Impact of a Focused Online Teaching Module on Airway Intervention: Can an Online Teaching Module Enable Knowledge Acquisition and Increased Confidence in Airway Management?

OBJECTIVE: Teaching procedural skills via digital platforms is challenging. There is a paucity of literature on the feasibility of implementing an online asynchronous web-based learning (WBL) module for endotracheal intubation in Emergency Medicine. Learners completed a pre-test questionnaire prior to reviewing the module to assess their current knowledge. After completion of the online module, another assessment on airway management competency was completed. The purpose of our pilot study was to determine the feasibility of implementing an online airway module and investigate knowledge acquisition among learners who completed it. Additionally, we compared the relationship between pre-module confidence and knowledge between various training levels of those who completed the module. METHODS: The study was IRB exempt. We conducted a quasi-experimental pre- and post-test study, where learners took a multiple-choice question-based test before watching content module, and after completion of modules, they went on to complete post-test questions. All responses were collected using Google survey and the data were collected over a period of 6 months. We performed descriptive statistics for the pre- and post-module. Frequency distribution was used for data summarization and chi-square test was used to assess the difference between variables. RESULTS: We received 366 responses in the pre-test module and 105 in post-test module. Responses were summarized into 5 broad categories which assessed knowledge about airway technique, anatomical landmarks, formulas for selecting blade size, tube size, depth of tube, and case-based scenarios. All questions showed a higher percentage of correct answers in the post-assessment compared to the pre-assessment. CONCLUSION: The results demonstrated that this WBL airway module resulted in significant knowledge acquisition, as well as increased confidence when approaching airway management. The study demonstrated that a WBL airway module is a feasible method of asynchronous education for healthcare providers in all levels of training.

Risk of Radiation Exposure to Emergency Department Personnel From Portable Radiographs.

BACKGROUND: There are concerns that emergency health care workers are exposed to ionizing radiation as the result of frequent portable radiographs obtained in the emergency department (ED) during active patient care. OBJECTIVE: Our aim was to investigate whether ED staff are exposed to significant radiation due to scatter from portable radiography at a busy trauma center and whether exposure was related to factors such as location or distance. METHODS: This was a prospective cohort study performed during 3 consecutive months in the ED at a large, academic trauma center. Volunteer attendings, nurses, and resident physicians were asked to wear dosimeter badges during their shifts throughout the study period. Twelve stationary dosimeters were placed in selected locations in the ED, particularly in the resuscitation rooms, where most of the portable radiographs were obtained. RESULTS: During the 3-month study period, 1464 portable radiographs were obtained in the resuscitation rooms in the ED, mostly chest and pelvic radiographs. Analysis from stationary dosimeters placed in the ED showed a median of 0.18 mSv (95% CI 0.16-0.22 mSv) for the main resuscitation room and 0 mSv for other critical care patient rooms. Analysis of dosimeters worn by staff showed no measurable radiation exposure (0.00 mSv). CONCLUSIONS: The level of radiation exposure to ED staff found in this study was well below the recommended allowable occupational exposure of 50 mSv/y. Radiation exposure is not a significant occupational hazard in a busy ED level I trauma center. Existing precautions should adequately protect staff from occupational exposure, and use of further protective gear, or the need for individual monitoring using dosimeters, appears unwarranted.

"Parenteral" Diarrhea Associated With Pediatric Urinary Tract Infections: A Retrospective Chart Review.

