The prognostic impact of tumor deposits in colorectal cancer: More than just N1c.

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.

NCCN Guidelines® Insights: Rectal Cancer, Version 3.2024.

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.

The Learning Curve for Robotic Lateral Pelvic Lymph Node Dissection for Rectal Cancer: A View From the West.

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 ).

Early Postoperative Prediction of Complications and Readmission After Colorectal Cancer Surgery Using an Artificial Neural Network.

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 ).

Improving Surgical Care and Outcomes in Older Cancer Patients Through Implementation of a Presurgical Toolkit (OPTI-Surg)-Final Results of a Phase III Cluster Randomized Trial (Alliance A231601CD).

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.

Estimated Financial Impact of 2021 Office-Visit Work Relative Unit Updates on Surgical Global Periods.

This cross-sectional study assesses the impact of changes to medical billing and coding work relative value units in 2021.

Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

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.

Testing Machine Learning Models to Predict Postoperative Ileus after Colorectal Surgery.

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.

Para-aortic Lymph Node Dissection for Colorectal Cancer: Predicting Pathologic Lymph Node Positivity and Optimizing Outcomes.

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.

Total Neoadjuvant Therapy for Rectal Cancer: Which Regimens to Use?

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.

The current multidisciplinary management of rectal cancer.

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.

Cancer Surveillance in Solid Organ Transplant Recipients With a Pretransplant History of Malignancy: Multidisciplinary Collaborative Expert Opinion.

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.

Automated, High-Throughput Platform to Generate a High-Reliability, Comprehensive Rectal Cancer Database.

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.

Perioperative and oncological outcomes following robotic en bloc multivisceral resection for colorectal cancer.

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.

Novel Multiplexed High Throughput Screening of Selective Inhibitors for Drug-Metabolizing Enzymes Using Human Hepatocytes.

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.

Characterization and Applications of Permeabilized Hepatocytes in Drug Discovery.

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.

Modifier 22 Use in Fee-for-Service Medicare.

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.

Consideration of Metastasis-Directed Therapy for Patients With Metastatic Colorectal Cancer: Expert Survey and Systematic Review.

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.

Characteristics of Health Care Settings Where Adolescents and Young Adults Receive Care for ALL.

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.