Prediction of Pathologic Complete Response for Rectal Cancer Based on Pretreatment Factors Using Machine Learning.

BACKGROUND: Pathologic complete response after neoadjuvant therapy is an important prognostic indicator for locally advanced rectal cancer and may give insights into which patients might be treated nonoperatively in the future. Existing models for predicting pathologic complete response in the pretreatment setting are limited by small data sets and low accuracy. OBJECTIVE: We sought to use machine learning to develop a more generalizable predictive model for pathologic complete response for locally advanced rectal cancer. DESIGN: Patients with locally advanced rectal cancer who underwent neoadjuvant therapy followed by surgical resection were identified in the National Cancer Database from years 2010 to 2019 and were split into training, validation, and test sets. Machine learning techniques included random forest, gradient boosting, and artificial neural network. A logistic regression model was also created. Model performance was assessed using an area under the receiver operating characteristic curve. SETTINGS: This study used a national, multicenter data set. PATIENTS: Patients with locally advanced rectal cancer who underwent neoadjuvant therapy and proctectomy. MAIN OUTCOME MEASURES: Pathologic complete response defined as T0/xN0/x. RESULTS: The data set included 53,684 patients. Pathologic complete response was experienced by 22.9% of patients. Gradient boosting showed the best performance with an area under the receiver operating characteristic curve of 0.777 (95% CI, 0.773-0.781), compared with 0.684 (95% CI, 0.68-0.688) for logistic regression. The strongest predictors of pathologic complete response were no lymphovascular invasion, no perineural invasion, lower CEA, smaller size of tumor, and microsatellite stability. A concise model including the top 5 variables showed preserved performance. LIMITATIONS: The models were not externally validated. CONCLUSIONS: Machine learning techniques can be used to accurately predict pathologic complete response for locally advanced rectal cancer in the pretreatment setting. After fine-tuning a data set including patients treated nonoperatively, these models could help clinicians identify the appropriate candidates for a watch-and-wait strategy. See Video Abstract . EL CNCER DE RECTO BASADA EN FACTORES PREVIOS AL TRATAMIENTO MEDIANTE EL APRENDIZAJE AUTOMTICO: ANTECEDENTES:La respuesta patológica completa después de la terapia neoadyuvante es un indicador pronóstico importante para el cáncer de recto localmente avanzado y puede dar información sobre qué pacientes podrían ser tratados de forma no quirúrgica en el futuro. Los modelos existentes para predecir la respuesta patológica completa en el entorno previo al tratamiento están limitados por conjuntos de datos pequeños y baja precisión.OBJETIVO:Intentamos utilizar el aprendizaje automático para desarrollar un modelo predictivo más generalizable para la respuesta patológica completa para el cáncer de recto localmente avanzado.DISEÑO:Los pacientes con cáncer de recto localmente avanzado que se sometieron a terapia neoadyuvante seguida de resección quirúrgica se identificaron en la Base de Datos Nacional del Cáncer de los años 2010 a 2019 y se dividieron en conjuntos de capacitación, validación y prueba. Las técnicas de aprendizaje automático incluyeron bosque aleatorio, aumento de gradiente y red neuronal artificial. También se creó un modelo de regresión logística. El rendimiento del modelo se evaluó utilizando el área bajo la curva característica operativa del receptor.ÁMBITO:Este estudio utilizó un conjunto de datos nacional multicéntrico.PACIENTES:Pacientes con cáncer de recto localmente avanzado sometidos a terapia neoadyuvante y proctectomía.PRINCIPALES MEDIDAS DE VALORACIÓN:Respuesta patológica completa definida como T0/xN0/x.RESULTADOS:El conjunto de datos incluyó 53.684 pacientes. El 22,9% de los pacientes experimentaron una respuesta patológica completa. El refuerzo de gradiente mostró el mejor rendimiento con un área bajo la curva característica operativa del receptor de 0,777 (IC del 95%: 0,773 - 0,781), en comparación con 0,684 (IC del 95%: 0,68 - 0,688) para la regresión logística. Los predictores más fuertes de respuesta patológica completa fueron la ausencia de invasión linfovascular, la ausencia de invasión perineural, un CEA más bajo, un tamaño más pequeño del tumor y la estabilidad de los microsatélites. Un modelo conciso que incluye las cinco variables principales mostró un rendimiento preservado.LIMITACIONES:Los modelos no fueron validados externamente.CONCLUSIONES:Las técnicas de aprendizaje automático se pueden utilizar para predecir con precisión la respuesta patológica completa para el cáncer de recto localmente avanzado en el entorno previo al tratamiento. Después de realizar ajustes en un conjunto de datos que incluye pacientes tratados de forma no quirúrgica, estos modelos podrían ayudar a los médicos a identificar a los candidatos adecuados para una estrategia de observar y esperar. (Traducción-Dr. Ingrid Melo ).

