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Introduction: Colorectal cancer is a leading cause of cancer mortality in the USA and occurs most frequently in older adults. These patients are at increased risk of adverse outcomes following major cancer surgery. While prehabilitation has been shown to mitigate this risk, multiple barriers to implementation remain. Our team created a digital tool co-designed with older adults that employs an algorithm to assess patient-specific geriatric vulnerabilities and generate personalised prehabilitation programmes before surgery., Methods and Analysis: We have designed a multisite, unblinded randomised trial to be completed at three high-volume academic cancer centres located in California or Texas. Our study population is individuals aged 65 and older with planned colorectal cancer resection who are proficient in English and have home internet access. We aim to enroll 132 patients who will be randomised in a 2:1 ratio to receive the intervention (assistance from a home health coach and access to the web application (web app)) or control (usual care with written prehabilitation materials). Our primary outcome is patient engagement with prehabilitation activities., Ethics and Dissemination: A properly executed, written, informed consent will be obtained from each subject prior to entering the subject into the trial. Information will be given in both oral and written form, and subjects may withdraw at any time from the study without effect on their medical care. The protocol and consent form have been approved by the Institutional Review Board (IRB) of each participating centre. We anticipate publication of results in a peer-reviewed journal., Trial Registration Number: NCT05520866., Competing Interests: Competing interests: EF is a co-creator of content for PrehabPal and a co-founder of Ooney INC. As such, a conflict of interest (COI) plan was developed by the Conflict-of-Interest Advisory Committee by the UCSF Office of Ethics and Compliance. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.) more...

Background: Among patients with rectal cancer who achieve a complete clinical response (cCR) after neoadjuvant therapy and undergo nonoperative management (NOM), a subset experience tumor regrowth and require salvage surgery. We sought to identify clinicopathologic factors associated with tumor regrowth to assist in patient selection for NOM., Methods: Patients treated for rectal cancer at a single National Cancer Institute (NCI)-designated Comprehensive Cancer Center in whom NOM was pursued based on cCR or near-cCR were identified. Patients were stratified based on whether they developed tumor regrowth during follow-up. Tumor and treatment details were compared to identify factors affecting regrowth-free survival (RFS)., Results: Among 125 patients, 26 (20.8%) experienced local regrowth and 8 (6.4%) experienced distant metastasis at a median follow-up of 35 months. Extramural vascular invasion (EMVI) and clinically positive pelvic sidewall lymph nodes (PSW) were associated with worse RFS (hazard ratio [HR] 2.48, 95% confidence interval [CI] 1.08-5.72, p = 0.03; HR 2.77, 95% CI 1.16-6.61, p = 0.002). Among 107 patients eligible for post hoc endoscopic evaluation, those with cCR (n = 80) at first endoscopic re-evaluation had trended towards higher RFS than those with near-cCR (n = 27; HR 2.12, 95% CI 0.95-4.75, p = 0.07), with a significant difference in patients without regrowth at 1 year (HR 5.58, 95% CI 1.23-25.32, p = 0.03)., Conclusions: Rectal cancer patients with high-risk magnetic resonance imaging (MRI) features, namely EMVI and positive PSW nodes, are more likely to experience tumor regrowth despite an excellent clinical response. Patients with a near-complete endoscopic response may also be at higher risk of later regrowth. The decision to attempt NOM should be carefully weighed against the increased risk of tumor regrowth., Competing Interests: Disclosures: Oliver Peacock is a Proctor for Device Technology/Intuitive. Abhineet Uppal has received honorarium from Bayer Pharmaceuticals, 9/2022. Neal Bhutiani, Kentaro Ochiai, Y. Nancy You, Brian K. Bednarski, Craig Messick, John M. Skibber, Michael G. White, George J. Chang, and Tsuyoshi Konishi have no conflicts of interest to declare that may be relevant to the contents of this study., (© 2025. Society of Surgical Oncology.) more...

Introduction: Extramural vascular invasion (EMVI) is associated with distant recurrence after treatment of locogionally advanced rectal adenocarcinomas (LARCs), but its use as a marker for response to neoadjuvant therapy is less well understood. We examined the relationship between EMVI and tumor or nodal category downstaging after treatment of LARCs with neoadjuvant therapy., Methods: Patients with EMVI categorized on initial staging pelvic MRI for LARC who underwent curative-intent surgery after neoadjuvant therapy at MD Anderson Cancer Center from 2016 to 2022 were identified. Patients received either preoperative chemoradiation or total neoadjuvant therapy (TNT). Associations between EMVI and demographic, radiologic, and clinicopathologic variables were analyzed., Results: EMVI was associated with higher rates of lymphovascular invasion (LVI) (46.2% vs. 27.8%, P = .001) and perineural invasion (PNI) (51.9% vs. 28.4%, P < .001) on final pathology. Patients with EMVI were more likely to have cT4 tumors (31.7% vs. 16.3%, P = .004) and cN+ status (86.8% vs. 66.3%, P = .001) and more likely to be treated with TNT rather than chemoradiation alone (62.3% vs. 41.9%, P = .005). EMVI was associated with a lower rate of pathologic complete or near-complete response (20.1% vs. 34.2%, P = .018), downstaging to ypT0-2 from cT3/4 tumors (14.9% vs. 44.4%, P = .0001), and downstaging to ypN0 from cN+ status (47.9% vs. 66.4%, P = .015)., Conclusions: Rectal tumors with EMVI are more likely to have higher clinical stage, less likely to respond to neoadjuvant therapy despite increased use of TNT, and more likely to have high-risk features for recurrence. This suggests EMVI is a marker of disease with poorer response to neoadjuvant therapy. Disease biology should be strongly considered in treatment decision-making, and new treatment strategies are needed to improve disease response., Competing Interests: Disclosure John-Paul Shen Consulting / Stock ownership: Engine Biosciences, NaDeNo Nanoscience. Intellectual Property – Patents and Copyrights: SMALL MOLECULE FOR TREATMENT OF CANCER OF THE APPENDIX. Filed July 17, 2023, PCT/US2023/027939., (Copyright © 2025 Elsevier Inc. All rights reserved.) more...

Background: While detection of circulating tumor DNA (ctDNA) weeks after surgery is linked to recurrence for other solid tumors, the optimal time point for ctDNA assessment as a prognostic biomarker following chemoradiation for anal cancer is undefined., Methods: Patients with stages I-III anal cancer treated with chemoradiation between 12/2020-5/2024 were evaluated for HPV ctDNA status at baseline, at the end of chemoradiation, and during surveillance using a droplet digital HPV ctDNA PCR assay targeting HPV E6 and E7 oncogenes for 13 oncogenic HPV types. Median recurrence-free survival (RFS) according to HPV ctDNA status was estimated via Kaplan-Meier and compared using a log-rank test., Results: Detection of HPV ctDNA at ≥3 months after chemoradiation was associated with recurrence (80% versus 2%; odds ratio 168, 95% CI 13.6-2080; p<.0001) and inferior RFS (4.9 months versus not reached (NR); hazard ratio (HR) 39.2, 95% CI 4.6-330; p<.0001) relative to HPV ctDNA-negative status. Sensitivity and specificity for recurrence according to HPV ctDNA detection were 89% and 95%, respectively, with positive and negative predictive values of 80% and 98%, respectively. Differences in RFS according to HPV ctDNA status were not observed at the end of treatment (median RFS NR for both; HR 1.6, 95% CI .35-7.4; p=.48)., Conclusions: With a novel, highly sensitive assay, detection of HPV ctDNA at least 3 months after chemoradiation was associated with unfavorable survival. Future clinical trials should incorporate this 3-month post-treatment time point to identify patients with HPV-positive anal cancer at elevated recurrence risk according to HPV ctDNA status. more...

Background: Minimally invasive surgery is associated with improved short-term outcomes and similar long-term oncologic outcomes for colorectal cancer patients compared with open surgery. Although the robotic approach has ergonomic and technical benefits, how it has impacted utilization of traditional laparoscopic surgery and minimally invasive surgery overall is unclear., Objective: Describe trends in open, robotic, and laparoscopic approaches for colorectal cancer resections and examine factors associated with minimally invasive surgery., Design: Retrospective cohort study using data from the National Cancer Database from 2010 through 2020., Setting: Commission on Cancer-accredited U.S. facilities., Patients: Patients diagnosed with nonmetastatic colon or rectal adenocarcinoma., Main Outcomes Measures: Surgical approach rates (open, robotic, laparoscopic)., Results: We identified 475,001 patients diagnosed with nonmetastatic colorectal adenocarcinoma, of whom 192,237 (40.5%) underwent open surgery, 64,945 (13.7%) underwent robotic surgery, and 217,819 (45.9%) underwent laparoscopic surgery. For colon cancer, laparoscopic minimally invasive surgery use steadily increased, with a peak prevalence of 54.0% in 2016, and total minimally invasive surgery (robotic + laparoscopic) was performed more often than open surgery from 2013 through 2020. For rectal cancer, laparoscopic minimally invasive surgery had a peak prevalence of 37.2% in 2014 and declined from 2014 through 2020; robotic surgery prevalence increased throughout the study period (5.5% in 2010, 24.7% in 2015, 48.8% in 2020). Minimally invasive surgery use increased in facilities performing robotic surgery every year during the study period. For both colon and rectal cancer, use of open surgery decreased across all facilities throughout the study period., Limitations: Utilized National Cancer Database which may not be generalizable to non-Commission on Cancer institutions., Conclusions: Minimally invasive surgery steadily increased across all facilities from 2010 through 2020. Open resections declined, laparoscopic resections plateaued, and robotic resections increased for colon and rectal cancer. Minimally invasive surgery increases may be driven by increases in robot-assisted surgery. See Video Abstract., Competing Interests: Financial Disclosures: The authors have no conflicts of interest to report. This study has not been previously presented or published., (Copyright © The ASCRS 2025.) more...