OBJECTIVES: The association of noninfectious diarrhea with extraintestinal infections such as otitis media, pneumonia, or febrile urinary tract infections (UTIs) is commonly known as parenteral diarrhea. Although this association has been described for over a century and parenteral diarrhea is mentioned in current reference literature, available evidence for this association seems to be limited. The primary research question was to determine if there is an association between UTIs and reports of diarrhea. METHODS: A retrospective chart review was performed using the medical records from October 1, 2017, to March 29, 2019 at our tertiary pediatric medical center. We searched for all cases of afebrile and febrile UTIs evaluated in the pediatric emergency department or admitted directly to the hospital for treatment. All children younger than 5 years were eligible for inclusion. Exclusion criteria included children with recent urological procedures, known urinary tract disease, immune suppression, sepsis, or known gastrointestinal diseases. The medical records of each of the pediatric patients with culture-positive UTIs were reviewed for reports of concurrent diarrhea or diarrhea-like illness. In addition, using a comparative quantitative design, we performed a retrospective chart review of all children younger than 5 years with 1 of 2 noninfectious chief complaints, head trauma, and extremity fractures, presenting during the same period to assess the background rate of reported diarrhea.This research project received the approval of the University of South Alabama's Institutional Review Board. RESULTS: A total of 236 children with a culture-positive UTI presented to our pediatric medical center from October 1, 2017 to March 29, 2019. Reports of diarrhea were documented in the medical record for 44 of the 236 UTIs (18.6%). Escherichia coli was the predominant infectious agent in 32 of the 44 children (72.7%) with culture-positive UTIs and diarrhea. Of the 368 comparison group patients who visited the pediatric emergency department for a noninfectious complaint, diarrhea was reported in 2 patients (0.01%). CONCLUSIONS: Our retrospective review of pediatric patients younger than 5 years with culture-proven UTIs found an association of reported diarrhea. It is our opinion based on our single-center retrospective chart review that the current available evidence suggests an association between UTIs and extraintestinal diarrhea. Future prospective studies are recommended to confirm this association.

Stethoscope hygiene: A call to action. Recommendations to update the CDC guidelines.

Healthcare-acquired infections are a tremendous challenge to the US medical system. Stethoscopes touch many patients, but current guidance from the Centers for Disease Control and Prevention does not support disinfection between each patient. Stethoscopes are rarely disinfected between patients by healthcare providers. When cultured, even after disinfection, stethoscopes have high rates of pathogen contamination, identical to that of unwashed hands. The consequence of these practices may bode poorly in the coronavirus 2019 disease (COVID-19) pandemic. Alternatively, the CDC recommends the use of disposable stethoscopes. However, these instruments have poor acoustic properties, and misdiagnoses have been documented. They may also serve as pathogen vectors among staff sharing them. Disposable aseptic stethoscope diaphragm barriers can provide increased safety without sacrificing stethoscope function. We recommend that the CDC consider the research regarding stethoscope hygiene and effective solutions to contemporize this guidance and elevate stethoscope hygiene to that of the hands, by requiring stethoscope disinfection or change of disposable barrier between every patient encounter.

Aseptic Stethoscope Barriers Prevent C difficile Transmission In Vitro.

OBJECTIVE: To evaluate whether Clostridioides (formerly Clostridium) difficile-contaminated stethoscope diaphragms remained aseptic by the placement of an aseptic diaphragm barrier. METHODS: On November 1, 2019, fresh cultures of C difficile were diluted to 107 colony-forming units (CFU)/mL and used to inoculate 16 stethoscope diaphragms; 8 had an aseptic diaphragm barrier applied and 8 served as nonbarrier controls. Contaminated stethoscopes were anaerobically incubated, then swabbed at 15 and 30 minutes, 2 and 4 hours, and 1, 2, 3, and 7 days after inoculation and subsequently plated onto blood, chocolate, and cycloserine-cefoxitin fructose agar. Plates were incubated for 48 hours and on November 9, 2019, the resulting colonies were manually counted. Statistical analyses (RStudio, version 1.0.153) used analysis of variance with post hoc Tukey honestly significant difference. RESULTS: Overall, mean colony count was 33 CFU on stethoscopes without barriers vs zero on those with barriers (P≤.05). Growth was greatest at 48 hours, with colony counts as high as 160 CFU. The presence of the barrier resulted in no growth in 100% of stethoscope diaphragms for up to 1 week. CONCLUSION: We found that stethoscope diaphragm barriers provide an aseptic patient contact point, thus reducing the potential for transmission of C difficile during the physical examination. In critical care environments, in which many hospitals use acoustically inferior disposable stethoscopes, the option of a disposable aseptic stethoscope barrier may allow high-quality auscultation while reducing the potential for pathogen transmission.

