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Ability to predict the risk of intraoperative adverse events (IOAEs) for patients undergoing partial nephrectomy (PN) can be of great clinical significance.To develop and internally validate a preoperative nomogram predicting IOAEs for robot-assisted PN (RAPN).In this observational study, data for demographic, preoperative, and postoperative variables for patients who underwent RAPN were extracted from the Vattikuti Collective Quality Initiative (VCQI) database.IOAEs were defined as the occurrence of intraoperative surgical complications, blood transfusion, or conversion to open surgery/radical nephrectomy. Backward stepwise logistic regression analysis was used to identify predictors of IOAEs. The nomogram was validated using bootstrapping, the area under the receiver operating characteristic curve (AUC), and the goodness of fit. Decision curve analysis (DCA) was used to determine the clinical utility of the model.Among the 2114 patients in the study cohort, IOAEs were noted in 158 (7.5%). Multivariable analysis identified five variables as independent predictors of IOAEs: RENAL nephrometry score (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.02-1.25); clinical tumor size (OR 1.01, 95% CI 1.001-1.024); PN indication as absolute versus elective (OR 3.9, 95% CI 2.6-5.7) and relative versus elective (OR 4.2, 95% CI 2.2-8); Charlson comorbidity index (OR 1.17, 95% CI 1.05-1.30); and multifocal tumors (OR 8.8, 95% CI 5.4-14.1). A nomogram was developed using these five variables. The model was internally valid on bootstrapping and goodness of fit. The AUC estimated was 0.76 (95% CI 0.72-0.80). DCA revealed that the model was clinically useful at threshold probabilities5%. Limitations include the lack of external validation and selection bias.We developed and internally validated a nomogram predicting IOAEs during RAPN.We developed a preoperative model than can predict complications that might occur during robotic surgery for partial removal of a kidney. Tests showed that our model is fairly accurate and it could be useful in identifying patients with kidney cancer for whom this type of surgery is suitable.

NVL-520 Modeling, Properties, Biochemical Activity, Cellular Activity, and In Vivo Activity

ROS1 tyrosine kinase inhibitors (TKI) have been approved (crizotinib and entrectinib) or explored (lorlatinib, taletrectinib, and repotrectinib) for the treatment of ROS1 fusion–positive cancers, although none of them simultaneously address the need for broad resistance coverage, avoidance of clinically dose-limiting TRK inhibition, and brain penetration. NVL-520 is a rationally designed macrocycle with >50-fold ROS1 selectivity over 98% of the kinome tested. It is active in vitro against diverse ROS1 fusions and resistance mutations and exhibits 10- to 1,000-fold improved potency for the ROS1 G2032R solvent-front mutation over crizotinib, entrectinib, lorlatinib, taletrectinib, and repotrectinib. In vivo, it induces tumor regression in G2032R-inclusive intracranial and patient-derived xenograft models. Importantly, NVL-520 has an ∼100-fold increased potency for ROS1 and ROS1 G2032R over TRK. As a clinical proof of concept, NVL-520 elicited objective tumor responses in three patients with TKI-refractory ROS1 fusion–positive lung cancers, including two with ROS1 G2032R and one with intracranial metastases, with no observed neurologic toxicities.Significance:The combined preclinical features of NVL-520 that include potent targeting of ROS1 and diverse ROS1 resistance mutations, high selectivity for ROS1 G2032R over TRK, and brain penetration mark the development of a distinct ROS1 TKI with the potential to surpass the limitations of earlier-generation TKIs for ROS1 fusion–positive patients.This article is highlighted in the In This Issue feature, p. 517