Background: Current American Joint Committee on Cancer (AJCC) staging for colorectal cancer utilizes TNM framework groups disease based on extent and provides prognostic information, ideally with a hierarchical logic. We sought to evaluate survival as a function of stage within the 8 th edition AJCC staging system for colon and rectal cancer., Methods: Patients with primary colon or rectal cancer diagnosed 2010-2016 were identified from the National Cancer Database (NCDB). Survival curves were used to determine staging hierarchy for colon and rectal cancer. Multivariable modeling was used to identify relative contributions of variables (z-score) to survival, and hazard ratio (HR)-based groupings were constructed., Results: Among 270,584 colon and 53,846 rectal cancer patients, AJCC summary staging was non-hierarchical (e.g. HR IIC=2.92, HR IIIA=0.85-1.31). Multivariable analysis demonstrated high T category (T4a, T4b) confers the greatest mortality (colon: T4a HR 2.76, T4b HR 3.04; rectum: T4a HR 3.29, T4b HR 3.73), while high T category as well as high N category (colon: T4a z=66.9, T4b z=64.6, N2b z=55.7; rectum: T4b z=31.1, N2b z=25.1) contributed substantially to the survival model. HR based TN groupings resulted in hierarchical stage organization., Conclusions: Current AJCC stage groups for colorectal cancer are non-hierarchical. High T category has a greater impact on survival than N category for patients with early N disease, while high N category was more important for patients with early T disease. An organizational framework based on HR groupings is hierarchical and provides more accurate prognostic information., Competing Interests: Disclosure GJC serves as an advisor for Iota Biosciences, Medicaroid, Medtronic, and Tempus. JC and BP are employed by the American College of Surgeons, which serves as administrator for the National Cancer Database. QS reports consulting/advisory role from Yivira, Inc, Regeneron Pharmaceuticals, Inc, Hoosier Cancer Research Network, Kronos Bio, and Mirati Therapeutics as well as research funds from Regeneron, BMS, Roche/Genentech, Janssen, Novartis, and MPAACT to her institution. All the other authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

Background: The identification of tumor deposits (TD) currently plays a limited role in staging for colorectal cancer (CRC) aside from N1c lymph node designation. The objective of this study was to determine the prognostic impact, beyond American Joint Committee on Cancer N1c designation, of TDs among patients with primary CRC., Methods: Patients who had resected stage I-III primary CRC diagnosed between 2010 and 2019 were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Cancer-specific survival (CSS) stratified by TD status and lymph node (N) status was calculated using the Kaplan-Meier method and multivariable Cox proportional hazards regression analyses., Results: In total, 147,783 patients with primary CRC were identified. TDs were present in 15,444 patients (10.5%). The presence of TDs was significantly associated with adverse tumor characteristics, including advanced pathologic stage, nodal status, and metastasis status. The presence of TDs was associated with worse CSS (hazard ratio [HR], 3.12; 95% confidence interval [CI], 3.02-3.22), as it was for each given N category (e.g., N2a and TD-negative [HR, 2.50; 95% CI, 2.37-2.64] vs. N2a and TD-positive [HR, 3.75; 95% CI, 3.49-4.03]). The presence of multiple TDs was also associated with decreased CSS for each given N category compared with a single TD (e.g. N2a with one TD [HR, 3.09; 95% CI, 2.65-3.61] vs. N2a with two or more TDs [HR, 4.32; 95% CI, 3.87-4.82])., Conclusions: TDs were identified as an independent predictor of a worse outcome in patients with CRC. The presence of TDs confers distinctly different CSS and provides important prognostic information among patients with CRC and warrants further investigation as a unique variable in future iterations of CRC staging., (© 2024 American Cancer Society.) more...

With improved medical treatments, the prognosis for many malignancies has improved, and more patients are presenting for transplant evaluation with a history of treated cancer. Solid organ transplant (SOT) recipients with a prior malignancy are at higher risk of posttransplant recurrence or de novo malignancy, and they may require a cancer surveillance program that is individualized to their specific needs. There is a dearth of literature on optimal surveillance strategies specific to SOT recipients. A working group of transplant physicians and cancer-specific specialists met to provide expert opinion recommendations on optimal cancer surveillance after transplantation for patients with a history of malignancy. Surveillance strategies provided are mainly based on general population recurrence risk data, immunosuppression effects, and limited transplant-specific data and should be considered expert opinion based on current knowledge. Prospective studies of cancer-specific surveillance models in SOT recipients should be supported to inform posttransplant management of this high-risk population., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.) more...

Background: Posttreatment surveillance affects millions of cancer survivors, but empiric data to guide clinical practice are lacking. This study assessed whether the intensity of surveillance testing after radical prostatectomy or radiation therapy for localized prostate cancer is associated with overall survival., Methods: Men diagnosed with localized prostate cancer between 2005 and 2010 who underwent radical prostatectomy or radiation therapy at a Commission on Cancer-accredited facility were randomly sampled. Primary data collected from 10 147 patients sampled across 1007 facilities were linked with existing data from the National Cancer Database. Analysis examined whether intensity of surveillance measured as the number of prostate-specific antigen (PSA) tests in the first year after primary treatment (categorized as 0-1 [low intensity], 2 [medium], or ≥3 [high intensity] PSA tests) was associated with overall survival. Secondary outcomes included recurrence-free survival (RFS) and subsequent use of imaging tests, biopsy procedures, and salvage treatment., Results: Median follow-up exceeded 8 years from prostate cancer diagnosis. Overall survival was not statistically significantly different across surveillance intensity groups among radiation therapy (P = .59) or radical prostatectomy (P = .29) patients. RFS was not statistically significantly different across surveillance intensity groups for radiation therapy (P = .13) patients but was for radical prostatectomy (P = .01) patients with high intensity associated with the worst RFS. In both treatments, higher surveillance intensity was associated with more procedures and salvage treatments., Conclusions: In patients with localized prostate cancer, more frequent PSA surveillance testing after radical prostatectomy or radiation therapy was associated with increased procedures and salvage treatments but not overall survival., (© The Author(s) 2024. Published by Oxford University Press.) more...

Background: Reconstruction of female oncologic peripelvic defects is challenging due to complex anatomy, neoadjuvant chemoradiation, operative resection margins, and wound healing risks. Functional restoration requires thoughtful management focused on defect reconstruction and patient-reported outcomes., Methods: A retrospective chart review of peripelvic reconstruction in female patients at MD Anderson Cancer Center from 2016 to 2023. Data collected included the patient's comorbidities, tumor characteristics, and reconstructive details. Complications were classified as nonoperative or operative within 30 days. Patient outcomes included hernia rates, sexual activity, and revision needs., Results: In the study period, 164 patients underwent peripelvic defect reconstruction. Most had colorectal (57%), anal (17%), or gynecologic malignancies (10%). 83% had prior radiation. 33.3% had Class II or III obesity. The most common resection was open colorectal resection with partial vaginectomy (66%). Pedicled flaps (93%) were frequently used, mainly vertical rectus abdominis muscle (65%) and gracilis (11%). For multi-visceral resections, abdominal-based flaps were used in 95% of open cases and thigh-based flaps in 88.9% of robotic cases. 51% had formal abdominal wall repair. Complications occurred in 47%, with 9.1% needing surgery. Postoperative hernias were reported in 4.9%, with 3% requiring repair. Approximately 11% reported being sexually active at the last follow-up. Of those instructed on vaginal dilator therapy (42%), 24.6% were sexually active., Conclusion: Peri-pelvic soft tissue reconstruction in the oncologic population is safe. Operative complications and hernia rates are low. In robotic surgery, thigh-based flaps are increasingly used to reconstruct the peripelvic region. Return to sexual activity is higher in patients when given dilator therapy instruction., (© 2024 Wiley Periodicals LLC.) more...

Objective: To assess the effect of a practice-level preoperative frailty screening and optimization toolkit (OPTI-Surg) on postoperative functional recovery and complications in elderly cancer patients undergoing major surgery., Background: Frailty is common in older adults. It increases the risk of poor postoperative functional recovery and complications. The potential for a practice-level screening/optimization intervention to improve outcomes is unknown., Methods: Thoracic, gastrointestinal, and urologic oncological surgery practices within the National Cancer Institute Community Oncology Research Program (NCORP) were randomized 1:1:1 to usual care (UC), OPTI-Surg, or OPTI-Surg with an implementation coach. OPTI-Surg consisted of the Edmonton Frail Scale and guided recommendations for referral interventions. Patients 70 years old or above undergoing curative intent surgery were eligible. The primary outcome was 8 weeks postoperative function (kcal/wk). The key secondary outcome was complications within 90 days. Mixed models were used to compare UC to the 2 OPTI-Surg arms combined., Results: From July 2019 to September 2022, 325 patients were enrolled in 29 practices. One hundred ninety-nine (64 UC, 135 OPTI-Surg) and 279 (78 UC, 201 OPTI-Surg) were evaluable for primary and secondary analysis, respectively. UC and OPTI-Surg patients did not significantly differ in total caloric expenditure (2.2 UC, 2.0 OPTI-Surg) after adjusting for baseline function ( P =0.53). UC and OPTI-Surg patients did not significantly differ in postoperative complications (25.6% UC, 35.3% OPTI-Surg, P =0.5)., Conclusions: Frailty assessment was successfully performed, but the OPTI-Surg intervention did not improve postoperative function nor reduce postoperative complications compared with UC. Future analysis will explore practice-level factors associated with toolkit implementation and the differences between the coaching and noncoaching arms., Competing Interests: E.F. is a founding shareholder of Ooney. The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.) more...

