Development of an MRI-Based Prediction Model for Anti-TNF Treatment Failure in Perianal Crohn's Disease: A Multicenter Study.

BACKGROUND & AIMS: Clinical and radiologic variables associated with perianal fistula (PAF) outcomes are poorly understood. We developed prediction models for anti-tumor necrosis factor (TNF) treatment failure in patients with Crohn's disease-related PAF. METHODS: In a multicenter retrospective study between 2005 and 2022 we included biologic-naive adults (>17 years) who initiated their first anti-TNF therapy for PAF after pelvic magnetic resonance imaging (MRI). Pretreatment MRI studies were prospectively reread centrally by blinded radiologists. We developed and internally validated a prediction model based on clinical and radiologic parameters to predict the likelihood of anti-TNF treatment failure, clinically, at 6 months. We compared our model and a simplified version of MRI parameters alone with existing imaging-based PAF activity indices (MAGNIFI-CD and modified Van Assche MRI scores) by De Long statistical test. RESULTS: We included 221 patients: 32 ± 14 years, 60% males, 76% complex fistulas; 68% treated with infliximab and 32% treated with adalimumab. Treatment failure occurred in 102 (46%) patients. Our prediction model included age at PAF diagnosis, time to initiate anti-TNF treatment, and smoking and 8 MRI characteristics (supra/extrasphincteric anatomy, fistula length >4.3 cm, primary tracts >1, secondary tracts >1, external openings >1, tract hyperintensity on T1-weighted imaging, horseshoe anatomy, and collections >1.3 cm). Our full and simplified MRI models had fair discriminatory capacity for anti-TNF treatment failure (concordance statistic, 0.67 and 0.65, respectively) and outperformed MAGNIFI-CD (P = .002 and < .0005) and modified Van Assche MRI scores (P < .0001 and < .0001), respectively. CONCLUSIONS: Our risk prediction models consisting of clinical and/or radiologic variables accurately predict treatment failure in patients with PAF.

The effects of estrogens on spatial learning and memory in female rodents - A systematic review and meta-analysis.

Estrogens have inconsistent effects on learning and memory in both the clinical and preclinical literature. Preclinical literature has the advantage of investigating an array of potentially important factors contributing to the varied effects of estrogens on learning and memory, with stringently controlled studies. This study set out to identify specific factors in the animal literature that influence the effects of estrogens on cognition, for possible translation back to clinical practice. The literature was screened and studies meeting strict inclusion criteria were included in the analysis. Eligible studies included female ovariectomized rodents with an adequate vehicle for the estrogen treatment, with an outcome of spatial learning and memory in the Morris water maze. Training days of the Morris water maze were used to assess acquisition of spatial learning, and the probe trial was used to evaluate spatial memory recall. Continuous outcomes were pooled using a random effects inverse variance method and reported as standardized mean differences with 95 % confidence intervals. Subgroup analyses were developed a priori to assess important factors. The overall analysis favoured treatment for the later stages of training and for the probe trial. Factors including the type of estrogen, route, schedule of administration, age of animals, timing relative to ovariectomy, and duration of treatment were all found to be important. The subgroup analyses showed that chronic treatment with 17ß-estradiol, either cyclically or continuously, to young animals improved spatial recall. These results, observed in animals, can inform and guide further clinical research on hormone replacement therapy for cognitive benefits.

Air pollution, weather and positive airway pressure treatment adherence in adults with sleep apnea: a retrospective community-based repeated-measures longitudinal study.