Background Postoperative renal function impairment represents a main limitation for delivering adjuvant chemotherapy after radical nephroureterectomy (RNU). Objective To create a model predicting renal function decline after minimally invasive RNU. Design, setting, and participants A total of 490 patients with nonmetastatic UTUC who underwent minimally invasive RNU were identified from a collaborative database including 17 institutions worldwide (February 2006 to March 2020). Renal function insufficiency for cisplatin-based regimen was defined as estimated glomerular filtration rate (eGFR) 50 ml/min/1.73 m2 (n = 361) were geographically divided into a training set (n = 226) and an independent external validation set (n = 135) for further analysis. Outcome measurements and statistical analysis Using transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, a nomogram to predict postoperative eGFR Results and limitations The model that incorporated age, body mass index, preoperative eGFR, and hydroureteronephrosis was developed with an area under the curve of 0.771, which was confirmed to be 0.773 in the external validation set. The calibration curve demonstrated good agreement. Besides, the model was converted into a risk score with a cutoff value of 0.583, and the difference between the low- and high-risk groups both in overall death risk (hazard ratio [HR]: 4.59, p Conclusions A nomogram incorporating immediately available clinical variables can accurately predict renal insufficiency for cisplatin-based adjuvant chemotherapy after minimally invasive RNU and may serve as a tool facilitating patient selection. Patient summary We have developed a model for the prediction of renal function loss after radical nephroureterectomy to facilitate patient selection for perioperative chemotherapy.

ROS1 tyrosine kinase inhibitors (TKI) have been approved (crizotinib and entrectinib) or explored (lorlatinib, taletrectinib, and repotrectinib) for the treatment of ROS1 fusion–positive cancers, although none of them simultaneously address the need for broad resistance coverage, avoidance of clinically dose-limiting TRK inhibition, and brain penetration. NVL-520 is a rationally designed macrocycle with >50-fold ROS1 selectivity over 98% of the kinome tested. It is active in vitro against diverse ROS1 fusions and resistance mutations and exhibits 10- to 1,000-fold improved potency for the ROS1 G2032R solvent-front mutation over crizotinib, entrectinib, lorlatinib, taletrectinib, and repotrectinib. In vivo, it induces tumor regression in G2032R-inclusive intracranial and patient-derived xenograft models. Importantly, NVL-520 has an ∼100-fold increased potency for ROS1 and ROS1 G2032R over TRK. As a clinical proof of concept, NVL-520 elicited objective tumor responses in three patients with TKI-refractory ROS1 fusion–positive lung cancers, including two with ROS1 G2032R and one with intracranial metastases, with no observed neurologic toxicities.Significance:The combined preclinical features of NVL-520 that include potent targeting of ROS1 and diverse ROS1 resistance mutations, high selectivity for ROS1 G2032R over TRK, and brain penetration mark the development of a distinct ROS1 TKI with the potential to surpass the limitations of earlier-generation TKIs for ROS1 fusion–positive patients.This article is highlighted in the In This Issue feature, p. 517

Background The use of a nephron-sparing surgery for the treatment of localized renal masses is being pushed to more challenging cases. However, this procedure is not devoid of risks, and the Radius, Exophytic/Endophytic, Nearness, Anterior/Posterior, Location (RENAL) and Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) classifications are commonly employed in the prediction of complications. Recently, the Simplified PADUA REnal (SPARE) scoring system has been proposed with the aim to provide a more simple system, to improve its reproducibility to predict postoperative risks. Objective We aim to retrospectively validate and compare the proposed new SPARE system in a multi-institutional population. Design, setting, and participants The Transatlantic Robotic Nephron-sparing Surgery (TRoNeS) study group collected data from 737 patients subjected to robot-assisted partial nephrectomy (RAPN) between 2010 and 2016 at three tertiary care referral centers. Of these patients, 536 presented complete demographic and clinical data. Outcome measurements and statistical analysis Renal masses were classified according to the SPARE, RENAL, and PADUA nephrometry scores, and surgical success was defined according to the margin, ischemia, and complication scores. Results and limitations Of 536 patients, 340 were male; the median age was 61 (53–69) yr and preoperative tumor size was 30 (22–43) mm. The margin, ischemia, and complication score was achieved in 399 of cases (74.4%). All three nephrometry scores were significant predictors of surgical outcomes both in univariate and in adjusted multivariate logistic regression model analysis. In accuracy analysis, the area under the curve (AUC) of the SPARE scoring system (0.73) was significantly higher than those of the PADUA (0.65) and RENAL (0.68) nephrometry scores in predicting surgical success. Conclusions The SPARE score appears to be a promising and reliable score for the prediction of surgical outcomes of RAPN, showing a higher accuracy relative to the traditional PADUA and RENAL nephrometry scores. Further, prospective studies are warranted before its introduction in clinical practice. Patient summary The Simplified PADUA REnal (SPARE) score is a reproducible and simple nephrometry score, offering better predictive capabilities of surgical success and complications.

Intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) has an incidence of approximately 20%-50%. Studies to date have been composed of mixed treatment cohorts-open, laparoscopic and robotic. The objective of this study is to assess clinicopathological risk factors for intravesical recurrence after RNU for UTUC in a completely minimally invasive cohort.We performed a multicenter, retrospective analysis of 485 patients with UTUC without prior or concurrent bladder cancer who underwent robotic or laparoscopic RNU. Patients were selected from an international cohort of 17 institutions across the United States, Europe and Asia. Univariate and multiple Cox regression models were used to identify risk factors for bladder recurrence.A total of 485 (396 robotic, 89 laparoscopic) patients were included in analysis. Overall, 110 (22.7%) of patients developed IVR. The average time to recurrence was 15.2 months (SD 15.5 months). Hypertension was a significant risk factor on multiple regression (HR 1.99, CI 1.06; 3.71, p=0.030). Diagnostic ureteroscopic biopsy incurred a 50% higher chance of developing IVR (HR 1.49, CI 1.00; 2.20, p=0.048). Treatment specific risk factors included positive surgical margins (HR 3.36, CI 1.36; 8.33, p=0.009) and transurethral resection for bladder cuff management (HR 2.73, CI 1.10; 6.76, p=0.031).IVR after minimally invasive RNU for UTUC is a relatively common event. Risk factors include a ureteroscopic biopsy, transurethral resection of the bladder cuff, and positive surgical margins. When possible, avoidance of transurethral resection of the bladder cuff and alternative strategies for obtaining biopsy tissue sample should be considered.

Planning complex operations such as robotic-assisted radical prostatectomy requires surgeons to review 2-dimensional magnetic resonance imaging (MRI) cross-sectional images to understand 3-dimensional (3D), patient-specific anatomy. We sought to determine surgical outcomes for robotic-assisted radical prostatectomy when surgeons reviewed 3D, virtual reality (VR) models for operative planning.A multicenter, randomized, single-blind clinical trial was conducted from January 2019 to December 2020. Patients undergoing robotic-assisted laparoscopic radical prostatectomy were prospectively enrolled and randomized to either a control group undergoing usual preoperative planning with prostate biopsy results and MRI only or to an intervention group where MRI and biopsy results were supplemented with a 3D VR model. The primary outcome measure was margin status, and secondary outcomes were oncologic control, sexual function and urinary function.Ninety-two patients were analyzed, with trends toward lower positive margin rates (33% vs 25%) in the intervention group, no significant difference in functional outcomes and no difference in traditional operative metrics (p0.05). Detectable postoperative prostate specific antigen was significantly lower in the intervention group (31% vs 9%, p=0.036). In 32% of intervention cases, the surgeons modified their operative plan based on the model. When this subset was compared to the control group, there was a strong trend toward increased bilateral nerve sparing (78% vs 92%), and a significantly lower rate of postoperative detectable prostate specific antigen in the intervention subset (31% vs 0%, p=0.038).This randomized clinical trial demonstrated patients whose surgical planning involved 3D VR models have better oncologic outcomes while maintaining functional outcomes.

