish hospitals. A secondary objective involved determining barriers to biosimilar usage., Methods: This project involved a retrospective chart review to analyse the usage of reference and biosimilar versions of trastuzumab and rituximab. Additionally, a prospective cross-sectional study identified barriers to the usage of biosimilars via the distribution of a novel questionnaire to patients, pharmacists, doctors and students., Results: The utilisation of biosimilar intravenous trastuzumab and rituximab ranged from 39 to 100%, and 0 to 89%, respectively. A total of n = 479 questionnaire responses were included. Biosimilar awareness was significantly lower among 'Doctors and Medical Students' (45.3%; 95% [CI, 33.8-57.3%]) compared to 'Pharmacists and Pharmacy Students' (97.1%; 95% [CI, 94-98.8%; comparison p < 0.001]). A significant majority of healthcare professionals agreed biosimilars should have consistent nomenclature (p < 0.001). A significant majority of patients (87.3%, 95% [CI, 81.3-92%; p < 0.001]) indicated that they would agree to commence using a biosimilar medicine., Conclusion: Biosimilar versions of trastuzumab and rituximab were in use to a variable extent. There remains a considerable opportunity to further increase the usage to maximise their potential benefits. A series of challenges were identified including reduced awareness among the medical profession and lack of clear nomenclature., (© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)
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- 2024
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10. Patient and Public Involvement to Optimise a Patient Information Leaflet Format.
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Johnston KE, Medved K, Raigal-Aran L, Crowley EK, Corkery S, Cahill A, Bambury RM, Noonan B, and Gleeson JP
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- Humans, Patient Education as Topic, Community Participation, Pamphlets, Patient Participation
- Abstract
Competing Interests: None declared.
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- 2024
11. Room to Improve: An Audit of In-Hospital End-of-Life Care for Oncology Patients in a Tertiary Cancer Centre in Ireland During the COVID-19 Pandemic.
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Carroll HK, Broderick A, McCarthy O, Bambury RM, Power DG, Collins DC, Connolly RM, Noonan SA, Collins D, Cunningham E, Kennedy M, O'Driscoll K, Nuzum D, Twomey K, O'Riordan A, O'Sullivan F, Roe C, Lowney AC, O'Leary MJ, and O'Reilly S
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The COVID-19 pandemic compounded isolation for patients through social distancing measures and staff shortages. We were concerned about the impact of COVID-19 on the quality of care provided at end-of-life in 2021 in a national cancer centre, and instigated the first ever review of the care of the dying. Quality of care was assessed retrospectively using a validated instrument developed by the United Kingdom's National Quality Board. Sixty-six patient deaths occurred in our cancer centre in 2021. The 'risk of dying' was documented in 65.2% of records. Palliative care services were involved in 77%, and pastoral care in 10.6%. What was important to the patient was documented in 24.2%. The 'quality-of-death' score was satisfactory for most but poor in 21.2%. Our study prompted change, including appointment of an end-of-life coordinator, development of a checklist to ensure comprehensive communication, expansion of the end-of-life committee to include junior doctors, and regular audit., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2023
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12. Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study.
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Abida W, Campbell D, Patnaik A, Bryce AH, Shapiro J, Bambury RM, Zhang J, Burke JM, Castellano D, Font A, Ganju V, Hardy-Bessard AC, McDermott R, Sautois B, Spaeth D, Voog E, Piulats JM, Pintus E, Ryan CJ, Merseburger AS, Daugaard G, Heidenreich A, Fizazi K, Loehr A, Despain D, Simmons AD, Dowson M, Go J, Watkins SP, and Chowdhury S
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- Male, Humans, Indoles therapeutic use, Genes, BRCA2, DNA Damage, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Background: Initial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration., Objective: To present the final data from TRITON2., Design, Setting, and Participants: TRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy., Outcome Measurements and Statistical Analysis: The primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint., Results and Limitations: As of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35-57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40-100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5-57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46-61%), 55% (23-83%), 3.4% (0.4-12), 6.7% (0.2-32%), 14% (0.4-58%), and 23% (5.0-54%), respectively., Conclusions: The final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene., Patient Summary: Almost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)
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- 2023
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13. Supportive care interventions for men with urological cancers: a scoping review.
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Saab MM, McCarthy M, Murphy M, Medved K, O'Malley M, Bambury RM, Gleeson JP, and Noonan B
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- Male, Humans, Quality of Life, Body Mass Index, Urologic Neoplasms therapy, Prostatic Neoplasms, Cognitive Behavioral Therapy
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Purpose: To identify supportive care interventions for men with urological cancers., Methods: Experimental studies conducted among men with any urological cancer were eligible for inclusion. Academic Search Complete, CINAHL Plus with Full Text, MEDLINE, APA PsycArticles, APA PsycInfo, Social Sciences Full Text (H.W. Wilson), SocINDEX with Full Text, ERIC, Google Scholar and ClinicalTrials.gov were searched on 6 December 2022. No database limits were applied. The included studies were methodologically appraised. A narrative synthesis of the results was conducted., Results: Thirty studies were included with 10 categories of interventions identified. Over 300 outcomes were measured, and more than 100 instruments were used. Multicomponent interventions generally led to positive changes in physiological outcomes like body mass index, as well as exercise tolerance and quality of life. This change, however, was not sustained in the long term. Cognitive-behavioural interventions significantly improved psychological symptoms but seldom physical symptoms. Telephone and web-based interventions showed great promise in improving outcomes like depression, positive affect, negative affect, perceived stress, spiritual wellbeing and fatigue. Findings from physical activity/exercise-based interventions were promising for both, physical and psychological outcomes. Rehabilitative interventions were associated with significant improvements in quality of life, urinary symptoms and psychological symptoms, albeit in the short term. Mixed results were reported for nurse-led interventions, family-based interventions and nutritional interventions., Conclusion: All but one study focused exclusively on prostate cancer. The included studies were significantly heterogeneous. Multicomponent, cognitive-behavioural, telephone and web-based, physical activity/exercise-based and rehabilitative interventions showed great promise in improving various outcomes. This improvement, however, was often short-lived., (© 2023. The Author(s).)