Post-operative Crohn's Disease Recurrence and Infectious Complications: A Transcriptomic Analysis.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory condition affecting the gastrointestinal tract, characterized by complications such as strictures, fistulas, and neoplasia. Despite medical advancements, a significant number of patients with Crohn's disease require surgery, and many experience post-operative complications and recurrence. Previous studies have analyzed gene expression to study recurrence and post-operative complications independently. This study aims to identify overlapping differentially expressed genes and pathways for recurrence and post-operative complications. METHODS: A dataset including 45 patients with Crohn's disease, including gene expression from ileum and colon tissue, endoscopic recurrence, and intra-abdominal septic complications was analyzed. Gene set enrichment analysis was used to identify gene pathways associated with the outcomes. Finally, a multi-variable logistic regression model was created to assess whether gene pathways were independently associated with both outcomes. RESULTS: In ileum tissue, several inflammatory pathways, including interferon alpha and gamma response were upregulated in patients with endoscopic recurrence and intra-abdominal septic complications. In addition, there was upregulation of the epithelial mesenchymal transition pathway. In colon tissue, metabolic processes, such as myogenesis and oxidative phosphorylation were downregulated in both outcomes. In a multivariate model, downregulation of myogenesis in colon tissue was significantly associated with both endoscopic recurrence and intra-abdominal septic complications. CONCLUSION: These findings shed light on the underlying biology of these outcomes and suggest potential biomarkers or therapeutic targets to reduce their occurrence. Further validation and multi-institutional studies are warranted to confirm these results and improve post-operative outcomes for patients with Crohn's disease.

Analysis of Specimen Mammography with Artificial Intelligence to Predict Margin Status.

BACKGROUND: Intraoperative specimen mammography is a valuable tool in breast cancer surgery, providing immediate assessment of margins for a resected tumor. However, the accuracy of specimen mammography in detecting microscopic margin positivity is low. We sought to develop an artificial intelligence model to predict the pathologic margin status of resected breast tumors using specimen mammography. METHODS: A dataset of specimen mammography images matched with pathologic margin status was collected from our institution from 2017 to 2020. The dataset was randomly split into training, validation, and test sets. Specimen mammography models pretrained on radiologic images were developed and compared with models pretrained on nonmedical images. Model performance was assessed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). RESULTS: The dataset included 821 images, and 53% had positive margins. For three out of four model architectures tested, models pretrained on radiologic images outperformed nonmedical models. The highest performing model, InceptionV3, showed sensitivity of 84%, specificity of 42%, and AUROC of 0.71. Model performance was better among patients with invasive cancers, less dense breasts, and non-white race. CONCLUSIONS: This study developed and internally validated artificial intelligence models that predict pathologic margins status for partial mastectomy from specimen mammograms. The models' accuracy compares favorably with published literature on surgeon and radiologist interpretation of specimen mammography. With further development, these models could more precisely guide the extent of resection, potentially improving cosmesis and reducing reoperations.

Application of machine learning to predict postoperative gastrointestinal bleed in bariatric surgery.

