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PDF file 97K, Table S1 shows the clinical demographics of the patient cohort treated with radiotherapy for prostate cancer

Purpose: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation.Experimental Design: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry, and positron emission tomography (PET) imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 patients with localized prostate cancer treated with curative-intent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan–Meier method.Results: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry, and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately before irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (P = 0.0106).Conclusion: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio. Clin Cancer Res; 19(24); 6741–50. ©2013 AACR.

PDF file 209K, Figure S1 illustrates the method for IHC analysis. It also shows a reduction in hypoxic fraction after metformin exposure in POP-92S and LNCaP xenografts

PDF file 80K, Figure S2 shows data from in vitro and ex vivo clonogenic assays of metformin treatment in combination with radiation

PDF file 54K, Figure S5 shows blood glucose levels in mice after metformin treatment

PDF file 92K, Figure S4 shows the effect of metformin on bRFR in the matched cohort of 172 prostate cancer patients

PDF file 81K, Supplementary Legends

PDF file 77K, Figure S3 shows propensity score distribution in the unmatched and matched patient cohort

Admitting hospitalized patients to off-service wards ("bedspacing") is common and may affect quality of care and patient outcomes.To compare in-hospital mortality, 30-day readmission to general internal medicine (GIM), and hospital length-of-stay among GIM patients admitted to GIM wards or bedspaced to off-service wards.Retrospective cohort study including all emergency department admissions to GIM between 2015 and 2017 at six hospitals in Ontario, Canada. We compared patients admitted to GIM wards with those who were bedspaced, using multivariable regression models and propensity score matching to control for patient and situational factors.Among 40,440 GIM admissions, 10,745 (26.6%) were bedspaced to non-GIM wards and 29,695 (73.4%) were assigned to GIM wards. After multivariable adjustment, bedspacing was associated with no significant difference in mortality (adjusted hazard ratio 0.95, 95% confidence interval [CI]: 0.86-1.05, p = .304), slightly shorter median hospital length-of-stay (-0.10 days, 95% CI:-0.20 to -0.001, p = .047) and lower 30-day readmission to GIM (adjusted OR 0.89, 95% CI: 0.83-0.95, p = .001). Results were consistent when examining each hospital individually and outcomes did not significantly differ between medical or surgical off-service wards. Sensitivity analyses focused on the highest risk patients did not exclude the possibility of harm associated with bedspacing, although adverse outcomes were not significantly greater.Overall, bedspacing was associated with no significant difference in mortality, slightly shorter hospital length-of-stay, and fewer 30-day readmissions to GIM, although potential harms in high-risk patients remain uncertain. Given that hospital capacity issues are likely to persist, future research should aim to understand how bedspacing can be achieved safely at all hospitals, perhaps by strengthening the selection of low-risk patients.

Objectives We reviewed the published literature on antimicrobial stewardship training in undergraduate and postgraduate medical education to determine which interventions have been implemented, the extent to which they have been evaluated, and to understand which are most effective. Methods We searched Ovid MEDLINE and EMBASE from inception to December 2016. Four thousand three hundred eighty-five (4385) articles were identified and underwent title and abstract review. Only those articles that addressed antimicrobial stewardship interventions for medical trainees were included in the final review. We employed Kirkpatrick’s four levels of evaluation (reaction, learning, behaviour, results) to categorize intervention evaluations. Results Our review included 48 articles. The types of intervention varied widely amongst studies worldwide. Didactic teaching was used heavily in all settings, while student-specific feedback was used primarily in the postgraduate setting. The high-level evaluation was sparse, with 22.9% reporting a Kirkpatrick Level 3 evaluation; seventeen reported no evaluation. All but one article reported positive results from the intervention. No articles evaluated the impact of an intervention on undergraduate trainees’ prescribing behaviour after graduation. Conclusions This study enhances our understanding of the extent of antimicrobial stewardship in the context of medical education. While our study demonstrates that medical schools are implementing antimicrobial stewardship interventions, rigorous evaluation of programs to determine whether such efforts are effective is lacking. We encourage more robust evaluation to establish effective, evidence-based approaches to training prescribers in light of the global challenge of antimicrobial resistance.

Purpose: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation. Experimental Design: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry, and positron emission tomography (PET) imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 patients with localized prostate cancer treated with curative-intent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan–Meier method. Results: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry, and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately before irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (P = 0.0106). Conclusion: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio. Clin Cancer Res; 19(24); 6741–50. ©2013 AACR.

Background and purpose: AMPK is a metabolic sensor and an upstream inhibitor of mTOR activity. AMPK is phosphorylated by ionizing radiation (IR) in an ATM dependent manner, but the cellular consequences of this phosphorylation event have remained unclear. The objective of this study was to assess whether AMPK plays a functional role in regulating cellular responses to IR. Methods: The importance of AMPK expression for radiation responses was investigated using both MEFs (mouse embryo fibroblasts) double knockout for AMPK alpha 1/alpha 2 subunits and human colorectal carcinoma cells (HCT 116) with AMPK alpha 1/alpha 2 shRNA mediated knockdown. Results: We demonstrate here that IR results in phosphorylation of both AMPK and its substrate, ACC. IR moderately stimulated mTOR activity, and this was substantially exacerbated in the absence of AMPK. AMPK was required for IR induced expression of the mTOR inhibitor REDD1, indicating that AMPK restrains mTOR activity through multiple mechanisms. Likewise, cellular metabolism was deregulated following irradiation in the absence of AMPK, as evidenced by a substantial increase in oxygen consumption rates and lactate production. AMPK deficient cells showed impairment of the G1/S cell cycle checkpoint, and were unable to support long-term proliferation during starvation following radiation. Lastly, we show that AMPK proficiency is important for clonogenic survival after radiation during starvation. Conclusions: These data reveal novel functional roles for AMPK in regulating mTOR signaling, cell cycle, survival and metabolic responses to IR.