Contemporary stethoscope cleaning practices: What we haven't learned in 150 years.

BACKGROUND: Stethoscopes can be microorganism reservoirs. The US Centers for Disease Control and Prevention (CDC) has published medical equipment disinfection guidelines to minimize infection transmission risk, but studies of guideline adherence have been predominately survey based, with little direct observation of disinfection practices. METHODS: We performed an observational, cross-sectional, anonymous study of patient-provider interactions, assessing practitioners' frequency and methods of stethoscope and hand disinfection practices. RESULTS: Stethoscopes were disinfected in 18% of 400 observed interactions, with less than 4% verified as conforming to CDC guidelines. None was disinfected before patient examinations involving open chest or abdominal wounds, as recommended by the CDC. Hands were cleaned before and after encounters 27 times (6.8%) but were not cleaned at all in 231 (58%) encounters, although gloves were worn in 197 (85.3%) of these cases. DISCUSSION: Stethoscope disinfection is grossly overlooked, possibly jeopardizing patient safety, particularly in acute care interactions. Periodic stethoscope disinfection, although inconvenient, helps reduce bacterial contamination and may reduce health care-associated infections. CONCLUSIONS: Stethoscopes were disinfected per CDC guidelines in less than 4% of encounters and were not disinfected at all in 82% of encounters. Although hands were rarely cleaned (6.8%) per CDC guidelines, gloves were usually worn, but no convenient stethoscope equivalent exists. Stethoscope cleanliness must be addressed.

Changes in Treatment Patterns and Overall Survival in Patients With Early-Stage Non-Small Cell Lung Cancer in the United States After the Incorporation of Stereotactic Ablative Radiation Therapy: A Population-based Analysis.

PURPOSE: Technologic developments have made radiation therapy (RT) more effective and have introduced new treatment options, such as stereotactic ablative radiation therapy (SABR). This study sought to determine changes in practice patterns for treatment of stage IA non-small cell lung cancer (NSCLC) after the introduction of SABR into the United States. This population-based study also examined changes in survival during this time period for all patients and specifically for patients treated with RT, surgery, or observation. METHODS: We included patients in the Surveillance, Epidemiology, and End Results database diagnosed with stage IA NSCLC diagnosed between 2004 and 2012. Changes in treatment patterns were assessed. Outcomes were compared across 2 time periods: 2004 to 2008 (pre-SABR) and 2009 to 2012 (post-SABR). Kaplan-Meier and Cox regression were performed to compare overall survival (OS) for patients treated with surgery, RT, or observation. RESULTS: A total of 32,249 patients met the specified criteria. Comparing patients diagnosed in 2004 to those diagnosed in 2012, RT use increased from 13% to 29% (P<0.001), surgery use decreased from 76% to 61% (P<0.001), and patients observed decreased from 11% to 10% (P=0.3). There was no significant OS improvement in all patients or those patients who were observed; there were significant improvements in OS for patients treated with RT (hazard ratio=0.768; 95% confidence interval, 0.711-0.829) and those patients treated with surgery (hazard ratio=0.9; 95% confidence interval, 0.855-0.962). CONCLUSIONS: There has been an increase in RT utilization and decrease in surgical utilization after the incorporation of SABR by radiation oncologists within the United States. In addition, there has been an improvement in OS for patients treated with definitive RT for early-stage NSCLC between 2004 and 2012 that may be associated with increased utilization of SABR.

Outcomes of Patients With Metastatic Renal Cell Carcinoma and Bone Metastases in the Targeted Therapy Era.

