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Abstract Objectives Functional problems, including nasal flow problems, are associated with specific skeletal and dental features. Further, maxillary expansion has been associated with nasal airway resistance alterations. This study aimed to investigate whether there is a correlation between skeletal features and nasal airflow‐ and olfaction‐related problems. Materials and methods This prospective study included 68 patients (30 boys, 38 girls; mean age 9 ± 2 years) examined at the Ohu University Hospital. We classified patients into three skeletal Classes (Class I, II, and III) based on the ANB angle. Olfactory disorder history was collected from the guardians. Maxillofacial measurements, nasal airflow assessments, and olfactory tests were performed using cephalometric analysis, rhinomanometry, and T&T olfactometer, respectively. Results Malocclusion, resulting from skeletal mandibular protrusion and smaller maxilla, was associated with reduced olfaction in children. The detection and recognition thresholds of skeletal Class III were significantly higher than those of Classes I (p = .01) and II (p = .01). Significant correlations were observed between SNA and the detection threshold (r = −.50) as well as between nasion perpendicular‐point A and the recognition threshold (r = −.53). The detection and recognition thresholds were significantly higher in Class III than in Classes I (r = .3) and II (r = −.1). Conclusions Maxillary growth and development may be associated with olfaction in children. Changing the maxillofacial morphology may improve olfactory function. In the future, we will investigate how malocclusion treatment affects olfactory function.

Summary: Initial studies of cancer metabolism in the early 1920s found that cancer cells were phenotypically characterized by aerobic glycolysis, in that these cells favor glucose uptake and lactate production, even in the presence of oxygen. This property, called the Warburg effect, is considered a hallmark of cancer. The mechanism by which these cells acquire aerobic glycolysis has been uncovered. Acidic extracellular fluid, secreted by cancer cells, induces a malignant phenotype, including invasion and metastasis. Cancer cells survival depends on a critical balance of redox status, which is regulated by amino acid metabolism. Glutamine is extremely important for oxidative phosphorylation and redox regulation. Cells highly dependent on glutamine and that cannot survive with glutamine are called glutamine-addicted cells. Metabolic reprogramming has been observed in cancer stem cells, which have the property of self-renewal and are resistant to chemotherapy and radiotherapy. These findings suggest that studies of cancer metabolism can reveal methods of preventing cancer recurrence and metastasis. Keywords: Glycolysis, Warburg effect, Glutamine metabolism, Acidic extracellular pH

Maxillary sinus floor elevation (sinus lift) is a widely recognized dental-surgical approach for dental implant placement. However, for an otorhinolaryngological high-risk patient with severe anatomic-structural impairments of the maxillary sinus drainage pathway, surgical intervention is recommended before sinus lift to avoid postsinus lift maxillary sinusitis. Here, we show a case that postsinus lift maxillary sinusitis in such a high-risk patient was noninvasively prevented by the collaboration of otorhinolaryngologist and dentist. A 48-year-old Japanese male intended to undergo a sinus lift for dental implant placement by periodontist. Otorhinolaryngologist found septal deviation, concha bullosa, the presence of Haller cell, and nasal mucosal swelling by the nasal allergy, while no sinusitis and diagnosed him as a “high-risk case” for postsinus lift maxillary sinusitis. The patient was administered preoperative topical steroid and leukotriene receptor antagonist in addition to perioperative antibiotic prophylaxis so that his complication was noninvasively prevented. Thus, this case suggested that consultation from dentist to otorhinolaryngologist provides benefit to the patients who have been diagnosed as “high-risk case” for postsinus lift maxillary sinusitis.

Mineral trioxide aggregate (MTA) has been recommended for various uses in endodontics. To understand the effects of MTA on alveolar bone, we examined whether MTA induces osteoblastic differentiation using MC3T3-E1 cells. MTA enhanced mineralization concomitant with alkaline phosphatase activity in a dose- and time-dependent manner. MTA increased production of collagens (Type I and Type III) and matrix metalloproteinases (MMP-9 and MMP-13), suggesting that MTA affects bone matrix remodeling. MTA also induced Bglap (osteocalcin) but not Bmp2 (bone morphogenetic protein-2) mRNA expression. We observed induction of Atf6 (activating transcription factor 6, an endoplasmic reticulum (ER) stress response transcription factor) mRNA expression and activation of Atf6 by MTA treatment. Forced expression of p50Atf6 (active form of Atf6) markedly enhanced Bglap mRNA expression. Chromatin immunoprecipitation assay was performed to investigate the increase in p50Atf6 binding to the Bglap promoter region by MTA treatment. Furthermore, knockdown of Atf6 gene expression by introduction of Tet-on Atf6 shRNA expression vector abrogated MTA-induced mineralization. These results suggest that MTA induces in vitro osteoblastogenesis through the Atf6–osteocalcin axis as ER stress signaling. Therefore, MTA in endodontic treatment may affect alveolar bone healing in the resorbed region caused by pulpal infection.

Laryngeal carcinoma and laryngeal papilloma are the most commonly encountered tumorous lesions in the larynx. Herein, we report a case of the mass arising from the left vocal cord in a 49-year-old Japanese man. Endoscopic examination suggested that the mass is a tumor such as carcinoma and papilloma. Pathological examination showed that the specimen demonstrated actinomycosis in the left vocal cord. Although vocal cord actinomycosis is extremely rare, the otolaryngologist should recognize this condition during the inspection of the larynx.