Background: Early predictors of postoperative complications can risk-stratify patients undergoing colorectal cancer surgery. However, conventional regression models have limited power to identify complex nonlinear relationships among a large set of variables. We developed artificial neural network models to optimize the prediction of major postoperative complications and risk of readmission in patients undergoing colorectal cancer surgery., Objective: This study aimed to develop an artificial neural network model to predict postoperative complications using postoperative laboratory values and compare the accuracy of models to standard regression methods., Design: This retrospective study included patients who underwent elective colorectal cancer resection between January 1, 2016, and July 31, 2021. Clinical data, cancer stage, and laboratory data from postoperative days 1 to 3 were collected. Complications and readmission risk models were created using multivariable logistic regression and single-layer neural networks., Setting: National Cancer Institute-Designated Comprehensive Cancer Center., Patients: Adult patients with colorectal cancer., Main Outcome Measures: The accuracy of predicting postoperative major complications, readmissions, and anastomotic leaks using the area under the receiver operating characteristic curve., Results: Neural networks had larger areas under the curve for predicting major complications compared to regression models (neural network 0.811; regression model 0.724, p < 0.001). Neural networks also showed an advantage in predicting anastomotic leak ( p = 0.036) and readmission using postoperative day 1 to 2 values ( p = 0.014)., Limitations: Single-center, retrospective design limited to cancer operations., Conclusions: In this study, we generated a set of models for the early prediction of complications after colorectal surgery. The neural network models provided greater discrimination than the models based on traditional logistic regression. These models may allow for early detection of postoperative complications as early as postoperative day 2. See the Video Abstract ., Prediccin Post Operatoria Temprana De Complicaciones Y Reingreso Despus De La Ciruga De Cncer Colorrectal Mediante Una Red Neuronal Artificial: ANTECEDENTES:Los predictores tempranos de complicaciones postoperatorias pueden estratificar el riesgo de los pacientes sometidos a cirugía de cáncer colorrectal. Sin embargo, los modelos de regresión convencionales tienen un poder limitado para identificar relaciones no lineales complejas entre un gran conjunto de variables. Desarrollamos modelos de redes neuronales artificiales para optimizar la predicción de complicaciones postoperatorias importantes y riesgo de reingreso en pacientes sometidos a cirugía de cáncer colorrectal.OBJETIVO:El objetivo de este estudio fue desarrollar un modelo de red neuronal artificial para predecir complicaciones postoperatorias utilizando valores de laboratorio postoperatorios y comparar la precisión de estos modelos con los métodos de regresión estándar.DISEÑO:Este estudio retrospectivo incluyó a pacientes que se sometieron a resección electiva de cáncer colorrectal entre el 1 de enero de 2016 y el 31 de julio de 2021. Se recopilaron datos clínicos, estadio del cáncer y datos de laboratorio del día 1 al 3 posoperatorio. Se crearon modelos de complicaciones y riesgo de reingreso mediante regresión logística multivariable y redes neuronales de una sola capa.AJUSTE:Instituto Nacional del Cáncer designado Centro Oncológico Integral.PACIENTES:Pacientes adultos con cáncer colorrectal.PRINCIPALES MEDIDAS DE RESULTADO:Precisión de la predicción de complicaciones mayores postoperatorias, reingreso y fuga anastomótica utilizando el área bajo la curva característica operativa del receptor.RESULTADOS:Las redes neuronales tuvieron áreas bajo la curva más grandes para predecir complicaciones importantes en comparación con los modelos de regresión (red neuronal 0,811; modelo de regresión 0,724, p < 0,001). Las redes neuronales también mostraron una ventaja en la predicción de la fuga anastomótica ( p = 0,036) y el reingreso utilizando los valores del día 1-2 postoperatorio ( p = 0,014).LIMITACIONES:Diseño retrospectivo de un solo centro limitado a operaciones de cáncer.CONCLUSIONES:En este estudio, generamos un conjunto de modelos para la predicción temprana de complicaciones después de la cirugía colorrectal. Los modelos de redes neuronales proporcionaron una mayor discriminación que los modelos basados en regresión logística tradicional. Estos modelos pueden permitir la detección temprana de complicaciones posoperatorias tan pronto como el segundo día posoperatorio. (Traducción-Dr. Mauricio Santamaria )., (Copyright © The ASCRS 2024.) more...

Background: Lateral pelvic lymph node dissection is performed for selected patients with rectal cancer with persistent lateral nodal disease after neoadjuvant therapy. This technique has been slow to be adopted in the West because of concerns regarding technical difficulty. This is the first report on the learning curve for lateral pelvic lymph node dissection in the United States or Europe., Objective: This study aimed to analyze the learning curve associated with robotic lateral pelvic lymph node dissection., Design: Retrospective observational cohort., Setting: Tertiary academic cancer center., Patients: Consecutive patients from 2012 to 2021., Intervention: All patients underwent robotic lateral pelvic lymph node dissection., Main Outcome Measures: The primary end points were the learning curves for the maximum number of nodes retrieved and urinary retention, which was evaluated with simple cumulative sum and 2-sided Bernoulli cumulative sum charts., Results: Fifty-four procedures were included. A single-surgeon learning curve (n = 35) and an institutional learning curve are presented in the analysis. In the single-surgeon learning curve, a turning point marking the end of a learning phase was detected at the 12th procedure for the number of retrieved nodes and at the 20th procedure for urinary retention. In the institutional learning curve analysis, 2 turning points were identified at the 13th procedure, indicating progressive improvements for the number of retrieved nodes, and at the 27th procedure for urinary retention. No sustained alarm signals were detected at any time point., Limitations: The retrospective nature, small sample size, and the referral center nature of the reporting institution may limit generalizability., Conclusions: In a setting of institutional experience with robotic colorectal surgery, including beyond total mesorectal excision resections, the learning curve for robotic lateral pelvic lymph node dissection is acceptably short. Our results demonstrate the feasibility of the acquisition of this technique in a controlled setting, with sufficient case volume and proctoring to optimize the learning curve. See Video Abstract., La Curva De Aprendizaje De La Diseccin Robtica De Los Ganglios Linfticos Plvicos Laterales En El Cncer De Recto Una Visin Desde Occidente: ANTECEDENTES:La disección lateral de los ganglios linfáticos pélvicos se realiza en pacientes seleccionados con cáncer de recto con enfermedad ganglionar lateral persistente tras el tratamiento neoadyuvante. La adopción de esta técnica en Occidente ha sido lenta debido a la preocupación por su dificultad técnica. Éste es el primer informe sobre la curva de aprendizaje de la disección de los ganglios linfáticos pélvicos laterales en EE.UU. o Europa.OBJETIVO:El objetivo de este estudio fue analizar la curva de aprendizaje asociada a la disección robótica de los ganglios linfáticos pélvicos laterales.DISEÑO:Cohorte observacional retrospectiva.LUGAR:Centro oncológico académico terciario.PACIENTES:Pacientes consecutivos desde 2012 al 2021.INTERVENCIÓN:Todos los pacientes fueron sometieron a disección robótica de ganglios linfáticos pélvicos laterales.PRINCIPALES MEDIDAS DE RESULTADO:Los criterios de valoración primarios fueron las curvas de aprendizaje tomando en cuenta el mayor número de ganglios recuperados y la retención urinaria que fueron evaluados con gráficos de suma acumulativa simple y de suma acumulativa de Bernoulli de dos caras.RESULTADOS:Fueron incluidos 54 procedimientos. En el análisis se presentan una curva de aprendizaje de un solo cirujano (n = 35) y una curva de aprendizaje institucional. En la curva de aprendizaje de un solo cirujano, se detectó un punto de inflexión que marcaba el final de una fase de aprendizaje en el duodécimo procedimiento para el número de ganglios extraídos y en el vigésimo para la retención urinaria. En el análisis de la curva de aprendizaje institucional, se identificaron dos puntos de inflexión en las intervenciones 13.ª y 26.ª, que indicaron mejoras progresivas en el número de ganglios extraídos, y en la 27.ª en la retención urinaria. No se detectaron señales de alarma sostenidas en ningún momento.LIMITACIONES:La naturaleza retrospectiva, el pequeño tamaño de la muestra y la naturaleza de centro de referencia de la institución informante que pueden limitar la capacidad de generalizarse.CONCLUSIONES:En un entorno de experiencia institucional con cirugía robótica colorrectal incluyendo más allá de las resecciones TME, la curva de aprendizaje para la disección robótica de ganglios linfáticos pélvicos laterales es aceptablemente corta. Nuestros resultados demuestran la viabilidad de la adquisición de esta técnica en un entorno controlado, con un volumen de casos suficiente y una supervisión que puede optimizar la curva de aprendizaje. (Traducción-Dr. Osvaldo Gauto )., (Copyright © The ASCRS 2024.) more...

Objectives: To estimate the proportion and correlates of self-reported financial difficulty among patients with multiple myeloma (MM) or chronic lymphocytic leukemia (CLL)., Setting: 23 U.S. community and minority oncology practice sites affiliated with the National Cancer Institute Community Oncology Research Program (NCORP)., Participants: 521 patients (≥18 years) with MM or CLL were consented and 416 responded to a survey (completion rate=79.8%). Respondents had a MM diagnosis (74.0%), an associate degree or higher (53.4%), were White (89.2%), insured (100%) and treated with clinician-administered drugs (68.0%)., Interventions: Observational, prospective, protocol-based survey administered in 2019-2020., Primary and Secondary Outcome Measures: Financial difficulty was assessed using a single-item standard measure, the EORTC QLQC30: "Has your physical condition or medical treatment caused you financial difficulties in the past year?" and using an 'any-or-none' composite measure of 22 items assessing financial difficulty, worries and the use of cost-coping strategies. Multivariable logistic regression models assessed the association between financial difficulty, diagnosis, and socioeconomic and treatment characteristics., Results: 16.8% reported experiencing financial difficulty using the single-item measure and 60.3% using the composite measure. Most frequently endorsed items in the composite measure were financial worry about having to pay large medical bills related to cancer and difficulty paying medical bills. Financial difficulty using the single-item measure was associated with having MM versus CLL (adjusted odds ratio [aOR], 0.34; 95% CI, 0.13-0.84; P =.02), having insurance other than Medicare (aOR, 2.53; 95% CI, 1.37-4.66; P =.003), being non-White (aOR, 2.21; 95% CI, 1.04-4.72; P =.04), and having a high school education or below (aOR, 0.36; 95% CI, 0.21-0.64; P =.001). Financial difficulty using the composite measure was associated with having a high school education or below (aOR, 0.62; 95% CI, 0.41-0.94; P =.03)., Conclusions: U.S. patients with blood cancer report financial difficulty, especially those with low socio-economic status. Evidence-based and targeted interventions are needed., Competing Interests: Competing Interest Statement: Conti reports research support from the National Science Foundation, the National Cancer Institute, the National Institute on Drug Abuse, the Veterans Administration, the Leukemia and Lymphoma Society, the Sloan Foundation and Arnold Ventures and consulting fees from Greylock McKinnon Associates unrelated to this manuscript. All other authors declare no conflicts of interest to disclose. more...