BACKGROUND: Bone metastases (BMs) occur commonly in patients with metastatic renal cell carcinoma (mRCC). Tyrosine kinase inhibitors (TKIs) have improved the outcomes for patients with mRCC. However, data on the outcomes of mRCC patients with BMs treated with TKIs are limited. We describe the outcomes of patients with BMs treated with TKI therapy and compare them with the outcomes from a pre-TKI group. PATIENTS AND METHODS: Using an institutional tumor registry, a retrospective review of patients with mRCC from 2002 to 2003 and 2006 to 2007 was performed. The baseline characteristics were analyzed, and overall survival (OS) was estimated using the Kaplan-Meier method. The predictors of OS were analyzed using Cox regression analysis. RESULTS: The data from 375 patients were reviewed. Of these patients, 188 (50%) started treatment with TKIs and 187 (50%) had started treatment in the pre-TKI era. The distribution of patient characteristics was similar. The sites of organ metastases were equally distributed, including BMs in 48% of the patients in each cohort. The median OS for the patients treated in the TKI era was 22 months (95% confidence interval [CI], 17-25 months) compared with 14 months (95% CI, 10-19 months; P < .01) for the historical controls. A subset analysis of patients with BM in the TKI era demonstrated a median OS of 24 months (95% CI, 17-28 months) compared with 18 months (95% CI, 10-21 months; P < .01) in pre-TKI era. The predictors of shorter OS were a higher Memorial Sloan Kettering Cancer Center score; liver, lung, and brain metastases; and multiple sites of BMs (hazard ratio, 1.38; 95% CI, 1.02-1.91; P = .04). The rate of new BM development was the same in the pre- and post-TKI era. CONCLUSION: The rate of BM development was the same in the pre- and post-TKI era. The management of BMs in patients with mRCC remains challenging.

Outcomes of Patients With Metastatic Non-Clear-Cell Renal Cell Carcinoma Treated With Pazopanib.

BACKGROUND: Pazopanib is associated with increased progression-free survival (PFS) in clear-cell renal cell carcinoma (RCC) and has become a standard of care in this disease. The drug is used in metastatic non-clear-cell RCC, but data on outcomes in this setting are limited. PATIENTS AND METHODS: We conducted a retrospective data analysis of records of consecutive metastatic non-clear-cell RCC patients who received pazopanib in front-line and salvage settings between November 2009 and November 2012. Tumor response rate was assessed by a blinded radiologist using Response Evaluation Criteria in Solid Tumors version 1.1. PFS and overall survival (OS) times were estimated using Kaplan-Meier methods. RESULTS: Twenty-nine patients were identified with non-clear-cell metastatic RCC, 9 received pazopanib in the front-line setting, 20 in the salvage setting after progression of disease with other targeted therapies. Seven patients (24%) had papillary RCC, 4 (14%) had chromophobe, 5 (17%) had unclassified histopathology, and 13 (45%) had other subtypes including collecting duct, translocation Xp11.2, and various subtypes with sarcomatoid differentiation. All patients discontinued pazopanib before analysis. Median PFS was 8.1 months (95% CI, 5.7-NA [not available]) in the front-line group, and 4 months (95% CI, 2.1-9.9) in the salvage group. Median OS was 31 months (95% CI, 9.2-NA) in the front-line group, and 13.6 months (95% CI, 6.4-NA) in the salvage group. CONCLUSION: Pazopanib showed efficacy in patients with metastatic non-clear-cell RCC in the front-line and salvage settings. Toxicity was mild to moderate and manageable. Further studies are needed to evaluate pazopanib's role in non-clear-cell RCC in terms of efficacy and safety.

Time to Cooling Is Associated with Resuscitation Outcomes.

