Ben Boursi

The effect of past antibiotic exposure on diabetes risk

OBJECTIVE Gut microbiota influence metabolic pathways related to the pathogenesis of obesity, insulin-resistance and diabetes. Antibiotic therapy can alter the microbiota, and is commonly used in western countries. We sought to evaluate whether past antibiotic exposure increases diabetes risk. RESEARCH DESIGN AND METHODS We conducted a nested case-control study using a large population-based database from the UK. The cases were defined as those with incident diagnosis of diabetes. For every case, four eligible controls matched on age, sex, practice-site, and duration of follow-up before index-date were selected using incidence-density sampling. Exposure of interest was antibiotic therapy >1 year before index-date. Odds ratios (ORs) and 95% CIs were estimated using conditional logistic regression. The risk was adjusted for BMI, smoking, last glucose level, and number of infections before index-date, as well as past medical history of coronary artery disease and hyperlipidaemia. RESULTS The study included 208 002 diabetic cases and 815 576 matched controls. Exposure to a single antibiotic prescription was not associated with higher adjusted diabetes risk. Treatment with two to five antibiotic courses was associated with increase in diabetic risk for penicillin, cephalosporins, macrolides and quinolones with adjusted OR ranging from 1.08 (95% CI 1.05-1.11) for penicillin to 1.15 (95% CI 1.08-1.23) for quinolones. The risk increased with the number of antibiotic courses and reached 1.37 (95% CI 1.19-1.58) for more than 5 courses of quinolones. There was no association between exposure to anti-virals and anti-fungals and diabetes risk. CONCLUSIONS Exposure to certain antibiotic groups increases diabetes risk.

Current and future clinical strategies in colon cancer prevention and the emerging role of chemoprevention

In the third millennium preventive medicine is becoming a corner stone in our concept of health. Colorectal cancer (CRC) fits the criteria of a disease suitable for prevention interventions. It is a prevalent disease that is associated with considerable mortality and morbidity rates, with more than 1,000,000 new cases and 500,000 deaths annually. CRC has a natural history of transition from precursor to malignant lesion that spans, on average, 10-15 years, providing a window of opportunity for effective interventions and prevention. Indeed, CRC is preventable in up to 90% of the cases. Simple life style modifications (balanced diet avoidance of smoking and alcohol, and moderate physical activity) can prevent up to 50% of the cases of colorectal cancer. Compliance with current screening methods is a major barrier to the achievement of optimal results, a large part of the average risk population has not been screened by any method. Several newly developed screening modalities, such as the virtual colonoscopy and stool genetic testing may improve compliance. In addition, chemoprevention, a new science that has emerged during the last decade, presents an alternative approach to reducing mortality from colorectal cancer as well as other cancers. Chemoprevention involves the long-term use of a variety of oral agents that can delay, prevent or even reverse the development of adenomas in the large bowel. In light of the recent evidence of the efficacy of chemoprevention in persons at high risk for CRC cancer, it seems only appropriate to consider similar strategies for the general population.

Antibiotic Exposure and the Risk for Depression, Anxiety, or Psychosis: A Nested Case-Control Study

OBJECTIVE Changes in the microbiota (dysbiosis) were suggested to increase the risk of several psychiatric conditions through neurologic, metabolic, and immunologic pathways. Our aim was to assess whether exposure to specific antibiotic groups increases the risk for depression, anxiety, or psychosis. METHOD We conducted 3 nested case-control studies during the years 1995-2013 using a large population-based medical record database from the United Kingdom. The study included 202,974 patients with depression, 14,570 with anxiety, and 2,690 with psychosis and 803,961, 57,862, and 10,644 matched controls, respectively. Cases were defined as individuals aged 15-65 years with any medical Read code for depression, anxiety, or psychosis. Subjects with diagnosis-specific psychotropic prescriptions > 90 days before index date were excluded. For every case, 4 controls were selected using incidence density sampling, matching on age, sex, practice site, calendar time, and duration of follow-up before index date. The primary exposure of interest was therapy with 1 of 7 antibiotic classes > 1 year before index date. Odds ratios (ORs) and 95% CIs were calculated for the association between each psychiatric disorder and exposure to individual classes of antibiotics using conditional logistic regression analysis. The risk was adjusted for obesity, smoking history, alcohol consumption, socioeconomic status, and number of infectious events before diagnosis. RESULTS Treatment with a single antibiotic course was associated with higher risk for depression with all antibiotic groups, with an adjusted OR (AOR) of 1.23 for penicillins (95% CI, 1.18-1.29) and 1.25 (95% CI, 1.15-1.35) for quinolones. The risk increased with recurrent antibiotic exposures to 1.40 (95% CI, 1.35-1.46) and 1.56 (95% CI, 1.46-1.65) for 2-5 and > 5 courses of penicillin, respectively. Similar association was observed for anxiety and was most prominent with exposures to penicillins and sulfonamides, with an AOR of 1.17 (95% CI, 1.01-1.36) for a single course of penicillin and 1.44 (95% CI, 1.18-1.75) for > 5 courses. There was no change in risk for psychosis with any antibiotic group. There was a mild increase in the risk of depression and anxiety with a single course of antifungals; however, there was no increase in risk with repeated exposures. CONCLUSION Recurrent antibiotic exposure is associated with increased risk for depression and anxiety but not for psychosis.