BACKGROUND: Postoperative gastrointestinal bleeding (GIB) is a rare but serious complication of bariatric surgery. The recent rise in extended venous thromboembolism regimens as well as outpatient bariatric surgery may increase the risk of postoperative GIB or lead to delay in diagnosis. This study seeks to use machine learning (ML) to create a model that predicts postoperative GIB to aid surgeon decision-making and improve patient counseling for postoperative bleeds. METHODS: The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database was used to train and validate three types of ML methods: random forest (RF), gradient boosting (XGB), and deep neural networks (NN), and compare them with logistic regression (LR) regarding postoperative GIB. The dataset was split using fivefold cross-validation into training and validation sets, in an 80/20 ratio. The performance of the models was assessed using area under the receiver operating characteristic curve (AUROC) and compared with the DeLong test. Variables with the strongest effect were identified using Shapley additive explanations (SHAP). RESULTS: The study included 159,959 patients. Postoperative GIB was identified in 632 (0.4%) patients. The three ML methods, RF (AUROC 0.764), XGB (AUROC 0.746), and NN (AUROC 0.741) all outperformed LR (AUROC 0.709). The best ML method, RF, was able to predict postoperative GIB with a specificity and sensitivity of 70.0% and 75.4%, respectively. Using DeLong testing, the difference between RF and LR was determined to be significant with p < 0.01. Type of bariatric surgery, pre-op hematocrit, age, duration of procedure, and pre-op creatinine were the 5 most important features identified by ML retrospectively. CONCLUSIONS: We have developed a ML model that outperformed LR in predicting postoperative GIB. Using ML models for risk prediction can be a helpful tool for both surgeons and patients undergoing bariatric procedures but more interpretable models are needed.

Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2.

Tyrosyl-DNA phosphodiesterase 2 (TDP2) reverses Topoisomerase 2 DNA-protein crosslinks (TOP2-DPCs) in a direct-reversal pathway licensed by ZATTZNF451 SUMO2 E3 ligase and SUMOylation of TOP2. TDP2 also binds ubiquitin (Ub), but how Ub regulates TDP2 functions is unknown. Here, we show that TDP2 co-purifies with K63 and K27 poly-Ubiquitinated cellular proteins independently of, and separately from SUMOylated TOP2 complexes. Poly-ubiquitin chains of ≥ Ub3 stimulate TDP2 catalytic activity in nuclear extracts and enhance TDP2 binding of DNA-protein crosslinks in vitro. X-ray crystal structures and small-angle X-ray scattering analysis of TDP2-Ub complexes reveal that the TDP2 UBA domain binds K63-Ub3 in a 1:1 stoichiometric complex that relieves a UBA-regulated autoinhibitory state of TDP2. Our data indicates that that poly-Ub regulates TDP2-catalyzed TOP2-DPC removal, and TDP2 single nucleotide polymorphisms can disrupt the TDP2-Ubiquitin interface.

Does an endocrinology subspecialty residency rotation enhance resident endocrine clinical knowledge?

BACKGROUND: Internal Medicine (IM) programs offer elective subspecialty rotations in which residents may enroll to supplement the experience and knowledge obtained during general inpatient and outpatient rotations. Objective evidence that these rotations provide enhanced subspecialty specific knowledge is lacking. The purpose of this study was to determine whether exposure to an endocrinology subspecialty rotation enhanced a resident's endocrinology-specific knowledge beyond that otherwise acquired during IM residency. METHODS: Data were collected on internal medicine resident scores on the American College of Physicians Internal Medicine In-Training Examinations (IM-ITE) for calendar years 2012 through 2018 along with enrollment data as to whether residents had completed an endocrinology subspecialty rotation prior to sitting for a given IM-ITE. Three hundred and six internal medicine residents in the University of Minnesota Internal Medicine residency program with 664 scores total on the IM-ITE for calendar years 2012 through 2018. Percentage of correct answers on the overall and endocrine subspecialty content areas on the IM-ITE for each exam were determined and the association between prior exposure to an endocrinology subspecialty rotation and percentage of correct answers in the endocrinology content area was analyzed using generalized linear mixed-effects models. RESULTS: Two hundred and thirty-three residents (76%) completed an endocrinology subspecialty rotation at some point during their residency; 121 (40%) residents had at least one IM-ITE both before and after exposure to an endocrine subspecialty rotation. Exposure to an endocrinology subspecialty rotation exhibited a positive association with the expected IM-ITE percent correct on the endocrinology content area (5.5% predicted absolute increase). Advancing year of residency was associated with a predicted increase in overall IM-ITE score but did not improve the predictive model for endocrine subspecialty score. CONCLUSIONS: Completion of an endocrinology subspecialty elective was associated with an increase in resident endocrine specific knowledge as assessed by the IM-ITE. These findings support the value of subspecialty rotations in enhancing a resident's subspecialty specific medical knowledge.