Exostosis, osteoma, and adenoma are the most commonly encountered benign lesions in the external auditory canal. Herein, we report a case of the mass arising from the external auditory canal in a 24-year-old Japanese man. CT revealed the soft tissue mass without bony erosion, and MRI revealed that the mass showed a homogenous, iso signal intensity on a both T1- and T2-weighted image, suggesting that the mass is a benign tumor such as adenoma. Pathological examination showed that the specimen demonstrated xanthogranuloma in the external auditory canal. Although xanthogranuloma of the external auditory canal is extremely rare, otolaryngologists should recognize this condition during the inspection of the external auditory canal.

A critique of genomic risk classifiers is potential correlation with readily available clinical data. For these classifiers to enhance clinical decision making, they must demonstrate additional discrimination from clinical variables alone with regards to prognostic and/or predictive value. A 22-gene classifier is increasingly employed to inform treatment decisions in prostate cancer. This study aimed to assess whether its risk score remained independent of available clinical variables when using machine learning (ML) to predict genomic risk score outputs. This was a retrospective study of males with localized prostate cancer treated at one of twenty sites within a single hospital network. Patients whose tumors were sent for genomic risk profiling were eligible. Clinical features including year of biopsy, age, clinical stage, prostate specific antigen (PSA), Gleason score, and National Comprehensive Cancer Network (NCCN) risk group were extracted from the medical record and genomic risk score/category were extracted from the pathology results. Logistic regression for binary classification and linear regression for continuous classification plus 5 ML models were trained to predict the risk score, low-risk disease, and high-risk disease. Model performance was measured using area under the curve (AUC) for binary classification and Spearman rho (ρ) for regression. The best-performing model was explained using SHapley Additive exPlanation (SHAP) values. A total of 354 patients with biopsy specimens obtained between 2010 and 2024 were identified. Median age was 66.7 (IQR = 61.4-73.2). A total of 27.1%, 57.9%, and 15.0% of patients were NCCN low, intermediate, and high risk, respectively. Median genomic risk score was 0.385 (IQR = 0.26-0.58). A total of 57.6%, 18.1%, and 24.3% of patients had genomic risk classified as low, intermediate, and high, respectively. An extreme gradient boosting tree achieved the best performance at predicting genomic risk score (ρ: 0.526; 95% CI = 0.355-0.668). A random forest model achieved the best performance at predicting high-risk (AUC: 0.790; 95% CI = 0.671-0.909) and low-risk (AUC: 0.749; 95% CI = 0.631-0.867) genomic score. The most important variables for predicting risk score were primary Gleason, NCCN risk category, and total Gleason. Risk factors predicting high-risk disease included primary Gleason, NCCN risk group, and total Gleason. For low-risk disease they were primary Gleason, age, and total Gleason. ML predicted the output of genomic risk classifiers with favorable albeit imperfect performance using clinical variables alone. Future analyses should evaluate whether genomic risk classifiers may be particularly useful in the subset of patients whose genomic risk score differs from what was predicted using clinical variables alone. ML in combination with genomic risk should also be evaluated as synergistic tools to predict actuarial outcomes once sufficient follow-up is available. [ABSTRACT FROM AUTHOR]

Prediction of pathologic stage in patients with clinical node-negative (cN0) prostate cancer is critical for determination of optimal treatment options. Though several nomograms exist (with only the Partin tables capable of multi-class prediction [or classification within more than two categories]), machine learning (ML) approaches might allow for improved performance through their ability to capture and model complex interactions. Herein, we developed a multi-class ML model to predict pathologic stage and explained how variables were used to produce model predictions using an explainable artificial intelligence (XAI) framework. Patients with cN0 prostate adenocarcinoma diagnosed from 2018-2020 were identified in the National Cancer Database. The query was limited to patients with known clinical staging and biopsy results who did not receive neoadjuvant therapy prior to pelvic nodal examination. Patients were classified as having organ confined disease (OC), extracapsular extension (ECE), seminal vesicle invasion (SVI), or lymph node involvement (LNI). These were considered mutually exclusive, so patients were classified as the highest stage they met criteria for. Variables incorporated into the model were age, core biopsy results, Gleason score, preoperative prostate-specific antigen (PSA), and clinical T-stage. Model performance was measured using one-versus-rest area under the receiver operator characteristic curve (AUC) on a holdout testing dataset. The best-performing model was explained using SHapley Additive exPlanation (SHAP) values. For model interpretation, SHAP values were converted into odds ratios (OR), confidence intervals (CI), and P values. A total of 23,131 patients met inclusion criteria; 8517 (49.5%), 4898 (28.4%), 1660 (9.6%), and 2140 (12.4%) had OC, ECE, SVI, and LNI, respectively. Random Forest model outperformed all other models with an AUC of 0.706 (95% CI = 0.691-0.720) compared to 0.691 logistic regression (95% CI = 0.676-0.705; p<.001) and the Partin Tables 0.674 (95% CI = 0.659-0.688; p<.001). The most important overall model features were primary Gleason, percentage of positive cores (PPC), and PSA. The most important features for each class are summarized in Table 1. Our ML achieved improved performance relative to logistic regression and the Partin Tables at predicting pathologic stage. XAI provided insight into the inner workings of the ML model. ML can be used to identify patients at risk for pathologic upstaging and therefore inform clinical decision-making. [ABSTRACT FROM AUTHOR]