Introduction: In colorectal cancer, the presence of para-aortic lymph nodes (PALN) indicates extraregional disease. Appropriately selecting patients for whom PALN dissection will provide oncologic benefit remains challenging. This study identified factors to predict survival among patients undergoing PALN dissection for colorectal cancer., Methods: An institutional database was queried for patients who underwent curative-intent resection of clinically positive PALN for colorectal cancer between 2007 and 2020. Preoperative radiologic images were reviewed, and patients who did and did not have positive PALN on final pathology were compared. Survival analysis was performed to evaluate the impact of pathologically positive PALN on recurrence-free (RFS) and overall survival (OS)., Results: Of 74 patients who underwent PALN dissection, 51 had PALN metastasis at the time of primary tumor diagnosis, whereas 23 had metachronous PALN disease. Preoperative chemotherapy ± radiotherapy was given in 60 cases (81.1%), and 28 (37.8%) had pathologically positive PALN. Independent factors associated with positive PALN pathology included metachronous PALN disease and pretreatment and posttreatment radiographically abnormal PALN. On multivariable analysis, pathologically positive PALN was significantly associated with decreased RFS (hazard ratio 3.90) and OS (HR 4.49). Among patients with pathologically positive PALN, well/moderately differentiated histology was associated with better OS, and metachronous disease trended toward an association with better OS., Conclusions: Pathologically positive PALN are associated with poorer RFS and OS after PALN dissection for colorectal cancer. Clinicopathologic factors may predict pathologic PALN positivity. Curative-intent surgery may provide benefit, especially in patients with well-to-moderately differentiated primary tumors and possibly metachronous PALN disease., (© 2024. Society of Surgical Oncology.) more...

The determination of an optimal treatment plan for an individual patient with rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative or palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. Particularly for patients with distal rectal cancer, finding a balance between curative-intent therapy while having minimal impact on quality of life can be challenging. Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis. Careful patient selection and the use of sequenced multimodality therapy following a multidisciplinary approach is recommended. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Rectal Cancer, including the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer, updates to the total neoadjuvant therapy approach based on the results of recent clinical trials, and the addition of a "watch-and-wait" nonoperative management approach for clinical complete responders to neoadjuvant therapy. more...

Background: Postoperative ileus (POI) is a common complication after colorectal surgery, leading to increased hospital stay and costs. This study aimed to explore patient comorbidities that contribute to the development of POI in the colorectal surgical population and compare machine learning (ML) model accuracy to existing risk instruments. Study Design: In a retrospective study, data were collected on 316 adult patients who underwent colorectal surgery from January 2020 to December 2021. The study excluded patients undergoing multi-visceral resections, re-operations, or combined primary and metastatic resections. Patients lacking follow-up within 90 days after surgery were also excluded. Eight different ML models were trained and cross-validated using 29 patient comorbidities and four comorbidity risk indices (ASA Status, NSQIP, CCI, and ECI). Results: The study found that 6.33% of patients experienced POI. Age, BMI, gender, kidney disease, anemia, arrhythmia, rheumatoid arthritis, and NSQIP score were identified as significant predictors of POI. The ML models with the greatest accuracy were AdaBoost tuned with grid search (94.2%) and XG Boost tuned with grid search (85.2%). Conclusions: This study suggests that ML models can predict the risk of POI with high accuracy and may offer a new frontier in early detection and intervention for postoperative outcome optimization. ML models can greatly improve the prediction and prevention of POI in colorectal surgery patients, which can lead to improved patient outcomes and reduced healthcare costs. Further research is required to validate and assess the replicability of these results. more...

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer. more...

Background: A survey of medical oncologists (MOs), radiation oncologists (ROs), and surgical oncologists (SOs) who are experts in the management of patients with metastatic colorectal cancer (mCRC) was conducted to identify factors used to consider metastasis-directed therapy (MDT)., Materials and Methods: An online survey to assess clinical factors when weighing MDT in patients with mCRC was developed based on systematic review of the literature and integrated with clinical vignettes. Supporting evidence from the systematic review was included to aid in answering questions., Results: Among 75 experts on mCRC invited, 47 (response rate 62.7%) chose to participate including 16 MOs, 16 ROs, and 15 SOs. Most experts would not consider MDT in patients with 3 lesions in both the liver and lung regardless of distribution or timing of metastatic disease diagnosis (6 vs. 36 months after definitive treatment). Similarly, for patients with retroperitoneal lymph node and lung and liver involvement, most experts would not offer MDT regardless of timing of metastatic disease diagnosis. In general, SOs were willing to consider MDT in patients with more advanced disease, ROs were more willing to offer treatment regardless of metastatic site location, and MOs were the least likely to consider MDT., Conclusions: Among experts caring for patients with mCRC, significant variation was noted among MOs, ROs, and SOs in the distribution and volume of metastatic disease for which MDT would be considered. This variability highlights differing opinions on management of these patients and underscores the need for well-designed prospective randomized trials to characterize the risks and potential benefits of MDT., Competing Interests: Disclosure Eric D. Miller, Kathryn E. Hitchcock, Paul B. Romesser, Sepideh Gholami are part of the study team for A022101, the ERASur trial. No other authors have interests to declare that are relevant to this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) more...

Total neoadjuvant therapy (TNT) is a novel strategy for rectal cancer that administers both (chemo)radiotherapy and systemic chemotherapy before surgery. TNT is expected to improve treatment compliance, tumor regression, organ preservation, and oncologic outcomes. Multiple TNT regimens are currently available with various combinations of the treatments including induction or consolidation chemotherapy, triplet or doublet chemotherapy, and long-course chemoradiotherapy or short-course radiotherapy. Evidence on TNT is rapidly evolving with new data on clinical trials, and no definitive consensus has been established on which regimens to use for improving outcomes. Clinicians need to understand the advantages and limitations of the available regimens for multidisciplinary decision making. This article reviews currently available evidence on TNT for rectal cancer. A decision making flow chart is provided for tailor-made use of TNT regimens based on tumor location and local and systemic risk. more...

Importance: Modifier 22 is a mechanism designed for surgeons to identify cases that are more complex than their Current Procedural Terminology code accounts for. However, empirical studies of the use and efficacy of modifier 22 are lacking., Objective: To assess the use of modifier 22 in common surgical procedures and the association of use with compensation., Design, Setting, and Participants: This was a cross-sectional analysis of the 2021 Physician/Supplier Procedure Summary Limited Data Set including all Part B carrier and durable medical equipment fee-for-service claims. Claims for 10 common surgical procedures were evaluated, including mastectomy, total hip arthroplasty, total knee arthroplasty, coronary artery bypass grafting, laparoscopic right colectomy, laparoscopic appendectomy, laparoscopic cholecystectomy, kidney transplant, laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy, and lumbar laminectomy. Data were analyzed from August to November 2023., Main Outcomes and Measures: Rate of modifier 22 use, rate of claim denial, mean charges, mean payment for accepted claims, and mean payment for all claims., Results: The sample included 625 316 surgical procedures performed in calendar year 2021. The proportion of modifier 22 coding for a procedure ranged from 5725 of 251 521 (2.3%) in total knee arthroplasty to 1566 of 18 459 (8.5%) in laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy. Submitted charges were 11.1% (95% CI, 9.1-13.2) to 22.8% (95% CI, 21.3-24.3) higher for claims with modifier 22, depending on the procedure. Among accepted claims, those with modifier 22 had increased payments ranging from 0.8% (95% CI, 0.7-1.0) to 4.8% (95% CI, 4.5-5.1). However, claims with modifier 22 were more likely to be denied (7.4% vs 4.0%; P < .001). As a result, overall mean payments were mixed, with 4 procedures having lower payments when modifier 22 was appended, 4 procedures having higher payments with modifier 22, and 2 procedures with no difference. The largest increase in mean payment for modifier 22 claims was for kidney transplant with an increased payment of $71.46 (95% CI, 55.32-87.60), which translates to a relative increase of 3.4% (95% CI, 2.9-4.6)., Conclusions and Relevance: The findings in this study suggest that modifier 22 had little to no financial benefit when appended to claims for a diverse panel of surgical procedures. In the current system, surgeons have little reason to request modifier 22, and no mechanisms currently exist for surgeons to recoup payment for difficult operations. more...

Purpose: Dynamic operations platforms allow for cross-platform data extraction, integration, and analysis, although application of these platforms to large-scale oncology enterprises has not been described. This study presents a pipeline for automated, high-fidelity extraction, integration, and validation of cross-platform oncology data in patients undergoing treatment for rectal cancer at a single, high-volume institution., Methods: A dynamic operations platform was used to identify patients with rectal cancer treated at MD Anderson Cancer Center between 2016 and 2022 who had magnetic resonance imaging (MRI) imaging and preoperative treatment details available in the electronic health record (EHR). Demographic, clinicopathologic, tumor mutation, radiographic, and treatment data were extracted from the EHR using a methodology adaptable to any disease site. Data accuracy was assessed by manual review. Accuracy before and after implementation of synoptic reporting was determined for MRI data., Results: A total of 516 patients with localized rectal cancer were included. In the era after institutional adoption of synoptic reports, the dynamic operations platform extracted T (tumor) category data from the EHR with 95% accuracy compared with 87% before the use of synoptic reports, and N (lymph node) category with 88% compared with 58%. Correct extraction of pelvic sidewall adenopathy was 94% compared with 78%, and extramural vascular invasion accuracy was 99% compared with 89%. Neoadjuvant chemotherapy and radiation data were 99% accurate for patients who had synoptic data sources., Conclusion: Using dynamic operations platforms enables automated cross-platform integration of multiparameter oncology data with high fidelity in patients undergoing multimodality treatment for rectal cancer. These pipelines can be adapted to other solid tumors and, together with standardized reporting, can increase efficiency in clinical research and the translation of actionable findings toward optimizing patient outcomes. more...

Aim: As multidisciplinary treatment strategies for colorectal cancer have improved, aggressive surgical resection has become commonplace. Multivisceral and extended resections offer curative-intent resection with significant survival benefit. However, limited data exist regarding the feasibility and oncological efficacy of performing extended resection via a minimally invasive approach. The aim of this study was to determine the perioperative and long-term outcomes following robotic extended resection for colorectal cancer., Method: We describe the population of patients undergoing robotic multivisceral resection for colorectal cancer at our single institution. We evaluated perioperative details and investigated short- and long-term outcomes, using the Kaplan-Meier method to analyse overall and recurrence-free survival., Results: Among the 86 patients most tumours were T3 (47%) or T4 (47%) lesions in the rectum (78%). Most resections involved the anterior compartment (72%): bladder (n = 13), seminal vesicle/vas deferens (n = 27), ureter (n = 6), prostate (n = 15) and uterus/vagina/adnexa (n = 27). Three cases required conversion to open surgery; 10 patients had grade 3 complications. The median hospital stay was 4 days. Resections were R0 (>1 mm) in 78 and R1 (0 to ≤1 mm) in 8, with none being R2. The average nodal yield was 26 and 48 (55.8%) were pN0. Three-year overall survival was 88% and median progression-free survival was 19.4 months. Local recurrence was 6.1% and distant recurrence was 26.1% at 3 years., Conclusion: Performance of multivisceral and extended resection on the robotic platform allows patients the benefit of minimally invasive surgery while achieving oncologically sound resection of colorectal cancer., (© 2024 Association of Coloproctology of Great Britain and Ireland.) more...

