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Objectives Anecdotal evidence suggests that oropharyngeal squamous cell carcinoma (OPSCC) should be suspected in patients presenting with symptoms of peritonsillar abscess (PTA) or cellulitis (PTC). The aim of this study was to estimate the prevalence of OPSCC in patients presenting with symptoms of PTA/PTC. Method, Setting and Participants We retrospectively identified all adults with a coded diagnosis of PTA or PTC who presented between 2012-2016 inclusive, across six ENT units in ——–. Records were compared to that of the centralised regional head and neck cancer database. The clinical records of a subset of patients were reviewed for the purposes of data validation. Results A total of 1975 patients with PTA/PTC were identified. Three patients were subsequently diagnosed with OPSCC. None of the three actually had an objective underlying diagnosis of PTA/PTC on the same side. The prevalence of OPSCC in patients admitted with symptoms of PTA/PTC was 0.15%, or approximately 1:650 admissions. The records of 510 patients who presented over a one-year period (2016) were reviewed in even greater detail. There were 298 patients with PTA (59.4%), 151 with PTC (29.1%) and 61 had an alternative diagnosis (11.9%). High risk features (age ≥40, tonsillar asymmetry or tonsillar lesion) were present in 106 patients (24%). Urgent follow up was expedited for 77 patients (73%). Conclusion This study estimates the risk of OPSCC in patients with peritonsillar symptoms. The prevalence is low, even in a region with a relatively heavy disease burden. Clinicians should, however, retain a high level of suspicion in patients with persistent symptoms.

BACKGROUND The objective of this study was to describe bladder cancer outcomes as a function of race among patients with high-risk non-muscle-invasive bladder cancer (NMIBC) in an equal-access setting. METHODS A total of 412 patients with high-risk NMIBC who received bacille Calmette-Guerin (BCG) from January 1, 2010, to December 31, 2015, were assessed. The authors used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine the association between race and recurrence, progression, disease-specific, and overall survival outcomes. RESULTS A total of 372 patients who had complete data were included in the analysis; 48 (13%) and 324 (87%) were Black and White, respectively. There was no difference in age, sex, smoking status, or Charlson Comorbidity Index by race. White patients had a higher socioeconomic status with a greater percentage of patients living above the poverty level in comparison with Black patients (median, 85% vs 77%; P < .001). A total of 360 patients (97%) received adequate induction BCG, and 145 patients (39%) received adequate maintenance BCG therapy. There was no significant difference in rates of adequate induction or maintenance BCG therapy according to race. There was no significant difference in recurrence (hazard ratio [HR], 1.53; 95% confidence interval [CI], 0.64-3.63), progression (HR, 0.77; 95% CI, 0.33-1.82), bladder cancer-specific survival (HR, 1.01; 95% CI, 0.30-3.46), or overall survival (HR, 0.97; 95% CI, 0.56-1.66) according to Black race versus White race. CONCLUSIONS In this small study from an equal-access setting, there was no difference in the receipt of BCG or any differences in bladder cancer outcomes according to race.

OBJECTIVE Older patients diagnosed with cancer are at increased risk of physical and emotional distress; however, prescription utilization patterns largely remain to be elucidated. Our objective was to comprehensively assess prescription patterns and predictors in older patients with bladder cancer. METHODS A total of 10,516 older patients diagnosed with clinical stage T1-T4a, N0, M0 bladder urothelial carcinoma from 1 January 2008 to 31 December 2012 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare were analyzed. We used multivariable analysis to determine predictors associated with psychotropic prescription rates (one or more). Medication possession ratio (MPR) was used as an index to measure adherence in intervals of 3 months, 6 months, 1 year, and 2 years. Evaluation of psychotropic prescribing patterns and adherence across different drugs and demographic factors was done. RESULTS Of the 10,516 older patients, 5621 (53%) were prescribed psychotropic drugs following cancer diagnosis. Overall, 3972 (38%) patients had previous psychotropic prescriptions prior to cancer diagnosis, and these patients were much more likely to receive a post-cancer diagnosis prescription. Prescription rates for psychotropic medications were higher among patients with higher stage BC (p

We used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex (DLPFC). We identified extensive layer-enriched expression signatures, and refined associations to previous laminar markers. We overlaid our laminar expression signatures onto large-scale single nuclei RNA sequencing data, enhancing spatial annotation of expression-driven clusters. By integrating neuropsychiatric disorder gene sets, we showed differential layer-enriched expression of genes associated with schizophrenia and autism spectrum disorder, highlighting the clinical relevance of spatially-defined expression. We then developed a data-driven framework to define unsupervised clusters in spatial transcriptomics data, which can be applied to other tissues or brain regions where morphological architecture is not as well-defined as cortical laminae. We lastly created a web application for the scientific community to explore these raw and summarized data to augment ongoing neuroscience and spatial transcriptomics research (http://research.libd.org/spatialLIBD).

Rationale Chronic fatigue syndrome (CFS) is a common and burdensome illness with a poorly understood pathophysiology, though many of the characteristic symptoms are likely to be of brain origin. The use of high-field proton magnetic resonance spectroscopy (MRS) enables the detection of a range of brain neurochemicals relevant to aetiological processes that have been linked to CFS, for example, oxidative stress and mitochondrial dysfunction. Methods We studied 22 CFS patients and 13 healthy controls who underwent MRS scanning at 7 T with a voxel placed in the anterior cingulate cortex. Neurometabolite concentrations were calculated using the unsuppressed water signal as a reference. Results Compared to controls, CFS patients had lowered levels of glutathione, total creatine and myo-inositol in anterior cingulate cortex. However, when using N-acetylaspartate as a reference metabolite, only myo-inositol levels continued to be significantly lower in CFS participants. Conclusions The changes in glutathione and creatine are consistent with the presence of oxidative and energetic stress in CFS patients and are potentially remediable by nutritional intervention. A reduction in myo-inositol would be consistent with glial dysfunction. However, the relationship of the neurochemical abnormalities to the causation of CFS remains to be established, and the current findings require prospective replication in a larger sample.