Our purpose was to analyze evidence related to timing of cooling from studies of targeted temperature management (TTM) after return of spontaneous circulation (ROSC) after cardiac arrest and to recommend directions for future therapy optimization. We conducted a preliminary review of studies of both animals and patients treated with post-ROSC TTM and hypothesized that a more rapid cooling strategy in the absence of volume-adding cold infusions would provide improved outcomes in comparison with slower cooling. We defined rapid cooling as the achievement of 34°C within 3.5 hours of ROSC without the use of volume-adding cold infusions, with a ≥3.0°C/hour rate of cooling. Using the PubMed database and a previously published systematic review, we identified clinical studies published from 2002 through 2014 related to TTM. Analysis included studies with time from collapse to ROSC of 20-30 minutes, reporting of time from ROSC to target temperature and rate of patients in ventricular tachycardia or ventricular fibrillation, and hypothermia maintained for 20-24 hours. The use of cardiopulmonary bypass as a cooling method was an exclusion criterion for this analysis. We compared all rapid cooling studies with all slower cooling studies of ≥100 patients. Eleven studies were initially identified for analysis, comprising 4091 patients. Two additional studies totaling 609 patients were added based on availability of unpublished data, bringing the total to 13 studies of 4700 patients. Outcomes for patients, dichotomized into faster and slower cooling approaches, were determined using weighted linear regression using IBM SPSS Statistics software. Rapid cooling without volume-adding cold infusions yielded a higher rate of good neurological recovery than slower cooling methods. Attainment of a temperature below 34°C within 3.5 hours of ROSC and using a cooling rate of more than 3°C/hour appear to be beneficial.

The implications of ageing and life expectancy in prostate cancer treatment.

In patients diagnosed with prostate cancer, the selection of treatment, including the type of therapy and its aggressiveness, is often based on a patient's age and life expectancy. Life expectancy estimates are too often calculated solely on the patient's chronological age, overlooking comorbid conditions and their severity, which can greatly affect life expectancy. If, in addition to chronological age, comorbid conditions are used to assess a patient's life expectancy, the most appropriate treatment options are more likely to be selected. Older, healthy patients might be able to tolerate more aggressive treatment than would be administered on the basis of their age alone, and younger patients with numerous comorbid conditions could avoid harsh therapy that might not be appropriate given their current state of health. The key idea to consider in treatment selection is what a patient's quality of life would be like with or without a particular treatment option. In an era of precision medicine, decisions regarding the provision of health care should be made rationally and on the basis of objective estimates of the threat of disease and the benefits and costs of intervention and within the context of the patient's characteristics and desires.

Outcomes of unselected patients with metastatic clear-cell renal cell carcinoma treated with first-line pazopanib therapy followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors or mammalian target of rapamycin inhibitors: a single institution experience.

OBJECTIVE: To explore the efficacy and safety of pazopanib in a 'real-world' setting in unselected patients, as data regarding unselected patients with metastatic clear-cell renal cell carcinoma (ccRCC) treated with first-line pazopanib are limited. PATIENTS AND METHODS: We reviewed records of patients with metastatic ccRCC treated with first-line pazopanib from 1 November 2009 through to 1 November 2012. Cox models were fitted to evaluate the association of progression-free survival (PFS) and overall survival (OS) with patient co-variables. RESULTS: In all, 88 patients were identified; 74 were evaluable for response: two (3%) had a complete response, 27 (36%) a partial response, 36 (49%) had stable disease and nine (12%) had progressive disease. The median PFS was 13.7 months [95% confidence interval (CI) 8.7-18.3]. PFS was correlated with a Karnofsky Performance Status score of <80 [hazard ratio (HR) 3.26, P < 0.001] and serum lactate dehydrogenase of >1.5 × upper limit of normal (HR 3.25, P = 0.014). The median OS was 29.1 months (95% CI 20.2-not reached). The OS was correlated with brain metastasis (HR 2.55, P = 0.009), neutrophilia (HR 1.179, P = 0.018), and anaemia (HR 3.51, P < 0.001). There were no treatment-related deaths. In all, 53 patients received second-line therapy [vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) in 22 patients, mammalian target of rapamycin inhibitors (mTORi) in 22 patients, and other therapy in nine patients]; the median PFS was 8.6 months (95% CI 3.3-25.7) with VEGFR-TKI and 5 months (95% CI 3.5-15.2) with mTORi (P = 0.41); the median OS was 19.9 months (95% CI 12.9-not reached) and 14.2 months (95% CI 8.1-not reached), from initiation of second-line VEGFR-TKI or mTORi, respectively (P = 0.37). CONCLUSIONS: In this retrospective study, first-line pazopanib confirmed its efficacy in metastatic ccRCC. Trends for longer PFS and OS were seen with VEGFR-TKI compared with mTORi after first-line pazopanib.