Bisphosphonates combined with sunitinib may improve the response rate, progression free survival and overall survival of patients with bone metastases from renal cell carcinoma

BACKGROUND Bisphosphonates are used to prevent skeletal events of bone metastases, and may exhibit antitumour effects. We aimed to evaluate whether bisphosphonates can bring a response rate (RR), progression free survival (PFS) and overall survival (OS) benefit to patients with bone metastasis from renal cell carcinoma (RCC) that is treated with sunitinib. METHODS We performed a multicentre retrospective study of patients with bone metastases from RCC that was treated with sunitinib. The effect of bisphosphonates on RR, PFS and OS was tested with adjustment for known prognostic factors using a chi-square test from contingency table and partial likelihood test from Cox regression model. RESULTS Between 2004 and 2011, 209 patients with metastatic RCC were treated with sunitinib, 76 had bone metastases, 35 bisphosphonates users and 41 non-users. The groups of bisphosphonates users and non-users were balanced regarding known prognostic factors. Objective response was partial response/stable disease 86% (n = 30) versus 71% (n = 29), and progressive disease 14% (n = 5) versus 29% (n = 12) (p = 0.125, OR 2.48) in users versus non-users, respectively. Median PFS was 15 versus 5 months (HR = 0.55, p<0.0001), and median OS was not reached (with a median follow-up time of 45 months) versus 14 months (HR = 0.4, p = 0.029), in favour of users. In multivariate analysis of the entire patient cohort (n = 76), factors associated with PFS were bisphosphonates use (HR = 0.58, p = 0.035), and pre-treatment neutrophil to lymphocyte ratio >3 (HR = 3.5, p = 0.009). Factors associated with OS were bisphosphonates use (HR = 0.5, p = 0.008), elevated pre-treatment alkaline phosphatase (HR = 2.9, p = 0.003) and sunitinib induced HTN (HR = 0.63, p<0.0001). CONCLUSIONS Bisphosphonates may improve the RR, PFS and OS of sunitinib treatment in RCC with bone metastases.

Recurrent antibiotic exposure may promote cancer formation – Another step in understanding the role of the human microbiota?

BACKGROUND Bacterial dysbiosis was previously described in human malignancies. In a recent animal model, tumour susceptibility was transmitted using faecal transplantation. Our aim was to evaluate possible association between antibiotic exposure and cancer risk. METHODS We conducted nested case-control studies for 15 common malignancies using a large population-based electronic medical record database. Cases were defined as those with any medical code for the specific malignancy. Individuals with familial cancer syndromes were excluded. For every case, four eligible controls matched on age, sex, practice site and duration of follow-up before index-date were selected using incidence-density sampling. Exposure of interest was antibiotic therapy >1 year before index-date. Adjusted odds-ratios (AORs) and 95% confidence intervals (CIs) were estimated for each antibiotic type using conditional logistic regression. RESULTS 125,441 cases and 490,510 matched controls were analysed. For gastro-intestinal malignancies, the use of penicillin was associated with an elevated risk of oesophageal, gastric and pancreatic cancers. The association increased with the number of antibiotic courses and reached 1.4 for gastric cancers associated with >5 courses of penicillin (95% CI 1.2-1.8). Lung cancer risk increased with the use of penicillin, cephalosporins, or macrolides (AOR for >5 courses of penicillin: 1.4 95% CI 1.3-1.6). The risk of prostate cancer increased modestly with the use of penicillin, quinolones, sulphonamides and tetracyclines. The risk of breast cancer was modestly associated with exposure to sulphonamides. There was no association between the use of anti-virals and anti-fungals and cancer risk. CONCLUSION Recurrent exposure to certain antibiotics may be associated with cancer risk in specific organ sites.