BACKGROUND: Disparity in mental health care among cancer patients remains understudied. METHODS: We conducted a large, retrospective, single tertiary-care institution cohort study based on de-identified electronic health record data of 54,852 adult cancer patients without prior mental health diagnosis (MHD) diagnosed at the University of California, San Francisco between 1/2012 and 9/2019. The exposure of interest was early onset MHD with or without psychotropic medication (PM) within 12 months of cancer diagnosis and primary outcome was all-cause mortality. RESULTS: 8.2% of patients received a new MHD at a median of 197 days (interquartile-range [IQR] 61-553) after incident cancer diagnosis, 31.0% received a PM prescription, and 3.7% a MHRV. 62.6% of patients were non-Hispanic white (NHW), 10.8% Asian, 9.8% Hispanic, and 3.8% Black. Compared to NHWs, minority cancer patients had reduced adjusted odds of MHDs, PM prescriptions, and MHRVs, particularly for generalized anxiety (Asian: odds ratio [OR] 0.66, 95% confidence interval 0.55-0.78; Black: OR 0.60, 0.45-0.79; Hispanic: OR 0.72, 0.61-0.85) and selective-serotonin-reuptake-inhibitors (SSRI; Asian: OR 0.43, 0.37-0.50; Black: OR 0.51, 0.40-0.61; Hispanic: OR 0.79, 0.70-0.89). New early MHD with PM was associated with elevated all-cause mortality (12-24 months: hazard ratio [HR] 1.43, 1.25-1.64) that waned by 24-36 months (HR 1.18, 0.95-1.45). CONCLUSIONS AND RELEVANCE: New mental health diagnosis with psychotropic medication was a marker of early mortality among cancer patients. Minority cancer patients were less likely to receive documentation of mental health diagnoses or treatment, which may represent missed opportunities to identify and treat cancer related mental health conditions.

Context Immune therapy has emerged as a powerful treatment of metastatic urothelial carcinoma. Over 20 ongoing studies are exploring this strategy in the neoadjuvant setting in patients with localized muscle-invasive bladder cancer. Objective To summarize the rationale and the clinical outcomes regarding the use of immune checkpoint blockade in the neoadjuvant setting before radical cystectomy. Evidence acquisition A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, mice, human, immunotherapy, neoadjuvant therapy, atezolizumab, pembrolizumab, durvalumab, nivolumab, avelumab, ipilimumab, and tremelimumab. The search was limited to publications between January 2008 and February 2020. Publicly available relevant abstracts from recent meetings were also included. Evidence synthesis Phase II trials investigating neoadjuvant immune checkpoint blockade as a single agent before radical cystectomy reported a rate of pathological complete response (CR), ranging from 31% with an anti–PD-L1 monoclonal antibody (mAb) atezolizumab (n = 27/88) to 37% with anti–PD-1 mAb pembrolizumab (n = 42/114). Overall, 92% (n = 87/95) and 98% (n = 112/114) of the patients underwent radical cystectomy. Neoadjuvant immune checkpoint blockade did not delay planned surgery. Checkpoint inhibitor monotherapy was well tolerated, with no unexpected toxicity in the presurgical setting. Early phase I/II trials investigating neoadjuvant combination chemotherapy strategies with immune checkpoint blockers reported enhanced antitumor efficacy, with a pathological CR ranging from 33% to 50%. Conclusions Although limited clinical data are available on long-term survival, neoadjuvant immune checkpoint blockade demonstrated effective antitumor efficacy for localized muscle-invasive bladder cancer. Phase III trials are currently investigating this strategy in the presurgical setting. Patient summary Immunotherapy prior to surgery has been evaluated for patients with muscle-invasive bladder cancer. Although long-term survival benefit is unknown, such treatment strategy revealed a promising antitumor response rate for patients who underwent radical cystectomy. Ongoing prospective clinical trials will define the potential advantage of this approach over current cisplatin-based chemotherapeutic regimens alone or in combination.

Context Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions. Objective To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma. Evidence acquisition A PubMed/MEDLINE-based literature search was conducted using the key terms “urothelial carcinoma”, “variant histology”, “nested”, “micropapillary”, “microcystic”, “sarcomatoid”, “squamous differentiation”, “glandular differentiation”, “clear cell”, “plasmacytoid”, “lymphoepithelioma-like carcinoma”, “squamous cell carcinoma”, “small cell carcinoma”, “adenocarcinoma”, “radiotherapy”, “neoadjuvant chemotherapy”, and “adjuvant chemotherapy”. Evidence synthesis The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive. Conclusions Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment. Patient summary It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.

Background One out of five patients with muscle-invasive bladder cancer undergo radical cystectomy—a guideline-recommended treatment. Previous studies have primarily evaluated patient characteristics associated with the use of radical cystectomy, ignoring potential nesting of data. Objective To determine the impact of patient, diagnosing urologist, and hospital characteristics on the variation in the use of radical cystectomy. Design, setting, and participants This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results Registry (SEER)-Medicare linked database. Outcome measurements and statistical analysis A total of 7097 muscle-invasive bladder cancer patients and 4601 diagnosing urologists affiliated to 822 hospitals from January 1, 2002 to December 31, 2012 were analyzed. Multilevel logistic regression analyses were used to determine variation and factors associated with the use of radical cystectomy. Results and limitations Of the 7097 patients, only 27% underwent radical cystectomy. The intraclass correlation coefficient for variation in the use of radical cystectomy attributed to the hospital level was 4.3%. Higher radical cystectomy volume by diagnosing urologists (more than five vs zero to one surgery: odds ratio [OR], 1.27; 95% confidence interval [CI], 1.00–1.62) and hospitals (more than five vs zero to four surgeries: OR,1.48; 95% CI, 1.14–1.93) was associated with increased use of radical cystectomy. Patients diagnosed by female rather than male urologists were more likely to undergo radical cystectomy (OR, 1.32; 95% CI, 1.07–1.62). Conclusions We found that 4.3% variation in the use of radical cystectomy was attributed to the hospital level, leaving 95.7% variation in use unexplained. We identified significantly increased use among higher-volume and female diagnosing urologists. These findings support further investigation into measures beyond hospital volume, which largely impact the utilization of radical cystectomy. Patient summary In this large population-based study, we found that 4.3% of variation in the use of radical cystectomy was attributed to the hospital level, leaving 95.7% variation in use unexplained. Higher radical cystectomy volume of diagnosing urologists and female urologists were independently associated with increased use of radical cystectomy. These findings support further investigation into measures beyond hospital volume, which largely impact the utilization of radical cystectomy., In this large population-based study, we found that 4.3% of variation in the use of radical cystectomy was attributed to the hospital level, leaving 95.7% variation in use unexplained. Higher radical cystectomy volume of diagnosing urologists and female urologists were independently associated with increased use of radical cystectomy. These findings support further investigation into measures beyond hospital volume, which largely impact the utilization of radical cystectomy.