Analysis of patient safety event report categories at one large academic hospital.

Given the persistent safety incidents in operating rooms (ORs) nationwide (approx. 4,000 preventable harmful surgical errors per year), there is a need to better analyze and understand reported patient safety events. This study describes the results of applying the Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) supported by the Teamwork Evaluation of Non-Technical Skills (TENTS) instrument to analyze patient safety event reports at one large academic medical center. Results suggest that suboptimal behaviors stemming from poor communication, lack of situation monitoring, and inappropriate task prioritization and execution were implicated in most reported events. Our proposed methodology offers an effective way of programmatically sorting and prioritizing patient safety improvement efforts.

Operating Room Teams Display Acceptable Levels of Patient Safety Behaviors During Surgical Cases.

INTRODUCTION: Cornerstones of patient safety include reliable safety behaviors proposed by Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) practices. A better quantification of these behaviors is needed to establish a baseline for future improvement efforts. METHODS: At one large academic medical center, OR Teams were prospectively assigned to be observed during surgical cases, and patient safety behaviors were quantified using the Teamwork Evaluation of Non-Technical Skills (TENTS) instrument. Mean scores of each TENTS behavior were calculated with 95% confidence intervals and compared using a paired t-test with a false discovery rate (FDR) control. Using the TENTS instrument, one hundred one surgical cases were observed by purposefully trained medical student volunteers. The average with 95% confidence interval (CI) of observed safety behaviors quantified using the TENTS instrument (including 20 types of safety behaviors scored 0 = expected but not observed, 1 = observed but poorly performed or counterproductive, 2 = observed and acceptable, and 3 = observed and excellent). RESULTS: All safety behaviors averaged slightly above 2, and the lower bound of 95% CI was above 2 for all behaviors except one. Statistically significant differences (p < 0.05) were detected between a few safety behaviors, with the lowest-rated safety behavior being "employs conflict resolution" (2.07, 95% CI: 1.96-2.18) and the highest-rated behavior being "willingness to support others across roles" (2.36, 95% CI: 2.27-2.45). There were no significant differences (p > 0.05) based on the number of persons present during the case, case duration, or by surgical department. CONCLUSIONS: Given the persistent patient safety incidents in ORs nationwide, it might be necessary to advance these behaviors from acceptable to exceptional to advance patient safety.

Outcomes in Obese Adult Veno-Venous Extracorporeal Membrane Oxygenation: A Systematic Review.

Obesity is associated with an overall increased risk of morbidity and mortality. However, in patients with critical illness, sepsis, and acute respiratory distress syndrome, obesity may be protective, termed "the obesity paradox." This is a systematic literature review of articles published from 2000 to 2022 evaluating complications and mortality in adults with respiratory failure on veno-venous extracorporeal membrane oxygenation (VV ECMO) based on body mass index (BMI). Eighteen studies with 517 patients were included. Common complications included acute renal failure (175/377, 46.4%), venous thrombosis (175/293, 59.7%), and bleeding (28/293, 9.6%). Of the six cohort studies, two showed improved mortality among obese patients, two showed a trend toward improved mortality, and two showed no difference. Comparing all patients in the studies with BMI of less than 30 to those with BMI of greater than or equal to 30, we noted decreased mortality with obesity (92, 37.1% of BMI <30 vs. 30, 11% of BMI ≥30, p ≤ 0.0001). Obesity may be protective against mortality in adult patients undergoing VV ECMO. Morbid and super morbid obesity should not be considered a contraindication to cannulation, with patients with BMI ≥ 80 surviving to discharge. Complications may be high, however, with higher rates of continuous renal replacement therapy and thrombosis among obese patients.