Background: Though several nomograms exist, machine learning (ML) approaches might improve prediction of pathologic stage in patients with prostate cancer. To develop ML models to predict pathologic stage that outperform existing nomograms that use readily available clinicopathologic variables., Methods: Patients with prostate adenocarcinoma who underwent surgery were identified in the National Cancer Database. Seven ML models were trained to predict organ-confined (OC) disease, extracapsular extension, seminal vesicle invasion (SVI), and lymph node involvement (LNI). Model performance was measured using area under the curve (AUC) on a holdout testing data set. Clinical utility was evaluated using decision curve analysis (DCA). Performance metrics were confirmed on an external validation data set., Results: The ML-based extreme gradient boosted trees model achieved the best performance with an AUC of 0.744, 0.749, 0.816, 0.811 for the OC, ECE, SVI, and LNI models, respectively. The MSK nomograms achieved an AUC of 0.708, 0.742, 0.806, 0.802 for the OC, ECE, SVI, and LNI models, respectively. These models also performed the best on DCA. Findings were consistent on both a holdout internal validation data set as well as an external validation data set., Conclusions: Our ML models better predicted pathologic stage relative to existing nomograms at predicting pathologic stage. Accurate prediction of pathologic stage can help oncologists and patients determine optimal definitive treatment options for patients with prostate cancer., (© 2024 Wiley Periodicals LLC.)

Purpose: Preoperative prediction of postoperative complications (PCs) in inpatients with cancer is challenging. We developed an explainable machine learning (ML) model to predict PCs in a heterogenous population of inpatients with cancer undergoing same-hospitalization major operations., Methods: Consecutive inpatients who underwent same-hospitalization operations from December 2017 to June 2021 at a single institution were retrospectively reviewed. The ML model was developed and tested using electronic health record (EHR) data to predict 30-day PCs for patients with Clavien-Dindo grade 3 or higher (CD 3+) per the CD classification system. Model performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), and calibration plots. Model explanation was performed using the Shapley additive explanations (SHAP) method at cohort and individual operation levels., Results: A total of 988 operations in 827 inpatients were included. The ML model was trained using 788 operations and tested using a holdout set of 200 operations. The CD 3+ complication rates were 28.6% and 27.5% in the training and holdout test sets, respectively. Training and holdout test sets' model performance in predicting CD 3+ complications yielded an AUROC of 0.77 and 0.73 and an AUPRC of 0.56 and 0.52, respectively. Calibration plots demonstrated good reliability. The SHAP method identified features and the contributions of the features to the risk of PCs., Conclusion: We trained and tested an explainable ML model to predict the risk of developing PCs in patients with cancer. Using patient-specific EHR data, the ML model accurately discriminated the risk of developing CD 3+ complications and displayed top features at the individual operation and cohort level.

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of β2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.

Background: The feasibility of remote perioperative telemonitoring of patient-generated physiologic health data and patient-reported outcomes in a high risk complex general and urologic oncology surgery population is evaluated., Methods: Complex general surgical/urologic oncology patients wore a pedometer, completed ePROs (electronic patient-reported outcome surveys) and record their vitals (weight, pulse, pulse oximetry, blood pressure, and temperature) via a telehealth app platform. Feasibility (% adherence) was assessed as the primary outcome measure., Results: Twenty-one patients with a median age 58 (32-82) years were included. The readmission rate was 33% and the incidence of ≥Grade 3a morbidity was 24%. Adherence to vital sign and ePRO measurements was 95% before surgery, 91% at discharge, and 82%, 68%, and 64% at postdischarge d2, 7, 14, and 30, respectively. There was significant worsening of mobility, self-care and usual daily activity at postdischarge d2 compared to preoperative baseline (p < 0.05). Median daily preoperative steps taken by patients with