We assessed the relation between air pollution, weather, and adherence to positive airway pressure (PAP) therapy in a retrospective community-based repeated-measures study of adults with obstructive sleep apnea who purchased PAP devices from a registered provider between 2013 and 2017 (Ottawa, Ontario, Canada) and had at least one day of data. Daily PAP-derived data, air pollution, and weather databases were linked using postal code. The exposures were mean nocturnal (8:00 p.m. to 8:00 a.m.) (i) residential concentrations of nitrogen dioxide (NO2 ), fine particulate matter <=2.5 µm (PM2.5 ), ozone (O3 ), and Air Quality Health Index (AQHI), and (ii) temperature, relative humidity, and barometric pressure. Covariates in the main model were demographics, season, exposure year, and PAP therapy mode. We analysed 8148 adults (median age of 54 years and 61% men) and 2,071,588 days of data. Based on daily data, the median (interquartile range) daily PAP usage was 416 (323-487) min. Using mixed-effect regression analyses to incorporate daily data and clustering by individuals, we found a statistically significant decrease in adherence for increased levels of NO2 , PM2.5 , and AQHI. The largest effect was for NO2 : a decrease in daily PAP use while comparing the highest versus lowest quartiles (Qs) was 3.4 (95% confidence interval [CI] 2.8-3.9) min. Decreased PAP adherence was also associated with increased temperature (Q4 versus Q1: 2.6 [95% CI: 1.5-3.7] min) and decreased barometric pressure (Q1 versus Q4: 2.0 [95% CI 1.5-2.5] min). We observed modest but statistically significant acute effects of air pollution and weather on daily PAP adherence.

Inherited thrombophilia gene mutations and risk of venous thromboembolism in patients with cancer: A systematic review and meta-analysis.

In the general population, individuals with an inherited thrombophilia have a higher risk of thrombosis, but the effect of inherited thrombophilia on the risk of cancer-associated venous thromboembolism (VTE) remains controversial. Our objective was to determine the risk of VTE in cancer patients with inherited thrombophilia. We conducted a systematic review and meta-analysis of studies reporting on VTE after a cancer diagnosis in adult patients who were tested for inherited thrombophilia. In September 2022, we searched Medline, EMBASE, and Cochrane Central. Two reviewers screened the abstracts/full texts and assessed study quality using the Quality in Prognostic Studies tool. We used Mantel-Haenszel random-effects models to estimate pooled odds ratios (OR) of VTE and 95% confidence intervals (95%CI). We included 37 and 28 studies in the systematic review and meta-analysis, respectively. Most studies focused on specific cancer types and hematologic malignancies were rare. The risk of VTE was significantly higher in cancer patients with non-O (compared with O) blood types (OR: 1.56 [95% CI: 1.28-1.90]), Factor V Leiden, and Prothrombin Factor II G20210A mutations compared with wild types (OR: 2.28 [95% CI: 1.51-3.48] and 2.14 [95% CI: 1.14-4.03], respectively). Additionally, heterozygous and homozygous methylenetetrahydrofolate reductase C677T had ORs of 1.50 (95% CI: 1.00-2.24) and 1.38 (95% CI: 0.87-2.22), respectively. Among those with Plasminogen-Activator Inhibitor-1 4G/5G, Vascular Endothelial Growth Factor (VEGF) A C634G, and VEGF C2578A mutations, there was no significant association with VTE. In conclusion, this meta-analysis provided evidence that non-O blood types, Factor V Leiden, and Prothrombin Factor II G20210A mutations are important genetic risk factors for VTE in cancer patients.

Prevalence and Predictors of Bladder Outlet Obstruction in Women With Chronic Urinary Symptoms and a History of Urethral Sling Surgery.

PURPOSE: The objective of this study is to review patients with chronic urinary symptoms and remote urethral sling surgery to determine the prevalence and predictors of obstruction. MATERIALS AND METHODS: A single-center retrospective review was performed on patients referred with chronic lower urinary tract symptoms (>6 months) and a history of urethral sling surgery. Obstruction was identified by urodynamics using the Blaivas criteria or fluoroscopy. Clinical findings for patients with and without obstruction were compared. Logistic regression was applied to identify predictors of urodynamic obstruction. The need for sling revision and post-revision outcomes were evaluated. RESULTS: In total 105 patients were included, median age 61 years (IQR 19), median time since sling surgery 5.0 years (IQR 8). Sixty percent (63/105) met the definition for obstruction. Patients with obstruction had higher mean detrusor pressure at maximum urinary flow rate (35 vs 19 cm H2O) and lower maximum urinary flow rate (6.0 vs 14 mL/s; P < .05). A tight suburethral band and increased post-void residuals were significantly associated with urodynamic obstruction (P < .05). Fifty-nine (59/105; 56%) patients underwent suburethral sling excision. The incidence of improvement in storage and voiding symptoms at 6 months was 43% and 87%, respectively. At 30 months post-excision, the probability of being incontinence-free was 56% (95% CI 41, 69) and the probability of being free from redo sling surgery was 75% (95% CI 55, 87). CONCLUSIONS: Obstruction is common in patients with chronic urinary symptoms and history of urethral sling surgery. Patients undergoing sling revision should be observed for persistent storage symptoms and recurrent incontinence.