Predicting readmission after bariatric surgery using machine learning.

BACKGROUND: While bariatric surgery is an effective method for achieving long-term weight loss, postoperative readmissions are associated with negative clinical outcomes and significant costs. OBJECTIVES: We aimed to use machine learning (ML) algorithms to predict readmissions and compare results to logistic regression. SETTING: Hospitals participating in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, United States. METHODS: Patients who underwent sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and biliopancreatic diversion with duodenal switch between 2016 and 2020 were selected from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database. Patient variables reported by the MBSAQIP database were analyzed by ML algorithms random forest (RF), gradient boosting (XGB), and deep neural networks (NN), and the results of the predictive models were compared to logistic regression using area under the receiver operating characteristic curve (AUROC). RESULTS: Our study included 863,348 patients, of which 39,068 (4.52%) were readmitted. AUROC scores were XGB .785 (95% CI .784-.786), RF .785 (95% CI .784-.785), and NN .754 (95% CI .753-.754), compared with .62 (95% CI .62-.621) for logistic regression (LR) (P < .001). The sensitivity and specificity for XGB, the best performing model, were 73.81% and 70%, compared with 52.94% and 70% for logistic regression. The most important variables were intervention or reoperation prior to discharge, unplanned ICU admission, initial procedure, and the intraoperative transfusion. CONCLUSIONS: ML demonstrates significant advantages over logistic regression when predicting 30-day readmission following bariatric surgery. With external validation, models could identify the best candidates for early discharge or targeted postdischarge resources.

Computer Vision Analysis of Specimen Mammography to Predict Margin Status.

Intra-operative specimen mammography is a valuable tool in breast cancer surgery, providing immediate assessment of margins for a resected tumor. However, the accuracy of specimen mammography in detecting microscopic margin positivity is low. We sought to develop a deep learning-based model to predict the pathologic margin status of resected breast tumors using specimen mammography. A dataset of specimen mammography images matched with pathology reports describing margin status was collected. Models pre-trained on radiologic images were developed and compared with models pre-trained on non-medical images. Model performance was assessed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). The dataset included 821 images and 53% had positive margins. For three out of four model architectures tested, models pre-trained on radiologic images outperformed domain-agnostic models. The highest performing model, InceptionV3, showed a sensitivity of 84%, a specificity of 42%, and AUROC of 0.71. These results compare favorably with the published literature on surgeon and radiologist interpretation of specimen mammography. With further development, these models could assist clinicians with identifying positive margins intra-operatively and decrease the rate of positive margins and re-operation in breast-conserving surgery.

Vapor Cannabis Exposure Generationally Affects Male Reproductive Functions in Mice.

This study was performed to examine whether vapor exposure to cannabis plant matter negatively impacts male reproductive functions and testis development in mice. Adult CD-1 male mice (F0) were exposed to air (control) or 200 mg of vaporized cannabis plant matter 3×/day over a 10-day period. Subsequently, F0 males were bred with drug-naïve CD-1 females to generate F1 males, and F1 offspring were used to generate F2 males. Cannabis vapor exposure decreased sperm count and/or motility in F0 and F1 males and disrupted the progression of germ cell development, as morphometric analyses exhibited an abnormal distribution of the stages of spermatogenesis in F0 males. Although plasma levels of testosterone were not affected by cannabis exposure in any ages or generations of males, dysregulated steroidogenic enzymes, Cyp11a1 and Cyp19a1, were observed in F0 testis. In the neonatal testis from F1 males, although apoptosis was not altered, DNA damage and DNMT1, but not DNMT3A and DNMT3B, were increased in germ cells following cannabis exposure. In contrast, the alterations of DNA damage and DNMT1 expression were not observed in F2 neonatal males. These results suggest that cannabis vapor exposure generationally affects male reproductive functions, probably due to disruption of spermatogenesis in the developing testis.

A Novel Theory-Based Virtual Reality Training to Improve Patient Safety Culture in the Department of Surgery of a Large Academic Medical Center: Protocol for a Mixed Methods Study.