Background: Men with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy. This study aimed to investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localised grade group 2 or 3 intermediate-risk prostate cancer., Methods: In this single-arm, multicentre, phase 2b study conducted at eight health-care centres in the USA, we recruited men aged 50 years and older with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma (prostate-specific antigen ≤20 ng/mL, grade group 2 or 3; tumour classification ≤T2) confirmed on combined biopsy (combining MRI-targeted and systematic biopsies). MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60-70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcomes were oncological outcomes (absence of grade group 2 and higher cancer in the treated area at 6-month and 24-month combined biopsy; when 24-month biopsy data were not available and grade group 2 or higher cancer had occurred in the treated area at 6 months, the 6-month biopsy results were included in the final analysis) and safety (adverse events up to 24 months) in all patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT01657942, and is no longer recruiting., Findings: Between May 4, 2017, and Dec 21, 2018, we assessed 194 patients for eligibility and treated 101 patients with MRI-guided focused ultrasound. Median age was 63 years (IQR 58-67) and median concentration of prostate-specific antigen was 5·7 ng/mL (IQR 4·2-7·5). Most cancers were grade group 2 (79 [78%] of 101). At 24 months, 78 (88% [95% CI 79-94]) of 89 men had no evidence of grade group 2 or higher prostate cancer in the treated area. No grade 4 or grade 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths., Interpretation: 24-month biopsy outcomes show that MRI-guided focused ultrasound focal therapy is safe and effectively treats grade group 2 or 3 prostate cancer. These results support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term., Funding: Insightec and the National Cancer Institute., Competing Interests: Declaration of interests BE attends the medical advisory board of Insightec as an unpaid consultant, and has previously received consulting funds from Myriad Genetics. CMT reports consulting funds from Profound. DDS reports consulting funds from OPKO Health and Steba. ASK is on the medical advisory board of Insightec, Profound, and Janssen, and has received consulting funds from Advantagene DSMC, Bristol Myers Squibb, Merck, Bayer, and General Electric. Q-DT reports consulting funds from Astellas, Bayer, Intuitive Surgical, and Janssen. JCD is the Chief Clinical Officer for Ajax Health and Cordis Accelco and has equity interests in Cordis; is on the advisory board and has ownership or equity interests in Serpex Health and Adient Medical; and serves as the past chair of the Society of Interventional Radiology Foundation. OA has ownership or equity interests in Ezra AI. AJV is named on a patent for a statistical method to detect prostate cancer that has been commercialised by OPKO Health (from which he receives royalties and stock options) and has received consulting funds from Insightec and Steba. PTS is named on a patent for a statistical method to detect prostate cancer that has been commercialised by OPKO Health (from which he receives royalties and stock options) and chairs the medical advisory board of Insightec as an unpaid consultant. DS is the medical director and founder of Sperling Prostate Center, a private facility for prostate cancer treatment in Delray Beach, FL, USA. LAM has collaborative and research agreements with Philips Healthcare and Biobot Surgical. GAS is on the medical advisory board of miR Scientific. PG is on the medical advisory boards of Insightec and SonALASense and has ownership or equity interests in SonALASense. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Approximately 7% of patients with newly diagnosed prostate cancer (PCa) in the US will have have metastatic disease. The dogma that there is no role for surgery in this population has been questioned recently. Here we report long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy., Materials and Methods: This is a multicenter phase 1 trial. The major inclusion criterion was biopsy proven N1M0 or NxM1a/b PCa. Primary end point was the Clavien-Dindo-based major complication rate. Secondary outcomes were biochemical progression and overall survival. RNA-seq correlative study was conducted in nine select cases as a pilot study., Results: Final accrual was 32 patients of which 25 and 7 were cNxM1 and cN1M0, respectively. With the median follow-up of 46 months (interquartile range 31.7 - 52.7 months), 25 out of the 32 patients (75%) were alive at the time of last contact. There were three disparate groups based on the oncologic outcome: favorable, intermediate, and poor. In seven men with favorable response, androgen deprivation therapy was switched to intermittent approach and five remain free of any evidence of disease after more than two years off all systemic therapy with the normalization of serum testosterone. Of these five patients, three had M1 disease. Long-term use of one pad or less per day was 80%. RNA-seq analysis revealed an enriched downregulation of tumor necrosis factor (TNF)-α signature in the favorable group., Conclusion: Overall long-term oncologic outcome of cytoreductive radical prostatectomy was significantly higher than historical results. Importantly, the combination of surgery with systemic therapy may result in a long durable response in a minority of men who present with metastatic PCa., Competing Interests: All authors have no significant conflict of interest., (© 2022 Asian Pacific Prostate Society. Publishing services by Elsevier B.V.)

Background: Prostate cancer is the most commonly diagnosed cancer in American men, with striking differences between ethnic groups. Given the potential for lifestyle or genetic variations between subsets of Asian-American men to impact prostate cancer behavior, we sought to define the outcomes after radical prostatectomy among various Asian groups treated at an NCI-designated comprehensive cancer center., Methods: The City of Hope IRB-approved prostatectomy database was searched from 2003 to 2015 to identify Asian-American men. Clinical and pathologic features were collected and analyzed for association with biochemical recurrence-free survival and overall survival (OS). Categorical data were evaluated using χ 2 and Fisher's exact tests. Survival curves were compared between groups using log-rank testing., Results: Three hundred and eighty-three Asian-American men were included in the dataset. While Asian men as a group had lower BMI than African-American and white men in the database, there was a wide range between ethnic sub-groups. Chinese men more commonly presented with D'Amico low risk disease features (P= .04) compared to other Asian men. Pacific Islander men had the lowest rate of ≥T3 stage and the highest biochemical recurrence-free survival. OS for Chinese men was better than for all Asian patients combined (P= .046). After controlling for D'Amico risk and in multivariate analysis, Chinese men still had improved OS than other Asian men after prostatectomy (P= .03)., Conclusions: Asian-American men have differing prostate cancer characteristics. Future efforts to delineate and impact upon prostate cancer outcomes should categorize Asian men by subgroup in order to better elucidate biology, lifestyle factors and/or treatment preferences that may contribute to observed differences., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Evaluation of safety is of paramount importance with adoption of novel surgical technology. Although robotic surgery has become widely used in oncologic surgery, analysis of safety is lacking in comparison to traditional techniques. Standardized assessment of robotic surgical outcomes and adverse events following oncologic surgery is necessary for quality improvement with innovative technology. Between 2003 and 2016, 10,013 unique robotic operations were performed in 9,858 patients. Our prospectively maintained database was retrospectively reviewed for hospital readmissions and Clavien-Dindo grade ≥ 2 complications within 30 days. Multivariable logistic regression was used to identify predictors of surgical complications and hospital readmissions. Cases were stratified by discipline: genitourinary (n = 8240), gynecologic (n = 857), thoracic (n = 457), gastrointestinal (n = 322), hepatobiliary (n = 60), ear/nose/throat (n = 44) and general (n = 33). Intraoperative complications occurred in 42 surgeries (0.4%). Postoperative complications occurred in 946 patients [9.4%, highest grade 2 (n = 574), 3 (n = 288), 4 (n = 72), 5 (n = 10)]. Most frequent complications were ileus (154, 16.3%), anemia (91, 9.6%), cardiac arrhythmia (62, 6.6%), deep vein thrombosis/pulmonary embolus (47, 5.0%), wound infection (45, 4.8%) and urinary leak (43, 4.5%). 405 patients (4.0%) required readmission. Most common causes for hospital readmission were ileus (44, 10.9%), urinary leak (23, 5.7%), urinary tract infection (23, 5.7%), intra-abdominal abscess/fluid collection (23, 5.7%), and small bowel obstruction (19, 4.7%). On multivariable analysis, longer operative time and older age predicted complications and readmissions (p ≤ 0.02). Robotic-assisted surgery appears a safe for oncologic surgery with acceptable hospital readmission and complication rates. Older age and longer operative time were associated with complications and readmission.