BackgroundThe tumor microenvironment (TME) is composed of highly heterogeneous extracellular structures and cell types such as endothelial cells, immune cells, and fibroblasts that dynamically influence and communicate with each other. The constant interaction between a tumor and its microenvironment plays a critical role in cancer development and progression and can significantly affect a tumor’s response to therapy and capacity for multi-drug resistance. High resolution analyses of gene and protein expression with spatial context can provide deeper insights into the interactions between tumor cells and surrounding cells within the TME, where a better understanding of the underlying biology can improve treatment efficacy and patient outcomes. Here, we demonstrated the ability to perform streamlined multi-omic tumor analyses by utilizing the 10X Genomics Visium Spatial Gene Expression Solution for FFPE with multiplex protein enablement. This technique simultaneously assesses gene and protein expression to elucidate the immunological profile and microenvironment of different breast cancer samples in conjunction with standard pathological methods.MethodsSerial (5 µm) sections of FFPE human breast cancer samples were placed on Visium Gene Expression (GEX) slides. The Visium GEX slides incorporate ~5,000 molecularly barcoded, spatially encoded capture spots onto which tissue sections are placed, stained, and imaged. Following incubation with a human whole transcriptome, probe-based RNA panel and an immuno-oncology oligo-tagged antibody panel, developed with Abcam conjugated antibodies, the tissues are permeabilized and the representative probes are captured. Paired GEX and protein libraries are generated for each section and then sequenced on an Illumina NovaSeq at a depth of ~50,000 reads per spot. Resulting reads from both libraries are aligned and overlaid with H&E-stained tissue images, enabling analysis of both mRNA and protein expression. Additional analyses and data visualizations were performed on the Loupe Browser v4.1 desktop software.ConclusionsSpatial transcriptomics technology complements pathological examination by combining histological assessment with the throughput and deep biological insight of highly-multiplexed protein detection and RNA-seq. Taken together, our work demonstrated that Visium Spatial technology provides a spatially-resolved, multi-analyte view of the tumor microenvironment, where a greater understanding of cellular behavior in and around tumors can help drive discovery of new biomarkers and therapeutic targets.

Background Upper tract urothelial carcinoma (UTUC) is a heterogeneous disease that presents a clinical management challenge for the urologic surgeon. We assessed treatment patterns, costs, and survival outcomes among patients with nonmetastatic UTUC. Methods We identified 4114 patients diagnosed with nonmetastatic UTUC from 2004 to 2013 in the Survival Epidemiology, and End Results–Medicare population-based database. Patients were stratified into low- or high-risk disease groups. Median total costs from 30 days prior to diagnosis through 365 days after diagnosis were compared between groups. Overall and cancer-specific survival were evaluated using Cox proportional hazards regression. All statistical tests were 2-sided. Results After risk stratification, 1027 (24.9%) and 3087 (75.0%) patients were classified into low- vs high-risk UTUC groups. Most patients underwent at least 1 surgical intervention (95.1%); 68.4% underwent at least 1 endoscopic intervention. Patients diagnosed with high- vs low-risk UTUC were more likely to undergo nephroureterectomy (83.6% vs 72.0%; P Conclusions UTUC continues to be managed primarily with nephroureterectomy, regardless of risk stratification, and patients with high-risk UTUC have worse overall and cancer-specific survival. Substantial costs are associated with management of low- and high-risk UTUC, with the latter being more costly up to 1 year from diagnosis.

INTRODUCTION AND OBJECTIVE:The standard of care for patients with muscle-invasive bladder cancer (MIBC) consists of neoadjuvant chemotherapy and radical cystectomy (RC) or chemoradiotherapy (CRT). ...

This editorial highlights submissions to part II of the 3rd IBCN Seminars Series particularly focusing on the tools required for conduction of translational research in bladder cancer. One of the submissions describe the ex vivo culture of primary tumor cells from N-methyl-N-nitrosourea-induced bladder tumors in rats and subsequent establishment of an immortalized cell line. In a next step the authors thoroughly characterize this cell line. They conclude that differentiation marker expression patterns observed in the original tumors are largely retained in the spheroids. Although new cancer models, such as organoid tissue cultures, hold great promise for studying cancer progression and might have a potential for development and selection of an optimal treatment, their limitations must be kept in mind. The second submission, therefore, critically questions the current role of organoid tissue culture as a predictive tool in urothelial cancer patients. The third manuscript of this series provides a broader overview of post-translational modification in bladder cancer is presented and how PTMs can be exploited as potential therapeutic targets. The 3 manuscripts featured in this issue demonstrate especially how basic research is being channeled to inform clinically actionable discoveries.

Objective Length of hospital stay for patients following radical cystectomy is an important determinant for improved quality of care. We sought to develop and validate a predictive model for length of hospital stay following radical cystectomy. Methods Patients aged 66 to 90 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer who underwent radical cystectomy were included from January 1, 2002 through December 31, 2011 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Linear regression analyses were used to develop and validate a predictive model for length of hospital stay. Results A total of 2,448 patients met inclusion criteria. After random assignment, 1,224 patients were included in the discovery cohort and 1,224 patients included in the validation cohort. The cohorts were well balanced with no significant difference in any of the preoperative variables. A best model was developed using marital status, Surveillance, Epidemiology, and End Results (SEER) region, clinical stage, Charlson comorbidity index, logarithm of hospital cystectomy volume, and use of neoadjuvant chemotherapy in a backward selection to predict the length of stay. There was robust internal validation (sum square error (SSE): 258.1 vs. predicted sum of squares (PRESS): 264.0 at SLS = 0.10), consistent with the external validation (average square error (ASE): discovery (0.248) vs. validation (0.258)) cohort. The strength of the model in predicting length of stay for the entire cohort was (R2 = 0.048). Conclusion In this large population-based study, we developed and validated a model to predict length of hospital stay following radical cystectomy. Identification of at-risk patients for prolonged hospital stay may aid in targeted interventions to reduce length of stay, improve quality of care, and decrease healthcare costs.

Objective To develop and validate a claims-based comorbidity score for patients undergoing major surgery, and compare its performance with established comorbidity scores. Data source Five percent Medicare data from 2007 to 2014. Study design Retrospective cohort study of patients aged ≥65 years undergoing six major operations (N = 99 250). Data collection One-year mortality was the primary outcome. Secondary outcomes were hospital mortality, 30-day mortality, 30-day readmission, and length of stay. The comorbidity score was developed in the derivation cohort (70 percent sample) using logistic regression model. The comorbidity score was calibrated and validated in the validation cohort (30 percent sample), and compared against the Charlson, Elixhauser, and Centers for Medicare and Medicaid Services Hierarchical Condition Categories (CMS-HCC) comorbidity scores using c-statistic, net reclassification improvement, and integrated discrimination improvement. Principal findings In the validation cohort, the surgery-specific comorbidity score was well calibrated and performed better than the Charlson, Elixhauser, and CMS-HCC comorbidity scores for all outcomes; the performance was comparable to the CMS-HCC for 30-day readmission. For example, the surgery-specific comorbidity score (c-statistic = 0.792; 95% CI, 0.785-0.799) had greater discrimination than the Charlson (c-statistic = 0.747; 95% CI, 0.739-0.755), Elixhauser (c-statistic = 0.747; 95% CI, 0.735-0.755), or CMS-HCC (c-statistic = 0.755; 95% CI, 0.747-0.763) scores in predicting 1-year mortality. The net reclassification improvement and integrated discrimination improvement were greater for surgery-specific comorbidity score compared to the Charlson, Elixhauser, and CMS-HCC scores. Conclusions Compared to commonly used comorbidity measures, a surgery-specific comorbidity score better predicted outcomes in the surgical population.

