Protocol for Phase I Study of Pembrolizumab in Combination with Bacillus Calmette-Guérin for Patients with High-Risk Non-Muscle Invasive Bladder Cancer

INTRODUCTION: The initial treatment for high-risk non-muscle invasive bladder cancer (NMIBC) is endoscopic resection of the tumour followed by BCG therapy. In those who develop recurrence, the standard treatment is radical cystectomy. Despite the advancement in surgical technique and postoperative care, the degree of morbidity associated with radical cystectomy remains high, therefore less invasive treatment modalities are desirable. Therapies targeting the programmed death (PD) pathway have shown promise in urothelial carcinoma. We undertook the current study to determine the safety and efficacy of administering pembrolizumab (a monoclonal antibody targeting the interaction between PD-1 and its ligand) in combination with BCG in high-risk NMIBC. METHODS: This is a single-centre phase I safety and efficacy study of pembrolizumab used in combination with intravesicular BCG treatment for subjects with pathologically documented high-risk NMIBC despite having received two courses of induction therapy or BCG treatment followed by maintenance BCG. Fifteen subjects will be enrolled, patients will receive treatment with 200 mg of pembrolizumab every 21 days, starting 2 weeks from the initial endoscopic resection and continuing for 6 weeks after the final dose of BCG. The primary objective is to determine the safety of administering pembrolizumab at a fixed dose of 200 mg every 3 weeks in conjunction with intravesicular BCG treatment in patients with high-risk NMIBC who have failed previous treatment. Secondary objectives are to determine the 19 weeks and the 3, 12 and 24 months post-treatment completion complete response rate with combined pembrolizumab and intravesicular BCG therapy in the aforementioned patients. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board of the Henry Ford Hospital. The results of this study will be published in a peer-reviewed journal and presented at a scientific conference. TRIAL REGISTRATION NUMBER: NCT02324582

Grassroots Reform in the Global South (2017)

In 2016, USAID's Center of Excellence on Democracy, Human Rights, and Governance launched its Learning Agenda—a set of research questions designed to address the issues that confront staff in USAID field offices working on the intersection of development and democracy, human rights, and governance. This literature review—produced by a team of sociologists and political scientists—synthesizes scholarship from diverse research traditions on the following Learning Agenda question:How and when does grassroots reform scale up? When citizen participation has led to local reforms in a particular sector (e.g., health), what processes lead to these reforms' influencing the regional or national levels of that sector (e.g., citizen groups monitoring medicine supplies in local clinics leads eventually to pharmaceutical procurement reform in the Ministry of Health)?The report itself is divided into four principal sections:Section 1 outlines the context for the report by discussing the importance of grassroots reform, defining key terms, and describing its methodology.Section 2 documents the experiences of different regions with an eye toward intra-regional comparisons.Section 3 distills two types of lessons from the regional experiences: relatively abstract lessons of broad relevance and relatively precise lessons of less general relevance.Section 4 discusses the translation of the authors' findings into actionable lessons and concludes by discussing the limits to their knowledge base, pending research questions, and methodological impediments to their resolution

Ex-vivo ureteroscopy for the treatment of nephrolithiasis in a deceased donor kidney prior to transplantation

Background: There are over 100,000 adult patients awaiting renal transplantation in the United States, with less than 25% who undergo eventual transplantation [1]. This disparity has motivated providers to seek ways to increase the number of kidneys available for transplantation. Historically, the presence of kidney stones in a renal allograft was a relative contraindication for renal transplantation [2]. Ex-vivo ureteroscopy, or, “back-table ureteroscopy”, is a technique which has been employed as a potential solution to increase the total number of available kidneys which were initially deemed ineligible [3,4]. Objective: To demonstrate our step by step technique for ex-vivo ureteroscopy and to demonstrate its safety and efficacy as a method of stone removal prior to transplantation. Methods: Following procurement and back table preparation of the donor kidney by the transplant surgery team, the kidney was replaced in an ice bath for ex-vivo ureteroscopy. A combination of holmium laser lithotripsy and stone basketing were used to extract the stone. Following complete removal of the renal calculus, the renal allograft was reprepared and the renal transplantation was carried forth in the standard fashion by the transplant surgery team. Results: The total operative time for the ex-vivo ureteroscopy was 70 min. No intra-operative complications were identified during ex-vivo ureteroscopy or during allograft transplantation. Six months following transplantation, the patients renal function remains normal. Conclusions: Ex-Vivo ureteroscopy can be a safe and effective treatment for the management of renal stones prior to transplantation. This method can be used with existing resources to increase the number of donor kidneys available for transplantation each year