Active Smoking May Negatively Affect Response Rate, Progression-Free Survival, and Overall Survival of Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib

BACKGROUND Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). METHODS An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. RESULTS Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002). CONCLUSION Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

Impact of antibiotic exposure on the risk of colorectal cancer

Gut microbiota has been postulated to serve as a significant promoter of CRC formation, and colonic dysbiosis was previously reported in CRC tissue. Our aim was to evaluate the association between the type and cumulative duration of antibiotic exposure and CRC risk.

Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710

Risk stratification is a major challenge in bladder cancer (BC), and a biomarker is needed. Multiple studies have reported the neutrophil‐to‐lymphocyte ratio (NLR) as a promising candidate; however, these analyses have methodological limitations. Therefore, the authors performed a category B biomarker study to test whether NLR is prognostic for overall survival (OS) after curative treatment or is predictive for the survival benefit from neoadjuvant chemotherapy (NAC).

Validation of a Coding Algorithm to Identify Bladder Cancer and Distinguish Stage in an Electronic Medical Records Database

Studies on outcomes in bladder cancer rely on accurate methods to identify patients with bladder cancer and differentiate bladder cancer stage. Medical record and administrative databases are increasingly used to study cancer incidence, but few have distinguished cancer stage, and none have focused on bladder cancer. In this study, we used data from The UK Health Improvement Network (THIN) to identify patients with bladder cancer using at least one diagnostic code for bladder cancer, and distinguish muscle-invasive from non-invasive disease using a subsequent code for cystectomy. Algorithms were validated against a gold standard of physician-completed questionnaires, pathology reports, and consultant letters. Algorithm performance was evaluated by measuring positive predictive value (PPV) and corresponding 95% confidence interval (CI). Among all patients coded with bladder cancer (n = 194), PPV for any bladder cancer was 99.5% (95% CI, 97.2–99.9). PPV for incident bladder cancer was 93.8% (95% CI, 89.4–96.7). PPV for muscle-invasive bladder cancer was 70.1% (95% CI, 59.4–79.5) in patients with cystectomy (n = 95) and 83.9% (95% CI, 66.3–94.5) in those with cystectomy plus additional codes for metastases and death (n = 31). Using our codes for bladder cancer, the age- and sex-standardized incidence rate (SIR) of bladder cancer in THIN approximated that measured by cancer registries (SIR within 20%), suggesting that sensitivity was high as well. THIN is a valid and novel database for the study of bladder cancer. Our algorithm can be used to examine the epidemiology of muscle-invasive bladder cancer or outcomes following cystectomy for patients with muscle invasion. Cancer Epidemiol Biomarkers Prev; 24(1); 303–7. ©2014 AACR.

A Clinical Prediction Model to Assess Risk for Pancreatic Cancer Among Patients With New-Onset Diabetes

BACKGROUND & AIMS Approximately 50% of all patients with pancreatic ductal adenocarcinoma (PDA) develop diabetes mellitus before their cancer diagnosis. Screening individuals with new-onset diabetes might allow earlier diagnosis of PDA. We sought to develop and validate a PDA risk prediction model to identify high-risk individuals among those with new-onset diabetes. METHODS We conducted a retrospective cohort study in a population representative database from the United Kingdom. Individuals with incident diabetes after the age of 35 years and 3 or more years of follow-up after diagnosis of diabetes were eligible for inclusion. Candidate predictors consisted of epidemiologic and clinical characteristics available at the time of diabetes diagnosis. Variables with P values <.25 in the univariable analyses were evaluated using backward stepwise approach. Model discrimination was assessed using receiver operating characteristic curve analysis. Calibration was evaluated using the Hosmer-Lemeshow test. Results were internally validated using a bootstrapping procedure. RESULTS We analyzed data from 109,385 patients with new-onset diabetes. Among them, 390 (0.4%) were diagnosed with PDA within 3 years. The final model (area under the curve, 0.82; 95% confidence interval, 0.75-0.89) included age, body mass index, change in body mass index, smoking, use of proton pump inhibitors, and anti-diabetic medications, as well as levels of hemoglobin A1C, cholesterol, hemoglobin, creatinine, and alkaline phosphatase. Bootstrapping validation showed negligible optimism. If the predicted risk threshold for definitive PDA screening was set at 1% over 3 years, only 6.19% of the new-onset diabetes population would undergo definitive screening, which would identify patients with PDA with 44.7% sensitivity, 94.0% specificity, and a positive predictive value of 2.6%. CONCLUSIONS We developed a risk model based on widely available clinical parameters to help identify patients with new-onset diabetes who might benefit from PDA screening.