Prognosis of patients with metastatic renal cell carcinoma and pancreatic metastases.

OBJECTIVES: To identify the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) with pancreatic metastases (PM) treated with either pazopanib or sunitinib and assess whether PM is an independent prognostic variable in the current therapeutic environment. PATIENTS AND METHODS: A retrospective review of patients with mRCC in an outpatient clinic was carried out for the period January 2006 to November 2011. Patient characteristics, including demographics, laboratory data and outcomes, were analysed. Baseline characteristics were compared using chi-squared and t-tests and overall survival (OS) and cancer-specific survival (CSS) rates were estimated using Kaplan-Meier methods. Predictors of OS were analysed using Cox regression. RESULTS: A total of 228 patients were reviewed, of whom 44 (19.3%) had PM and 184 (81.7%) had metastases to sites other than the pancreas. The distribution of baseline characteristics was equal in both groups, with the exception of a higher incidence of previous nephrectomy, diabetes and number of metastatic sites in the PM group. Four patients had isolated PM, but the majority of patients (68%) with PM had at least three different organ sites of metastases, as compared with 29% in patients without PM (P < 0.01). The distribution of organ sites of metastases was similar, excluding the pancreas, in those with and those without PM (P > 0.05). The median OS was 39 months (95% confidence interval [CI] 24-57, hazard ratio 0.66, 95% CI 0.42-0.94; P = 0.02) for patients with PM, compared with 26 months (95% CI 21-31) for patients without PM (P < 0.01). CSS was 42 months (95% CI 30-57) in the PM group and 27 months (95% CI 22-33) in the control group (P = 0.05). CONCLUSIONS: Despite a higher number of affected organ sites in the PM cohort, mRCC behaviour in this cohort appears to be more indolent, as demonstrated by a higher median OS. These findings suggest that host or tumour features associated with PM may represent a less aggressive tumour phenotype.

Profile of Patients Hospitalized through the Emergency Room to the Medicine Ward and their Short-term Outcome at a Tertiary Care Hospital in Delhi.

INTRODUCTION: With an increasing number of sicker patients, limited hospital beds, and an emphasis on day care, the profile of patients hospitalized to medicine wards has undergone a radical re-definition. The increasing share of patients hospitalized through the emergency department for acute care to medicine wards has left little space for hospitalization through the outpatient department (OPD). There are some global data available on the profile of patients presenting to the emergency rooms (ERs) and their subsequent outcome. Data from developing countries, especially India, in this regard are lacking. METHODS: This cross-sectional study included all patients hospitalized to the medicine ward through the medical emergency services, provided by the Department of Medicine, each Wednesday and every sixth Sunday for the entire year (a total of 62 days), from November 2010 through October 2011, and followed their outcome up to seven days after hospitalization. RESULTS: Of the 3,618 cases presenting to medicine emergency on these days, 1,547 (42.3%) were advised admission. Nine hundred sixty-seven reported to the medicine wards. One hundred eleven (7.73%) expired within 24 hours; others absconded, were lost in transit, did not consent to participation, or were discharged. During the next seven days, 452 (46.7%) recovered sufficiently and were discharged to go home. Two hundred thirty (23.8%) left the hospital without informing the medical staff. Fourteen (1.4%) patients were transferred to other departments. One hundred thirty-seven (8.8%) patients died during the next six days of hospitalization. After Multivariate Logistic Regression analysis, abnormal Glasgow Coma Scale (GCS) score, high systolic blood pressure (BP), age, increased total leucocyte count, increased globulin, low bicarbonate in arterial blood, low Mini Mental Status Examination (MMSE) score, and a raised urea >40 mg/dL were found to be associated significantly with mortality. CONCLUSION: Of the 1,547 patients who needed urgent hospitalization, 248 (16%) died within the first week, one-half of them within the first 24 hours. An advanced age, abnormal GCS score, low MMSE score, increased systolic BP, leukocytosis, acidosis, and uremia were found to be associated with a fatal outcome. Therefore, nearly one-half of the patients who would have a fatal short-term outcome were likely to do so within the first 24 hours, making the first day of presentation "the golden day" period.