Impact of Hospital Teaching Status on Healthcare Utilization, Length of Stay (LOS), and Cost of Hospitalization of Radiation Cystitis (RC) in the United States

Background: Limited data exist regarding in-hospital use of resources, LOS, and cost of RC-associated admissions in teaching hospital (TH) versus nonteaching hospital (NTH) settings. The goal of this study was to address the above void in literature. Methods:We focused on 13,272 admissions for RC between 2008-2014 within the National Inpatient Sample. Patients with concurrent diagnosis of other bladder conditions (n=914) were excluded. ICD-9 diagnosis and procedure codes were used to study inpatient procedures performed during admission. Type of admissions, receipt of a procedure, type of procedures performed, LOS, and total inflation-adjusted cost were then compared between TH and NTH. Complex survey chi-squared test and analysis of variance procedures were used to account for the NIS sampling design. Results: Of the 12,358 assessable records, 49% were at THs. Patients were more commonly admitted to emergency department at NTH (85%) compared to TH (80%; p\u3c0.001). Weekend admissions were more common at NTH (24%) compared to TH (21%) (p=0.004). Receipt of a procedure during admission was higher in TH (65%) compared to NTH (60%; p\u3c0.001). Number of procedure codes recorded was higher in TH (\u3e= 2 codes; 28.9% in TH vs 24.5% in NTH; p \u3c0.001. More complex procedures like cystectomy were almost exclusively performed at TH (cystectomy 2.4% in TH vs 0.4% in NTH admissions; p \u3c0.001), whereas there was no difference in procedures like blood transfusion (TH 34%; NTH 33%; p=0.3), suprapubic cystostomy (TH 1.3%; NTH 1.4%; p=0.8), and transurethral procedures (TH 14%; NTH 16%; p=0.06). Despite statistically significant difference in LOS between the two groups (Median days (IQR): TH 5 (3-9); NTH 5 (3-8); p\u3c0.001) the difference was not clinically significant. Cost of admission was higher in TH (10,377$TH; 8504$ NTH; p\u3c0.001). Conclusions: In the United States, patients with RC are more frequently admitted to the emergency department in NTH. Patients admitted to TH receive a procedure more often, receive a higher number of procedures, and more complex procedures, compared to NTH. This explains higher cost of admission in TH. Further research is needed to study the readmission rates and outcomes of patients treated in both types of health systems to know the best practices that can reduce morbidity and readmissions.https://scholarlycommons.henryford.com/merf2019qi/1021/thumbnail.jp

Associations Between Left Ventricular Dysfunction and Brain Structure and Function: Findings From the SABRE (Southall and Brent Revisited) Study

Background Subclinical left ventricular (LV) dysfunction has been inconsistently associated with early cognitive impairment, and mechanistic pathways have been poorly considered. We investigated the cross‐sectional relationship between LV dysfunction and structural/functional measures of the brain and explored the role of potential mechanisms. Method and Results A total of 1338 individuals (69±6 years) from the Southall and Brent Revisited study underwent echocardiography for systolic (tissue Doppler imaging peak systolic wave) and diastolic (left atrial diameter) assessment. Cognitive function was assessed and total and hippocampal brain volumes were measured by magnetic resonance imaging. Global LV function was assessed by circulating N‐terminal pro–brain natriuretic peptide. The role of potential mechanistic pathways of arterial stiffness, atherosclerosis, microvascular disease, and inflammation were explored. After adjusting for age, sex, and ethnicity, lower systolic function was associated with lower total brain (beta±standard error, 14.9±3.2 cm3; P<0.0001) and hippocampal volumes (0.05±0.02 cm3, P=0.01). Reduced diastolic function was associated with poorer working memory (−0.21±0.07, P=0.004) and fluency scores (−0.18±0.08, P=0.02). Reduced global LV function was associated with smaller hippocampal volume (−0.10±0.03 cm3, P=0.004) and adverse visual memory (−0.076±0.03, P=0.02) and processing speed (0.063±0.02, P=0.006) scores. Separate adjustment for concomitant cardiovascular risk factors attenuated associations with hippocampal volume and fluency only. Further adjustment for the alternative pathways of microvascular disease or arterial stiffness attenuated the relationship between global LV function and visual memory. Conclusions In a community‐based sample of older people, measures of LV function were associated with structural/functional measures of the brain. These associations were not wholly explained by concomitant risk factors or potential mechanistic pathways