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- 2023
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14. A pilot project investigating the use of ONCOpatient®-An electronic patient-reported outcomes app for oncology patients.
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Macanovic B, O'Reilly D, Harvey H, Hadi D, Cloherty M, O'Dea P, Power DG, Collins DC, Connolly RM, Bambury RM, and O'Reilly S
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Purpose: To investigate the feasibility of implementing a remote patient monitoring system using an electronic patient-reported outcomes (ePROs) platform in a tertiary cancer center in the Republic of Ireland., Methods: Patients receiving oral chemotherapy and oncology clinicians were invited to participate in the study. Patients were asked to submit weekly symptom questionnaires through an ePRO mobile phone application (app)-ONCOpatient®. Clinical staff were invited to use the ONCOpatient® clinician interface. After 8 weeks all participants submitted evaluation questionnaires., Results: Thirteen patients and five staff were enrolled in the study. The majority of patients were female (85%) with a median age of 48 years (range 22-73). Most (92%) were enrolled over telephone requiring on average 16 minutes. Compliance with the weekly assessments was 91%. Alerts were triggered by 40% of patients who then required phone calls to aid with symptom management. At the end of study, 87% of patients reported they would use the app frequently, 75% reported that the platform met their expectations, and 25% that it exceeded their expectations. Similarly, 100% of staff reported they would use the app frequently, 60% reported that it met their expectations, and 40% that it exceeded their expectations., Conclusions: Our pilot study showed that it is feasible to implement ePRO platforms in the Irish clinical setting. Small sample bias was recognized as a limitation, and we plan to confirm our findings on a larger cohort of patients. In the next phase we will integrate wearables including remote blood pressure monitoring., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)
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- 2023
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15. Real-world outcomes and toxicity of adjuvant chemotherapy in NSCLC: a single-center experience.
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Cronin C, Iqbal S, Farooq AR, O'Dea P, Burke L, O'Reilly S, O'Mahony D, Power DG, Bambury RM, and Collins DC
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Aim: Adjuvant chemotherapy in NSCLC is associated with modest benefits and significant toxicity. We sought to evaluate the toxicity of adjuvant chemotherapy and disease-specific outcomes in a real-world population., Methods: We performed a retrospective analysis of patients undergoing adjuvant chemotherapy for NSCLC in an Irish center over a 7-year period. We described treatment-associated toxicity, recurrence-free survival and overall survival., Results: 62 patients underwent adjuvant chemotherapy. Treatment-associated hospitalisation occurred in 29% of patients. Relapse was recorded in 56% of patients and median recurrence-free survival was 27 months., Conclusion: High rates of disease recurrence and treatment-associated morbidity were observed in patients receiving adjuvant chemotherapy for NSCLC. Novel therapeutic strategies are required to improve outcomes in this population., (© 2023 The Authors.)
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- 2023
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16. Cost and public reimbursement of cancer medicines in the UK and the Republic of Ireland.
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O'Reilly D, McLaughlin R, Ronayne C, De Frein AM, Macanovic B, Chu RW, Noonan SA, Connolly RM, Power DG, Bambury RM, O'Reilly S, and Collins DC
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- Humans, United States, Ireland, United Kingdom, Treatment Outcome, United States Food and Drug Administration, Neoplasms drug therapy
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Introduction/aims: There are disparities in the availability of systemic anticancer therapies (SACTs) globally. We set out to investigate the cost and reimbursement of SACTs in the United Kingdom (UK) and the Republic of Ireland (ROI) in conjunction with efficacy and licensing authority decisions in the United States (US) and the European Union (EU)., Methods: We sought data pertaining to licensing in the EU, reimbursement in ROI/UK and cost/efficacy of SACTs licensed by the Food and Drug Administration (FDA) between January 2015 and May 2021. Independent samples t tests, chi-square test and Pearson's correlation were used for statistical analysis., Results: We identified that the majority of FDA-approved regimens are licensed by the European Medicines Agency (EMA) (n = 91, 67.9%). However, only a minority of these are currently reimbursed in the UK (n = 60, 45%) or the ROI (n = 28, 21%) as of the 1
st of May 2021. In addition, only a minority of regimens have demonstrated a statistically significant OS benefit (n = 54, 40%). There was no association between cost of regimens and either the presence (t = 0.846, p = 0.40) or duration of OS benefit (t = - 0.84, p = 0.64)., Conclusions: Our study highlights that many licensed systemic anticancer treatments are not currently reimbursed in ROI/UK. The high cost of these medicines is independent of the presence of an OS benefit. Collaboration between regulatory agencies, governments and industry partners is needed to ensure health expenditure is directed towards the most effective treatments., (© 2022. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)- Published
- 2023
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17. Rucaparib or Physician's Choice in Metastatic Prostate Cancer.