Comorbidity polypharmacy score and its clinical utility: A pragmatic practitioner's perspective.

Modern medical management of comorbid conditions has resulted in escalating use of multiple medications and the emergence of the twin phenomena of multimorbidity and polypharmacy. Current understanding of how the polypharmacy in conjunction with multimorbidity influences trauma outcomes is limited, although it is known that trauma patients are at increased risk for medication-related adverse events. The comorbidity-polypharmacy score (CPS) is a simple clinical tool that quantifies the overall severity of comorbidities using the polypharmacy as a surrogate for the "intensity" of treatment necessary to adequately control chronic medical conditions. Easy to calculate, CPS is derived by counting all known pre-injury comorbid conditions and medications. CPS has been independently associated with mortality, increased risk for complications, lower functional outcomes, readmissions, and longer hospital stays. In addition, CPS may help identify older trauma patients at risk of post-emergency department undertriage. The goal of this article was to review and refine the rationale for CPS and to provide an evidence-based outline of its potential clinical applications.

Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between antiangiogenic therapy and the tumor immune microenvironment and determined their impact on clinical outcome. We found that antiangiogenic therapy-treated RCC primary tumors showed increased infiltration of CD4(+) and CD8(+) T lymphocytes, which was inversely related to patient overall survival and progression-free survival. Furthermore, specimens from patients treated with antiangiogenic therapy showed higher infiltration of CD4(+)FOXP3(+) regulatory T cells and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that antiangiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy and will guide the development of combination therapy with PD-1/PD-L1-blocking agents.

Association of tumor necrosis factor (TNF) promoter polymorphisms with plasma TNF-α levels and susceptibility to diabetic nephropathy in North Indian population.

AIM: The concept of diabetic nephropathy (DN) as a metabolic disease is now being replaced by chronic low-grade inflammatory disease. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine which plays an important role in the pathogenesis and clinical outcome of DN. Therefore, this work was planned to evaluate the association of -863C/A (rs1800630) and -1031T/C (rs1799964) polymorphisms in TNF gene with plasma TNF-α levels and DN among subjects with type 2 diabetes (T2DM) in a population from North India. METHODS: Age and sex matched 100 healthy controls (HC), 100 T2DM subjects without nephropathy (DM) and 100 subjects with DN were screened for above polymorphisms using the PCR-RFLP methods. Plasma TNF-α levels were measured by ELISA. Analysis of variance and logistic regression were used to associate individual polymorphisms with plasma TNF-α levels and DN. RESULTS: The allelic frequencies of -863C/A were 0.86/0.14 in HC, 0.72/0.23 in DM and 0.84/0.16 in DN, and that of -1031T/C were 0.89/0.11 in HC, 0.95/0.05 in DM and 0.80/0.20 in DN. The carriers of -863A allele had significantly lower plasma TNF-α levels (p<0.05). The -863C/A (OR=0.439, 95% CI=0.244-0.789, p=0.006) and -1031T/C (OR=3.0, 95% CI=1.355-6.642, p=0.007) were strongly associated with risk of development of DN. CONCLUSIONS: -863C/A was associated with low whereas -1031T/C with high TNF-α levels. The, results suggest that -863C/A polymorphism might be protective whereas -1031T/C may be associated with increased risk for DN in subjects with T2DM from North India.