Inpatient morbidity and cost of cytoreductive radical prostatectomy in the United States

INTRODUCTION AND OBJECTIVES: Clinical trials are currently examining the role of local therapy in metastatic prostate cancer (mPCa). While the safety of RP in localized disease is proven, few studies have looked at perioperative complications and cost of cytoreductive RP (cRP). We used the National Inpatient Sample (NIS) to study the inpatient morbidity, and cost of cRP in the United States (US). METHODS: Analyzing the NIS dataset from 2008-2014, we identified 90,662 patients (weighted estimate 449,025 in the US) who underwent RP for non-metastatic disease, and 1,173 patients (weighted estimate 5,835) who underwent cRP for mPCa (see Fig. 1). Outcomes of interest were inpatient complications, individual complications, hospital stay, and total cost. Covariates included age, race, Charlson Comorbidity score, insurance status, rural/semi-urban/urban location, income, hospital location (rural/urban), teaching status, geographical location of hospital, and hospital volume. Multivariable logistic regression was used to evaluate the effect of metastatic disease on morbidity after adjusting for covariates. RESULTS: Inpatient complication rates were 14.9% (13,688/91,835) overall, 14.9% (13,464/90,662) in the non-metastatic group, and 19.1% (224/1,173) in the cRP group (p = 0.01). On multivariable analysis, metastasis was an independent predictor of inpatient complications (OR 1.329; 95% CI: 1.077-1.640; p = 0.01). The cRP group also had higher rates of blood transfusion (6.9% [82/1,173] vs 4.3% [3,869/90,662]; p \u3c 0.001), longer hospital stay (median 1.25 vs 0.97 days; p \u3c 0.001), and higher cost (median $14,123 vs$11,591; p \u3c 0.001) compared to the non-metastatic group (see table 1). Majority of cRP was performed in urban teaching hospitals. CONCLUSIONS: cRP is associated with higher inpatient morbidity, longer hospital stay, and higher cost compared to RP for non-metastatic disease. This information may be valuable for informed decision-making in practice and before recruiting patients in clinical trials on this subject. Source of Funding: Nonehttps://scholarlycommons.henryford.com/merf2019hvc/1006/thumbnail.jp

Long-term risk of recurrence in surgically treated intermediate-high risk renal cell carcinoma: a post-hoc analysis of the Eastern Cooperative Oncology Group - American College of Radiology Imaging Network E2805 Trial cohort

Background: Surgical resection remains the gold standard treatment modality for clinically localized renal cell carcinoma (RCC). However, the optimal follow-up period in these individuals is controversial, and the current recommendations are based on retrospective data, which inevitably contain attrition bias. Our objective was to re-visit the recurrence rate of surgically treated intermediate-high risk RCC patients using randomized clinical trial data. MethodsWe performed a post-hoc analysis of all the patients that were included in the ECOG-ACRIN E2805 Trial. We assessed post-operative recurrence rates using the cumulative incidence method. Conditional estimates of a 36-month recurrence for patients whom did not have recurrence at set intervals following surgery was performed. Assessment of routinely available clinical and pathological features in predicting disease recurrence at time 0-months after surgery was compared it to that of the same features at 60-months after surgery.ResultsThe original cohort consisted of 1943 patients . Median follow-up for the 1508 patients whom were alive at the end of the study was 67.9 months (IQR 56.7 – 82.0). 730 patients developed disease recurrence. The 36-month cumulative incidence of recurrence was found to be 31.1% (IQR 29.3 – 33.6) for the entire cohort at 0-months from surgery. The rate changed to 26.0% (IQR 23.7 – 28.2), 18.8% (IQR 16.5 – 21.1), 16.1% (IQR 13.6 – 18.8), 18.9% (IQR 15.0 – 23.1) and 20.3% (IQR 12.5 – 28.1) for patients whom did not have recurrence at 12-, 24-, 36-, 48- and 60-months from surgery, respectively. At time 0-month from surgery, age (hazard ratio [HR]: 1.01, 95% confidence interval [CI]: 1.00-1.02), pathologic T3/4 stage (HR: 1.557, 95%CI: 1.17 - 2.07), pathologic N1/2 stage (HR: 2.38, 95%CI: 1.85 - 3.07), Fuhrman grade 3 (HR: 1.36, 95%CI: 1.14 - 1.62) and Fuhrman grade 4 (HR: 2.41, 95%CI: 1.96 - 2.96) were independent predictors of recurrence. Conversely, none of the aforementioned covariates were predictors of disease recurrence at 60-months following surgery. Conclusions: Long-term follow-up, beyond 5-years, is supported by the findings within the present study. Also, the usual independent predictors that are frequently used to guide patient follow-up demonstrated validity immediately following surgery however lose their predictive power at 5 years from surgery.https://scholarlycommons.henryford.com/merf2019clinres/1028/thumbnail.jp