Cancer stem cells (CSC) play a critical role in metastasis, relapse, and therapy resistance in colorectal cancer. While characterization of the normal lineage of cell development in the intestine has led to the identification of many genes involved in the induction and maintenance of pluripotency, recent studies suggest significant heterogeneity in CSC populations. Moreover, while many canonical colorectal cancer CSC marker genes have been identified, the ability to use these classical markers to annotate stemness at the single-cell level is limited. In this study, we performed single-cell RNA sequencing on a cohort of 6 primary colon, 9 liver metastatic tumors, and 11 normal (nontumor) controls to identify colorectal CSCs at the single-cell level. Finding poor alignment of the 11 genes most used to identify colorectal CSC, we instead extracted a single-cell stemness signature (SCS&#95;sig) that robustly identified "gold-standard" colorectal CSCs that expressed all marker genes. Using this SCS&#95;sig to quantify stemness, we found that while normal epithelial cells show a bimodal distribution, indicating distinct stem and differentiated states, in tumor epithelial cells stemness is a continuum, suggesting greater plasticity in these cells. The SCS&#95;sig score was quite variable between different tumors, reflective of the known transcriptomic heterogeneity of CRC. Notably, patients with higher SCS&#95;sig scores had significantly shorter disease-free survival time after curative intent surgical resection, suggesting stemness is associated with relapse., Implications: This study reveals significant heterogeneity of expression of genes commonly used to identify colorectal CSCs, and identifies a novel stemness signature to identify these cells from scRNA-seq data., (©2023 American Association for Cancer Research.) more...

Purpose: Individuals diagnosed with cancer between 15 and 39 years (adolescent and young adult [AYA]) face unique vulnerability. Detail is lacking about care delivery for these patients, especially those with ALL. We address these knowledge gaps by describing AYA ALL care delivery details at National Cancer Institute Community Oncology Research Program (NCORP) (sub)affiliates by model of care., Methods: Participating institutions treated at least one AYA with ALL from 2012 to 2016. Study-specific criteria were used to determine the number of unique clinical facilities (CFs) per NCORP and their model of care (adult/internal medicine [IM], pediatric, mixed [both]). Surveys completed by NCORPs for each CF by model of care captured size, resources, services, and communication., Results: Among 84 participating CFs (adult/IM, n=47; pediatric, n=15; mixed, n=24), 34% treated 5-10 AYAs with ALL annually; adult/IM CFs more often treated <5 (adult/IM, 60%; pediatric, 40%; mixed, 29%). Referral decisions were commonly driven by an age/diagnosis combination (58%), with frequent ALL-specific age minimums (87%) or maximums (80%). Medical, navigational, and social work services were similar across models while psychology was available at more pediatric CFs (pediatric, 80%; adult/IM, 40%; mixed, 46%-54%). More pediatric or mixed CFs reported oncologists interacting with pediatric/adult counterparts via tumor boards (pediatric, 93%; adult/IM, 26%; mixed, 96%) or initiating contact (pediatric, 100%; adult/IM, 77%; mixed 96%); more pediatric CFs reported an affiliated counterpart (pediatric, 53%; adult, 19%). Most CFs reported no AYA-specific resources (79%) or meetings (83%-98%)., Conclusion: System-level aspects of AYA ALL care delivery have not been examined previously. At NCORPs, these characteristics differ by models of care. Additional work is ongoing to investigate the impact of these facility-level factors on guideline-concordant care in this population. Together, these findings can inform a system-level intervention for diverse practice settings. more...

Hepatocytes are one of the most physiologically relevant in vitro liver systems for human translation of clearance and drug-drug interactions (DDI). However, the cell membranes of hepatocytes can limit the entry of certain compounds into the cells for metabolism and DDI. Passive permeability through hepatocytes can be different in vitro and in vivo, which complicates the human translation. Permeabilized hepatocytes offer a useful tool to probe mechanistic understanding of permeability-limited metabolism and DDI. Incubation with saponin of 0.01% at 0.5 million cells/mL and 0.05% at 5 million cells/mL for 5 min at 37°C completely permeabilized the plasma membrane of hepatocytes, while leaving the membranes of subcellular organelles intact. Permeabilized hepatocytes maintained similar enzymatic activity as intact unpermeabilized hepatocytes and can be stored at -80°C for at least 7 months. This approach reduces costs by preserving leftover hepatocytes. The relatively low levels of saponin in permeabilized hepatocytes had no significant impact on the enzymatic activity. As the cytosolic contents leak out from permeabilized hepatocytes, cofactors need to be added to enable metabolic reactions. Cytosolic enzymes will no longer be present if the media are removed after cells are permeabilized. Hence permeabilized hepatocytes with and without media removal may potentially enable reaction phenotyping of cytosolic enzymes. Although permeabilized hepatocytes work similarly as human liver microsomes and S9 fractions experimentally requiring addition of cofactors, they behave more like hepatocytes maintaining enzymatic activities for over 4 h. Permeabilized hepatocytes are a great addition to the drug metabolism toolbox to provide mechanistic insights., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.) more...

Selective chemical inhibitors are critical for reaction phenotyping to identify drug-metabolizing enzymes that are involved in the elimination of drug candidates. Although relatively selective inhibitors are available for the major cytochrome P450 enzymes (CYP), they are quite limited for the less common CYPs and non-CYPs. To address this gap, we developed a multiplexed high throughput screening (HTS) assay using 20 substrate reactions of multiple enzymes to simultaneously monitor the inhibition of enzymes in a 384-well format. Four 384-well assay plates can be run at the same time to maximize throughput. This is the first multiplexed HTS assay for drug-metabolizing enzymes reported. The HTS assay is technologically enabled with state-of-the-art robotic systems and highly sensitive modern LC-MS/MS instrumentation. Virtual screening is utilized to identify inhibitors for HTS based on known inhibitors and enzyme structures. Screening of ~4600 compounds generated many hits for many drug-metabolizing enzymes including the two time-dependent and selective aldehyde oxidase inhibitors, erlotinib and dibenzothiophene. The hit rate is much higher than that for the traditional HTS for biological targets due to the promiscuous nature of the drug-metabolizing enzymes and the biased compound selection process. Future efforts will focus on using this method to identify selective inhibitors for enzymes that do not currently have quality hits and thoroughly characterizing the newly identified selective inhibitors from our screen. We encourage colleagues from other organizations to explore their proprietary libraries using a similar approach to identify better inhibitors that can be used across the industry., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.) more...

Tumor binding is an important parameter to derive unbound tumor concentration to explore pharmacokinetics (PK) and pharmacodynamics (PD) relationships for oncology disease targets. Tumor binding was evaluated using eleven matrices, including various commonly used ex vivo human and mouse xenograft and syngeneic tumors, tumor cell lines and liver as a surrogate tissue. The results showed that tumor binding is highly correlated among the different tumors and tumor cell lines except for the mouse melanoma (B16F10) tumor type. Liver fraction unbound (f u ) has a good correlation with B16F10 tumor binding. Liver also demonstrates a two-fold equivalency, on average, with binding of other tumor types when a scaling factor is applied. Predictive models were developed for tumor binding, with correlations established with LogD (acids), predicted muscle f u (neutrals) and measured plasma protein binding (bases) to estimate tumor f u when experimental data are not available. Many approaches can be applied to obtain and estimate tumor binding values. One strategy proposed is to use a surrogate tumor tissue, such as mouse xenograft ovarian cancer (OVCAR3) tumor, as a surrogate for tumor binding (except for B16F10) to provide an early assessment of unbound tumor concentrations for development of PK/PD relationships., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.) more...

Background: The standard treatment for recurrent or persistent anal squamous cell carcinoma is surgical salvage, but disease control and survival are suboptimal., Patients/methods: Patients treated for recurrent or persistent anal squamous cell carcinoma at our institution from 2002 to 2022 were included. Patients were classified by type of salvage treatment received: surgery alone vs. reirradiation followed by surgery and by whether they received intraoperative radiation at the time of surgery. Clinical and pathologic variables were collected and assessed for association with risk of second local recurrence and death from any cause., Results: Sixty four patients were included; 55(85.9%) were treated with surgery alone and 9 (14.1%) were treated with reirradiation followed by surgery. Median (IQR) follow up from the time of salvage treatment was 40.0 (20.3-68.0) months. The 3-year cumulative incidence of second local recurrence (95% CI) after salvage surgery was 36% (24%-48%); 39% (26%-52%) for patients treated with surgery alone and 15% (0.46%-51%) for patients treated with reirradiation followed by surgery. Factors associated with increased second local recurrence after salvage surgery included a locoregional recurrence, lymphovascular space invasion and positive surgical margins. The 3-year overall survival (95% CI) after salvage surgery was 70% (59%-83%); 68% (7%-56%) after surgery alone and 89% (10.5%-70.6%) after reirradiation followed by surgery. Factors associated with worse overall survival included male sex, a larger recurrent tumor and positive surgical margins., Conclusions: Approximately 60% of patients achieved pelvic control after salvage therapy for recurrent or persistent anal squamous cell carcinoma. Although receipt of reirradiation and intraoperative radiation were not associated with improved second local recurrence or overall survival in our cohort, patients with positive surgical margins and lymphovascular space invasion on surgical pathology had higher rates of pelvic recurrence after salvage surgery and may benefit from escalated salvage therapy., Competing Interests: Disclosure None., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...

Multidisciplinary management of rectal cancer has rapidly evolved over the last several years. This review describes recent data surrounding total neoadjuvant therapy, organ preservation, and management of lateral pelvic lymph nodes. It then presents our treatment algorithm for management of rectal cancer at The University of Texas MD Anderson Cancer Center in the context of this and other existing literature. As part of this discussion, the review describes how we tailor management based upon both patient and tumor-related factors in an effort to optimize patient outcomes., Competing Interests: Dr. George J. Chang serves as a member of the editorial board for Annals of Gastroenterological Surgery., (© 2024 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.) more...

Background: Despite the increasing utilization of sphincter and/or organ-preservation treatment strategies, many patients with low-lying rectal cancers require abdominoperineal resection (APR), leading to permanent ostomy. Here, we aimed to characterize overall, sexual-, and bladder-related patient-reported quality of life (QOL) for individuals with low rectal cancers. We additionally aimed to explore potential differences in patient-reported outcomes between patients with and without a permanent ostomy., Methods: We distributed a comprehensive survey consisting of various patient-reported outcome measures, including the FACT-G7 survey, ICIQ MLUTS/FLUTS, IIEF-5/FSFI, and a specific questionnaire for ostomy patients. Descriptive statistics and univariate comparisons were used to compared demographics, treatments, and QOL scores between patients with and without a permanent ostomy., Results: Of the 204 patients contacted, 124 (60.8%) returned completed surveys; 22 (18%) of these had a permanent ostomy at the time of survey completion. There were 25 patients with low rectal tumors (≤5 cm from the anal verge) who did not have an ostomy at the time of survey completion, of whom 13 (52%) were managed with a non-operative approach. FACTG7 scores were numerically lower (median 20.5 vs. 22, p = 0.12) for individuals with an ostomy. Sexual function measures IIEF and FSFI were also lower (worse) for individuals with ostomies, but the results were not significantly different. MLUTS and FLUTS scores were both higher in individuals with ostomies (median 11 vs. 5, p = 0.06 and median 17 vs. 5.5, p = 0.01, respectively), suggesting worse urinary function. Patient-reported ostomy-specific challenges included gastrointestinal concerns (e.g., gas, odor, diarrhea) that may affect social activities and personal relationships., Conclusions: Despite a limited sample size, this study provides patient-centered, patient-derived data regarding long-term QOL in validated measures following treatment of low rectal cancers. Ostomies may have multidimensional negative impacts on QOL, and these findings warrant continued investigation in a prospective setting. These results may be used to inform shared decision making for individuals with low rectal cancers in both the settings of organ preservation and permanent ostomy. more...

Accurate prediction of human pharmacokinetics (PK) remains one of the key objectives of drug metabolism and PK (DMPK) scientists in drug discovery projects. This is typically performed by using in vitro-in vivo extrapolation (IVIVE) based on mechanistic PK models. In recent years, machine learning (ML), with its ability to harness patterns from previous outcomes to predict future events, has gained increased popularity in application to absorption, distribution, metabolism, and excretion (ADME) sciences. This study compares the performance of various ML and mechanistic models for the prediction of human IV clearance for a large (645) set of diverse compounds with literature human IV PK data, as well as measured relevant in vitro end points. ML models were built using multiple approaches for the descriptors: (1) calculated physical properties and structural descriptors based on chemical structure alone (classical QSAR/QSPR); (2) in vitro measured inputs only with no structure-based descriptors (ML IVIVE); and (3) in silico ML IVIVE using in silico model predictions for the in vitro inputs. For the mechanistic models, well-stirred and parallel-tube liver models were considered with and without the use of empirical scaling factors and with and without renal clearance. The best ML model for the prediction of in vivo human intrinsic clearance (CL int ) was an in vitro ML IVIVE model using only six in vitro inputs with an average absolute fold error (AAFE) of 2.5. The best mechanistic model used the parallel-tube liver model, with empirical scaling factors resulting in an AAFE of 2.8. The corresponding mechanistic model with full in silico inputs achieved an AAFE of 3.3. These relative performances of the models were confirmed with the prediction of 16 Pfizer drug candidates that were not part of the original data set. Results show that ML IVIVE models are comparable to or superior to their best mechanistic counterparts. We also show that ML IVIVE models can be used to derive insights into factors for the improvement of mechanistic PK prediction. more...

Importance: Circumferential resection margin (CRM) in rectal cancer surgery is a major prognostic indicator associated with local recurrence and overall survival. Facility rates of CRM positivity have recently been established as a new quality measure by the Commission on Cancer (CoC); however, the completeness of CRM status reporting is not well characterized., Objective: To describe the changes in CRM reporting and factors associated with low rates of reporting., Design, Setting, and Participants: A retrospective cohort study was conducted using data from the National Cancer Database between January 2010 and December 2019. Data were analyzed between October 1, 2021, and February 1, 2022. Data from the National Cancer Database included patients diagnosed with nonmetastatic rectal adenocarcinoma receiving surgical treatment at CoC-accredited facilities throughout the US., Exposures: Patient, tumor, and facility-level factors. Facilities were divided by surgical volume, safety-net status, and CoC facility type., Main Outcomes and Measures: Circumferential resection margin missingness rates., Results: A total of 110 571 patients (59.3% men) with rectal adenocarcinoma who underwent curative-intent surgery at 1307 CoC-accredited hospitals were included for analysis. Reporting of CRM improved over the study period, with a mean (SE) missing 12.0% (0.32%) decreased from 16.3% (0.36%). Academic facilities had a higher missingness than other facility types (14.3% vs 10.5%-12.7%; P < .001). Mean (SE) rates of missingness were similar between hospitals of varying volume (lowest quartile: 12.2% [0.93%] vs highest quartile: 12.4% [0.53%]; P = .96). Cases in which fewer than 12 lymph nodes were removed had higher rates of missingness (18.1% vs 11.4%; P < .001). Increased odds of CRM missingness were noted with T category (odds ratio [OR], 1.50; 95% CI, 1.35-1.65) and N category (OR, 2.00; 95% CI, 1.82-2.20). Black race was associated with missingness (OR, 1.13; 95% CI, 1.06-1.14)., Conclusion and Relevance: Although CRM positivity reporting has improved over the last decade, the findings of this study suggest there is substantial room for improvement as it becomes a quality standard. Missingness appears to be associated with poor performance on other quality metrics and facility type. This measure appears to be ideal for targeted institution-level feedback to improve quality of care nationally. more...

Background: Neoadjuvant immune checkpoint blockade (IO) is emerging as a therapeutic option for patients with deficient mismatch repair (dMMR) colorectal cancer (CRC) given high pathological response rates. The aim of the study was to characterise imaging and endoscopic response to IO., Methods: A retrospective analysis of patients with localised dMMR CRC that received at least one cycle of neoadjuvant anti-PD-1 therapy was conducted. Endoscopy, imaging, and pathological outcomes were reviewed to determine response to treatment according to standardised criteria., Results: Thirty-eight patients had received IO for the treatment of localised CRC (median eight cycles). Among evaluable cases (n = 31 for endoscopy and n = 34 for imaging), the best endoscopic response was complete response (CR) in 45% of cases, and the best radiographic response was CR in 23% of cases. Imaging CR rate after ≤4 cycles of IO (n = 1) was 6% compared to 44% after >4 IO cycles (n = 7). Among 28 patients with imaging and endoscopy available, a discrepancy in best response was noted in 15 (54%) cases. At a median follow-up of 28.2 months from IO start, 18 patients underwent surgical resection of which 11 (61%) had pathological CR (pCR). Despite pCR or no evidence of progression ≥6 months after completion of IO among non-operatively managed patients, 72% and 42% of patients had non-CR on imaging and endoscopy, respectively., Conclusions: Discrepancies between imaging and endoscopy are prevalent, and irregularities identified on these modalities can be identified despite pathological remission. Improved clinical response criteria are warranted., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Tsuyoshi Konishi: travel, accommodations, expenses – advent health; Michener Institute of Education at UHN. Kanwal Pratap Singh Raghav: Honoraria - Bayer; Daiichi Sankyo/Astra Zeneca; Eisai; Merck; Seagen. Consulting or advisory role – Bayer; Daiichi Sankyo/Astra Zeneca; Eisai; Merck; Seagen. Research funding – Abbvie (Inst); Abbvie (Inst); Bayer (Inst); Daiichi Sankyo/Astra Zeneca (Inst); Eisai (Inst); Guardant Health (Inst); HiberCell (Inst); Innovent Biologics (Inst); Janssen (Inst); Merck Serono (Inst); Roche/Genentech (Inst); UCB (Inst); Xencor (Inst). Phillip S. Ge: consulting or advisory role – Alira Health; Boston Scientific; Neptune Medical; Ovesco Endoscopy. Benny Johnson: consulting or advisory role – Gritstone Bio; Incyte; Insmed; Pfizer; Taiho Oncology. Research funding – Bristol-Myers Squibb (Inst); Gateway Foundation (Inst); Syntrix Biosystems (Inst). Van K. Morris: consulting or advisory role – Axiom Healthcare Strategies; Bicara Therapeutics; BioMedical Insights; Boehringer Ingelheim; Incyte. Research funding – Bicara Therapeutics (Inst); BioNTech (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Immatics; Pfizer (Inst). Scott Kopetz: stock and other ownership interests – Frontier Medicines; Iylon; Lutris; Navire; Xilis. Consulting or advisory role – Abbvie; Accademia Nazionale Di Medicina; Amal Therapeutics; Amgen; Astra Zeneca/MedImmune; Bayer Health; Bicara Therapeutics; Black Diamond Therapeutics; Boehringer Ingelheim; Bristol-Myers Squibb/Medarex; Cardiff Oncology; Carina Biotech; CureTeq; EMD Serono; Endeavor BioMedicines; Flame Biosciences; Foundation Medicine; Frontier Medicines; Genentech; Genomic Health; Gilead Sciences; GlaxoSmithKline; HalioDx; Harbinger Oncology, Inc; Holy Stone Healthcare; Inivata; Ipsen; Iylon; Jacobio; Jazz Pharmaceuticals; Johnson & Johnson/Janssen; Lilly; Lutris; Merck; Mirati Therapeutics; NeoGenomics Laboratories; Novartis; Numab; Ono Pharmaceutical; Pfizer; Redx Pharma; Repare Therapeutics; Replimune; Servier; Taiho Pharmaceutical; Takeda; Tempus; Xilis; Zentalis. Research funding – Amgen; Array BioPharma; Biocartis; Daiichi Sankyo; EMD Serono; Genentech/Roche; Guardant Health; Lilly; MedImmune; Novartis; Sanofi. George J. Chang: consulting or advisory role – Medicaroid. Kaysia Ludford: research funding – Merck (Inst). Michael J. Overman: consulting or advisory role – 3D Medicines; Array BioPharma; Bristol-Myers Squibb; Eisai; Gritstone Bio; Janssen; Janssen; MedImmune; Merck; Novartis; Pfizer; Pfizer; Promega; Roche/Genentech; Spectrum Pharmaceuticals. Research funding – Bristol-Myers Squibb; MedImmune; Merck; Roche. The remining authors do not have any disclosures., (Copyright © 2023 Elsevier Ltd. All rights reserved.) more...

Introduction: Testing healthcare delivery interventions in rigorous clinical trials is a critical step in improving patient care, but conducting multisite randomized clinical trials to test the effect of care delivery interventions has unique challenges and requires foresight and planning., Methods: We conducted the first care delivery trial (A191402CD) in the Alliance for Clinical Trials in Oncology, a National Cancer Institute Community Oncology Research Program research base, which tested the effectiveness of two different decision aids for supporting shared decision-making about prostate cancer treatment. Our experience illustrates the kind of challenges that confront care delivery researchers as they seek to test interventions to improve the experiences of patients., Results: Lessons learned include the following: cluster-randomized designs introduce complexity; workflow disruption can discourage site participation; evidence-based methods may not always be sufficient., Conclusion: We conclude with the following recommendations: assessing feasibility requires special rigor; relationships and interpersonal dynamics must be leveraged. Our experiences may inform future care delivery research. more...

Objective: External exposures, the host, and the microbiome interact in oncology. We aimed to investigate tumoral microbiomes in young-onset rectal cancers (YORCs) for profiles potentially correlative with disease etiology and biology., Background: YORC is rapidly increasing, with 1 in 4 new rectal cancer cases occurring under the age of 50 years. Its etiology is unknown., Methods: YORC (<50 y old) or later-onset rectal cancer (LORC, ≥50 y old) patients underwent pretreatment biopsied of tumor and tumor-adjacent normal (TAN) tissue. After whole genome sequencing, metagenomic analysis quantified microbial communities comparing tumors versus TANs and YORCs versus LORCs, controlling for multiple testing. Response to neoadjuvant therapy (NT) was categorized as major pathological response (MPR, ≤10% residual viable tumor) versus non-MPR., Results: Our 107 tumors, 75 TANs from 37 (35%) YORCs, and 70 (65%) LORCs recapitulated bacterial species were previously associated with colorectal cancers (all P <0.0001). YORC and LORC tumoral microbiome signatures were distinct. After NT, 13 patients (12.4%) achieved complete pathologic response, whereas MPR occurred in 47 patients (44%). Among YORCs, MPR was associated with Fusobacterium nucleaum , Bacteroides dorei, and Ruminococcus bromii (all P <0.001), but MPR in LORC was associated with R. bromii ( P <0.001). Network analysis of non-MPR tumors demonstrated a preponderance of oral bacteria not observed in MPR tumors., Conclusions: Microbial signatures were distinct between YORC and LORC. Failure to achieve an MPR was associated with oral bacteria in tumors. These findings urge further studies to decipher correlative versus mechanistic associations but suggest a potential for microbial modulation to augment current treatments., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.) more...

The concept of multidisciplinary team discussion of patient's care has been a part of routine medical practice for several decades [Monson et al. in Bull Am Coll Surg 101:45-46, 2016; NHS. Improving outcomes in colorectal cancer-the manual. (Guidance on commissioning cancer services-improving outcomes). 1997.]. The idea of bringing multiple specialties and ancillary services together to help optimize patient outcomes has been implemented in several clinical arenas from burns to physical medicine and rehabilitation to oncology. In the oncology realm, multidisciplinary tumor boards (MDTs) originated as a broad-based meeting that would permit the review and discussion of cancer patients to optimize treatment strategies [Cancer Co. Optimal Resources for Cancer Care: 2020 Standards. Chicago, IL: 2019.]. Over time, as further specialization occurred and clinical treatment algorithms have become more complex, multidisciplinary tumor boards have become more disease site specific. In this article we will discuss the importance of MDTs, specifically focusing on rectal cancer MDTs including their impact on treatment planning as well as the unique interplay of clinical specialties that provide internal quality control and improvement. Additionally, we will discuss some of the potential benefits of MDTs beyond the direct impact on patient care and review some of the challenges of implementation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...

Background: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain., Methods: We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects., Results: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy., Conclusions: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.)., (Copyright © 2023 Massachusetts Medical Society.) more...

Purpose: The standard of care for locally advanced rectal cancer in North America is neoadjuvant pelvic chemoradiation with fluorouracil (5FUCRT). Neoadjuvant chemotherapy with fluorouracil and oxaliplatin (FOLFOX) is an alternative that may spare patients the morbidity of radiation. Understanding the relative patient experiences with these options is necessary to inform treatment decisions., Methods: PROSPECT was a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX versus 5FUCRT, which enrolled adults with rectal cancer clinically staged as T2N+, cT3N-, or cT3N+ who were candidates for sphincter-sparing surgery. Neoadjuvant FOLFOX was given in six cycles over 12 weeks, followed by surgery. Neoadjuvant 5FUCRT was delivered in 28 fractions over 5.5 weeks, followed by surgery. Adjuvant chemotherapy was suggested but not mandated in both groups. Enrolled patients were asked to provide patient-reported outcomes (PROs) at baseline, during neoadjuvant treatment, and at 12 months after surgery. PROs included 14 symptoms from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Additional PRO instruments measured bowel, bladder, sexual function, and health-related quality of life (HRQL)., Results: From June 2012 to December 2018, 1,194 patients were randomly assigned, 1,128 initiated treatment, and 940 contributed PRO-CTCAE data (493 FOLFOX; 447 5FUCRT). During neoadjuvant treatment, patients reported significantly lower rates of diarrhea and better overall bowel function with FOLFOX while anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting were lower with 5FUCRT (all multiplicity adjusted P < .05). At 12 months after surgery, patients randomly assigned to FOLFOX reported significantly lower rates of fatigue and neuropathy and better sexual function versus 5FUCRT (all multiplicity adjusted P < .05). Neither bladder function nor HRQL differed between groups at any time point., Conclusion: For patients with locally advanced rectal cancer choosing between neoadjuvant FOLFOX and 5FUCRT, the distinctive PRO profiles inform treatment selection and shared decision making. more...

Background: The use of the robotic approach is increasing for colorectal cancer operations, but the added cost of the platform has the potential to introduce challenges in its dissemination. We hypothesized that adoption of the robot is introducing new disparities in access to minimally invasive surgery (MIS) for colorectal cancer, especially across patient insurance groups., Methods: This cross-sectional study analyzed surgical cases of stage I-III colorectal cancer from the National Cancer Database (NCDB) between 2010 and 2019. The primary outcome was surgical approach (robotic, laparoscopic, or the composite "MIS"). The predictor was a patient's primary payor. Potential confounders included sociodemographics, tumor characteristics, and the facility. Hierarchical multivariable models were generated, and sensitivity analyses were performed., Results: For colorectal cancer operations, the MIS approach increased from 39% in 2010 to 73% in 2019, driven predominantly by an increase in the robotic approach from 2 to 24%. For laparoscopy, the size of the disparity between patients with Private insurance and Medicaid shrank from 11% (2010) to 4% (2019), whereas this disparity increased for the robotic approach from 1% (2010) to 5% (2019). On adjusted analysis, patients with Medicaid (odds ratio [OR] 0.86 [CI 0.79-0.95]) and the Uninsured (OR 0.67 [CI 0.56-0.79]) had lower odds of receiving a robotic operation than those with Private insurance in 2019. This disparity remained consistent across five sensitivity analyses., Conclusions: As the field of colorectal cancer surgery shifts away from laparoscopy and toward robotics, new inequities across patient insurance are emerging. Proactive efforts are needed to ensure all patients benefit from a minimally invasive approach., (© 2023. Society of Surgical Oncology.) more...

Introduction: Multimodality treatment for locally advanced rectal cancer (LARC) can include long-course radiotherapy (LCRT) or short course radiotherapy (SCRT). Nonoperative management is increasingly pursued for those achieving a complete clinical response. Data regarding long-term function and quality-of-life (QOL) are limited., Methods: Patients with LARC treated with radiotherapy from 2016 to 2020 completed the Functional Assessment of Cancer Therapy- General (FACT-G7), the Low Anterior Resection Syndrome Score (LARS) and the Fecal Incontinence QOL Scale (FIQOL). Univariate and multivariable linear regression analyses identified associations between clinical variables including radiation fractionation and the use of surgery versus non-operative management., Results: Of 204 patients surveyed, 124 (60.8%) responded. Median (interquartile range) time from radiation to survey completion was 30.1 (18.3-43) months. Seventy-nine (63.7%) respondents received LCRT, and 45 (36.3%) received SCRT; 101 (81.5%) respondents underwent surgery, and 23 (18.5%) pursued nonoperative management. There were no differences in LARS, FIQoL or FACT-G7 between patients receiving LCRT versus SCRT. On multivariable analysis, only nonoperative management was associated with lower LARS score signifying less bowel dysfunction. Nonoperative management and female sex were associated with a higher FIQoL score signifying less disruption and distress from fecal incontinence issues. Finally, lower BMI at the time of radiation, female sex, and higher FIQoL score were associated with higher FACT-G7 scores signifying better overall QOL., Conclusions: These results suggest long-term patient-reported bowel function and QOL may be similar for individuals receiving SCRT and LCRT for the treatment of LARC, but nonoperative management may lead to improved bowel function and QOL., Competing Interests: Disclosure All other authors state that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...

Studies have demonstrated that a low-protein diet supplemented with ketoanalogs (KAs) could significantly retard progression of renal function in patients with chronic kidney disease (CKD) stages 3-5. However, its effects on endothelial function and serum levels of protein-bound uremic toxins remain elusive. Therefore, this study explored whether a low-protein diet (LPD) supplemented with KAs affects kidney function, endothelial function, and serum uremic toxin levels in a CKD-based cohort. In this retrospective cohort, we enrolled 22 stable CKD stage 3b-4 patients on LPD (0.6-0.8 g/day). Patients were categorized into control (LPD only) and study groups (LPD + KAs 6 tab/day). Serum biochemistry, total/free indoxyl sulfate (TIS/FIS), total/free p-cresyl sulfate (TPCS/FPCS), and flow-mediated dilation (FMD) were measured before and after 6 months of KA supplementation. Before the trial, there were no significant differences in kidney function, FMD, or uremic toxin levels between the control and study groups. When compared with the control group, the paired t -test showed a significant decrease in TIS and FIS (all p < 0.05) and a significant increase in FMD, eGFR, and bicarbonate (all p < 0.05). In multivariate regression analysis, an increase in FMD ( p < 0.001) and a decrease in FPCS ( p = 0.012) and TIS ( p < 0.001) remained persistent findings when adjusted for age, systolic blood pressure (SBP), sodium, albumin, and diastolic blood pressure (DBP). LPD supplemented with KAs significantly preserves kidney function and provides additional benefits on endothelial function and protein-bound uremic toxins in patients with CKD. more...

In vitro-in vivo extrapolation ((IVIVE) and empirical scaling factors (SF) of human intrinsic clearance (CL int ) were developed using one of the largest dataset of 455 compounds with data from human liver microsomes (HLM) and human hepatocytes (HHEP). For extended clearance classification system (ECCS) class 2/4 compounds, linear SFs (SF lin ) are approximately 1, suggesting enzyme activities in HLM and HHEP are similar to those in vivo under physiological conditions. For ECCS class 1A/1B compounds, a unified set of SFs was developed for CL int . These SFs contain both SF lin and an exponential SF (SF β ) of fraction unbound in plasma (f u,p ). The unified SFs for class 1A/1B eliminate the need to identify the transporters involved prior to clearance prediction. The underlying mechanisms of these SFs are not entirely clear at this point, but they serve practical purposes to reduce biases and increase prediction accuracy. Similar SFs have also been developed for preclinical species. For HLM-HHEP disconnect (HLM > HHEP) ECCS class 2/4 compounds that are mainly metabolized by cytochrome P450s/FMO, HLM significantly overpredicted in vivo CL int , while HHEP slightly underpredicted and geometric mean of HLM and HHEP slightly overpredicted in vivo CL int. This observation is different than in rats, where rat liver microsomal CL int correlates well with in vivo CL int for compounds demonstrating permeability-limited metabolism. The good CL int IVIVE developed using HLM and HHEP helps build confidence for prospective predictions of human clearance and supports the continued utilization of these assays to guide structure-activity relationships to improve metabolic stability., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.) more...

Background: Colorectal cancer is being increasingly diagnosed in people younger than 50 years. An inheritable cancer predisposition has been reported in 22% of the young-onset cases. Assessment of germline risk is critical for personalized cancer care., Objective: The study aimed to implement universal germline cancer risk assessment and testing and to define the germline cancer risk profiles of patients presenting with young-onset disease., Design: This is a prospective cohort study., Settings: This study was conducted at a tertiary-referral academic medical center., Patients: This study included newly diagnosed patients presenting to surgical clinics between September 2019 and February 2021 who were treated on a standardized care pathway including the universal germline risk assessment., Interventions: Patients received educational material on young-onset disease, genetic testing, and insurance coverage followed by genetic counseling (either remotely by telegenetics or in person). Consenting patients were assessed on a 47-gene common hereditary cancer panel., Main Outcome Measures: The primary outcome was a proportion of patients with identifiable germline cancer predisposition., Results: Among 500 patients with colorectal cancer, 185 (37%) were 50 years of age or younger (median: 44). A family history was absent for the majority of patients (123; 67%), and in 15 patients, tumors (8.1%) were deficient in DNA mismatch repair. Germline testing was completed in 130 patients (70%); the remainder were pending (7%), deceased (1%), or declined (22%). Pathogenic germline mutations were identified in 25 of 130 (19%) patients: 12 in mismatch repair genes and 13 in other genes. A variant of uncertain significance was found in 23 (18%) patients. Importantly, a pathogenic germline mutation was identified in 12% of the patients without a family history (versus 32% with; p = 0.015) and in 13% of those with proficient mismatch repair colorectal cancers (versus 71% if deficient; p < 0.001)., Limitations: The study is limited by its implementation at a single tertiary academic institution., Conclusions: One in 5 patients with young-onset disease harbored germline cancer predisposition. This detection rate, coupled with a high level of interest and acceptance from patients and feasibility of implementation, supports universal germline cancer risk assessment in this patient population. See Video Abstract at http://links.lww.com/DCR/B925 ., Perfiles De Riesgo De Cncer De Lnea Germinal De Pacientes Con Cncer Colorrectal De Inicio Joven Hallazgos De Un Programa Universal Prospectivo De Pruebas De Lnea Germinal Y Telegentica: ANTECEDENTES:El cáncer colorrectal se diagnostica cada vez más en personas menores de 50 años. Se ha informado una predisposición hereditaria al cáncer en el 22 % de los casos de aparición temprana. La evaluación del riesgo de la línea germinal es fundamental para la atención personalizada del cáncer.OBJETIVO:Implementar la evaluación y las pruebas universales de riesgo de cáncer de línea germinal, y definir los perfiles de riesgo de cáncer de línea germinal de los pacientes que presentan una enfermedad de aparición temprana.DISEÑO:Un estudio de cohorte prospectivo.AJUSTE:Un centro médico académico de referencia terciaria.PACIENTES:Los pacientes recién diagnosticados que se presentaron en clínicas quirúrgicas entre Septiembre de 2019 y Febrero de 2021 fueron tratados en una vía de atención estandarizada que incluye una evaluación de riesgo de línea germinal universal.INTERVENCIÓN:Los pacientes recibieron material educativo sobre enfermedades de aparición temprana, pruebas genéticas y cobertura de seguro, seguido de asesoramiento genético (ya sea a distancia por telegenética o en persona). Los pacientes que dieron su consentimiento fueron evaluados en un panel de cánceres hereditarios comunes de 47 genes.MEDIDA DE RESULTADO PRINCIPAL:Proporción de pacientes con predisposición identificable al cáncer de línea germinal.RESULTADOS:Entre 500 pacientes con cáncer colorrectal, 185 (37%) tenían 50 años o menos (mediana: 44). No había antecedentes familiares en la mayoría (123, 67%) y 15 tumores (8,1%) eran deficientes en la reparación del desajuste de ácido desoxirribonucleico. La prueba de línea germinal se completó en 130 pacientes (70%); el resto estaban pendientes (7%), fallecidos (1%) o declinados (22%). Se identificaron mutaciones patogénicas de la línea germinal en 25 (de 130, 19%) pacientes: 12 en genes de reparación de errores de emparejamiento y 13 en otros genes. Se encontró una variante de significado incierto en 23 (18%) pacientes. Es importante señalar que se identificó una mutación germinal patogénica en el 12% de los pacientes sin antecedentes familiares (frente al 32% con; p = 0,015) y en el 13% de aquellos con cánceres colorrectales competentes en la reparación de errores de emparejamiento (frente al 71% si eran deficientes; p < 0,001).LIMITACIÓN:Implementado en una sola institución académica terciaria.CONCLUSIÓN:Uno de cada cinco pacientes con enfermedad de inicio joven albergaba predisposición al cáncer de línea germinal. Esta tasa de detección, junto con un alto nivel de interés y aceptación por parte de los pacientes y la viabilidad de la implementación, respaldan la evaluación universal del riesgo de cáncer de línea germinal en esta población de pacientes. Consulte el Video Resumen en http://links.lww.com/DCR/B925 . (Traducción-Dr. Yesenia Rojas-Khalil )., (Copyright © The ASCRS 2022.) more...

Introduction: This report is intended to provide insight into the presentation, diagnosis, and treatment of prostatic sarcomas. A literature review is included to compare variables in demographics, histology, prognosis, and treatment strategies among previously reported incidences., Case Presentation: In this case, we have a 72-year-old man who initially presented with symptomatic nephrolithiasis that led to further workup. Magnetic resonance imaging revealed an enlarged, heterogeneous prostate with a dominant mass in the left lobe. A biopsy of the prostate revealed a high-grade, undifferentiated sarcoma in the left lobe along with concomitant adenocarcinoma in the right lobe., Conclusions: The patient underwent a radical prostatectomy, which according to existing literature remains the most effective treatment strategy. Staging is the most important prognostic indicator, making this cancer particularly dangerous as presenting symptoms are highly variable among patients., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.) more...

The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA. more...

Objective: To assess long-term outcomes with robotic versus laparoscopic/thoracoscopic and open surgery for colorectal, urologic, endometrial, cervical, and thoracic cancers., Background: Minimally invasive surgery provides perioperative benefits and similar oncological outcomes compared with open surgery. Recent robotic surgery data have questioned long-term benefits., Methods: A systematic review and meta-analysis of cancer outcomes based on surgical approach was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines using Pubmed, Scopus, and Embase. Hazard ratios for recurrence, disease-free survival (DFS), and overall survival (OS) were extracted/estimated using a hierarchical decision tree and pooled in RevMan 5.4 using inverse-variance fixed-effect (heterogeneity nonsignificant) or random effect models., Results: Of 31,204 references, 199 were included (7 randomized, 23 database, 15 prospective, 154 retrospective studies)-157,876 robotic, 68,007 laparoscopic/thoracoscopic, and 234,649 open cases. Cervical cancer: OS and DFS were similar between robotic and laparoscopic [1.01 (0.56, 1.80), P =0.98] or open [1.18 (0.99, 1.41), P =0.06] surgery; 2 papers reported less recurrence with open surgery [2.30 (1.32, 4.01), P =0.003]. Endometrial cancer: the only significant result favored robotic over open surgery [OS; 0.77 (0.71, 0.83), P <0.001]. Lobectomy: DFS favored robotic over thoracoscopic surgery [0.74 (0.59, 0.93), P =0.009]; OS favored robotic over open surgery [0.93 (0.87, 1.00), P =0.04]. Prostatectomy: recurrence was less with robotic versus laparoscopic surgery [0.77 (0.68, 0.87), P <0.0001]; OS favored robotic over open surgery [0.78 (0.72, 0.85), P <0.0001]. Low-anterior resection: OS significantly favored robotic over laparoscopic [0.76 (0.63, 0.91), P =0.004] and open surgery [0.83 (0.74, 0.93), P =0.001]., Conclusions: Long-term outcomes were similar for robotic versus laparoscopic/thoracoscopic and open surgery, with no safety signal or indication requiring further research (PROSPERO Reg#CRD42021240519)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.) more...