BACKGROUND Although skeletal-related events (SREs) are linked with a reduced quality of life and worse outcomes, to the authors' knowledge the factors that predict SREs are minimally understood. The objective of the current study was to identify predictors of SREs and all-cause mortality among men with metastatic castration-resistant prostate cancer (mCRPC). METHODS Data were collected on 837 men with bone mCRPC at 8 Veterans Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 2000 through 2017. Patients were followed to assess development of SREs (pathological fracture, radiotherapy to bone, spinal cord compression, or surgery to bone). Cox proportional hazards models were used to evaluate predictors of SREs and mortality. RESULTS Of the 837 men with bone mCRPC, 287 developed a SRE and 740 men died (median follow-up, 26 months). Bone pain was found to be the strongest predictor of SREs (hazard ratio [HR], 2.96; 95% CI, 2.25-3.89). A shorter time from CRPC to the development of metastasis (HR, 0.92; 95% CI, 0.85-0.99), shorter progression to CRPC (HR, 0.94; 95% CI, 0.91-0.98), and visceral metastasis at the time of diagnosis of bone metastasis (HR, 1.91; 95% CI, 1.18-3.09) were associated with an increased risk of SREs. Ten or more bone metastases (HR, 2.17; 95% CI, 1.72-2.74), undergoing radical prostatectomy (HR, 0.73; 95% CI, 0.61-0.89), shorter progression to CRPC (HR, 0.97; 95% CI, 0.94-0.99), older age (HR, 1.03; 95% CI, 1.02-1.04), higher prostate-specific antigen level at the time of diagnosis of metastasis (HR, 1.21; 95% CI, 1.14-1.28), bone pain (HR, 1.44; 95% CI, 1.23-1.70), and visceral metastasis (HR, 1.72; 95% CI, 1.23-2.39) were associated with an increased mortality risk. CONCLUSIONS Among men with bone mCRPC, bone pain was found to be the strongest predictor of SREs and the number of bone metastases was a strong predictor of mortality. If validated, these factors potentially may be used for risk stratification and for SRE prevention strategies.

Clinical factors and barriers affecting adoption of active surveillance (AS) for low-risk prostate cancer (PCa) remain poorly understood. We performed a national survey of radiation oncologists (RO) and urologists (URO) about the perceptions and recommendations of AS for low-risk PCa.In 2017, we surveyed 915 RO and 940 URO about AS for low-risk PCa in the United States. Survey items queried respondents about their attitudes toward AS and recommendations of AS for low-risk PCa. Pearson chi-square and multivariable logistic regression identified clinical and physician factors related toward AS for low-risk PCa.Overall, the response rate was 37.3% (n = 691) and was similar for RO and URO (35.7% vs. 38.7%; P = .18). RO were less likely to consider AS effective for low-risk PCa (86.5% vs. 92.0%; P = .04) and more likely to rate higher patient anxiety on AS (49.5% vs. 29.5%; P .001) than URO. Recommendations of AS varied modestly on the basis of age, prostate-specific antigen (PSA), and number of cores positive for Gleason 3 + 3 PCa. For a 55-year-old man with PSA 8 with 6 cores of Gleason 6 PCa, both RO and URO infrequently recommended AS (4.4% vs. 5.2%; adjusted odds ratio = 0.6; P = .28). For a 75-year-old patient with PSA 4 with 2 cores of Gleason 6 PCa, URO and RO most often recommended AS (89.6% vs. 83.4%; adjusted odds ratio = 0.5; P = .07).RO and URO consider AS to be effective in the clinical management of low-risk PCa, but this varies by clinical and physician factors.

Background Among patients with cancer, prior research suggests that patients with mental illness may have reduced survival. The objective was to assess the impact of psychiatric utilisation (PU) prior to cancer diagnosis on survival outcomes. Methods All residents of Ontario diagnosed with one of the top 10 malignancies (1997–2014) were included. The primary exposure was psychiatric utilisation gradient (PUG) score in 5 years prior to cancer: 0: none, 1: outpatient, 2: emergency department, 3: hospital admission. A multivariable, cause-specific hazard model was used to assess the effect of PUG score on cancer-specific mortality (CSM), and a Cox proportional hazard model for effect on all-cause mortality (ACM). Results A toal of 676,125 patients were included: 359,465 (53.2%) with PUG 0, 304,559 (45.0%) PUG 1, 7901 (1.2%) PUG 2, and 4200 (0.6%) PUG 3. Increasing PUG score was independently associated with worse CSM, with an effect gradient across the intensity of pre-diagnosis PU (vs PUG 0): PUG 1 h 1.05 (95% CI 1.04–1.06), PUG 2 h 1.36 (95% CI 1.30–1.42), and PUG 3 h 1.73 (95% CI 1.63–1.84). Increasing PUG score was also associated with worse ACM. Conclusions Pre-cancer diagnosis PU is independently associated with worse CSM and ACM following diagnosis among patients with solid organ malignancies.

Context Despite established guidelines for the treatment of muscle-invasive bladder cancer, it has been reported that radical cystectomy (RC) is markedly underused, especially among patients of advanced age and those with higher comorbidity burden and lower access to care. Understanding the interactions between patient, provider, and hospital factors may inform targeted interventions to optimize RC utilization. Objective To systematically review the literature regarding factors associated with RC utilization. Evidence acquisition A systematic search was conducted using Ovid and Medline according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify studies between 1970 and 2017 reporting on RC utilization. Prospective and retrospective studies were included. Evidence synthesis There are no published randomized control trials on RC utilization. Variations in study quality and design precluded a formal statistical meta-analysis. RC receipt significantly depended on patient, provider, and hospital factors. Patient factors associated with lower RC use included advanced age, African American and Hispanic race/ethnicity, higher comorbidity burden, unmarried marital status, higher tumor stage and grade, and lower socioeconomic status. Provider factors associated with underutilization included lower surgeon volume and a metropolitan location. Finally, hospital factors associated with lower RC use included low hospital volume, nonacademic affiliation, and hospital location in the Midwest. Conclusions RC is reportedly underutilized. We found that age, race, marital status, socioeconomic factors, cancer severity, comorbidity burden, surgeon volume, and facility type and location significantly determined RC receipt. Improved understanding of the varying contributions of the risk factors according to patient, provider, and hospital determinants may assist in developing targeted interventions to improve RC utilization. Patient summary In this review we explored the clinical evidence for factors predicting the utilization of radical cystectomy for muscle-invasive bladder cancer. Many factors related to the patient, provider, and hospital determine whether patients receive this guideline-recommended treatment. However, there remains a lack of understanding on characterization and targeted interventions according to these levels, which may improve use.