BACKGROUND: Preventable surgical errors of varying degrees of physical, emotional, and financial harm account for a significant number of adverse events. These errors are frequently tied to systemic problems within a health care system, including the absence of necessary policies/procedures, obstructive cultural hierarchy, and communication breakdown between staff. We developed an innovative, theory-based virtual reality (VR) training to promote understanding and sensemaking toward the holistic view of the culture of patient safety and high reliability. OBJECTIVE: We aim to assess the effect of VR training on health care workers' (HCWs') understanding of contributing factors to patient safety events, sensemaking of patient safety culture, and high reliability organization principles in the laboratory environment. Further, we aim to assess the effect of VR training on patient safety culture, TeamSTEPPS behavior scores, and reporting of patient safety events in the surgery department of an academic medical center in the clinical environment. METHODS: This mixed methods study uses a pre-VR versus post-VR training study design involving attending faculty, residents, nurses, technicians of the department of surgery, and frontline HCWs in the operation rooms at an academic medical center. HCWs' understanding of contributing factors to patient safety events will be assessed using a scale based on the Human Factors Analysis and Classification System. We will use the data frame theory framework, supported by a semistructured interview guide to capture the sensemaking process of patient safety culture and principles of high reliability organizations. Changes in the culture of patient safety will be quantified using the Agency for Healthcare Research and Quality surveys on patient safety culture. TeamSTEPPS behavior scores based on observation will be measured using the Teamwork Evaluation of Non-Technical Skills tool. Patient safety events reported in the voluntary institutional reporting system will be compared before the training versus those after the training. We will compare the Agency for Healthcare Research and Quality patient safety culture scores and patient safety events reporting before the training versus those after the training by using descriptive statistics and a within-subject 2-tailed, 2-sample t test with the significance level set at .05. RESULTS: Ethics approval was obtained in May 2021 from the institutional review board of the University of North Carolina at Chapel Hill (22-1150). The enrollment of participants for this study will start in fall 2022 and is expected to be completed by early spring 2023. The data analysis is expected to be completed by July 2023. CONCLUSIONS: Our findings will help assess the effectiveness of VR training in improving HCWs' understanding of contributing factors of patient safety events, sensemaking of patient safety culture, and principles and behaviors of high reliability organizations. These findings will contribute to developing VR training to improve patient safety culture in other specialties.

Impact of the Rural Physician Associate Program on Workforce Outcomes.

BACKGROUND AND OBJECTIVES: The Rural Physician Associate Program (RPAP) at the University of Minnesota Medical School (UMMS) is a 9-month rural longitudinal integrated clerkship (LIC) for third-year medical students built on a foundation of family medicine. The purpose of this study was to examine the relationships between participation in the RPAP program and the desired workforce outcomes of practice in Minnesota, primary care specialty (particularly family medicine), and rural practice. METHODS: We analyzed workforce outcomes for UMMS graduates who completed postgraduate training between 1975 and 2017, comparing RPAP participants (n=1,217) to noparticipants (n=7,928). We identified graduates through internal UMMS databases linked to the American Medical Association (AMA) Physician Masterfile and the National Provider Identifier (NPI) registry. We identified workforce outcomes of rural practice, practice in Minnesota, primary care specialty, and family medicine specialty based on practice specialty and practice location data available through the AMA and NPI data sets. RESULTS: Proportionally, more RPAP graduates practice in state (65.7% vs 54.4%, P<.01), in primary care (69.0% vs 33.4%, P<.01), in family medicine (61.1% vs 17.3%, P<.01), and rurally (41.2% vs 13.9%, P<.01) than non-RPAP graduates. CONCLUSIONS: We demonstrate a significant association between participation in RPAP and a career in family medicine, rural practice, and primary care, all outcomes that promote meeting urgent rural workforce needs.

ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links.

Topoisomerase 2 (TOP2) DNA transactions proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA-protein cross-links are resolved is unclear. We found that the SUMO (small ubiquitin-related modifier) ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc. The ZATT SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a "split-SIM" SUMO2 engagement platform. These findings uncover a ZATT-TDP2-catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc.