Application of STREAM-URO and APPRAISE-AI reporting standards for artificial intelligence studies in pediatric urology: A case example with pediatric hydronephrosis.

INTRODUCTION: Artificial intelligence (AI) and machine learning (ML) in pediatric urology is gaining increased popularity and credibility. However, the literature lacks standardization in reporting and there are areas for methodological improvement, which incurs difficulty in comparison between studies and may ultimately hurt clinical implementation of these models. The "STandardized REporting of Applications of Machine learning in UROlogy" (STREAM-URO) framework provides methodological instructions to improve transparent reporting in urology and APPRAISE-AI in a critical appraisal tool which provides quantitative measures for the quality of AI studies. The adoption of these will allow urologists and developers to ensure consistency in reporting, improve comparison, develop better models, and hopefully inspire clinical translation. METHODS: In this article, we have applied STREAM-URO framework and APPRAISE-AI tool to the pediatric hydronephrosis literature. By doing this, we aim to describe best practices on ML reporting in urology with STREAM-URO and provide readers with a critical appraisal tool for ML quality with APPRAISE-AI. By applying these to the pediatric hydronephrosis literature, we provide some tutorial for other readers to employ these in developing and appraising ML models. We also present itemized recommendations for adequate reporting, and critically appraise the quality of ML in pediatric hydronephrosis insofar. We provide examples of strong reporting and highlight areas for improvement. RESULTS: There were 8 ML models applied to pediatric hydronephrosis. The 26-item STREAM-URO framework is provided in Appendix A and 24-item APPRAISE-AI tool is provided in Appendix B. Across the 8 studies, the median compliance with STREAM-URO was 67 % and overall study quality was moderate. The highest scoring APPRAISE-AI domains in pediatric hydronephrosis were clinical relevance and reporting quality, while the worst were methodological conduct, robustness of results, and reproducibility. CONCLUSIONS: If properly conducted and reported, ML has the potential to impact the care we provide to patients in pediatric urology. While AI is exciting, the paucity of strong evidence limits our ability to translate models to practice. The first step toward this goal is adequate reporting and ensuring high quality models, and STREAM-URO and APPRAISE-AI can facilitate better reporting and critical appraisal, respectively.

Organ Preservation and Survival by Clinical Response Grade in Patients With Rectal Cancer Treated With Total Neoadjuvant Therapy: A Secondary Analysis of the OPRA Randomized Clinical Trial.

Importance: Assessing clinical tumor response following completion of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer is paramount to select patients for watch-and-wait treatment. Objective: To assess organ preservation (OP) and oncologic outcomes according to clinical tumor response grade. Design, Setting, and Participants: This was secondary analysis of the Organ Preservation in Patients with Rectal Adenocarcinoma trial, a phase 2, nonblinded, multicenter, randomized clinical trial. Randomization occurred between April 2014 and March 2020. Eligible participants included patients with stage II or III rectal adenocarcinoma. Data analysis occurred from March 2022 to July 2023. Intervention: Patients were randomized to induction chemotherapy followed by chemoradiation or chemoradiation followed by consolidation chemotherapy. Tumor response was assessed 8 (±4) weeks after TNT by digital rectal examination and endoscopy and categorized by clinical tumor response grade. A 3-tier grading schema that stratifies clinical tumor response into clinical complete response (CCR), near complete response (NCR), and incomplete clinical response (ICR) was devised to maximize patient eligibility for OP. Main Outcomes and Measures: OP and survival rates by clinical tumor response grade were analyzed using the Kaplan-Meier method and log-rank test. Results: There were 304 eligible patients, including 125 patients with a CCR (median [IQR] age, 60.6 [50.4-68.0] years; 76 male [60.8%]), 114 with an NCR (median [IQR] age, 57.6 [49.1-67.9] years; 80 male [70.2%]), and 65 with an ICR (median [IQR] age, 55.5 [47.7-64.2] years; 41 male [63.1%]) based on endoscopic imaging. Age, sex, tumor distance from the anal verge, pathological tumor classification, and clinical nodal classification were similar among the clinical tumor response grades. Median (IQR) follow-up for patients with OP was 4.09 (2.99-4.93) years. The 3-year probability of OP was 77% (95% CI, 70%-85%) for patients with a CCR and 40% (95% CI, 32%-51%) for patients with an NCR (P < .001). Clinical tumor response grade was associated with disease-free survival, local recurrence-free survival, distant metastasis-free survival, and overall survival. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, most patients with a CCR after TNT achieved OP, with few developing tumor regrowth. Although the probability of tumor regrowth was higher for patients with an NCR compared with patients with a CCR, a significant proportion of patients achieved OP. These findings suggest the 3-tier grading schema can be used to estimate recurrence and survival outcomes in patients with locally advanced rectal cancer who receive TNT. Trial Registration: ClinicalTrials.gov Identifier: NCT02008656.

Trends in Management of Fetuses with Suspected Lower Urinary Tract Obstruction (LUTO): A High-Risk Fetal and Pediatric Center Experience in a Universal-Access-to-Care System.

INTRODUCTION: Neonates with lower urinary tract obstruction (LUTO) experience high morbidity and mortality associated with the development of chronic kidney disease. The prenatal detection rate for LUTO is less than 50%, with late or missed diagnosis leading to delayed management and long-term sequelae in the remainder. We aimed to explore the trends in prenatal detection and management at a high-risk fetal center and determine if similar trends of postnatal presentations were noted for the same period. METHODS: Prenatal and postnatal LUTO databases from a tertiary fetal center and its associated pediatric center between 2009 and 2021 were reviewed, capturing maternal age, gestational age (GA) at diagnosis, and rates of termination of pregnancy (TOP). Time series analysis using autocorrelation was performed to investigate time trend changes for prenatally suspected and postnatally confirmed LUTO cases. RESULTS: A total of 161 fetuses with prenatally suspected LUTO were identified, including 78 terminations. No significant time trend was found when evaluating the correlation between time periods, prenatal suspicion, and postnatal confirmation of LUTO cases (Durbin-Watson [DW] = 1.99, p = 0.3641 and DW = 2.86, p = 0.9113, respectively). GA at referral was 20.0 weeks (interquartile range [IQR] 12, 35) and 22.0 weeks (IQR 13, 37) for TOP and continued pregnancies (p < 0.0001). GA at initial ultrasound was earlier in terminated fetuses compared to continued (20.0 [IQR 12, 35] weeks vs. 22.5 [IQR 13, 39] weeks, p < 0.0001). While prenatal LUTO suspicion remained consistently higher than postnatal presentations, the rates of postnatal presentations and terminations remained stable during the study years (p = 0.7913 and 0.2338), as were GA at TOP and maternal age at diagnosis (p = 0.1710 and 0.1921). CONCLUSION: This study demonstrated that more severe cases of LUTO are referred earlier and are more likely to undergo TOP. No significant trend was detected between time and prenatally suspected or postnatally confirmed LUTO, highlighting the need for further studies to better delineate factors that can increase prenatal detection.

Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively (P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group (P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.

Compliance and Toxicity of Total Neoadjuvant Therapy for Rectal Cancer: A Secondary Analysis of the OPRA Trial.

PURPOSE: Patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) may achieve organ preservation without a compromise to oncologic outcomes. However, reports on patient compliance with TNT and with treatment-related toxicities are limited. METHODS AND MATERIALS: The OPRA trial assessed organ preservation rates and oncologic outcomes in patients with clinical stage II/III rectal adenocarcinoma randomized to induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Systemic chemotherapy consisted of 8 cycles (16 weeks) of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or 5 cycles (15 weeks) of capecitabine and oxaliplatin (CAPEOX). Patients received >4500 cGy of radiation with sensitizing capecitabine or fluorouracil. In this report, we compare compliance and treatment-related toxicity in patients receiving INCT-CRT versus CRT-CNCT. Additionally, we evaluate the association of compliance to chemotherapy, compliance to chemoradiation, and toxicity with organ preservation and disease-free survival (DFS). RESULTS: Of the 324 patients randomized, fewer patients started chemoradiation in the INCT-CRT group compared with the CRT-CNCT group (93% vs 98%, P = .03), and fewer patients started systemic chemotherapy in the CRT-CNCT group compared with the INCT-CRT group (94% vs 99%, P = .04). Order of TNT did not affect the ability to complete all intended cycles of FOLFOX (86% INCT-CRT vs 83% CRT-CNCT, P = .60) or CAPEOX (74% INCT-CRT vs 77% CRT-CNCT, P = .80). A total of 97% of INCT and 98% of CRT-CNCT patients received >4500 cGy radiation (P = .93). Sixty-four patients (41%) treated with INCT-CRT and 57 CRT-CNCT patients (34%) experienced a grade 3+ adverse event (P = .30). Compliance and toxicity were not associated with organ preservation or DFS. CONCLUSIONS: We identified only minor differences in treatment compliance between patients treated with INCT-CRT and CRT-CNCT. No difference in adverse events was observed between groups. Treatment compliance and toxicity did not correlate with organ preservation rates or DFS.

Development and use of machine learning models for prediction of male sling success A proof-of-concept institutional evaluation.

INTRODUCTION: For mild to moderate male stress urinary incontinence (SUI), transobturator male slings remain an effective option for management. We aimed to use a machine learning (ML )-based model to predict those who will have a long-term success in managing SUI with male sling. METHODS: All transobturator male sling cases from August 2006 to June 2012 by a single surgeon were reviewed. Outcome of interest was defined as 'cure': complete dryness with 0 pads used, without the need for additional procedures. Clinical variables included in ML models were: number of pads used daily, age, height, weight, race, incontinence type, etiology of incontinence, history of radiation, smoking, bladder neck contracture, and prostatectomy. Model performance was assessed using area under receiver operating characteristic curve (AUROC), area under precision-recall curve (AUPRC), and F1-score. RESULTS: A total of 181 patients were included in the model. The mean followup was 56.4 months (standard deviation [SD ] 41.6). Slightly more than half (53.6%, 97/181) of patients had procedural success. Logistic regression, K-nearest neighbor (KNN ), naive Bayes, decision tree, and random forest models were developed using ML. KNN model had the best performance, with AUROC of 0.759, AUPRC of 0.916, and F1-score of 0.833. Following ensemble learning with bagging and calibration, KNN model was further improved, with AUROC of 0.821, AUPRC of 0.921, and F-1 score of 0.848. CONCLUSIONS: ML-based prediction of long-term transobturator male sling is feasible. The low numbers of patients used to develop the model prompt further validation and development of the model but may serve as a decision-making aid for practitioners in the future.

Implementation of a standardized clinical pathway in a dedicated posterior urethral valves clinic: short-term outcomes.

BACKGROUND: To determine if the implementation of a posterior urethral valves (PUV) clinic and standardized management pathway improves the short-term kidney outcomes of infants with PUV. METHODS: From 2016-2022, 50 consecutive patients were divided into groups after the implementation of the clinic (APUV, n = 29) and before (BPUV, n = 21) during a comparable timeframe. Assessed data included age at initial visit, timing and type of surgery, frequency of follow-up visits, medications, nadir creatinine, and development of CKD/kidney failure. Data are shown as median with interquartile range (IQR) and odds ratios (OR) with 95% confidence interval (CI). RESULTS: APUV had higher rates of prenatal diagnoses (12/29 vs. 1/21; p = 0.0037), earlier initial surgical intervention (8 days; IQR 0, 105 vs. 33 days; IQR 4, 603; p < 0.0001), and higher rates of primary diversions (10/29 vs. 0/21; p = 0.0028). Standardized management led to earlier initiation of alpha blockers (326 days; IQR 6, 860 vs. 991; IQR 149, 1634; p = 0.0019) and anticholinergics (57 days; IQR 3, 860 vs. 1283 days; IQR 477, 1718; p < 0.0001). Nadir creatinine was reached at earlier ages in APUV (105 days; IQR 2, 303 vs. 164 days; IQR 21, 447; p = 0.0192 BPUV). One patient progressed to CKD5 in APUV compared to CKD3, CKD5 and one transplant in BPUV. CONCLUSION: Implementing the PUV clinic with standardized treatment expedited postnatal management and resulted in a higher number of cases detected prenatally, a shift in primary treatment, younger ages at initial treatment, reduced time to nadir creatinine, and timely initiation of supportive medications. A higher resolution version of the Graphical abstract is available as Supplementary information.

Does VURD syndrome impact voiding efficiency in posterior urethral valves?

INTRODUCTION: There is debate regarding the effect of VURD syndrome, consisting of vesicoureteral reflux (VUR) and ipsilateral kidney dysplasia, on long-term outcomes in boys with posterior urethral valve (PUV). Here, we assessed whether VURD syndrome played a "protective" role on long-term bladder outcomes and voiding efficiency in boys with PUV. MATERIALS AND METHOD: A retrospective chart review was conducted for toilet-trained children with PUV managed at our institution between 2000 and 2022, only excluding cases without recorded uroflowmetry studies. Patients were stratified by VUR status and by the presence of VURD syndrome (high-grade VUR + ipsilateral kidney dysplasia). Outcomes included initial and final uroflowmetry parameters, and initiation of clean-intermittent catheterization (CIC). RESULTS: We identified a total of 101 patients who met study inclusion criteria, with an overall median follow-up of 114 months (IQR 67, 169). The median age of first and last uroflowmetry was 57 months (IQR 48, 82) and 120 months (IQR 89, 160), respectively. Patients with VURD syndrome had similar flow velocity, post-void residuals, and bladder voiding efficiency to other PUV patients at last follow-up uroflowmetry. On survival analysis, patients with VURD syndrome had no significant difference in risk of requiring CIC compared to patients without pop-offs (p = 0.06). DISCUSSION: Like more contemporary studies on pressure pop-offs, we show that this population is not at higher risk of poorer voiding and intermittent catheterization than others. VURD syndrome does not confer protection against poorer bladder function. Instead, our study suggests an independent association between kidney dysplasia and bladder outcomes which requires further attention. CONCLUSIONS: Among boys with PUV, VURD syndrome was not associated with significantly different uroflowmetry findings or rates of CIC by last follow-up.

Assessing the role of upside-down (inverted) renal allografts in pediatric kidney transplantation: a propensity-score matched analysis.

OBJECTIVE: To evaluate the implications of inverted (upside-down) kidney configuration in pediatric renal transplantation employing a comparative analysis with at least 1-year follow-up. METHODS: Patients who underwent kidney transplantation at our institution between January 2011 and June 2021 were reviewed. Patients who had an inverted renal transplant were propensity-score matched (PSM) in 1:2 ratio with those who had traditional orientation transplant. The outcomes assessed included delayed graft function (DGF), urine leak, lymphocele, rejection, allograft calculus, ureteric stricture, and nadir creatinine. RESULTS: A total of 24 patients with inverted orientation were identified. Following PSM, 41 patients were matched, with exclusions due to incompatible propensity scores. Baseline characteristics were appropriately matched, and no significant differences were noted between the two groups. There were no differences in: delayed graft function (0/24 vs. 3/41, p = 0.290), urine leak (3/24 vs. 2/41, p = 0.350), lymphocele (2/24 vs. 4/41, p = 1.000), rejection (3/24 vs. 5/41, p = 1.000), graft calculus (2/24 vs. 0/41, p = 0.133), and ureteric stricture (0/24 vs. 2/41, p = 0.527). The two cases of renal calculus seen in the inverted transplant group occurred on post-operative day 13 and 1584, both were managed without complications. There was no difference in nadir creatinine (median 34umol/L IQR23-57 vs. 35 umol/L IQR 20-50, p = 0.624) or time to nadir creatinine (8 days IQR 6-12 vs. 8 days IQR 7-28, p = 0.315). CONCLUSION: Inverting a renal allograft does not appear to significantly contribute to increased risk of post-operative adverse outcomes. When aiming to achieve the best anatomical placement to secure a comfortable vascular anastomosis, inverting the allograft should be considered.

Sentinel lymph node biopsy for head and neck cutaneous squamous cell carcinoma using the Brigham and Women's staging system: a cost analysis.

The objective is to determine the cost-effectiveness of sentinel lymph node biopsy (SLNB) for cutaneous squamous cell carcinoma (CSCC) according to the Brigham and Women's Hospital (BWH) Tumor Staging system. A decision analysis was utilized to examine costs and outcomes associated with the use of SLNB in patients with high-risk head and neck CSCC. Decision tree outcome probabilities were obtained from published literature. Costs were derived from Medicare reimbursement rates (US$) and effectiveness was represented by quality-adjusted life-years (QALYs). The primary outcome was the incremental cost-effectiveness ratio (ICER), with a willingness-to-pay set at $100,000 per QALY gained. SLNB was found to be a cost-effective tool for patients with T3 tumors, with an ICER of $18,110.57. Withholding SLNB was the dominant strategy for both T2a and T2b lesions, with ICERs of - $2468.99 and - $16,694.00, respectively. Withholding SLNB remained the dominant strategy when examining immunosuppressed patients with T2a or T2b lesions. In patients with head and neck CSCC, those with T3 or T2b lesions with additional risk factors not accounted for in the staging system alone, may be considered for SLNB, while in other tumor stages it may be impractical. SLNB should only be offered on an individual patient basis.

Deep Learning-Based Model for Identifying Tumors in Endoscopic Images From Patients With Locally Advanced Rectal Cancer Treated With Total Neoadjuvant Therapy.

BACKGROUND: A barrier to the widespread adoption of watch-and-wait management for locally advanced rectal cancer is the inaccuracy and variability of identifying tumor response endoscopically in patients who have completed total neoadjuvant therapy (chemoradiotherapy and systemic chemotherapy). OBJECTIVE: This study aimed to develop a novel method of identifying the presence or absence of a tumor in endoscopic images using deep convolutional neural network-based automatic classification and to assess the accuracy of the method. DESIGN: In this prospective pilot study, endoscopic images obtained before, during, and after total neoadjuvant therapy were grouped on the basis of tumor presence. A convolutional neural network was modified for probabilistic classification of tumor versus no tumor and trained with an endoscopic image set. After training, a testing endoscopic imaging set was applied to the network. SETTINGS: The study was conducted at a comprehensive cancer center. PATIENTS: Images were analyzed from 109 patients who were diagnosed with locally advanced rectal cancer between December 2012 and July 2017 and who underwent total neoadjuvant therapy. MAIN OUTCOME MEASURES: The main outcomes were accuracy of identifying tumor presence or absence in endoscopic images measured as area under the receiver operating characteristic for the training and testing image sets. RESULTS: A total of 1392 images were included; 1099 images (468 of no tumor and 631 of tumor) were for training and 293 images (151 of no tumor and 142 of tumor) for testing. The area under the receiver operating characteristic for training and testing was 0.83. LIMITATIONS: The study had a limited number of images in each set and was conducted at a single institution. CONCLUSIONS: The convolutional neural network method is moderately accurate in distinguishing tumor from no tumor. Further research should focus on validating the convolutional neural network on a large image set. See Video Abstract at http://links.lww.com/DCR/B959 . MODELO BASADO EN APRENDIZAJE PROFUNDO PARA IDENTIFICAR TUMORES EN IMGENES ENDOSCPICAS DE PACIENTES CON CNCER DE RECTO LOCALMENTE AVANZADO TRATADOS CON TERAPIA NEOADYUVANTE TOTAL: ANTECEDENTES:Una barrera para la aceptación generalizada del tratamiento de Observar y Esperar para el cáncer de recto localmente avanzado, es la imprecisión y la variabilidad en la identificación de la respuesta tumoral endoscópica, en pacientes que completaron la terapia neoadyuvante total (quimiorradioterapia y quimioterapia sistémica).OBJETIVO:Desarrollar un método novedoso para identificar la presencia o ausencia de un tumor en imágenes endoscópicas utilizando una clasificación automática basada en redes neuronales convolucionales profundas y evaluar la precisión del método.DISEÑO:Las imágenes endoscópicas obtenidas antes, durante y después de la terapia neoadyuvante total se agruparon en base de la presencia del tumor. Se modificó una red neuronal convolucional para la clasificación probabilística de tumor versus no tumor y se entrenó con un conjunto de imágenes endoscópicas. Después del entrenamiento, se aplicó a la red un conjunto de imágenes endoscópicas de prueba.ENTORNO CLINICO:El estudio se realizó en un centro oncológico integral.PACIENTES:Analizamos imágenes de 109 pacientes que fueron diagnosticados de cáncer de recto localmente avanzado entre diciembre de 2012 y julio de 2017 y que se sometieron a terapia neoadyuvante total.PRINCIPALES MEDIDAS DE VALORACION:La precisión en la identificación de la presencia o ausencia de tumores en imágenes endoscópicas medidas como el área bajo la curva de funcionamiento del receptor para los conjuntos de imágenes de entrenamiento y prueba.RESULTADOS:Se incluyeron mil trescientas noventa y dos imágenes: 1099 (468 sin tumor y 631 con tumor) para entrenamiento y 293 (151 sin tumor y 142 con tumor) para prueba. El área bajo la curva operativa del receptor para entrenamiento y prueba fue de 0,83.LIMITACIONES:El estudio tuvo un número limitado de imágenes en cada conjunto y se realizó en una sola institución.CONCLUSIÓN:El método de la red neuronal convolucional es moderadamente preciso para distinguir el tumor de ningún tumor. La investigación adicional debería centrarse en validar la red neuronal convolucional en un conjunto de imágenes mayor. Consulte Video Resumen en http://links.lww.com/DCR/B959 . (Traducción -Dr. Fidel Ruiz Healy ).

Characteristics of Mismatch Repair-Deficient Colon Cancer in Relation to Mismatch Repair Protein Loss, Hypermethylation Silencing, and Constitutional and Biallelic Somatic Mismatch Repair Gene Pathogenic Variants.

BACKGROUND: Mismatch repair-deficient colon cancer is heterogeneous. Differentiating inherited constitutional variants from somatic genetic alterations and gene silencing is important for surveillance and genetic counseling. OBJECTIVE: This study aimed to determine the extent to which the underlying mechanism of loss of mismatch repair influences molecular and clinicopathologic features of microsatellite instability-high colon cancer. DESIGN: This is a retrospective analysis. SETTINGS: This study was conducted at a comprehensive cancer center. PATIENTS: Patients with microsatellite instability-high colon cancer of stage I, II, or III were included. INTERVENTION: Patients underwent a curative surgical resection. MAIN OUTCOME MEASURES: The main outcome measures were hypermethylation of the MLH1 promoter, biallelic inactivation, constitutional pathogenic variants, and loss of specific mismatch repair proteins. RESULTS: Of the 157 identified tumors with complete genetic analysis, 66% had hypermethylation of the MLH1 promoter, 18% had constitutional pathogenic variants, (Lynch syndrome), 11% had biallelic somatic mismatch repair gene pathogenic variants, and 6% had unexplained high microsatellite instability. The distribution of mismatch repair loss was as follows: MLH1 and PMS2 co-loss, 79% of the tumors; MSH2 and MSH6 co-loss, 10%; MSH6 alone, 3%; PMS2 alone, 2%; other combinations, 2%; no loss, 2%. Tumor mutational burden was lowest in MLH1- and PMS2-deficient tumors. MSH6-deficient tumors had the lowest levels of tumor-infiltrating lymphocytes, lowest MSI scores, and fewest frameshift deletions. Patients with MLH1 promoter hypermethylation were significantly more likely to be older and female and to have right-sided colon lesions than patients with biallelic inactivation. Mutation was the most prevalent second hit in tumors with biallelic inactivation and tumors of patients with Lynch syndrome. LIMITATIONS: This study was limited by potential selection or referral bias, missing data for some patients, and relatively small sizes of some subgroups. CONCLUSIONS: Clinical characteristics of mismatch repair-deficient colon cancer vary with the etiology of microsatellite instability, and its molecular characteristics vary with the affected mismatch repair protein. See Video Abstract at http://links.lww.com/DCR/B984 . CARACTERSTICAS DEL CNCER DE COLON CON DEFICIENCIA EN LA REPARACIN DE ERRORES DE EMPAREJAMIENTO EN RELACIN CON LA PRDIDA DE PROTENAS MMR, SILENCIAMIENTO DE LA HIPERMETILACIN Y LAS VARIANTES PATGENAS SOMTICAS DE GENES MMR CONSTITUCIONAL Y BIALLICO: ANTECEDENTES:El cáncer de colon deficiente en la reparación de errores de emparejamiento es heterogéneo. La diferenciación de las variantes constitucionales heredadas de las alteraciones genéticas somáticas y el silenciamiento de genes es importante para la vigilancia y el asesoramiento genético.OBJETIVO:Determinar hasta qué punto el mecanismo subyacente de pérdida de reparación de desajustes influye en las características moleculares y clinicopatológicas del cáncer de colon con alta inestabilidad de microsatélites.DISEÑO:Análisis retrospectivo.ESCENARIO:Centro integral de cáncer.PACIENTES:Pacientes con cáncer de colon con inestabilidad de microsatélites alta en estadio I, II, o III.INTERVENCIÓN:Resección quirúrgica con intención curativa.PRINCIPALES RESULTADOS Y MEDIDAS:Hipermetilación del promotor MLH1, inactivación bialélica, variante patógena constitucional y pérdida de proteínas específicas reparadoras de desajustes.RESULTADOS:De los 157 tumores identificados con un análisis genético completo, el 66 % tenía hipermetilación del promotor MLH1, el 18 % tenía una variante patogénica constitucional (síndrome de Lynch), el 11 % tenía variantes patogénicas somáticas bialélicas de algún gen MMR y el 6 % tenía una alta inestabilidad de microsatélites sin explicación. La distribución de la pérdida según la proteína de reparación del desajuste fue la siguiente: pérdida conjunta de MLH1 y PMS2, 79 % de los tumores; co-pérdida de MSH2 y MSH6, 10%; MSH6 solo, 3%; PMS2 solo, 2%; otras combinaciones, 2%; sin pérdida, 2%. La carga mutacional del tumor fue más baja en los tumores deficientes en MLH1 y PMS2. Los tumores con deficiencia de MSH6 tenían los niveles más bajos de linfocitos infiltrantes de tumores, las puntuaciones más bajas del sensor de IMS y la menor cantidad de deleciones por cambio de marco. Los pacientes con hipermetilación del promotor MLH1 tenían significativamente más probabilidades de ser mayores y mujeres y de tener lesiones en el colon derecho que los pacientes con inactivación bialélica. La mutación fue el segundo golpe más frecuente en tumores con inactivación bialélica y tumores de pacientes con síndrome de Lynch.LIMITACIONES:Sesgo potencial de selección o referencia, datos faltantes para algunos pacientes y tamaños relativamente pequeños de algunos subgrupos.CONCLUSIONES:Las características clínicas del cáncer de colon deficiente en reparación de desajustes varían con la etiología de la inestabilidad de microsatélites, y sus características moleculares varían con la proteína de reparación de desajustes afectada. Vea Resumen de video en http://links.lww.com/DCR/B984 . (Traducción-Dr. Felipe Bellolio ).

Nephron-sparing surgery for renal cell carcinoma in children and young adults: A systematic review.

OBJECTIVE: To determine the patient characteristics and role of nephron-sparing surgery (NSS) in the treatment of children and young adults with renal cell carcinoma (RCC). METHODS: A systematic search of Embase, MEDLINE, and Scopus databases was conducted in December 2021 according to Cochrane collaboration recommendations. All included manuscripts were assessed for patient characteristics and all reported outcomes for patients undergoing partial nephrectomy (PN), and radical nephrectomy (RN) outcomes were abstracted as a comparison group. Primary outcomes included surgical outcomes, overall survival, kidney outcomes. Outcomes were pooled with weighted mean and ranges. Meta-analysis was not performed given study quality. This systematic review was prospectively registered on PROSPERO (CRD42022300261). RESULTS: We found a total of 16 studies describing 119 and 559 unique patients undergoing PN and RN, respectively, with a mean age of 12.2 years and mean follow-up of 59.1 months. The mean tumor size for patients undergoing PN was 3.5 cm. Of the 113 patients undergoing PN with available data, 109 were alive at follow-up (98%). No studies reported long-term kidney outcomes, and four studies reported surgical outcomes. All studies had at least moderate risk of bias. CONCLUSIONS: The use of NSS in children and young adults with RCC is feasible in selected patients. However, small sample sizes, confounding, and low study quality limit clinical recommendation on NSS in this population. There are significant opportunities for future research on the use of NSS in RCC, especially with systematic reporting of oncological, kidney, and surgical outcomes.

Sensitisation of cancer cells to radiotherapy by serine and glycine starvation.

BACKGROUND: Cellular metabolism is an integral component of cellular adaptation to stress, playing a pivotal role in the resistance of cancer cells to various treatment modalities, including radiotherapy. In response to radiotherapy, cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism, we hypothesised that controlling the exogenous availability of the non-essential amino acids serine and glycine would radiosensitise cancer cells. METHODS: We exposed colorectal, breast and pancreatic cancer cell lines/organoids to radiation in vitro and in vivo in the presence and absence of exogenous serine and glycine. We performed phenotypic assays for DNA damage, cell cycle, ROS levels and cell death, combined with a high-resolution untargeted LCMS metabolomics and RNA-Seq. RESULTS: Serine and glycine restriction sensitised a range of cancer cell lines, patient-derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic and transcriptomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only antioxidant response and nucleotide synthesis but had a marked inhibitory effect on the TCA cycle. CONCLUSION: Dietary restriction of serine and glycine is a viable radio-sensitisation strategy in cancer.

A Dynamic Clinical Calculator for Estimating Conditional Recurrence-Free Survival After Total Neoadjuvant Therapy for Rectal Cancer and Either Surgery or Watch-and-Wait Management.

Importance: The risk of recurrence in patients with locally advanced rectal cancer has historically been determined after surgery, relying on pathologic variables. A growing number of patients are being treated without surgery, and their risk of recurrence needs to be calculated differently. Objective: To develop a dynamic calculator for estimating the probability of recurrence-free survival (RFS) in patients with rectal cancer who undergo total neoadjuvant therapy (TNT) (induction systemic chemotherapy and chemoradiotherapy) and either surgery or watch-and-wait management. Design, Setting, and Participants: This cohort study included patients who presented with stage II or III rectal cancer between June 1, 2009, and March 1, 2015, at a comprehensive cancer center. Conditional modeling was incorporated into a previously validated clinical calculator to allow the probability of RFS to be updated based on whether the patient remained in watch-and-wait management or underwent delayed surgery. Data were analyzed from November 2021 to March 2022. Exposure: TNT followed by immediate surgery or watch-and-wait management with the possibility of delayed surgery. Main Outcomes and Measures: RFS, concordance index, calibration curves. Results: Of the 302 patients in the cohort, 204 (68%) underwent surgery within 3 months from TNT completion (median [range] age, 51 [22-82] years; 78 [38%] women), 54 (18%) underwent surgery more than 3 months from TNT completion (ie, delayed surgery; median [range] age, 62 [31-87] years; 30 [56%] female), and 44 (14%) remained in watch-and-wait management as of April 21, 2021 (median [range] age, 58 [32-89] years; 16 [36%] women). Among patients who initially opted for watch-and-wait management, migration to surgery due to regrowth or patient choice occurred mostly within the first year following completion of TNT, and RFS did not differ significantly whether surgery was performed 3.0 to 5.9 months (73%; 95% CI, 52%-92%) vs 6.0 to 11.9 months (71%; 95% CI, 51%-99%) vs more than 12.0 months (70%; 95% CI, 49%-100%) from TNT completion (P = .70). RFS for patients in the watch-and-wait cohort at 12 months from completion of TNT more closely resembled patients who had undergone surgery and had a pathologic complete response than the watch-and-wait cohort at 3 months from completion of TNT. Accordingly, model performance improved over time, and the concordance index increased from 0.62 (95% CI, 0.53-0.71) at 3 months after TNT to 0.66 (95% CI, 0-0.75) at 12 months. Conclusions and Relevance: In this cohort study of patients with rectal cancer, the clinical calculator reliably estimated the likelihood of RFS for patients who underwent surgery immediately after TNT, patients who underwent delayed surgery after entering watch-and-wait management, and patients who remained in watch-and-wait management. Delayed surgery following attempted watch-and-wait did not appear to compromise oncologic outcomes. The risk calculator provided conditional survival estimates at any time during surveillance and could help physicians counsel patients with rectal cancer about the consequences of alternative treatment pathways and thereby support informed decisions that incorporate patients' preferences.

Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer.

The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.

Comparison of continuous and interrupted suture techniques in pyeloplasty: a systematic review and meta-analysis.

Pelvi-ureteric anastomosis is a critical step to ensure good outcome of pyeloplasty. Continuous suturing technique, especially for laparoscopic surgeries, may offer faster operative time while allowing water-tight anastomosis and remains an alternative to interrupted suturing technique. There has been mixed data on comparison of outcomes of continuous and interrupted suturing techniques. This systematic review and meta-analysis aim to assess the outcomes of pyeloplasty based on continuous and interrupted suturing techniques. Following protocol registration on PROSPERO (CRD42021269706), a systematic review was performed in accordance with Cochrane Collaboration. A literature search was performed in September 2021 across Medline, EMBASE, Scopus, Cochrane Library, and ClinicalTrials.gov. Records comparing pyeloplasty outcomes between continuous and interrupted suture techniques were included. Five studies were identified for inclusion (2 prospective, 3 retrospective). Three studies involved pediatric patients. Three studies exclusively assessed laparoscopic technique. Four outcomes were meta-analyzed: operative time, length of stay, complications, and pyeloplasty failure. Interrupted sutures had longer OR time (mean difference 33.14 min [95% CI 29.35-36.94], p < 0.0001) and length of stay (mean difference 1.08 days [95% CI 0.84-1.32], p < 0.0001). However, there were similar complication (OR 1.73 [95% CI 0.98-3.06], p = 0.06) and failure rates (OR 1.21 [95% CI 0.43-3.43], p = 0.71) between the two suture types. The overall risk of bias in the studies was high. While limited by the number of studies available, continuous sutures for pelvi-ureteric anastomosis appear to confer benefits of faster operative time and decreased length of stay without increasing complication rates or failures.

Attaining competency and proficiency in open pyeloplasty: a learning curve configuration using cumulative sum analysis.

INTRODUCTION: The learning curves for minimally invasive pyeloplasty techniques have been described in the past. However, the learning curve in achieving competency in open pyeloplasty has not been described. Hence, we aim to evaluate a single surgeon series of open pyeloplasty technique using the cumulative sum (CUSUM) methodology. METHODS: We retrospectively reviewed all open pyeloplasties performed by a single surgeon (AJL) between January 2008 and March 2020. Collected variables included: sex, age at surgery, operative time, hospital stay, pre-operative ultrasound, pre-operative nuclear scans, pre-operative anteroposterior diameter, associated anomalies, laterality (left or right), type of stent, pre-operative split renal function, and duration of follow-up. A CUSUM analysis was used: the highest peak, plateau and downward trends for complications (defined as Clavien-Dindo classification ≥ 3b) were identified on the plot and set as the transition points between five phases (learning, competency, proficiency, case-mix, and mastery). RESULTS: Based on the CUSUM analysis, the index surgeon reached the competency phase after performing their 13th open pyeloplasty and became proficient after the 70th case. In the case-mix phase (104th-126th cases), where the surgeon may be performing more complex cases while increasing trainee involvement, there was a slight increase in complication rates. After the 126th case, the surgeon entered the mastery phase, where there was consistent decreasing trend in complications. CONCLUSIONS: Surgeons performing open pyeloplasty in children following completion of their surgical training will continue to learn through their early cases until achieving competency. Technical competency may be reached after the 13th case. In this report, we looked at the number of cases to become proficient in open pyeloplasty procedure in children. A surgeon may achieve technical proficiency in the procedure after their 13th case.

Intratumoral T-cell repertoires in DNA mismatch repair-proficient and -deficient colon tumors containing high or low numbers of tumor-infiltrating lymphocytes.

Colon tumors with deficient DNA mismatch repair (dMMR) are generally infiltrated by T cells more densely than tumors with proficient mismatch repair (pMMR). However, high numbers of tumor-infiltrating lymphocytes (TILs) are found in select pMMR tumors, and low numbers of TILs are seen in select dMMR tumors. In this study, we compared T-cell repertoires in 20 pMMR and 27 dMMR colon tumors with high and low TIL counts. We found that T cells in dMMR tumors are more clonal and their repertoire is less rich compared with T cells in pMMR tumors. In the dMMR group, T cells in TIL-high tumors were more clonal and their repertoire was less rich compared with T cells in TIL-low tumors, but in the pMMR group, T-cell diversity in TIL-high tumors was comparable to T-cell diversity in TIL-low tumors. These findings suggest that T cells clonally expand in dMMR tumors, possibly in response to MMR deficiency-induced tumor neoantigens.

Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy.

PURPOSE: Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited. METHODS: In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival. RESULTS: Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates. CONCLUSION: Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.