5070 Background: Metformin is an inhibitor of the complex 1 in the respiratory chain, and is widely used in diabetes due to its effect on reducing insulin resistance. It has also been recently described to have effects via AMPK on inhibiting the mTOR kinase. Significant preclinical and epidemiological studies suggest its role in chemoprevention. These actions provide significant rationale to evaluate its utility in prostate cancer. Methods: Men were required to have histologically confirmed prostate cancer involving at least 20% of at least 1 unfragmented biopsy core. Exclusion criteria included patients who were found to be on treatment with any drug used for the treatment of any form of diabetes, or patients that began treatment for any form of diabetes during the course of the study. Pts were treated with up to 500mg tid of metformin. The primary objectives were to demonstrate safety and tolerability of neoadjuvant metformin administration in men with prostate cancer and to document changes in phospho-AKT signalling indices. Results: 24 patients were enrolled with 21 patients evaluable; median age was 64 yrs (range, 45-70 yrs). Baseline characteristics included median PSA 6 ng/mL (range, 3.22-36.11ng/mL). Median duration of drug treatment was 41 days (range 18-81). No grade 3 adverse events were reported during treatment or radical prostatectomy that were related to metformin. Significant pre-and post changes were noted in serum IGF1 (p=0.02), fasting glucose (p=0.03), BMI (p

e15118 Background: Metformin is an inhibitor of the complex 1 in the respiratory chain, and is widely used in diabetes due to its effect on reducing insulin resistance. It has also been recently described to have effects via AMPK on inhibiting the mTOR kinase. Significant preclinical and epidemiological studies suggest its role in chemoprevention. These actions provide significant rationale to evaluate its utility in prostate cancer. We conducted a phase II single centre study of neoadjuvant metformin in localised prostate cancer. Methods: Men were required to have histologically confirmed prostate cancer involving at least 20% of at least 1 unfragmented biopsy core. Exclusion criteria included patients who on initial assessment are found to be on treatment with any drug used for the treatment of any form of diabetes, or patients that begin treatment for any form of diabetes during the course of the study. Pts were treated with up to 500mg tid of metformin. Primary objectives were to demonstrate safety and tolerability of neoadjuvant metformin administration in men with prostate cancer and document changes in phospho-AKT signalling indices. Results: 24 patients were enrolled with 22 evaluable; median age was 64 yrs (range, 45-70 yrs). Baseline characteristics included median PSA 6 ng/mL (range, 3.22-36.11ng/mL). Median duration of drug treatment was 41 days (range 18-81). No grade 3 adverse events were reported, all patients underwent subsequent radical prostatectomy with adverse effects related to metformin. Final Gleason scores ranged form 6-8, and final stage ranged from pT2a-pT3b. Significant pre-and post changes were noted in serum IGF1 (p=0.02), fasting glucose (p=0.03), BMI (p

Background: Metformin is an inhibitor of the complex 1 in the respiratory chain, and is widely used in diabetes due to its effect on reducing insulin resistance. It has also been recently described to have effects via AMPK on inhibiting the mTOR kinase. Significant preclinical and epidemiological studies suggest its role in chemoprevention. These actions provide significant rationale to evaluate its utility in prostate cancer. We conducted a phase II single centre study of neoadjuvant metformin in localized prostate cancer. Methods: Men were required to have histologically confirmed prostate cancer involving at least 20% of at least 1 unfragmented biopsy core. Exclusion criteria included patients who on initial assessment are found to be on treatment with any drug used for the treatment of any form of diabetes, or patients that begin treatment for any form of diabetes during the course of the study. Pts were treated with up to 500mg tid of metformin. The primary objectives were to demonstrate safety and tolerability of neoadjuvant metformin administration in men with prostate cancer and to document changes in phospho-AKT signaling indices. Results: 24 patients were enrolled with 22 evaluable; median age was 64 yrs (range, 45-70 yrs). Baseline characteristics included median PSA 6 ng/mL (range, 3.22–36.11 ng/mL). Median duration of drug treatment was 41 days (range 18–81). No grade 3 adverse events were reported, all patients underwent subsequent radical prostatectomy with adverse effects related to metformin. Significant pre-and post changes were noted in serum IGF1 (p=0.02), fasting glucose (p=0.03), BMI (p < 0.01) and waist/hip ratio (p < 0.01). There was a trend for a PSA reduction (p=0.08). There were no correlations between any metabolic, morphometric or cancer-related serum indices. Conclusions: Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicates promising effects on metabolic parameters, tissue results will be presented including proliferation indices and signaling pathway assessments. Citation Format: Anthony Michael Joshua, Neil Fleshner, Michael Pollak, Vanessa Zannella, Barbara Bowes, Marianne Koritzinsky, Joan Sweet, Andrew Evans, John Trachtenberg, Michael Jewett, Antonio Finelli. A phase 2 study of neoadjuvant metformin in prostatic carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A15.