Impact of treatment modality on overall survival in localized ductal prostate adenocarcinoma: A National Cancer Database analysis

INTRODUCTION AND OBJECTIVE: Ductal adenocarcinoma is considered a rare histological variant of prostate adenocarcinoma (PCa). Given the rarity of this subtype, optimal treatment strategies for men with nonmetastatic ductal PCa is largely unknown. We aimed to describe the impact of surgery, radiotherapy, and systemic therapy on overall survival (OS) in men with nonmetastatic ductal PCa. METHODS: We retrospectively selected 2209 cases of ductal PCa, diagnosed between 2004 and 2015, within the National Cancer Database (NCDB). Exclusion of metastatic patients yielded a total sample of 1993 individuals. Cox regression analysis tested the impact of treatment (surgery, radiotherapy, systemic therapy and no treatment) on OS. Covariates included age, race, Charlson comorbidity score (CCI), clinical T stage, biopsy Gleason score, serum prostate specific antigen (PSA), and income. Adjusted Kaplan-Meier estimates were used to visualize the impact of treatment modality on OS. RESULTS: In men with nonmetastatic ductal PCa, median (IQR) age and PSA were 67 (61-74) years and 6.3 (4.3-10.8) ng/mL, respectively. Further, 9.8% (n=195) of patients presented with cT3 disease or higher, 3.4% (n=68) presented a CCI score ≥ 4, and 40.6% (808) presented with a Gleason biopsy score ≥ 4. Further, 1212 (60.8%) patients were treated surgically, 406 (20.4%) with radiotherapy, 102 (5.1%) with systemic therapies, and 273 (13.7%) received no treatment. Multivariable analysis showed that in comparison to men treated surgically, OS was significantly lower for patients receiving radiotherapy (HR 2.6; 95% CI 1.7-4.0) and systemic therapies (HR 9.1; 95% CI 5.0-16.5). Adjusted Kaplan-Meier curves are shown in the associated figure. CONCLUSIONS: Our findings show that in the rare ductal PCa variant, starting treatment with surgery offers more favorable long-term OS outcomes than radiotherapy and systemic therapies. While residual selection bias might persist after adjustment, the rarity of this disease precludes the possibility of a future trial, and the presented data represents the best available level of evidence on this topic

Socio-economic impact of riverbank failure at Kg. Pohon Celagi in Pasir Mas, Kelantan, Malaysia

Riverbank failure is a geological phenomenon that occurs when the soil or rock comprising the bank of a river collapses, leading to the rapid erosion of land and the formation of large cracks and sinkholes. While it is a natural occurrence, riverbank failure can have severe consequences for nearby communities and the environment. A massive riverbank failure occurred along the Kelantan River in Kampung Pohon Celagi, Pasir Mas, Kelantan, Malaysia. In this study, the affected area of the riverbank failure was determined and the effects of the bank failure on the village socio-economics and community were investigated. This study utilized interview methods and field observations to collect data and information. The study shows that 0.58 km3 land in the village was affected by the riverbank failure. The local authorities designated the 50-m range from the riverside as the red zone where most houses and buildings collapsed with the riverbank movement, and the parameters were 51–100 m is the high-risk area, 101–150 m is moderate, and ≥ 151 m upwards is low risk area, respectively, from the riverbank. The affected communities were required to move to safer areas and leave their properties to be demolished or failure with the riverbank. Socioeconomically, businesses around the disaster area were affected as they were prohibited from operating in the high-risk area. Overall, the disaster resulted in the local communities losing their property and experiencing depression. As a result, it is expected that all stakeholders will work together to develop a solution that ensures the well-being and safety of the community from riverbank failure