Estimated glomerular filtration rate from the renal hypothermia trial: clinical implications.

OBJECTIVE: To assess if estimated glomerular filtration rate (eGFR) can replace measured GFR (mGFR) in partial nephrectomy (PN) trials, using data from a randomised clinical trial. PATIENTS AND METHODS: We conducted a post hoc analysis of the renal hypothermia trial. Patients underwent mGFR with diethylenetriaminepentaacetic acid (DTPA) plasma clearance preoperatively and 1 year after PN. The eGFR was calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equations incorporating age and sex, with and without race: 2009 eGFRcr(ASR) and 2009 eGFRcr(AS), and the 2021 equation that only incorporates age and sex: 2021 eGFRcr(AS). Performance was evaluated by determining the median bias, precision (interquartile range [IQR] of median bias), and accuracy (percentage of eGFR within 30% of mGFR). RESULTS: Overall, 183 patients were included. Pre- and postoperative median bias and precision were similar between the 2009 eGFRcr(ASR) (-0.2 mL/min/1.73 m2 , 95% confidence interval [CI] -2.2 to 1.7, IQR 18.8; and -2.9, 95% CI -5.1 to -1.5, IQR 15, respectively) and 2009 eGFRcr(AS) (-0.3 mL/min/1.73 m2 , 95% CI -2.4 to 1.5, IQR 18.8; and -3.0, 95% CI -5.7 to -1.7, IQR 15.0, respectively). Bias and precision were worse for the 2021 eGFRcr(AS) (-8.8 mL/min/1.73 m2 , 95% CI -10.9 to -6.3, IQR 24.7; and -12.0, 95% CI -15.8 to -8.9, IQR 23.5, respectively). Similarly, pre- and postoperative accuracy was >90% for the 2009 eGFRcr(ASR) and 2009 eGFRcr(AS) equations. Accuracy was 78.6% preoperatively and 66.5% postoperatively for 2021 eGFRcr(AS). CONCLUSION: The 2009 eGFRcr(AS) can accurately estimate GFR in PN trials and could be used instead of mGFR to reduce cost and patient burden.

Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

BACKGROUND: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown. OBJECTIVE: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation. DESIGN: Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818). SETTING: Eighteen sites between February 2011 and February 2021. PATIENTS: Patients with isolated subsegmental pulmonary embolism. INTERVENTION: At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy. MEASUREMENTS: The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period. RESULTS: Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism. LIMITATION: The study was restricted to patients with low-risk subsegmental pulmonary embolism. CONCLUSION: Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism. PRIMARY FUNDING SOURCE: Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.

BACKGROUND: Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. METHODS: We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. RESULTS: Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). CONCLUSIONS: Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).

A Comparison of Percutaneous Ablation Therapy to Partial Nephrectomy for cT1a Renal Cancers: Results from the Canadian Kidney Cancer Information System.

PURPOSE: Percutaneous ablation therapy (AT) and partial nephrectomy (PN) are successful management strategies for T1a renal cancer. Our objective was to compare AT to PN with respect to recurrence-free survival (RFS) and overall survival (OS). MATERIALS AND METHODS: Patients post-PN or -AT for cT1aN0M0 renal cancer from 2011 to 2021 were identified from the national Canadian Kidney Cancer information system. Inverse probability of treatment weighting (IPTW) using propensity score (PS) was used. The primary outcomes, RFS and OS, were compared using Kaplan-Meier log-rank test analyses and Cox proportional hazard regression models. RESULTS: A total of 275 patients underwent AT and 2,001 underwent PN, with a median followup of 2.0 years (IQR 0.6-4.1). Covariates were well balanced between the AT and PN cohorts following PS matching. Two-year RFS following IPTW PS analysis for patients undergoing AT and PN was 88.1% and 97.4% (p <0.0001), respectively, while 2-year OS was 97.4% and 99.0% (p=0.7), respectively. Five-year RFS following IPTW PS analysis for patients undergoing AT and PN was 86.0% and 95.1%, respectively (p=0.003), while 5-year OS was 94.2% and 95.1%, respectively (p=0.9). Following IPTW PS analysis, treatment modality (PN vs AT) was a predictor of disease recurrence (HR 0.36, p=0.003) but not for OS (HR 0.96, p=0.9). CONCLUSIONS: With short followup, PN offers better RFS than AT, although no significant difference in OS was detected following PS adjustments. Both modalities can be offered to appropriately selected patients while we await prospective randomized data.