As the US transitions from volume- to value-based cancer care, many cancer centers and community groups have joined to share resources to deliver measurable, high-quality cancer care and clinical research with the associated high patient satisfaction, provider satisfaction, and practice health at optimal costs that are the hallmarks of value-based care. Multidisciplinary oncology care pathways are essential components of value-based care and their payment metrics. Oncology pathways are evidence-based, standardized but personalizable care plans to guide cancer care. Pathways have been developed and studied for the major medical, surgical, radiation, and supportive oncology disciplines to support decision-making, streamline care, and optimize outcomes. Implementing multidisciplinary oncology pathways can facilitate comprehensive care plans for each cancer patient throughout their cancer journey and across large multisite delivery systems. Outcomes from the delivered pathway-based care can then be evaluated against individual and population benchmarks. The complexity of adoption, implementation, and assessment of multidisciplinary oncology pathways, however, presents many challenges. We review the development and components of value-based cancer care and detail City of Hope's (COH) academic and community-team-based approaches for implementing multidisciplinary pathways. We also describe supportive components with available results towards enterprise-wide value-based care delivery.

Objective: To compare the perioperative outcomes of intracorporeal (ICUD) vs extracorporeal urinary diversion (ECUD) after robot-assisted radical cystectomy (RARC)., Patients and Methods: We retrospectively reviewed the prospectively maintained International Robotic Cystectomy Consortium (IRCC) database. A total of 972 patients from 28 institutions who underwent RARC were included. Propensity score matching was used to match patients based on age, gender, body mass index (BMI), American Society of Anesthesiologists Score (ASA) score, Charlson Comorbidity Index (CCI) score, prior radiation and abdominal surgery, receipt of neoadjuvant chemotherapy, and clinical staging. Matched cohorts were compared. Multivariate stepwise logistic and linear regression models were fit to evaluate variables associated with receiving ICUD, operating time, 90-day high-grade complications (Clavien-Dindo Classification Grade ≥III), and 90-day readmissions after RARC., Results: Utilisation of ICUD increased from 0% in 2005 to 95% in 2018. The ICUD patients had more overall complications (66% vs 58%, P = 0.01) and readmissions (27% vs 17%, P = 0.01), but not high-grade complications (21% vs 24%, P = 0.22). A more recent RC era and ileal conduit diversion were associated with receiving an ICUD. Higher BMI, ASA score ≥3, and receiving a neobladder were associated with longer operating times. Shorter operating time was associated with male gender, older age, ICUD, and centres with a larger annual average RC volume. Longer intensive care unit stay was associated with 90-day high-grade complications. Higher CCI score, prior radiation therapy, neoadjuvant chemotherapy, and ICUD were associated with a higher risk of 90-day readmissions., Conclusions: Utilisation of ICUD has increased over the past decade. ICUD was associated with more overall complications and readmissions compared to ECUD, but not high-grade complications., (© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd.)

Purpose: Shapley additive explanation (SHAP) values represent a unified approach to interpreting predictions made by complex machine learning (ML) models, with superior consistency and accuracy compared with prior methods. We describe a novel application of SHAP values to the prediction of mortality risk in prostate cancer., Methods: Patients with nonmetastatic, node-negative prostate cancer, diagnosed between 2004 and 2015, were identified using the National Cancer Database. Model features were specified a priori: age, prostate-specific antigen (PSA), Gleason score, percent positive cores (PPC), comorbidity score, and clinical T stage. We trained a gradient-boosted tree model and applied SHAP values to model predictions. Open-source libraries in Python 3.7 were used for all analyses., Results: We identified 372,808 patients meeting the inclusion criteria. When analyzing the interaction between PSA and Gleason score, we demonstrated consistency with the literature using the example of low-PSA, high-Gleason prostate cancer, recently identified as a unique entity with a poor prognosis. When analyzing the PPC-Gleason score interaction, we identified a novel finding of stronger interaction effects in patients with Gleason ≥ 8 disease compared with Gleason 6-7 disease, particularly with PPC ≥ 50%. Subsequent confirmatory linear analyses supported this finding: 5-year overall survival in Gleason ≥ 8 patients was 87.7% with PPC < 50% versus 77.2% with PPC ≥ 50% ( P < .001), compared with 89.1% versus 86.0% in Gleason 7 patients ( P < .001), with a significant interaction term between PPC ≥ 50% and Gleason ≥ 8 ( P < .001)., Conclusion: We describe a novel application of SHAP values for modeling and visualizing nonlinear interaction effects in prostate cancer. This ML-based approach is a promising technique with the potential to meaningfully improve risk stratification and staging systems.

Purpose: The primary objectives of this study were to evaluate toxicity of escalating doses of prostate bed stereotactic body radiation therapy and to provide dose recommendations for a phase 2 study., Methods and Materials: Patients with organ-confined, node-negative prostate cancer who had biochemical failure (prostate-specific antigen [PSA] less than 2.0) after prostatectomy were eligible for this phase 1 dose-escalation trial. Doses delivered were 35 Gy, 40 Gy, and 45 Gy in 5 fractions, given every other day. Dose-limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events (version 4.0) grade 3 or higher gastrointestinal or genitourinary (GU) toxicity within 90 days of treatment. Maximum tolerated dose was the highest dose to be tested where fewer than 2 of the patients experienced DLT. Patients completed quality-of-life questionnaires at regular time intervals., Results: Twenty-six patients completed treatment between October 2013 and December 2017. Three patients received 35 Gy, 8 patients received 40 Gy, and 15 patients received 45 Gy. The median follow-up was 60 months for 35 Gy, 48 months for 40 Gy, and 33 months for 45 Gy. No acute DLT events were observed. Late grade ≥2 and ≥3 gastrointestinal toxicity occurred in 11% and 0%, respectively, and late grade ≥2 and ≥3 GU toxicity occurred in 38% and 15%, respectively. No difference was observed in late GU toxicity between 40 Gy and 45 Gy. Sexual function scores were significantly lower in the patients receiving androgen deprivation therapy (P < .01). In all patients, the crude rate of PSA control (<0.2 ng/mL) was 11 out of 26 (42%)., Conclusions: Dose escalation to 45 Gy did not result in acute DLT events, had similar rates of late grade 3 toxicity, and did not demonstrate higher rates of PSA control, compared with 40 Gy. While allowing for higher plan heterogeneity, the recommended dose for phase 2 study will be 40 Gy in 5 fractions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: We sought to determine the trend of neoadjuvant chemotherapy use for nonmetastatic muscle invasive urothelial bladder cancer and whether it is associated with adverse perioperative morbidity after robot-assisted radical cystectomy., Materials and Methods: We retrospectively reviewed the IRCC (International Robotic Cystectomy Consortium) database between 2006 and 2017. After excluding patients with nonmuscle invasive bladder cancer the patients were divided into 2 groups, including those who did vs did not receive neoadjuvant chemotherapy. Data were reviewed for demographics, preoperative, operative and 90-day perioperative outcomes. We used the Cochran-Armitage trend test to assess trends of neoadjuvant chemotherapy associations with high grade and overall complications with time. Multivariate stepwise regression analyses were done to determine whether neoadjuvant chemotherapy was associated with prolonged operative time, 90-day postoperative complications, readmissions, reoperations and mortality after robot-assisted radical cystectomy., Results: A total of 298 patients (26%) received neoadjuvant chemotherapy. These patients were younger (age 67 vs 69 years, p=0.01) and more frequently had an ASA™ (American Society of Anesthesiologists™) score of 3 or greater (62% vs 55%, p=0.02) and pathological T3 stage or greater disease (28% vs 22%, p=0.04). The use of neoadjuvant chemotherapy increased significantly from 10% in 2006 to 2007 to 42% in 2016 to 2017 (p <0.01). On multivariate analysis neoadjuvant chemotherapy was not significantly associated with prolonged operative time, hospital stay, 90-day postoperative complications, reoperation or mortality. Neoadjuvant chemotherapy was associated with 90-day readmissions after robot-assisted radical cystectomy (OR 5.90, 95% CI 3.30-10.90, p <0.01)., Conclusions: Neoadjuvant chemotherapy utilization has significantly increased in the last decade. It was not associated with perioperative surgical morbidity after robot-assisted radical cystectomy.

Optimal management of node-positive prostate cancer patients after prostatectomy remains a challenge. We evaluated clinically localized patients who demonstrated node positivity and identified predictors for secondary treatment. From 2010 to 2015, clinically localized prostate cancer patients who underwent robot prostatectomy with extended lymphadenectomy and node-positive disease on pathologic analysis were identified. Clinical N1, M1 or salvage cases were excluded. Patients were stratified based on secondary treatments. Kaplan-Meier method was used to determine the time to biochemical and metastatic recurrence. Multivariate logistic regression was used to identify predictors for additional treatment. 145 patients (45 no additional therapy, 47 adjuvant, 53 salvage) had a median follow-up of 31.2 months. Salvage patients had higher median pre-operative prostate-specific antigen (10.8 vs. 9.7 vs. 8.2, p = 0.1), higher percentage of pathologic Gleason ≥8 (50.9 vs. 38.3% and 22.2%, p < 0.01), and higher median-positive nodes (3 vs. 1 and 1, p < 0.0001) compared to adjuvant and no treatment groups, respectively. Pathologic Gleason ≥8 (OR = 3.5, p = 0.007) and positive nodes ≥2 (OR = 3.3, p = 0.006) were associated with additional therapy. In the no treatment group, two-year estimated BCRFS was 74.3%. Two-year metastatic recurrence-free rates for no treatment, adjuvant and salvage groups were 100, 87.5, and 80.9%, respectively (p = 0.01). Observation is a viable alternative for low metastatic burden patients. In the largest series of node-positive patients from robotic prostatectomy and extended lymphadenectomy, those with pathologic Gleason ≥8 and positive lymph nodes ≥2 were more likely to receive additional treatment.

Background and Objectives: Cytoreductive surgery with complete macroscopic resection in patients with ovarian cancer is associated with improved survival. Institutional reports of combined upper and lower abdominal cytoreductive surgery for more advanced disease have described multidisciplinary approaches. We sought to investigate outcomes in patients undergoing cytoreductive surgery in patients with upper and lower abdominal disease at our institution., Methods: Patients who underwent cytoreductive surgery for ovarian malignancies from 2008 to 2015 were retrospectively identified from an institutional database. Upper abdominal cytoreduction was defined anatomically as debulking of disease proximal to the ligament of Treitz. Perioperative outcomes were analyzed., Results: A total of 258 operations were performed, the majority for serous ovarian carcinoma (70%). The gynecologic oncologist was the primary surgeon and often assisted by either a surgical oncology fellow and/or attending. In operations with combined upper and lower abdominal cytoreduction, patients were more likely to have an American society of anesthesiologists physical status classification system (ASA) of 3, peritoneal implants, and liver/spleen metastases. Preoperative chemotherapy and optimal cytoreduction were similar between groups. Perioperative morbidity and mortality were not significantly different between groups., Conclusions: A collaborative surgical approach to combined upper and lower abdominal cytoreductive surgery in patients with ovarian cancer should be performed, if needed, to achieve an optimal cytoreduction., (© 2018 Wiley Periodicals, Inc.)

Introduction: Extended lymph node dissection (ELND) compared to limited lymph node dissection (LLND) at time of prostatectomy improves staging and lymph node (LN) yield. The effect on biochemical recurrence (BCR) and survival is less well understood. We sought to evaluate the benefit of robotic ELND and LLND with respect to BCR., Materials and Methods: Between 2008-2012, 584 consecutive men with intermediate or high risk clinically localized adenocarcinoma of the prostate underwent robotic assisted radical prostatectomy (RARP) with concomitant LLND (n = 326) or ELND (n = 258). Survival estimates were made using the Kaplan-Meier method. Log-rank statistic was used for comparison of curves. BCR predictors were determined with multivariable Cox regression analysis. Chi-square and Wilcoxon rank-sum tests were used to compare discrete and continuous variables, respectively, across the two groups., Results: Median follow up for ELND and LLND patients was 46 and 54 months, respectively. ELND yielded more LNs (20 versus 6, p < 0.0001) and had higher node positivity (15.1% versus 3.4%, p < 0.0001). BCR free survival (BCRFS) at 3 and 5 years for ELND and LLND was 85% and 75% (p = 0.01), and 76% and 67% (p = 0.10), respectively. In subgroup analysis, ELND was associated with higher 5 year BCRFS in node-negative patients (84% versus 68%, p = 0.0005) and in intermediate risk patients (93% versus 80%, p = 0.0002). In multivariable analysis, ELND was a significant predictor of BCRFS in node-negative (HR = 0.50, p = 0.003) and intermediate risk patients (HR = 0.54, p = 0.03)., Conclusions: ELND improves LN yield and detection of positive nodes. BCR analysis suggests a reduced risk of PSA failure for robotic ELND in intermediate risk and node-negative patients.

There is a significant controversy on whether race should be a factor in considering active surveillance for low-risk prostate cancer. To address this question, we analyzed a multi-institution database to assess racial disparity between African-American and White-American men with low risk prostate cancer who were eligible for active surveillance but underwent radical prostatectomy. A retrospective analysis of prospectively collected clinical, pathologic and oncologic outcomes of men with low-risk prostate cancer from seven tertiary care institutions that underwent radical prostatectomy from 2003-2014 were used to assess potential racial disparity. Of the 333 (14.8%) African-American and 1923 (85.2%) White-American men meeting active surveillance criteria, African-American men were found to be slightly younger (57.5 vs 58.5 years old; p = 0.01) and have higher BMI (29.3 v 27.9; p < 0.01), pre-op PSA (5.2 v 4.7; p < 0.01), and maximum percentage cancer on biopsy (15.1% v 13.6%; p < 0.01) compared to White-American men. Univariate and multivariate analysis demonstrated similar rates of upgrading, upstaging, positive surgical margin, and biochemical recurrence between races. These results suggest that single institution studies recommending more stringent AS enrollment criteria for AA men with a low-risk prostate cancer may not capture the complete oncologic landscape due to institutional variability in cancer outcomes. Since all seven institutions demonstrated no significant racial disparity, current active surveillance eligibility should not be modified based upon race until a prospective study has been completed., Competing Interests: CONFLICTS OF INTEREST None.

Objective: To determine if eliminating the prophylactic placement of a pelvic drain (PD) after robot-assisted radical prostatectomy (RARP) affects the incidence of early (90-day) postoperative adverse events., Patients and Methods: In this parallel-group, blinded, non-inferiority trial, we randomised patients planning to undergo RARP to one of two arms: no drain placement (ND) or PD placement. Patients with demonstrable intraoperative leakage upon bladder irrigation were excluded. Randomisation sequence was determined a priori using a computer algorithm, and included a stratified design with respect to low vs intermediate/high D'Amico risk classifications. Surgeons remained blinded to the randomisation arm until final eligibility was verified at the end of the RARP. The primary endpoint was overall incidence of 90-day complications which, based on our standard treatment using PD retrospectively, was estimated at 13%. The non-inferiority margin was set at 10%, and the planned sample size was 312. An interim analysis was planned and conducted when one-third of the planned accrual and follow-up was completed, to rule out futility if the delta margin was in excess of 0.1389., Results: From 2012 to 2016, 189 patients were accrued to the study, with 92 patients allocated to the ND group and 97 to the PD group. Due to lower than expected accrual rates, accrual to the study was halted by regulatory entities, and we did not reach the intended accrual goal. The ND and PD groups were comparable for median PSA level (6.2 vs 5.8 ng/mL, P = 0.5), clinical stage (P = 0.8), D'Amico risk classification (P = 0.4), median lymph nodes dissected (17 vs 18, P = 0.2), and proportion of patients receiving an extended pelvic lymph node dissection (70.7% vs 79.4%, P = 0.3). Incidence of 90-day overall and major (Clavien-Dindo grade >III) complications in the ND group (17.4% and 5.4%, respectively) was not inferior to the PD group (26.8% and 5.2%, respectively; P < 0.001 and P = 0.007 for difference of proportions <10%, respectively). Symptomatic lymphocoele rates (2.2% in the ND group, 4.1% in the PD group) were comparable between the two arms (P = 0.7)., Conclusions: Incidence of adverse events in the ND group was not inferior to the group who received a PD. In properly selected patients, PD placement after RARP can be safely withheld without significant additional morbidity., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Emerging evidence has suggested that cytoreductive prostatectomy (CRP) allows superior oncologic control when compared to current standard of care androgen deprivation therapy alone. However, the safety and benefit of cytoreduction in metastatic prostate cancer (mPCa) has not been proven. Therefore, we evaluated the incidence of complications following CRP in men newly diagnosed with mPCa. A total of 68 patients who underwent CRP from 2006 to 2014 at four tertiary surgical centers were compared to 598 men who underwent radical prostatectomy for clinically localized prostate cancer (PCa). Urinary incontinence was defined as the use of any pad. CRP had longer operative times (200 min vs 140 min, P < 0.0001) and higher estimated blood loss (250 ml vs 125 ml, P < 0.0001) compared to the control group. However, both overall (8.82% vs 5.85%) and major complication rates (4.41% vs 2.17%) were comparable between the two groups. Importantly, urinary incontinence rate at 1-year after surgery was significantly higher in the CRP group (57.4% vs 90.8%, P < 0.0001). Univariate logistic analysis showed that the estimated blood loss was the only independent predictor of perioperative complications both in the unadjusted model (OR: 1.18; 95% CI: 1.02-1.37; P = 0.025) and surgery type-adjusted model (OR: 1.17; 95% CI: 1.01-1.36; P = 0.034). In conclusion, CRP is more challenging than radical prostatectomy and associated with a notably higher incidence of urinary incontinence. Nevertheless, CRP is a technically feasible and safe surgery for selecting PCa patients who present with node-positive or bony metastasis when performed by experienced surgeons. A prospective, multi-institutional clinical trial is currently underway to verify this concept.

Objectives: To design a methodology to predict operative times for robot-assisted radical cystectomy (RARC) based on variation in institutional, patient, and disease characteristics to help in operating room scheduling and quality control., Patients and Methods: The model included preoperative variables and therefore can be used for prediction of surgical times: institutional volume, age, gender, body mass index, American Society of Anesthesiologists score, history of prior surgery and radiation, clinical stage, neoadjuvant chemotherapy, type, technique of diversion, and the extent of lymph node dissection. A conditional inference tree method was used to fit a binary decision tree predicting operative time. Permutation tests were performed to determine the variables having the strongest association with surgical time. The data were split at the value of this variable resulting in the largest difference in means for the surgical time across the split. This process was repeated recursively on the resultant data sets until the permutation tests showed no significant association with operative time., Results: In all, 2 134 procedures were included. The variable most strongly associated with surgical time was type of diversion, with ileal conduits being 70 min shorter (P < 0.001). Amongst patients who received neobladders, the type of lymph node dissection was also strongly associated with surgical time. Amongst ileal conduit patients, institutional surgeon volume (>66 RARCs) was important, with those with a higher volume being 55 min shorter (P < 0.001). The regression tree output was in the form of box plots that show the median and ranges of surgical times according to the patient, disease, and institutional characteristics., Conclusion: We developed a method to estimate operative times for RARC based on patient, disease, and institutional metrics that can help operating room scheduling for RARC., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Purpose: There are limited long-term data on patients treated with image guided intensity modulated radiation therapy (IG-IMRT) for prostate cancer recurrence or high-risk disease features after radical prostatectomy. We report single-institution results for patients treated with IG-IMRT and identify variables associated with outcome., Methods and Materials: This is a retrospective chart review consisting of 313 consecutive patients who were treated with adjuvant or salvage IG-IMRT from 2004 to 2013. Cox proportional hazards analysis was used to identify factors related to survival and toxicity. Toxicity was graded using the Common Terminology Criteria for Adverse Events Version 4.0., Results: The median follow-up was 55 months (range, 6-131 months). The median pre-radiation therapy (RT) prostate-specific antigen (PSA) was 0.3 ng/mL (range, <0.01-55.4). The vast majority of patients (87%) received elective pelvic nodal irradiation (median dose: 45 Gy). Androgen deprivation therapy (ADT) was given to 39% of patients for a median of 9 months. Five-year biochemical progression-free survival and distant metastasis-free survival were 59% (95% confidence interval, 53%-66%) and 89% (95% confidence interval, 85%-93%), respectively. On multivariate analysis, higher pre-RT PSA (>0.2 ng/mL), biopsy Gleason score (≥7 [4+3]), and duration of ADT (>6 months) were significantly associated ( P < .05) with biochemical progression-free survival. Actuarial late grade 3 genitourinary and gastrointestinal toxicities at 5 years were 10% and 2%, respectively., Conclusion: Our results suggest that lower pre-RT PSA level and longer duration of ADT are associated with improved biochemical control. The incidence of late grade 3 gastrointestinal toxicity was low, but late grade 3 genitourinary toxicity was higher than anticipated.