MBD5-associated neurodevelopmental disorder (MAND) is an autism spectrum disorder (ASD) characterized by intellectual disability, motor delay, speech impairment and behavioral problems; however, the biological role of methyl-CpG-binding domain 5, MBD5, in neurodevelopment and ASD remains largely undefined. Hence, we created neural progenitor cells (NPC) derived from individuals with chromosome 2q23.1 deletion and conducted RNA-seq to identify differentially expressed genes (DEGs) and the biological processes and pathways altered in MAND. Primary skin fibroblasts from three unrelated individuals with MAND and four unrelated controls were converted into induced pluripotent stem cell (iPSC) lines, followed by directed differentiation of iPSC to NPC. Transcriptome analysis of MAND NPC revealed 468 DEGs (q

Introduction Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between 4953 plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20-year follow-ups. Methods In the Whitehall II prospective cohort study proteins were measured using SOMAscan technology. Cognitive performance was tested five times over 20 years. Linkage to electronic health records identified incident dementia. The results were replicated in the Atherosclerosis Risk in Communities (ARIC) study. Results Fifteen non-amyloid/non-tau-related proteins were associated with cognitive decline and dementia, were consistently identified in both cohorts, and were not explained by known dementia risk factors. Levels of six of the proteins are modifiable by currently approved medications for other conditions. Discussion This study identified several plasma proteins in dementia-free people that are associated with long-term risk of cognitive decline and dementia.

Objective To determine the estimated budget impact to practices that incorporate blue light cystoscopy (BLC) with hexaminolevulinate HCl (HAL) for the surveillance of non-muscle-invasive bladder cancer (NMIBC) in the clinic setting. With the introduction of advanced technologies in the clinic setting such as HAL, further cost comparative research is needed to justify HAL as a high value option. Material and methods A budget impact model was developed from the facility perspective assessing projected costs at 2 years for a simulated facility with 50 newly diagnosed bladder cancer patients. Treatment and surveillance cystoscopy intervals were based on clinical guidelines. Clinical inputs, including tumor stage and grade at diagnosis, rates of recurrence and relative risk reduction when using BLC with HAL, were derived from published studies. Cost inputs were based on Medicare reimbursement rates and facility costs. Results Use of BLC identified 9 additional recurrences over two years compared to white light cystoscopy alone. Use of flexible BLC for surveillance marginally increased costs to the practice, with a net difference of $0.76 per cystoscopy over 2 years. Conclusions From the office/clinic perspective, the model suggests that the use of flexible BLC for the surveillance of NMIBC may not impact cost per cystoscopy and identifies 9 recurrences over 2 years that would be missed using white light cystoscopy alone. These findings could have important implications in the management of NIMBC and help guide clinical practice guidelines that promote cost-effective care and improved patient outcomes.

Bladder cancer is a heterogeneous disease with vastly differing levels of risk to the patient. Low-risk non-invasive disease poses little to no threat to a patient’s survival, whereas invasive disease is rapidly fatal without intervention. This chapter aims to address the more recent developments in risk stratification tools available in assessing patients with non-muscle invasive bladder cancer and muscle invasive bladder cancer.

EphB4 is a membrane tyrosine kinase receptor involved in a number of physiologic and pathologic conditions, cancer being the one drawing the highest attention. In mammalians, EphB4 regulates blood vessel growth and differentiation. EphB4 also mediates a number of cancer promoting effects including angiogenesis, invasion, and metastasis. Its effects have been linked to both EphrinB2-dependent and to EphrinB2-independent mechanisms. In spite of its emerging role in physiology and disease, the regulation of EphB4 cellular expression has been poorly described until recently. The present mini-review summarizes the latest findings on EphB4 regulation at the transcriptional and post-transcriptional level and discusses the biologic implications of such novel findings. Perspective on the scenarios opened by such findings and the open questions in EphB4 research is also provided.

Objectives To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. Design Multicohort study with three sets of analyses. Setting United Kingdom, Europe, and the United States. Participants Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. Main outcome measures Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. Results During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I 2 =0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted β −0.34, P Conclusions The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms.

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing APP and PSEN1 mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-adults (6 months (m)) to mid- (12 m) and advanced-stage (18 m, 25 m) of the disease. Methods: TgF344-AD rats and wild-type (WT) littermates were imaged at 6 m, 12 m and 18 m with [18F]DPA-714 (TSPO, neuroinflammation), [18F]Florbetaben (Aβ) and [18F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[18F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, Aβ, NeuN, NeuroChrom) and Tau (S)-[18F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. Results: [18F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. In vivo [18F]ASEM PET revealed an age-dependent increase uptake in the striatum and pallidum/nucleus basalis of Meynert in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. In vivo [18F]Florbetaben PET scanning detected Aβ accumulation at 18 m, and (S)-[18F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. Aβ plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to Aβ plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohistochemistry revealed a loss of neuronal staining at the Aβ plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both genotypes. Behavioural assessment using the novel object recognition task revealed that both WT & TgF344-AD animals discriminated the novel from familiar object at 3 m and 6 m of age. However, low levels of exploration observed in both genotypes at later time-points resulted in neither genotype successfully completing the task. Deficits in social interaction were only observed at 3 m in the TgF344-AD animals. By in vivo MRS, we showed a decrease in neuronal marker N-acetyl-aspartate in the hippocampus at 18 m (-18% vs age-matched WT, and -31% vs 6 m TG) and increased Taurine in the cortex of TG (+35% vs age-matched WT, and +55% vs 6 m TG). Conclusions: This multi-centre multi-modal study demonstrates, for the first time, alterations in brain metabolites, cholinergic receptors and neuroinflammation in vivo in this model, validated by robust ex vivo approaches. Our data confirm that, unlike mouse models, the TgF344-AD express Tau pathology that can be detected via PET, albeit later than by ex vivo techniques, and is a useful model to assess and longitudinally monitor early neurotransmission dysfunction and neuroinflammation in AD.

Background Multiple single-arm clinical trials showed promising pathologic complete response rates with neoadjuvant immune checkpoint inhibitors (ICIs) in muscle-invasive bladder cancer. We conducted a cost-effectiveness analysis comparing neoadjuvant ICIs with cisplatin-based chemotherapy (CBC). Methods We applied a decision analytic simulation model with a health care payer perspective to compare neoadjuvant ICIs vs. CBC. For the primary analysis we compared pembrolizumab with ddMVAC. We performed a secondary analysis with gemcitabine/cisplatin as CBC and exploratory analyses with atezolizumab or nivolumab/ipilimumab as ICI. We input pathologic complete response rates from trials or meta-analysis and costs from average sales price. Outcomes of interest included costs, 2-year recurrence-free survival (RFS), and incremental cost-effectiveness ratio (ICER) of cost per 2-year RFS. A threshold analysis estimated a price reduction for ICI to be cost-effective and one-way and probabilistic sensitivity analyses were performed. Results The incremental cost of pembrolizumab compared with ddMVAC was $8,041 resulting in an incremental improvement of 1.5% in 2-year RFS for an ICER of $522,143 per 2-year RFS. A 21% reduction in cost of pembrolizumab would render it more cost-effective with an ICER of $100,000 per 2-year RFS. GC required an 89% pembrolizumab cost reduction to achieve an ICER of $100,000 per 2-year RFS. Atezolizumab appeared to be more cost-effective than ddMVAC. Conclusions ICIs were not cost-effective as neoadjuvant therapies, except when atezolizumab was compared with ddMVAC. Randomized clinical trials, larger sample sizes and longer follow-up are required to better understand the value of ICIs as neoadjuvant treatments.