Improving health care facility birth rates in Rorya District, Tanzania: a multiple baseline trial.

BACKGROUND: Rates of maternal mortality and morbidity in Africa remain unacceptably high, as many women deliver at home, without access to skilled birth attendants and life-saving medications. In rural Tanzania, women face significant barriers accessing health care facilities for their deliveries. METHODS: From January 2017 to February 2019 we conducted a multiple baseline (interrupted time series) trial within the four divisions of Rorya District, Tanzania. We collected baseline data, then sequentially introduced a complex intervention in each of the divisions, in randomized order, over 3 month intervals. We allowed for a 6 month transition period to avoid contamination between the pre- and post-intervention periods. The intervention included using community health workers to educate about safe delivery, distribution of birth kits with misoprostol, and a transport subsidy for women living a distance from the health care facility. The primary outcome was the health facility birth rate, while the secondary outcomes were the rates of antenatal and postpartum care and postpartum hemorrhage. Outcomes were analyzed using fixed effects segmented logistic regression, adjusting for age, marital status, education, and parity. Maternal and baby morbidity/mortality were analyzed descriptively. RESULTS: We analyzed data from 9565 pregnant women (2634 before and 6913 after the intervention was implemented). Facility births increased from 1892 (71.8%) before to 5895 (85.1%) after implementation of the intervention. After accounting for the secular trend, the intervention was associated with an immediate increase in the odds of facility births (OR = 1.51, 95% CI 1.14 to 2.01, p = 0.0045) as well as a small gradual effect (OR = 1.03 per month, 95% CI 1.00 to 1.07, p = 0.0633). For the secondary outcomes, there were no statistically significant immediate changes associated with the intervention. Rates of maternal and baby morbidity/mortality were low and similar between the pre- and post-implementation periods. CONCLUSIONS: Access to health care facilities can be improved through implementation of education of the population by community health workers about the importance of a health care facility birth, provision of birth kits with misoprostol to women in late pregnancy, and access to a transport subsidy for delivery for women living at a distance from the health facility. CLINICAL TRIALS REGISTRATION: NCT03024905 19/01/2017.

Risk Factors for Urologic Injury in Women Undergoing Hysterectomy for Benign Indication.

OBJECTIVE: To investigate risk factors associated with urologic injury in women undergoing hysterectomy for benign indication. METHODS: A retrospective cohort study for the period of 2011-2018 was conducted using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. Women without urologic injury were compared with women with injury. A pre-specified multivariable logistic regression model, controlling for key patient demographic factors and intraoperative variables, was used to assess for surgical factors associated with urologic injury. RESULTS: Among 262 117 women who underwent hysterectomy for benign indication, 1539 (0.6%) sustained urologic injury. On average, patients with urologic injury were younger, had lower body mass index (BMI), and more frequently underwent a transabdominal surgical approach. Patients who underwent total hysterectomy had increased odds of urologic injury than those who underwent subtotal hysterectomy (adjusted OR [aOR] 1.49; 95% confidence interval [CI] 1.21-1.84). Patients with class III obesity had lower odds of injury than patients with normal BMI (aOR 0.64; 95% CI 0.51-0.80). For risk of urologic injury, an interaction was observed between surgical approach and surgical indication. Abdominal compared with laparoscopic approach was associated with urologic injury for women with endometriosis (aOR 2.98; 95% CI 1.99-4.47), pelvic pain (aOR 3.51; 95% CI 1.74-7.08), menstrual disorders (aOR 4.33; 95% CI 1.68-11.1), and fibroids (aOR 2.28; 95% CI 1.72-3.03). Vaginal compared with laparoscopic approach was associated with increased odds of injury for women with menstrual disorders (aOR 7.62; 95% CI 1.37-42.5). CONCLUSION: While the risk of urologic injury during hysterectomy for benign indication is low, the risk is dependent on patient disease factors and surgical approach.

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Performance Feedback May Not Improve Radical Prostatectomy Outcomes: The Surgical Report Card (SuRep) Study.

PURPOSE: Oncologic, urinary, and sexual outcomes are important to patients receiving prostate cancer surgery. The objective of this study was to determine if providing surgical report cards (SuReps) to surgeons resulted in improved patient outcomes. MATERIALS AND METHODS: A prospective before-and-after study was conducted at The Ottawa Hospital. A total of 422 consecutive patients undergoing radical prostatectomy were enrolled. The intervention was provision of report cards to surgeons. The control cohort was patients treated before report card feedback (pre-SuRep), and the intervention cohort was patients treated after report card feedback (post-SuRep). The primary outcomes were postoperative erectile function, urinary continence, and positive surgical margins. RESULTS: Baseline characteristics were similar between groups. Almost all patients (99%) were continent and the majority (59%) were potent prior to surgery. Complete 1-year followup was available for 400 patients (95%). Nerve sparing surgery increased from 70% pre-SuRep to 82% post-SuRep (p=0.01). There was a nonstatistically significant increase in the proportion of patients with a positive surgical margin post-SuRep (31% pre-SuRep vs 39% post-SuRep, p=0.08). There was no difference in postoperative erectile function (17% vs 18%, p=0.7) and a decrease in continence (75% vs 65%, p=0.02) at 1 year postoperatively. CONCLUSIONS: The SuRep platform allows accurate reporting of surgical outcomes that can be used for patient counseling. However, the provision of surgical report cards did not improve functional or oncologic outcomes. Longer durations of feedback, report card modifications, or targeted interventions are likely necessary to improve outcomes.

Hypothermia During Partial Nephrectomy for Patients with Renal Tumors: A Randomized Controlled Trial.

PURPOSE: Surgeons induce renal hypothermia during partial nephrectomy to preserve kidney function, without strong evidence of benefit. This trial examined the effectiveness and safety of renal hypothermia during partial nephrectomy. MATERIALS AND METHODS: We conducted a parallel randomized controlled trial of hypothermia versus no hypothermia (control group) during partial nephrectomy at 6 academic hospitals. Eligible patients had a planned open partial nephrectomy for the treatment of a renal tumor. During surgery, after clamping the renal hilum, patients were randomized to the intervention or control arm in a 1:1 ratio using permuted blocks of variable lengths (2 and 4), stratified by institution, using a computer-based program. Surgeons and study coordinators were masked to treatment allocation until the renal hilum was clamped. Overall glomerular filtration rates were determined before, and 1-year after, surgery. The primary outcome was measured glomerular filtration rate (mGFR) assessed by the plasma clearance of 99mTc-DTPA. The trial (NCT01529658) was designed with 90% power to detect a minimal clinically important difference in mGFR of 10 ml/minute/1.73 m2 at a 5% significance level. RESULTS: Of the 184 patients randomized, hypothermia and control patients had similar baseline mean mGFR (87.1 vs 81.0 ml/minute/1.73 m2). One hundred and sixty-one (79 hypothermia, 82 control) were alive with primary outcome data 1 year after surgery. The change in mGFR 1 year after surgery was -6.6 ml/minute/1.73 m2 in the hypothermia group and -7.8 ml/minute/1.73 m2 in the control group (mean difference 1.2 ml/minute/1.73 m2, 95% CI -3.3 to 5.6). Operated-kidney change in mGFR was similar between groups (-5.8 vs -6.3 ml/minute/1.73 m2; mean difference 0.5 ml/minute/1.73 m2, 95% CI -2.9 to 3.8). No clinically significant difference in the mGFR was observed when patients were stratified by pre-planned subgroups. Renal hypothermia did not impact the secondary outcomes of surgical complications and patient reported quality of life. CONCLUSIONS: Renal hypothermia during partial nephrectomy does not preserve kidney function in patients with normal or mildly impaired renal function.

Impact of Time to Surgery and Surgical Delay on Oncologic Outcomes for Renal Cell Carcinoma.

PURPOSE: The time between radiographic identification of a renal tumor and surgery can be concerning for patients and clinicians due to fears of tumor progression while awaiting treatment. This study aimed to evaluate the association between surgical wait time and oncologic outcomes for patients with renal cell carcinoma. MATERIALS AND METHODS: The Canadian Kidney Cancer Information System is a multi-institutional prospective cohort initiated in January 2011. Patients with clinical stage T1b or greater renal cell carcinoma diagnosed between January 2011 and December 2019 were included in this analysis. Outcomes of interest were pathological up staging, cancer recurrence, cancer specific survival and overall survival. Time to recurrence and death were estimated using Kaplan-Meier estimates and associations were determined using Cox proportional hazards models. RESULTS: A total of 1,769 patients satisfied the study criteria. Median wait times were 54 days (IQR 29-86) for the overall cohort and 81 days (IQR 49-127) for cT1b tumors (1,166 patients), 45 days (IQR 27-71) for cT2 tumors (672 cases) and 35 days (IQR 18-61) for cT3/4 tumors (563). Adjusting for comorbidity, tumor size, grade, histological subtype, margin status and pathological stage, there was no association between prolonged wait time and cancer recurrence or death. CONCLUSIONS: In the context of current surgeon triaging practices surgical wait times up to 24 weeks were not associated with adverse oncologic outcomes after 2 years of followup.

Thromboprophylaxis for patients with newly diagnosed vs. recurrent cancers: a post-hoc analysis of the avert trial.

Venous thromboembolic disease (VTE) is a common complication among patients with cancer. Data reporting risk of VTE among patients receiving chemotherapy for recurrent cancer compared to those with newly diagnosed tumors is scarce. Furthermore, it is unclear if thromboprophylaxis is beneficial and safe in these specific patient populations. Post-hoc analysis of the AVERT trial which was a randomized, placebo-controlled, double-blind trial comparing apixaban therapy to placebo for VTE prophylaxis among cancer patients who were intermediate-to-high risk for VTE and who were initiating chemotherapy. The HRs for recurrent VTE and major bleeding episodes in patients with newly diagnosed and recurrent cancers were calculated using a Cox regression model controlling for age, gender, and center. Of the 563 included patients 469 and 93 patients had newly diagnosed and recurrent cancers, respectively. Patients with recurrent cancer have a higher risk of VTE (Hazard ratio (HR): 1.53 (95% CI 1.0 to 2.33; p = 0.047) and major bleeding episodes (HR 2.89 (95% CI 1.52 to 5.49; p = 0.001) compared to those with newly diagnosed cancer. In patients with newly diagnosed cancers, the use of apixaban was associated with a significantly lower risk of VTE (HR 0.45; 95% CI 0.27-0.76; p = 0.002) and a higher rate of major bleeding (HR 2.10; 95% CI 1.09-4.08; p = 0.028). In patients with recurrent cancer, apixaban was associated with a significant lower rate of VTE (HR 0.26; 95% CI 0.13-0.53; p < 0.001) without an associated significantly increased risk of major bleeding (HR 1.82; 95% CI 0.36-9.15; p = 0.466). Patients with recurrent cancer seem to be at higher risk of recurrent VTE and major bleeding complications compared to those with newly diagnosed tumors. Apixaban appears to be safe and effective in these patient populations.

Technicity in Canada: A Nationwide Whole-Population Analysis of Temporal Trends and Variation in Minimally Invasive Hysterectomies.