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Fizazi K, Piulats JM, Reaume MN, Ostler P, McDermott R, Gingerich JR, Pintus E, Sridhar SS, Bambury RM, Emmenegger U, Lindberg H, Morris D, Nolè F, Staffurth J, Redfern C, Sáez MI, Abida W, Daugaard G, Heidenreich A, Krieger L, Sautois B, Loehr A, Despain D, Heyes CA, Watkins SP, Chowdhury S, Ryan CJ, and Bryce AH
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- Humans, Male, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Indoles therapeutic use, Progression-Free Survival, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Androgen Antagonists therapeutic use, Docetaxel therapeutic use, Disease Progression, Genes, BRCA1, Genes, BRCA2, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant secondary, Antineoplastic Agents therapeutic use
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Background: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study., Methods: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1 , BRCA2 , or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review., Results: Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea., Conclusions: The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.)., (Copyright © 2023 Massachusetts Medical Society.)
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- 2023
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18. Management of newly diagnosed glioblastoma multiforme: current state of the art and emerging therapeutic approaches.
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McMahon DJ, Gleeson JP, O'Reilly S, and Bambury RM
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- Antineoplastic Agents, Alkylating therapeutic use, Humans, Immunotherapy, Temozolomide therapeutic use, Brain Neoplasms drug therapy, Brain Neoplasms therapy, Glioblastoma diagnosis, Glioblastoma therapy
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Glioblastoma multiforme represent > 50% of primary gliomas and have five year survival rates of ~ 5%. Maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide remains the standard treatment since published by Stupp et al. (in N Engl J Med 352:987-996, 2005), with additional benefit for patients with MGMT-methylated tumors. We review the current treatment landscape and ongoing efforts to improve these outcomes. An extensive literature search of Pubmed and Google Scholar involving the search terms "glioblastoma," "glioblastoma multiforme," or "GBM" for papers published to July 2021 was conducted and papers evaluated for relevance. As well as current data that informs clinical practice, we review ongoing clinical research in both newly diagnosed and recurrent settings that provides hope for a breakthrough. The Stupp protocol remains standard of care in 2021. Addition of tumor treating fields improved mOS modestly, with benefit seen in MGMT-methylated and unmethylated cohorts and also improved time to cognitive decline but has not been widely adopted. The addition of lomustine to temozolomide, in MGMT-methylated patients, also showed a mOS benefit but further investigation is required. Other promising therapeutic strategies including anti-angiogenic therapy, targeted therapy, and immunotherapy have yet to show a survival advantage. Improvements in the multidisciplinary management, surgical techniques and equipment, early palliative care, carrier support, and psychological support may be responsible for improving survival over time. Despite promising preclinical rationale, immunotherapy and targeted therapy are struggling to impact survival. A number of ongoing clinical trials provide hope for a breakthrough., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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19. Radium-223 in the Treatment of Metastatic Castrate-Resistant Prostate Cancer.
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Peters N, Bambury RM, Power DG, McCarthy L, Lyons C, Kelly P, and Jamaluddin MF
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- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Bone Neoplasms radiotherapy, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant radiotherapy, Radium adverse effects
- Abstract
Background Radium 223 (Ra-223) has been successfully utilised for the treatment of men with metastatic castrate resistant prostate cancer (mCRPC). To date, no real world outcomes from its use in the Irish population have been described. Methods All men referred to our institution for Ra-223 from September 2016 to March 2019 were included. Patient demographics, treatments received, toxicities and outcomes were recorded. Overall survival (OS) and progression free survival (PFS) were analysed using the Kaplan-Meier method. Results Complete data was available for 54 men. Median age was 75 years (range 61-86 years). The median number of prior systemic treatments for mCRPC was 2 (range 0-4). Median ECOG performance status was 1 at the start of treatment and 2 at completion. The median number of Ra-223 cycles received was 4 with 37%(n=20) completing all 6 planned cycles. The most common treatment-related toxicity was fatigue seen in 52% of patients ( n=28). Improved pain scores were documented in 76% of men requiring opioid analgesia at the start of treatment. The median OS was 7 months. A good ECOG performance status, fewer than 6 bone metastases, normal alkaline phosphatase level at start of treatment and chemotherapy naivety were associated with improved OS. Conclusions Ra-223 is a moderately well tolerated palliative treatment amongst Irish men with mCRPC., Competing Interests: I can declare that there are no conflicts of interest relating to this article.
- Published
- 2022
20. Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study.
- Author
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Loehr A, Patnaik A, Campbell D, Shapiro J, Bryce AH, McDermott R, Sautois B, Vogelzang NJ, Bambury RM, Voog E, Zhang J, Piulats JM, Hussain A, Ryan CJ, Merseburger AS, Daugaard G, Heidenreich A, Fizazi K, Higano CS, Krieger LE, Sternberg CN, Watkins SP, Despain D, Simmons AD, Dowson M, Golsorkhi T, Chowdhury S, and Abida W
- Subjects
- Genetic Testing, Humans, Indoles therapeutic use, Male, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics
- Abstract
Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA
+ ), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA+ mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2., Patients and Methods: Patients had progressed after next-generation androgen receptor-directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized., Results: TRITON2 enrolled 115 patients with BRCA+ identified by central plasma ( n = 34), central tissue ( n = 37), or local ( n = 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA+ by tissue testing., Conclusions: Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA+ mCRPC who can benefit from treatment with the PARP inhibitor rucaparib., (©2021 American Association for Cancer Research.)- Published
- 2021
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21. High grade glioma and caregiver burden.
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O'Keeffe D, Bambury RM, and O'Reilly S
- Subjects
- Caregivers, Humans, Caregiver Burden, Glioma therapy
- Published
- 2021
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22. Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration.