The role of circulating proteins in Alzheimer’s disease and related dementias is unknown. Using a follow-up of two decades, 4953 plasma proteins, and discovery (Whitehall II) and replication cohort (ARIC), we examined plasma proteins associated with cognitive decline rate and dementia. After replication and adjustment for known dementia risk factors, fifteen proteins were associated with cognitive decline rate and dementia. None of these were amyloid, tau, or neurofilament-related proteins. Currently approved medications can target five of the proteins. The results support systemic pathogenesis of dementias, may aid in early diagnosis, and suggest potential targets for drug development.

Introduction: Surgical repair in anomalous aortic origin of a coronary artery (AAOCA) aims at mitigating the risk of sudden cardiac death in a subset of patients (pts). The pattern and behavior of electrocardiogram (ECG) changes in a large cohort of these pts is lacking. We aim to describe post-operative (post-op) ECG changes in this population with medium term follow up (f/u). Methods: Observational study evaluating ECGs before and after surgery to describe peri-operative changes through f/u. All patients Results: A total of 64 pts were identified (median age 13.7 yrs, 64% male). Two patients had evidence of STE and TWI pre-op and were not included. Of 62 pts: 47 (75%) had new STE early post-op and all but 1 had resolution at 90-day f/u; 50 (81%) had no evidence of new TWI or q waves early post-op and 96% of these remained stable at 90-day f/u. Conversely, 12 (19%) had new TWI in the early post-op: 8 had isolated changes (75% resolved at 90 days) and 4 associated with new q waves (50% resolved at 90 days). Including all ECG changes in the total cohort, 92% resolved completely at 90-day f/u. In those pts (8%) with persistent changes, none required late reintervention and all but 1 were cleared for return to exercise. All patients were alive at medium f/u of 4 yrs (IQR 2-6) with normal ventricular function. Conclusions: New STE is a common finding in the early post-op period following repair of AAOCA and is not correlated with persistent ECG changes at 90-day follow up. TWI is infrequently seen but less likely to resolve if associated with new q waves. Despite these changes in the early post-op, clinical outcomes medium-term are excellent.

African Americans endure a nearly two-fold greater risk of suffering a stroke and are 2–3 times more likely to die from stroke compared to those of European ancestry. African Americans also have a greater risk of recurrent stroke and vascular events, which are deadlier and more disabling than incident stroke. Stroke is a multifactorial disease with both heritable and environmental risk factors. We conducted an integrative, multi-omic study on 922 plasma metabolites, 473,864 DNA methylation loci, and 556 variants from 50 African American participants of the Vitamin Intervention for Stroke Prevention clinical trial to help elucidate biomarkers contributing to recurrent stroke rates in this high risk population. Sixteen metabolites, including cotinine, N-delta-acetylornithine, and sphingomyelin (d17:1/24:1) were identified in t-tests of recurrent stroke outcome or baseline smoking status. Serum tricosanoyl sphingomyelin (d18:1/23:0) levels were significantly associated with recurrent stroke after adjusting for covariates in Cox Proportional Hazards models. Weighted Gene Co-expression Network Analysis identified moderate correlations between sphingolipid markers and clinical traits including days to recurrent stroke. Integrative analyses between genetic variants in sphingolipid pathway genes identified 29 nominal associations with metabolite levels in a one-way analysis of variance, while epigenomic analyses identified xenobiotics, predominately smoking-associated metabolites and pharmaceutical drugs, associated with methylation profiles. Taken together, our results suggest that metabolites, specifically those associated with sphingolipid metabolism, are potential plasma biomarkers for stroke recurrence in African Americans. Furthermore, genetic variation and DNA methylation may play a role in the regulation of these metabolites.

Background Triple negative breast cancer (TNBC) accounts for 10–20% of all diagnosed breast cancer cases in the US and is characterized by loss of HER2, estrogen receptors, and progesterone receptors. TNBC is an aggressive, complex disease with a poor prognosis due to resistance to traditional therapies. Understanding the underlying biology and tumor microenvironment is critical to the development of diagnostic biomarkers and to guide the search for effective therapies. Here, we demonstrated the ability of the 10x Genomics Visium Spatial Gene Expression Solution to elucidate the immunological profile and microenvironment of TNBC samples in conjunction with standard pathological techniques. Methods Spatial transcriptomics technology complement pathological examination by combining the benefits of histological stains with the throughput and deep biological insight of RNA-seq. We investigated serial sections of TNBC by using the 10x Genomics Visium Spatial Gene Expression Solution to spatially resolve the samples’ cellular composition and expressed microenvironment. Visium incorporates ~5000 molecularly barcoded, spatially encoded capture probes in spots over which a tissue section is placed and imaged. The samples are permeabilized and native mRNA is captured. Imaging and RNA sequencing data are processed together, resulting in whole transcriptome gene expression mapped to the tissue image. Results We captured spatial patterns of gene expression and mapped the information back to H&E-stained images with regional annotations. Serial sections were then subject to fluorescence immunohistochemical staining for immune infiltrate paired with spatial gene expression capture. Subsequently, we combined these data with 3’ single-nuclei RNA-seq from the same tumor, generating expression profiles that were used to automatically annotate cell-types across the sections. This allowed for an understanding of the tumor microenvironment that could not be captured by image-based techniques alone. We resolved subgroups of spatially and biologically distinct immune, stem, and cancer progenitor cells. Finally, we digitally annotated tumor and normal tissue regions using expressed genetic mutations alone. Annotated tumor regions expressed more deleterious mutations than normal regions and we were able to automatically cluster regions of tumor vs. normal cells without any prior histopathological information. We also found intratumor gradients of mutational burden in oncogenes as well as non-cancer associated loci. Conclusions Taken together, we demonstrated that Visium can provide a powerful complement to traditional histopathology, enabling both targeted panels and whole-transcriptome discovery of gene expression. This spatially resolved molecular information provides an unprecedented view into the tumor microenvironment and a powerful new tool for discovery of new biomarkers and therapeutic targets.

Insulin receptor (IR) and IR-related signaling defects have been shown to trigger insulin-resistance in insulin-dependent cells and ultimately to give rise to type 2 diabetes in mammalian organisms. IR expression is ubiquitous in mammalian tissues, and its over-expression is also a common finding in cancerous cells. This latter finding has been shown to associate with both a relative and absolute increase in IR isoform-A (IR-A) expression, missing 12 aa in its EC subunit corresponding to exon 11. Since IR-A is a high-affinity transducer of Insulin-like Growth Factor-II (IGF-II) signals, a growth factor is often secreted by cancer cells; such event offers a direct molecular link between IR-A/IR-B increased ratio in insulin resistance states (obesity and type 2 diabetes) and the malignant advantage provided by IGF-II to solid tumors. Nonetheless, recent findings on the biological role of isoforms for cellular signaling components suggest that the preferential expression of IR isoform-A may be part of a wider contextual isoform-expression switch in downstream regulatory factors, potentially enhancing IR-dependent oncogenic effects. The present review focuses on the role of isoform- and paralog-dependent variability in the IR and downstream cellular components playing a potential role in the modulation of the IR-A signaling related to the changes induced by insulin-resistance-linked conditions as well as to their relationship with the benign versus malignant transition in underlying solid tumors.

BACKGROUND Postchemotherapy retroperitoneal lymphadenectomy (PC-RPLND) is an essential, yet potentially morbid, therapy for the management of patients with advanced germ cell tumors. In the current study, the authors sought to define the complication profile of PC-RPLND using validated grading systems for intraoperative adverse events (iAEs) and early postoperative complications. METHODS Between 2000 and 2018, all patients who underwent PC-RPLND were analyzed for iAEs and early postoperative complications using the Kaafarani and Clavien-Dindo classifications, respectively. Logistic regression models were conducted to assess patient and tumor factors associated with iAEs and postoperative complications. RESULTS Of the 453 patients identified, 115 patients (25%) and 252 patients (56%), respectively, experienced an iAE and postoperative complication. Major iAEs (grade ≥3) were observed in 15 patients (3%) and major postoperative complications (grade ≥3) were noted in 80 patients (18%). The most common iAE was vascular injury (112 of 132 events; 85%), which occurred in 92 patients (20%), and the most frequent postoperative complication was ileus, which occurred in 121 patients (27%). Original and postchemotherapy retroperitoneal mass size, nonretroperitoneal metastases, intermediate and/or poor International Germ Cell Cancer Collaborative Group classification, previous RPLND, elevated tumor markers at the time of RPLND, and anticipated adjuvant surgical procedures increased the risk of both iAEs and postoperative complications. Patients who experienced an iAE were significantly more likely to experience a postoperative complication (odds ratio, 2.50; 95% confidence interval, 1.58-3.97 [P

Occupational exposure to benzene at levels of 10 ppm or more has been associated with increased risk of acute myeloid leukaemia (AML). The mode of action (MOA) for AML development leading to mortality is anticipated to include multiple earlier key events, which can be observed in hematotoxicity and genetic toxicity in peripheral blood of exposed workers. Prevention of these early events would lead to prevention of the apical, adverse outcomes, the morbidity and mortality caused by the myelodysplastic syndrome (MDS) and AML.. Incorporation of key event information should modify the risk model, but few modification approaches have been suggested. To that end, two approaches to risk model modification are described that use sub-linear and segmented linear increases in risk below key events, while maintaining a linear increase in AML mortality risk beginning at 2 ppm, the lowest observed adverse effect concentration (LOAEC) identified for hemato- and geno- toxicity in high quality studies of human occupational exposure. Below 2 ppm two different modification approaches to quantitative risk models were applied: a continuously decreasing slope model and a segmented modification in slope. These two approaches provide greater flexibility to incorporate MOA information in risk model development and selection.

Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2+ macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed 'ecotypes', with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer.

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min−1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.

Background Chronic kidney disease ( CKD ) confers increased cardiovascular risk, not fully explained by traditional factors. Proteins regulate biological processes and inform the risk of diseases. Thus, in 938 patients with stable coronary heart disease from the Heart and Soul cohort, we quantified 1054 plasma proteins using modified aptamers ( SOMA scan) to: (1) discern how reduced glomerular filtration influences the circulating proteome, (2) learn of the importance of kidney function to the prognostic information contained in recently identified protein cardiovascular risk biomarkers, and (3) identify novel and even unique cardiovascular risk biomarkers among individuals with CKD . Methods and Results Plasma protein levels were correlated to estimated glomerular filtration rate (eGFR) using Spearman‐rank correlation coefficients. Cox proportional hazard models were used to estimate the association between individual protein levels and the risk of the cardiovascular outcome (first among myocardial infarction, stroke, heart failure hospitalization, or mortality). Seven hundred and nine (67.3%) plasma proteins correlated with eGFR at P eGFR moderately or strongly (ρ 0.2–0.74). Among the previously identified 196 protein cardiovascular biomarkers, just 87 remained prognostic after correction for eGFR . Among patients with CKD ( eGFR 2 ), we identified 21 protein cardiovascular risk biomarkers of which 8 are unique to CKD. Conclusions CKD broadly alters the composition of the circulating proteome. We describe protein biomarkers capable of predicting cardiovascular risk independently of glomerular filtration, and those that are prognostic of cardiovascular risk specifically in patients with CKD and even unique to patients with CKD .

Introduction Prior studies noted substantial costs associated with radical cystectomy, however, they lack surgical comparison to a less costly partial cystectomy. We compared costs associated with radical versus partial cystectomy. Methods A total of 2,305 patients aged 66-85 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer from January 1, 2002 through December 31, 2011 were included. Total Medicare costs within one year of diagnosis following radical versus partial cystectomy were compared using inverse probability of treatment-weighted propensity score models. Cox regression and competing risks analysis were used to determine overall and cancer-specific survival, respectively. Results Median total costs were not significantly different for radical than partial cystectomy in 90 days ($73,907 vs. $65,721; median difference $16,796, 95% CI $10,038 to $23,558), 180 days ($113,288 vs. $82,840; median difference $36,369, 95% CI $25,744 to $47,392), and 365 days ($143,831 vs. $107,359; median difference $34,628, 95% CI $17,819 to $53,558), respectively. Hospitalization, surgery, pathology/laboratory, pharmacy, and skilled nursing facility costs contributed largely to costs associated with either treatment. Patients who underwent partial cystectomy had similar overall survival but had worse cancer-specific survival (Hazard Ratio (HR) 1.45, 95% Confidence Interval (CI), 1.34-1.58, p Conclusions While treatments for bladder cancer are associated with substantial costs, we showed radical cystectomy had similar total costs when compared to partial cystectomy among patients with muscle-invasive bladder cancer. However, partial cystectomy resulted in worse cancer-specific survival further supporting radical cystectomy as a high-value surgical procedure for muscle-invasive bladder cancer.

Vascular bypass graft infection with Mycobacterium bovis following Bacillus Calmette–Guerin (BCG) immunotherapy for bladder cancer is an incredibly rare complication. We present the case of an 85-year-old man with a history of femorofemoral bypass who developed this complication over a year after BCG treatment. He was successfully treated with explantation of the polytetrafluoroethylene (PTFE) graft, redo bypass with vein graft, and antituberculous medical therapy.

INTRODUCTION AND OBJECTIVE:One out of five patients with muscle-invasive bladder cancer undergo radical cystectomy—a guideline-recommended treatment. Previous studies have primarily evaluated patie...

Insulin receptor overexpression is a common event in human cancer. Its overexpression is associated with a relative increase in the expression of its isoform A (IRA), a shorter variant lacking 11 aa in the extracellular domain, conferring high affinity for the binding of IGF-II along with added intracellular signaling specificity for this ligand. Since IGF-II is secreted by the vast majority of malignant solid cancers, where it establishes autocrine stimuli, the co-expression of IGF-II and IRA in cancer provides specific advantages such as apoptosis escape, growth, and proliferation to those cancers bearing such a co-expression pattern. However, little is known about the exact role of this autocrine ligand−receptor system in sustaining cancer malignant features such as angiogenesis, invasion, and metastasis. The recent finding that the overexpression of angiogenic receptor kinase EphB4 along with VEGF-A is tightly dependent on the IGF-II/IRA autocrine system independently of IGFIR provided new perspectives for all malignant IGF2omas (those aggressive solid cancers secreting IGF-II). The present review provides an updated view of the IGF system in cancer, focusing on the biology of the autocrine IGF-II/IRA ligand−receptor axis and supporting its underscored role as a malignant-switch checkpoint target.

The reasons for low clinical adoption of active surveillance (AS) for low-risk prostate cancer (PCa) remain poorly understood. Thus, we conducted a national survey of radiation oncologists (ROs) and urologists (UROs) to elucidate perceived barriers to AS for low-risk PCa. In 2017, we undertook a four-wave mail survey of 1855 ROs and UROs. The survey instrument assessed attitudes about possible barriers towards AS for low-risk PCa. We used Pearson Chi square and multivariable logistic regression analyses to identify physician characteristics associated with attitudes about AS. We received 691 completed surveys for an overall response rate of 37.3%. A majority of respondents indicated that they felt comfortable recommending AS (90.0%), agreed that high-level evidence supports it (82.3%), and considered AS equally effective for survival compared with surgery and radiation therapy (84.4%). UROs were less likely to agree that patients were not interested in AS for low-risk PCa compared with ROs (16.5 vs. 48.9%; adjusted odds ratio [OR] 0.18, p

Context Radical cystectomy continues to be associated with a significant risk of morbidity and all-cause mortality (ACM). Practice pattern data demonstrating underuse of surgery for patients with muscle-invasive and high-risk non–muscle invasive bladder cancer (BC) have been linked to the advanced age and higher comorbidity status of such patients, which suggests that rates of ACM as well as cancer-specific mortality should be incorporated into patient counseling and guideline recommendations. Objective To review the literature on risk assessment tools for preoperative comorbidity in BC that may aid in treatment decision-making. Evidence acquisition A systematic search was conducted using Ovid and Medline according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify studies between 1970 and 2017 reporting on comorbidity risk assessment (CRA) tools for BC. Prospective and retrospective studies were included. Evidence synthesis There are no published randomized control trials comparing CRA tools for BC. Patients undergoing radical cystectomy with combined high-risk comorbidity and performance scores may face up to a sevenfold greater risk of other-cause mortality compared to those with low scores. The Charlson Comorbidity Index is one of the most widely studied indices for 90-d perioperative mortality and overall and cancer-specific survival, with an area under the receiver operating characteristic curve of up to 0.810. Prospective studies of CRA tools for BC have consistently shown that patients with higher comorbidity have worse outcomes. While not specific for BC, comorbidity indices provide useful assessment of competing risks. Competing-risks assessment tools are lacking, with limited studies assessing the impact of these tools on treatment decision-making by patients and providers. We provide the impetus for incorporation of comorbidity risks into practice guidelines when discussing treatment options with patients. Conclusions CRA tools should be incorporated into preoperative treatment counseling and the assessment of postoperative outcomes. While retrospective evidence supports the use of CRA tools for BC, further comparative studies evaluating the effectiveness of these tools and identifying the patients most likely to benefit from a treatment according to competing-risks assessment are needed. Patient summary In this review we explored the clinical evidence for comorbidity risk assessment tools in bladder cancer. We found evidence to support incorporation of comorbidity risks into practice guidelines when discussing treatment options with patients.

Objectives To describe a step-by-step guide for using the first transperineal targeted prostate biopsy platform available in the USA. Patients and methods A total of 32 men with elevated prostate-specific antigen (PSA) levels were diagnosed with a region of interest on multiparametric magnetic resonance imaging (mpMRI) between February 2017 and January 2018. The transperineal targeted prostate biopsy procedure was accomplished via a transperineal approach and used a stepper, combined with advanced mpMRI/transrectal ultrasound fusion software, to perform targeted prostate biopsy. The detection of overall and clinically significant prostate cancer (PCa) was assessed as well as the rate of complications. Results The median patient age was 68.0 years and the median PSA was 8.0 ng/mL. Two patients (6%) were active surveillance candidates and 16 (50%) had a prior negative prostate biopsy. The detection rates for overall and clinically significant PCa were 81% and 59%, respectively. The two candidates for active surveillance and eight of the patients with a prior negative prostate biopsy had clinically significant PCa confirmed on targeted biopsy. There were no peri-operative complications. Conclusion These results demonstrate the promising potential of the first transperineal targeted prostate biopsy platform in the USA as an alternative diagnostic method for PCa.

Introduction This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC). Patients and Methods We enrolled 77 patients who had received no prior chemotherapy for CRPC between 1998 and 2000; a total of 74 subjects were eligible for the study. Each 8-week cycle included paclitaxel 90 mg/m2 provided intravenously weekly for 6 weeks, followed by 2 weeks off therapy and oral estramustine 280 mg twice daily for 3 days beginning 24 hours before the first dose of paclitaxel. The primary end point was rate of objective or prostate-specific antigen (PSA) response at 16 weeks. A 50% response rate was considered of further interest. Results Eligible patients received a median of 3 cycles (range, 1-10 cycles). The response rate among patients with measurable disease was 34% (95% confidence interval [CI], 19-52). The PSA response rate was 58% (95% CI, 47-70). Clinical benefit rate was 45% (95% CI, 33-57). The median progression-free survival was 5.9 months (95% CI, 4.4-6.7). The median overall survival was 17.6 months (95% CI, 14.6-20.8). The most common clinical grade 3/4 toxicities were fatigue (14%) and sensory neuropathy (7%). Grade 3/4 hematologic toxicities included lymphopenia (21%) and anemia (9%). There was one toxicity-related death. Quality-of-life scores improved by week 8, but the change was not statistically significant. Conclusion The combination has activity defined by PSA declines in CRPC but did not meet the protocol-specified end point for efficacy as defined by objective response rate. Since this study was conducted, more effective, better-tolerated regimens have been developed.