STUDY OBJECTIVE: The objective of our study was to provide a contemporary description of hysterectomy practice and temporal trends in Canada. DESIGN: A national whole-population retrospective analysis of data from the Canadian Institute for Health Information. SETTING: Canada. PATIENTS: All women who underwent hysterectomy for benign indication from April 1, 2007, to March 31, 2017, in Canada. INTERVENTIONS: Hysterectomy. MEASUREMENTS AND MAIN RESULTS: A total of 369 520 hysterectomies were performed in Canada during the 10-year period, during which the hysterectomy rate decreased from 313 to 243 per 100 000 women. The proportion of abdominal hysterectomies decreased (59.5% to 36.9%), laparoscopic hysterectomies increased (10.8% to 38.6%), and vaginal hysterectomies decreased (29.7% to 24.5%), whereas the national technicity index increased from 40.5% to 63.1% (p <.001, all trends). The median length of stay decreased from 3 (interquartile range 2-4) days to 2 (interquartile range 1-3), and the proportion of patients discharged within 24 hours increased from 2.1% to 7.2%. In year 2016-17, women aged 40 to 49 years had significantly increased risk of abdominal hysterectomy compared with women undergoing hysterectomy in other age categories (p <.001). Comparing women with menstrual bleeding disorders, women undergoing hysterectomy for endometriosis (adjusted relative risk [aRR] 1.36; 95% confidence interval [CI], 1.28-1.44) and myomas (aRR 2.01; 95% CI, 1.94-2.08) were at increased risk of abdominal hysterectomy, whereas women undergoing hysterectomy for pelvic organ prolapse and pelvic pain (aRR 1.47; 95% CI, 1.41-1.53) were at decreased risk. Using Ontario as the comparator, Nova Scotia (aRR 1.35; 95% CI, 1.27-1.43), New Brunswick (aRR 1.25; 95% CI, 1.18-1.32]), Manitoba (aRR 1.35; 95% CI, 1.28-1.43), and Newfoundland and Labrador (aRR 1.18; 95% CI, 1.10-1.27) had significantly higher risks of abdominal hysterectomy. In contrast, Saskatchewan (aRR 0.75; 95% CI, 0.74-0.77) and British Columbia (aRR 0.86; 95% CI, 0.85-0.88) had significantly lower risks, whereas Prince Edward Island, Quebec, and Alberta were not significantly different. CONCLUSION: The proportion of minimally invasive hysterectomies for benign indication has increased significantly in Canada. The declining use of vaginal approaches and the variation among provinces are of concern and necessitate further study.

Venous Thromboembolism After Blood Transfusions in Women Undergoing Hysterectomy for Non-Malignant Indications: A Retrospective Cohort Study.

OBJECTIVE: To quantify the effect of blood transfusion on the risk of venous thromboembolism (VTE) among women undergoing hysterectomy for non-malignant indications. METHODS: A retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) was conducted. Women who underwent hysterectomy for non-malignant indications between 2011 and 2016 were identified using the Current Procedural Terminology and Internationally Classification of Diseases codes. The primary outcome was development of VTE. Data on patient demographics and perioperative variables were obtained. Pair-wise comparison using χ2 tests were performed to compare women with and without VTE. Multivariable logistic regression was performed to adjust for potential confounders and identify independent predictors of VTE. RESULTS: Between 2011 and 2016, 169 593 women underwent hysterectomy for non-malignant indications. The overall incidence of VTE was 0.32%. Patient characteristics associated with VTE included obesity and higher American Society of Anesthesiologists (ASA) status. Associated operative factors included abdominal surgery, blood transfusion, and prolonged operative time (P < 0.05 for all). Following adjustment for potential confounders, abdominal hysterectomy was associated with greater odds of VTE than laparoscopic or vaginal approaches (adjusted odds ratio [aOR] 1.81; 95% CI 1.48-2.21 and aOR 2.31; 95% CI 1.62-3.28, respectively). Greater odds of VTE were also observed with OR time >150 minutes (aOR 1.88; 95% CI 1.46-2.42), ASA class ≥III (aOR 1.53; 95% CI 1.05-2.26), and intra- and postoperative transfusion (aOR 2.65; 95% CI 1.78-3.95 and aOR 2.98; 95% CI 1.95-4.55, respectively). CONCLUSION: The risk of VTE is low in women undergoing hysterectomy for non-malignant indications. Blood transfusion was associated with the highest risk of VTE.

Does Lymphocyte Count Impact Dosing of Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplantation?

Anti-thymocyte globulin (ATG) is used to reduce the incidence and severity of graft-versus-host disease (GVHD) with hematopoietic cell transplantation, yet optimum dosing has yet to be determined. We have previously demonstrated that 2.5 mg/kg ATG in conditioning can reduce the incidence of GVHD in unrelated donor transplants. Recent literature has suggested that ATG dosing based on absolute lymphocyte count (ALC) could lead to more optimum exposure of the drug. We sought to determine if ALC at the time of transplant could impact clinical outcomes. We conducted a retrospective single-center study analyzing all consecutive patients at The Ottawa Hospital who received a matched unrelated donor stem cell transplant with ATG between 2009 and 2014. Patients received rabbit ATG (thymoglobulin) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1. Univariate and multivariate analyses were used to determine if any patient- or transplant-related factors, including weight, ALC, and total ATG dose given, impacted GVHD, relapse, or mortality. In total, 111 patients met inclusion, with a median age of 50 years (range, 19 to 70). The most common diagnoses were acute myelogenous leukemia (43%), Myelodysplasia/myeloproliferative neoplasms (13%), and lymphoma (12%). The median weight at time of conditioning was 80.3 kg (range, 45 to 216). The median ALC on the first day of ATG administration was 0.1 × 109/L (range, 0 to 190). The median total dose of ATG received was 201 mg (range, 112 to 540 mg). The incidence of acute and chronic GVHD was 35.1% and 21.6%, respectively. In the multivariate model, the actual dose of ATG given to patients was not associated with GVHD (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.99 to 1.25; P = .07), relapse (HR, 1.13; 95% CI, 0.98 to 1.30; P = .1), or mortality (HR, 1.09; 95% CI, 0.92 to 1.28; P = .32). Similarly, the pretransplant ALC was not associated with GVHD (HR, 1; P = .82), relapse (HR, 1; P = .90), or mortality (HR, 1; P = .39). If patients had received ALC-based dosing according to previously published work (Admiraal et al., Lancet Haematol 2017), the mean total dose of ATG received would have been 1205 mg, more than 5 times the mean dose that was actually given based on weight. With GVHD outcomes being similar to that published by Admiraal et al. and ALC not independently associated with outcomes in our study, further studies are still needed to compare standard weight-based dosing to ALC-based dosing of ATG in matched unrelated donor stem cell transplant.

Potential Life-Years Lost: The Impact of the Cancer Drug Regulatory and Funding Process in Canada.

BACKGROUND: Canada has an established publicly funded health care system with a complex drug approval and funding process. After proof of efficacy (POE; key publication/presentation) and before becoming publicly accessible, each drug undergoes a Health Canada approval process, a health technology assessment (HTA), a pricing negotiation, and finally individual provincial funding agreements. We quantified potential life-years lost during this process. METHODS: We analyzed drugs for advanced lung, breast, and colorectal cancer that underwent the HTA process between 2011 and 2016. Life-years lost were calculated by multiplying documented improvement in progression-free and overall survival, number of eligible patients, and time from POE to first public funding. For conservative calculation, we assumed all eligible patients in Canada had access at the time of first public funding, whereas in reality provinces fund at different time points. RESULTS: We analyzed 21 drugs. Of these, 15 have been funded publicly. The time from POE to first public funding ranged from 14.0 to 99.2 months (median 26.6 months). Total overall life-years lost from POE to first public funding were 39,067 (lung 32,367; breast 6,691). Progression-free life-years lost from POE to first public funding were 48,037 (lung 9,139, breast 15,827, colorectal 23,071). CONCLUSION: The number of potential life-years lost during the drug regulatory and funding process in Canada is substantial, largely driven by delays to funding of colorectal cancer drugs. Recognizing that interprovincial differences exist and that eligible patients may not all receive a given drug, if even a fraction does so, the impact of delays remains substantive. Collaborative national initiatives are required to address this major barrier to treatment access. IMPLICATIONS FOR PRACTICE: Patients may spend lengthy periods of time awaiting access to new and effective cancer drugs. Patients with private drug insurance or personal funds or who reside in certain Canadian provinces may obtain some drugs sooner than others, potentially creating a two-tiered access system. The cancer drug access and public funding system must be expedited to improve equity.