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Abida W, Patnaik A, Campbell D, Shapiro J, Bryce AH, McDermott R, Sautois B, Vogelzang NJ, Bambury RM, Voog E, Zhang J, Piulats JM, Ryan CJ, Merseburger AS, Daugaard G, Heidenreich A, Fizazi K, Higano CS, Krieger LE, Sternberg CN, Watkins SP, Despain D, Simmons AD, Loehr A, Dowson M, Golsorkhi T, and Chowdhury S
- Subjects
- Aged, Aged, 80 and over, Clinical Trials, Phase II as Topic, Germ-Line Mutation, Humans, Indoles adverse effects, Male, Middle Aged, Neoplasm Metastasis, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Progression-Free Survival, Prostatic Neoplasms, Castration-Resistant pathology, BRCA1 Protein genetics, BRCA2 Protein genetics, Indoles therapeutic use, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics
- Abstract
Purpose: BRCA1 or BRCA2 ( BRCA ) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study., Methods: We enrolled patients who progressed after one to two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate., Results: Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients)., Conclusion: Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.
- Published
- 2020
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23. Lung cancer in young patients: tumour characteristics and treatment in an Irish population.
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Cullivan S, Ni Mhaolcatha S, Henry MT, Muhammad NK, Mullally W, Bambury RM, Burke L, and Kennedy MP
- Abstract
Background: Lung cancer is the leading cause of cancer death in both sexes in Ireland. Studies suggest that lung cancer in younger patients has distinct characteristics. The aim of this study is to define the characteristics of lung cancer in patients 55-year-old or younger in an Irish population., Methods: Data was collected retrospectively from local medical records and the hospital electronic database regarding all patients diagnosed with lung cancer aged 55-year-old and younger, from 2010-2016. Information regarding patient demographics, smoking status, tumour histology, molecular analysis, stage and location, diagnostic modality and initial treatment choice was collected. In all cases the diagnosis of lung cancer was confirmed at the regional lung cancer multidisciplinary team (MDT) meeting., Results: In total, 8% (n=130) of all cases of lung cancer diagnosed from 2010 to 2016 in our center occurred in patients aged 55 years old or younger; 83% (n=108) were 45 to 55-year-old, 15% (n=19) were 35 to 44-year-old and 2% (n=3) were younger than 35-year-old; 88% (n=115) of patients reported a smoking history. There was a female preponderance (58%, n=76), higher rates of NSCLC non-squamous subtype (53%, n=69) and an upper lobe predominance (42%, n=54); 53% (n=68) of patients had IV or extensive disease at presentation. Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and Kirsten rat sarcoma oncogene (KRAS) mutation rates were 9% (n=4) and 3% (n=1) and 80% (n=4) respectively., Conclusions: Lung cancer in younger patients has distinct characteristics. This study suggests a female preponderance, high smoking rates and a predilection for the upper lobes. Further large-scale multicenter studies are required to verify these results and to clarify the responsible mechanisms., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2019.06.22). The authors have no conflicts of interest to declare., (2019 Translational Cancer Research. All rights reserved.)
- Published
- 2019
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24. Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes.
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Grivas P, Mortazavi A, Picus J, Hahn NM, Milowsky MI, Hart LL, Alva A, Bellmunt J, Pal SK, Bambury RM, O'Donnell PH, Gupta S, Guancial EA, Sonpavde GP, Faltaos D, Potvin D, Christensen JG, Chao RC, and Rosenberg JE
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Carcinoma, Transitional Cell genetics, Carcinoma, Transitional Cell secondary, Female, Follow-Up Studies, Histone Deacetylase Inhibitors therapeutic use, Humans, Male, Middle Aged, Prognosis, Urologic Neoplasms genetics, Urologic Neoplasms pathology, Benzamides therapeutic use, CREB-Binding Protein genetics, Carcinoma, Transitional Cell drug therapy, E1A-Associated p300 Protein genetics, Gene Expression Regulation, Neoplastic drug effects, Mutation, Pyrimidines therapeutic use, Urologic Neoplasms drug therapy
- Abstract
Background: The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single-arm, open-label phase 2 study., Methods: Eligible patients with platinum-treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28-day cycles in a 3-stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate., Results: Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent-to-treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose-normalized maximum serum concentration [C
max ] after TIW dosing of 0.2 ng/mL/mg)., Conclusions: To the authors' knowledge, the current study represents the first clinical trial using genomic-based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting., (© 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)- Published
- 2019
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25. A regional analysis of epidermal growth factor receptor (EGFR) mutated lung cancer for HSE South.
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Kelly D, Mc Sorley L, O'Shea E, Mc Carthy E, Bowe S, Brady C, Sui J, Dawod MA, O'Brien O, Graham D, McCarthy J, Burke L, Power D, O'Reilly S, Bambury RM, and Mahony DO
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung epidemiology, Carcinoma, Non-Small-Cell Lung pathology, Cohort Studies, Female, Humans, Incidence, Ireland epidemiology, Lung Neoplasms epidemiology, Lung Neoplasms pathology, Male, Middle Aged, Prognosis, Retrospective Studies, Treatment Outcome, Carcinoma, Non-Small-Cell Lung genetics, ErbB Receptors genetics, Lung Neoplasms genetics, Mutation
- Abstract
Background: EGFR mutated lung cancer represents a subgroup with distinct clinical presentations, prognosis, and management requirements. We investigated the survival, prognostic factors, and real-world treatment of NSCLC patients with EGFR mutation in clinical practice., Methods: A retrospective review of all specimens sent for EGFR analysis from December 2009 to September 2015 was performed. Patient demographics, specimen type, EGFR mutation status/type, stage at diagnosis, treatment, response rate, and survival data were recorded., Results: 27/334 (8%) patient specimens sent for EGFR testing tested positive for a sensitising EGFR mutation. The median age was 65 years (40-85 years). Exon 19 deletion represented the most commonly detected alteration, accounting for 39% (n = 11). First-line treatment for those with Exon 18, 19, or 21 alterations (n = 24) was with an EGFR tyrosine kinase inhibitor (TKI) in 79% (n = 19). Objective response rate among these patients was 74% and median duration of response was 13 months (range 7-35 months)., Conclusion: The incidence of EGFR mutation in our cohort of NSCLC is 9% which is consistent with mutation incidence reported in other countries. The rate of EGFR mutation in our population is slightly below that reported internationally, but treatment outcomes are consistent with published data. Real-world patient data have important contributions to make with regard to quality measurement, incorporating patient experience into guidelines and identifying safety signals.
- Published
- 2017
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26. DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma.
- Author
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Teo MY, Bambury RM, Zabor EC, Jordan E, Al-Ahmadie H, Boyd ME, Bouvier N, Mullane SA, Cha EK, Roper N, Ostrovnaya I, Hyman DM, Bochner BH, Arcila ME, Solit DB, Berger MF, Bajorin DF, Bellmunt J, Iyer G, and Rosenberg JE
- Subjects
- Aged, Carcinoma genetics, Carcinoma pathology, Carcinoma, Transitional Cell genetics, Carcinoma, Transitional Cell pathology, DNA Damage drug effects, DNA Repair drug effects, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Platinum adverse effects, Urothelium drug effects, Urothelium pathology, Carcinoma drug therapy, Carcinoma, Transitional Cell drug therapy, DNA Damage genetics, DNA Repair genetics, Platinum administration & dosage
- Abstract
Purpose: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. Experimental Design: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features. Results: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable impact on clinical outcomes. Conclusions: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment. Clin Cancer Res; 23(14); 3610-8. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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27. Cancer Care Costs and Clinical Trials.
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Kelly D, Brady C, Sui J, Cronin E, O'Hare D, Waldron J, O'Mahony D, Power D, Bambury RM, and O'Reilly S
- Subjects
- Humans, Clinical Trials as Topic, Costs and Cost Analysis, Neoplasms therapy
- Published
- 2017
28. Novel and next-generation androgen receptor-directed therapies for prostate cancer: Beyond abiraterone and enzalutamide.
- Author
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Bambury RM and Rathkopf DE
- Subjects
- Androstadienes therapeutic use, Benzamides, Benzimidazoles therapeutic use, Humans, Male, Naphthalenes therapeutic use, Nitriles, Phenylthiohydantoin therapeutic use, Pyrazoles therapeutic use, Receptors, Androgen, Thiohydantoins therapeutic use, Triazoles therapeutic use, Androgen Receptor Antagonists therapeutic use, Androstenes therapeutic use, Phenylthiohydantoin analogs & derivatives, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
The approval of abiraterone and enzalutamide for the treatment of advanced castration-resistant prostate cancer heralded a paradigm shift in the management of this disease. Nevertheless, new and improved treatments are needed since the disease remains incurable for the majority of these patients. In this article, we review the biology of castration-resistant disease as well as emerging therapeutic compounds directed at the androgen receptor, including galeterone, VT-464, ARN-509, and ODM-201. Mechanisms of action, early clinical data, and ongoing clinical studies for these compounds are all reviewed. The need to find optimal sequencing and combination strategies as well as the need for predictive biomarkers of response to these agents is discussed., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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29. Enzalutamide: Development from bench to bedside.
- Author
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Bambury RM and Scher HI
- Subjects
- Benzamides, Cell Line, Tumor, Disease-Free Survival, Humans, Male, Nitriles, Phenylthiohydantoin administration & dosage, Phenylthiohydantoin therapeutic use, Signal Transduction, Phenylthiohydantoin analogs & derivatives, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Prostate tissue, whether benign or malignant, is heavily dependent on androgen receptor (AR) signaling for growth and proliferation. Androgen deprivation therapy has been standard of care for management of metastatic prostate cancer for the past 70 years. AR antagonists were developed to further abrogate signaling through this pathway by competitive inhibition of the receptor. First-generation compounds such as bicalutamide had modest efficacy, and in the setting of AR overexpression or specific mutations in the AR ligand-binding domain, these early compounds had partial agonist properties that could stimulate tumor growth. Enzalutamide was developed to overcome these deficiencies, and here, we present the story of its preclinical discovery, clinical development, and ultimate approval as a standard-of-care therapy for castration-resistant prostate cancer. Also discussed are ongoing efforts to elucidate mechanisms of resistance to this agent as well as studies that are investigating its role in other prostate cancer disease states and other cancer types., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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30. The safety and efficacy of single-agent pemetrexed in platinum-resistant advanced urothelial carcinoma: a large single-institution experience.
- Author
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Bambury RM, Benjamin DJ, Chaim JL, Zabor EC, Sullivan J, Garcia-Grossman IR, Regazzi AM, Ostrovnaya I, Apollo A, Xiao H, Voss MH, Iyer G, Bajorin DF, and Rosenberg JE
- Subjects
- Aged, Aged, 80 and over, Carcinoma, Transitional Cell pathology, Clinical Trials as Topic, Disease-Free Survival, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Pemetrexed adverse effects, Platinum administration & dosage, Prognosis, Treatment Outcome, Urinary Bladder Neoplasms pathology, Urothelium pathology, Carcinoma, Transitional Cell drug therapy, Drug Resistance, Neoplasm drug effects, Pemetrexed administration & dosage, Urinary Bladder Neoplasms drug therapy
- Abstract
Background: Pemetrexed is a commonly used treatment for platinum-resistant advanced urothelial carcinoma (UC) based on objective response rates of 8% and 28% in two small phase II studies. To address the discrepancy in reported response rates and to assess efficacy and toxicity outside of a clinical trial setting, we performed a large retrospective analysis of pemetrexed use at Memorial Sloan Kettering Cancer Center. We also investigated candidate prognostic factors for overall survival in this setting to explore whether the neutrophil-lymphocyte ratio (NLR) had independent prognostic significance., Patients and Methods: Patients receiving pemetrexed for platinum-resistant advanced UC between 2008 and 2013 were identified. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) were used to determine response rate. Kaplan-Meier and Cox regression analyses were used to examine the association of various factors with efficacy and survival outcomes. Hematologic toxicity and laboratory abnormalities were recorded., Results: One hundred and twenty-nine patients were treated with pemetrexed. The objective response rate was 5% (95% confidence interval: 1%-9%), and the median duration of response was 8 months. Median progression-free survival (PFS) was 2.4 months, and the 6-month PFS rate was 14%. There was no significant difference in response rate by age, Eastern Cooperative Oncology Group (ECOG) performance status, or number of prior therapies. On multivariable analysis, ECOG performance status (p < .01), liver metastases (p = .02), and NLR (p < .01) had independent prognostic significance for overall survival., Conclusion: This 129-patient series is the largest reported data set describing pemetrexed use in advanced UC. Activity was modest, although discovery of molecular biomarkers predictive of response would be valuable to identify the small subset of patients who do gain significant benefit. Overall, the data highlight the urgent need to develop novel therapies for these patients., (©AlphaMed Press.)
- Published
- 2015
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31. DNA copy number analysis of metastatic urothelial carcinoma with comparison to primary tumors.
- Author
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Bambury RM, Bhatt AS, Riester M, Pedamallu CS, Duke F, Bellmunt J, Stack EC, Werner L, Park R, Iyer G, Loda M, Kantoff PW, Michor F, Meyerson M, and Rosenberg JE
- Subjects
- Chromosome Aberrations, Cluster Analysis, Computational Biology methods, E2F3 Transcription Factor genetics, Gene Amplification, Gene Deletion, Gene Expression Profiling, Gene Frequency, Genetic Loci, Genomics methods, High-Throughput Nucleotide Sequencing, Humans, Neoplasm Metastasis, Neoplasm Staging, Transcriptome, Urologic Neoplasms metabolism, DNA Copy Number Variations, Urologic Neoplasms genetics, Urologic Neoplasms pathology
- Abstract
Background: To date, there have been no reports characterizing the genome-wide somatic DNA chromosomal copy-number alteration landscape in metastatic urothelial carcinoma. We sought to characterize the DNA copy-number profile in a cohort of metastatic samples and compare them to a cohort of primary urothelial carcinoma samples in order to identify changes that are associated with progression from primary to metastatic disease., Methods: Using molecular inversion probe array analysis we compared genome-wide chromosomal copy-number alterations between 30 metastatic and 29 primary UC samples. Whole transcriptome RNA-Seq analysis was also performed in primary and matched metastatic samples which was available for 9 patients., Results: Based on a focused analysis of 32 genes in which alterations may be clinically actionable, there were significantly more amplifications/deletions in metastases (8.6% vs 4.5%, p < 0.001). In particular, there was a higher frequency of E2F3 amplification in metastases (30% vs 7%, p = 0.046). Paired primary and metastatic tissue was available for 11 patients and 3 of these had amplifications of potential clinical relevance in metastases that were not in the primary tumor including ERBB2, CDK4, CCND1, E2F3, and AKT1. The transcriptional activity of these amplifications was supported by RNA expression data., Conclusions: The discordance in alterations between primary and metastatic tissue may be of clinical relevance in the era of genomically directed precision cancer medicine.
- Published
- 2015
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32. Empathy and the wounded healer: a mixed-method study of patients and doctors views on empathy.
- Author
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Brady C, Bambury RM, and O'Reilly S
- Subjects
- Female, Humans, Male, Patient Satisfaction, Referral and Consultation, Surveys and Questionnaires, Empathy, Patients psychology, Physician-Patient Relations, Physicians psychology
- Abstract
Empathy is increasingly being recognized as a crucial component for an effective doctor-patient relationship. Using a mixed method approach, we surveyed 125 patients and 361 medical practitioners (doctors and medical students) views of the doctor-patient relationship. We qualitatively assessed patients' views of what constituted a good doctor and qualitatively measured empathy using a validated scale in medical practitioners. Patients desire a doctor that is both clinically proficient 66 (55%) and caring 32 (27%). Doctors who have a personal experience of illness have a statistically higher empathy score. These doctors may be well placed to help develop and foster empathy in our profession.
- Published
- 2015
33. The search for novel therapeutic strategies in the treatment of recurrent glioblastoma multiforme.
- Author
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Bambury RM and Morris PG
- Subjects
- Angiogenesis Inhibitors therapeutic use, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Biomarkers, Tumor metabolism, Brain Neoplasms pathology, Chemoradiotherapy methods, Disease Progression, Glioblastoma pathology, Humans, Immunotherapy methods, Neoplasm Recurrence, Local, Survival Rate, Antineoplastic Agents therapeutic use, Brain Neoplasms therapy, Glioblastoma therapy
- Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with ≤10% patients surviving 5 years from the time of diagnosis. After tumor progression on frontline therapy with concomitant chemoradiotherapy followed by consolidation temozolomide there are few effective treatment options. Bevacizumab and nitrosureas are the most commonly used systemic options in this instance but no overall survival benefit has been demonstrated. In this review we outline the major avenues of research for treatment of recurrent GBM including anti-angiogenic, signaling pathway blockade and immunotherapy approaches. Results of recent trials as well as pertinent ongoing studies are discussed. Enrollment of patients to clinical trials as well as incorporation of correlative translational science studies to identify predictive biomarkers of treatment response will be key to improving outcomes in this devastating disease.
- Published
- 2014
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34. Novel investigational approaches for inhibiting angiogenesis in recurrent glioblastoma.
- Author
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Bambury RM and Morris PG
- Subjects
- Female, Humans, Male, Niacinamide therapeutic use, Sorafenib, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, Glioma drug therapy, Neoplasm Recurrence, Local, Niacinamide analogs & derivatives, Phenylurea Compounds therapeutic use
- Published
- 2014
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35. A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma.
- Author
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Rosenberg JE, Bambury RM, Van Allen EM, Drabkin HA, Lara PN Jr, Harzstark AL, Wagle N, Figlin RA, Smith GW, Garraway LA, Choueiri T, Erlandsson F, and Laber DA
- Subjects
- Adult, Aged, Aged, 80 and over, Aptamers, Nucleotide blood, Aptamers, Nucleotide pharmacokinetics, Carcinoma, Renal Cell blood, Carcinoma, Renal Cell drug therapy, Demography, Exome genetics, Female, Humans, INDEL Mutation genetics, Infusions, Intravenous, Kidney Neoplasms blood, Kidney Neoplasms pathology, Male, Middle Aged, Models, Molecular, Neoplasm Metastasis, Oligodeoxyribonucleotides blood, Oligodeoxyribonucleotides pharmacokinetics, Sequence Analysis, DNA, Treatment Outcome, Nucleolin, Aptamers, Nucleotide therapeutic use, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Oligodeoxyribonucleotides therapeutic use, Phosphoproteins antagonists & inhibitors, RNA-Binding Proteins antagonists & inhibitors
- Abstract
Background: DNA aptamers represent a novel strategy in anti-cancer medicine. AS1411, a DNA aptamer targeting nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 prior tyrosine kinase inhibitor., Methods: In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1-4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints., Results: 35 patients were enrolled and treated. One patient (2.9 %) had a response to treatment. The response was dramatic (84 % reduction in tumor burden by RECIST 1.0 criteria) and durable (patient remains free of progression 2 years after completing therapy). Whole exome sequencing of this patient's tumor revealed missense mutations in the mTOR and FGFR2 genes which is of interest because nucleolin is known to upregulate mTOR pathway activity by enhancing AKT1 mRNA translation. No other responses were seen. Thirty-four percent of patients had an AS1411-related adverse event, all of which were mild or moderate., Conclusions: AS1411 appears to have minimal activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. One patient in this study had an excellent response and was found to have FGFR2 and mTOR mutations which will be of interest in future efforts to discover and validate predictive biomarkers of response to nucleolin targeted compounds. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.
- Published
- 2014
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36. Actionable mutations in muscle-invasive bladder cancer.
- Author
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Bambury RM and Rosenberg JE
- Subjects
- Animals, Chemotherapy, Adjuvant, Cystectomy, Genetic Predisposition to Disease, Humans, Neoadjuvant Therapy, Neoplasm Invasiveness, Patient Selection, Phenotype, Precision Medicine, Predictive Value of Tests, Treatment Outcome, Urinary Bladder Neoplasms pathology, Urinary Bladder Neoplasms therapy, Biomarkers, Tumor genetics, Mutation, Urinary Bladder Neoplasms genetics
- Abstract
Purpose of Review: Thirty-five percent of bladder cancer patients either present with or develop muscle-invasive disease. The current standard of care for these patients is neoadjuvant chemotherapy followed by radical cystoprostatectomy or combined chemoradiotherapy. Despite these therapies, approximately 50% of patients will relapse after definitive locoregional treatment and eventually succumb to their disease., Recent Findings: Therapies targeted at altered genetic pathways have proven efficacy in localized solid tumors including breast cancer, head and neck cancer and GIST. No such treatments have proven clinical benefit in bladder cancer, but targets under active investigation include HER2, epidermal growth factor receptors, fibroblast growth factor receptor 3, mTOR and others. Efforts are also underway to genetically define the subgroup of patients, which benefit from systemic platinum-based chemotherapy in this setting., Summary: Ongoing clinical trials are investigating the role of treatments targeted at actionable genetic mutations in bladder cancer. The key to maximizing the potential benefit from this treatment approach will be the identification of predictive biomarkers of response, the identification of safe combinations which block multiple signaling molecules synchronously, and the availability of faster, cheaper genetic testing in the clinic.
- Published
- 2013
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37. Translocation renal cell carcinomas: an evolving entity and a member of the microphthalmia transcription factor-associated family of tumors.
- Author
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Bambury RM, Battley JE, McCarthy A, Brady C, O'Reilly S, Kelly PJ, O'Brien F, Sweeney P, Fleming S, Mayer NJ, and Power DG
- Subjects
- Adult, Aged, Female, Humans, Male, Microphthalmos genetics, Middle Aged, Promoter Regions, Genetic genetics, Translocation, Genetic, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Carcinoma, Renal Cell genetics, Kidney Neoplasms genetics, Microphthalmia-Associated Transcription Factor genetics
- Published
- 2013
- Full Text
- View/download PDF
38. The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme.
- Author
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Bambury RM, Teo MY, Power DG, Yusuf A, Murray S, Battley JE, Drake C, O'Dea P, Bermingham N, Keohane C, Grossman SA, Moylan EJ, and O'Reilly S
- Subjects
- Adolescent, Adult, Age Factors, Aged, Blood Cell Count, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Retrospective Studies, Statistics, Nonparametric, Young Adult, Brain Neoplasms mortality, Brain Neoplasms pathology, Glioblastoma mortality, Glioblastoma pathology, Lymphocytes pathology, Neutrophils pathology
- Abstract
Neutrophil-lymphocyte ratio (NLR) is a marker of systemic inflammatory response and its elevation has recently been shown to be a poor prognostic factor in many malignancies including colon, prostate and bladder cancer. The primary aim of this study was to assess the prognostic impact of NLR in a clinically annotated cohort of patients with glioblastoma multiforme (GBM). We hypothesised that elevated NLR would be associated with worse prognosis. Between 2004 and 2009, 137 patients had surgery for GBM and were assessed for consideration of adjuvant therapy at our institution. Of these, 84 patients with an evaluable pre-corticosteroid full blood count result were identified and included in the final analysis. Median overall survival was 9.3 months (range 0.7-82.1). On univariate analysis, age >65 years, gender, ECOG performance status ≥2, frontal tumour, extent of surgical resection, completion of adjuvant chemoradiation protocol and NLR > 4 were significantly correlated with overall survival. Patients with NLR > 4, had a worse median overall survival at 7.5 months versus 11.2 months in patients with NLR ≤ 4 (hazard ratio 1.6, 95 % CI 1.00-2.52, p = 0.048). On multivariate analysis NLR > 4 remained an independent prognostic indicator for poor outcome. These data are an important reminder of the potential relevance of host immunity in GBM. In our cohort, NLR > 4 conferred a worse prognosis independent of other well established prognostic factors. If validated in other cohorts NLR may prove to be a useful addition in predicting prognosis in GBM patients. The demonstration that host immunity plays a role in GBM biology suggests that investigation of emerging therapies which modulate host immune response are warranted in this disease.
- Published
- 2013
- Full Text
- View/download PDF
39. Specific PPAR gamma agonists may have different effects on cancer incidence.
- Author
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Bambury RM, Iyer G, and Rosenberg JE
- Subjects
- Female, Humans, Male, Diabetes Mellitus drug therapy, Hypoglycemic Agents therapeutic use, Neoplasms epidemiology, Thiazolidinediones therapeutic use
- Published
- 2013
- Full Text
- View/download PDF
40. Advanced Urothelial Carcinoma: Overcoming Treatment Resistance through Novel Treatment Approaches.
- Author
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Bambury RM and Rosenberg JE
- Abstract
The current standard of care for metastatic urothelial carcinoma is cisplatin-based chemotherapy but treatment is generally not curative. Mechanisms of resistance to conventional cytotoxic regimens include tumor cell drug efflux pumps, intracellular anti-oxidants, and enhanced anti-apoptotic signaling. Blockade of signaling pathways with small molecule tyrosine kinase inhibitors has produced dramatic responses in subsets of other cancers. Multiple potential signaling pathway targets are altered in Urothelial carcinoma (UC). Blockade of the PI3K/Akt/mTOR pathway may prove efficacious because 21% have activating PI3K mutations and another 30% have PTEN inactivation (which leads to activation of this pathway). The fibroblast growth factor receptor 3 protein may be overactive in 50-60% and agents which block this pathway are under development. Blockade of multiple other pathways including HER2 and aurora kinase also have potential efficacy. Anti-angiogenic and immunotherapy strategies are also under development in UC and are discussed in this review. Novel therapeutic approaches are needed in UC. We review the various strategies under investigation and discuss how best to evaluate and optimize their efficacy.
- Published
- 2013
- Full Text
- View/download PDF
41. Prostate cancer: germline prediction for a commonly variable malignancy.
- Author
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Bambury RM and Gallagher DJ
- Subjects
- Genetic Predisposition to Disease, Global Health, Humans, Incidence, Male, Genome-Wide Association Study methods, Germ-Line Mutation, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Unlabelled: What's known on the subject? and What does the study add? Prostate cancer is a heterogeneous disease and biomarkers to predict its incidence and subsequent clinical behaviour are needed to tailor screening, prevention and therapeutic strategies. Rare mutations in genes such as BRCA1, BRCA2 and HOXB13 can affect prostate cancer incidence and/or clinical behaviour. Genome wide association studies (GWAS) have identified more common genetic variations that explain an estimated 20% of familial prostate cancer risk. In this review, we focus on the potential of germline genetic variation to provide biomarkers for prostate cancer screening, prevention and management. We discuss how germline genetics may have a role in treatment selection if reliable pharmacogenetic predictors of efficacy and toxicity can be identified. We have outlined possible mechanisms for including germline investigation in future prostate cancer clinical trials., Objectives: • Prostate cancer is a heterogeneous disease and biomarkers to predict its incidence and subsequent clinical behaviour are needed to tailor screening, prevention and therapeutic strategies. • In this review we focus on the potential of germline genetic variation to provide these biomarkers., Methods: • We review the published literature on germline genetics in prostate cancer and examine the possibility of including germline genetic biomarkers in future prostate cancer clinical trials., Results: • Rare mutations in genes such as BRCA1, BRCA2 and HOXB13 can affect prostate cancer incidence and/or clinical behaviour. • Genome-wide association studies (GWAS) have identified more common genetic variations that explain an estimated 20% of familial prostate cancer risk. • Germline genetics may have a role in treatment selection, if reliable pharmacogenetic predictors of efficacy and toxicity can be identified., Conclusion: • This rapidly emerging area of prostate cancer research may provide answers to current clinical conundrums in the prostate cancer treatment paradigm. We have outlined possible mechanisms for including germline investigation in future prostate cancer clinical trial design., (© 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.)
- Published
- 2012
- Full Text
- View/download PDF
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