Background We previously reported a new post–radical prostatectomy (RP) prediction model for men with normal baseline erectile function (EF) using 90-d postoperative erection fullness to identify men who might benefit from early EF rehabilitation. Objective To prospectively internally and externally validate the use of this risk assessment model in predicting 1- and 2-yr post-RP EF recovery. Design, setting, and participants We randomly assigned 297 patients with a preoperative International Index of Erectile Function 5 score of 22–25 undergoing robot-assisted RP by a single surgeon to a training set and internal validation set at a ratio of 2:1. A prospective external validation set included 91 patients treated by five high-volume surgeons. Outcome measurements and statistical analysis Potency was defined as erections sufficient for intercourse. To predict 1- and 2-yr potency recovery, logistic regression models were developed in the training set based on 90-d erection fullness of 0–24% or 25–100%. The resultant models were applied to the internal and external validation sets to calculate risk scores for 1- and 2-yr potency for each patient. Predictive validity was assessed using receiver operating characteristic (ROC) curves. Results and limitations Percentage erection fullness was an independent predictor of 1- and 2-yr potency recovery in all data sets. Internal validation confirmed strong reliability in predicting 2-yr potency outcomes (area under the ROC curve [AUC] 0.87) and external validation illustrated similar reliability in predicting 1-yr potency outcomes (AUC 0.80). In the external validation, the model predicted a mean 1-yr potency recovery rate of 39.7% (standard deviation 3.2%), compared to the actual rate of 36.26%. Limitations include the short follow-up for this cohort. Conclusions We present internal and external validation of a 90-d percentage erection fullness score, confirming that this metric is a robust predictor of post-RP EF recovery. Patient summary Percentage erection fullness at 3 mo after radical prostatectomy discriminates patients with a low or a high probability of recovery of erectile function (EF), which can facilitate identification of a need for early EF rehabilitation.

OBJECTIVE To prospectively compare the effects of endoscopic stapling, division and suture ligation, and suture ligation with suspension of the dorsal venous complex (DVC) on continence during robot-assisted laparoscopic radical prostatectomy (RARP). PATIENTS AND METHODS In all, 300 consecutive patients undergoing RARP by a single surgeon were randomised to three groups: endoscopic stapling, cut and suture ligation, and suture ligation with suspension. The only difference between the groups was the technique to control the DVC. Pad-free continence (PFC) and overall continence (0 pads/day with or without security pad) were assessed with patient reported pad usage records and validated questionnaires (Expanded Prostate Cancer Index) at 3, 12, and 15 months. Secondary endpoints were erectile function (EF) recovery (defined as erections sufficient for sexual activity) and the rate of apical surgical margins. Univariate and multivariate analyses were conducted to determine predictors for recovery of both urinary continence and EF. RESULTS The three groups were comparable in terms of age, body mass index, prostate size, American Urological Association symptom score, Sexual Health Inventory for Men, and clinical stage. There were no differences found in terms of operative times, estimated blood loss, pathological stage, and positive apical margin. There was no difference between the three groups with regard to overall continence or PFC at 3 months. However, overall continence at 15 months for ligation and suspension was 99% and was superior to stapler (88%) (P = 0.002) and cut and suture ligation (88%) (P = 0.002). Additionally, PFC at 15 months was superior for ligation and suspension (87%) as compared to stapler (73%) and cut and suture ligation (75%) (P = 0.045). The technique of DVC control did not impact EF. Men with nerve sparing had better continence compared to no nerve sparing at 3 months (62% vs 42%, P = 0.045), but not at 15 months. The median time to continence was 2 months for patients receiving nerve sparing compared to 4.5 months for non-nerve sparing (P = 0.02). CONCLUSION Suture suspension of the DVC during RARP contributes to higher overall continence rates compared to stapling and cut and suture. Nerve sparing contributes to earlier return of continence than non-nerve sparing.

To prospectively compare standard and valve-less insufflation systems on pneumoperitoneum-related complications in robotic-assisted laparoscopic partial nephrectomy. A prospective randomized controlled trial was conducted during a 1.5-year period to compare insufflation-related complications in partial nephrectomy surgery by a single surgeon. Thirty-one patients were recruited for each group: AirSeal insufflation system at 12 mmHg (AIS12), AirSeal at 15 mmHg (AIS15), and conventional insufflation system at 15 mmHg (CIS). Primary outcome assessed was rate of subcutaneous emphysema. Secondary outcomes included rates of pneumothorax, pneumomediastinum, shoulder pain scores, overall pain scores, pain medication usage, insufflation time, recovery room time, length of hospital stay and impact of surgical approach. Predictors for subcutaneous emphysema were assessed with univariate and multivariate logistic models. 93 patients with similar baseline characteristics were randomized into the three insufflation groups. Incidence of subcutaneous emphysema was lower in the AIS12 group compared to CIS (19% vs 48%, p = 0.03,). Mean pain score was less for AIS12 compared to CIS at 12 h (3.1 vs 4.4, p = 0.03). Shoulder pain was less in AIS12 and AIS15 groups compared to CIS at 8 h (AIS12 vs CIS: 0.6 vs 1.6, p = 0.01, AIS15 vs CIS: 0.6 vs 1.6, p = 0.02), and between AIS12 as compared to CIS at 12 h (0.4 vs 1.4, p = 0.003) postoperatively. There was no difference between morphine equivalent use, insufflation time, recovery room time, and length of hospital stay. Multivariable regression analysis showed AirSeal at 12 mmHg and the transperitoneal approach to be the only significant predictors for lower risk of developing subcutaneous emphysema (p

Objective To predict intra-operative (IOEs) and postoperative events (POEs) consequential to the derailment of the ideal clinical course of patient recovery. Materials and methods The Vattikuti Collective Quality Initiative is a multi-institutional dataset of patients who underwent robot-assisted partial nephectomy for kidney tumours. Machine-learning (ML) models were constructed to predict IOEs and POEs using logistic regression, random forest and neural networks. The models to predict IOEs used patient demographics and preoperative data. In addition to these, intra-operative data were used to predict POEs. Performance on the test dataset was assessed using area under the receiver-operating characteristic curve (AUC-ROC) and area under the precision-recall curve (PR-AUC). Results The rates of IOEs and POEs were 5.62% and 20.98%, respectively. Models for predicting IOEs were constructed using data from 1690 patients and 38 variables; the best model had an AUC-ROC of 0.858 (95% confidence interval [CI] 0.762, 0.936) and a PR-AUC of 0.590 (95% CI 0.400, 0.759). Models for predicting POEs were trained using data from 1406 patients and 59 variables; the best model had an AUC-ROC of 0.875 (95% CI 0.834, 0.913) and a PR-AUC 0.706 (95% CI, 0.610, 0.790). Conclusions The performance of the ML models in the present study was encouraging. Further validation in a multi-institutional clinical setting with larger datasets would be necessary to establish their clinical value. ML models can be used to predict significant events during and after surgery with good accuracy, paving the way for application in clinical practice to predict and intervene at an opportune time to avert complications and improve patient outcomes.

To compare perioperative outcomes following robot-assisted partial nephrectomy (RAPN) in patients with age ≥ 70 years to age 70 years.Using Vattikuti Collective quality initiative (VCQI) database for RAPN we compared perioperative outcomes following RAPN between the two age groups. Primary outcome of the study was to compare trifecta outcomes between the two groups. Propensity matching using nearest neighbourhood method was performed with trifecta as primary outcome for sex, body mass index (BMI), solitary kidney, tumor size and Renal nephrometery score (RNS).Group A (age ≥ 70 years) included 461 patients whereas group B included 1932 patients. Before matching the two groups were statistically different for RNS and solitary kidney rates. After propensity matching, the two groups were comparable for baselines characteristics such as BMI, tumor size, clinical symptoms, tumor side, face of tumor, solitary kidney and tumor complexity. Among the perioperative outcome parameters there was no difference between two groups for operative time, blood loss, intraoperative transfusion, intraoperative complications, need for radical nephrectomy, positive margins and trifecta rates. Warm ischemia time was significantly longer in the younger age group (18.1 min vs. 16.3 min, p = 0.003). Perioperative complications were significantly higher in the older age group (11.8% vs. 7.7%, p = 0.041). However, there was no difference between the two groups for major complications.RAPN in well-selected elderly patients is associated with comparable trifecta outcomes with acceptable perioperative morbidity.

To compare perioperative outcomes following retroperitoneal robot-assisted partial nephrectomy (RPRAPN) and transperitoneal robot-assisted partial nephrectomy (TPRAPN).With this Vattikuti Collective Quality Initiative (VCQI) database, study propensity scores were calculated according to the surgical access (TPRAPN and RPRAPN) for the following independent variables, i.e., age, sex, side of the surgery, RENAL nephrometry scores (RNS), estimated glomerular filtration rate (eGFR) and serum creatinine. The study's primary outcome was the comparison of trifecta between the two groups.In this study, 309 patients who underwent RPRAPN were matched with 309 patients who underwent TPRAPN. The two groups matched well for age, sex, tumor side, polar location of the tumor, RNS, preoperative creatinine and eGFR. Operative time and warm ischemia time were significantly shorter with RPRAPN. Intraoperative blood loss and need for blood transfusion were lower with RPRAPN. There was a significantly higher number of intraoperative complications with RPRAPN. However, there was no difference in the two groups for postoperative complications. Trifecta outcomes were better with RPRAPN (70.2% vs. 53%, p 0.0001) compared to TPRAPN. We noted no significant change in overall results when controlled for tumor location (anteriorly or posteriorly). The surgical approach, tumor size and RNS were identified as independent predictors of trifecta on multivariate analysis.RPRAPN is associated with superior perioperative outcomes in well-selected patients compared to TPRAPN. However, the data for the retroperitoneal approach were contributed by a few centers with greater experience with this technique, thus limiting the generalizability of the results of this study.

Background Radical nephroureterectomy (RNU) represents the standard of care for high grade upper tract urothelial carcinoma (UTUC). Open and laparoscopic approaches are well-established treatments, but evidence regarding robotic RANU is growing. The introduction of the Xi® system facilitates the implementation of this multi-quadrant procedure. The aim of this video-article is to describe the surgical steps and the outcomes of Xi® robotic RNU. Methods Single stage Xi® robotic RNU without patients repositioning and robot re-docking were done between 2015 and 2019 and collected in a large worldwide multi-institutional study, the ROBotic surgery for Upper tract Urothelial cancer STudy (ROBUUST). Institutional review board approval and data share agreement were obtained at each center. Surgical technique is described in detail in the accompanying video. Descriptive statistics of baseline characteristics and surgical, pathological, and oncological outcomes were analyzed. RESULTSː Overall, 148 patients were included in the analysis; 14% had an ECOG >1 and 68.2% ASA ≥3. Median tumor dimension was 3.0 (IQR:2.0-4.2) cm and 34.5% showed hydronephrosis at diagnosis. Forty-eight% were cT1 tumors. Bladder cuff excision and lymph node dissection were performed in 96% and 38.1% of the procedures, respectively. Median operative time and estimated blood loss were 215.5 (IQR:160.5-290.0) minutes and 100.0 (IQR: 50.0-150.0) mL, respectively. Approximately 56% of patients took opioids during hospital stay for a total morphine equivalent dose of 22.9 (IQR:16.0-60.0) milligrams equivalent. Postoperative complications were 26 (17.7%), with 4 major (15.4%). Seven patients underwent adjuvant chemotherapy, with median number of cycles of 4.0 (IQR:3.0-6.0). Conclusions Single stage Xi® RNU is a reproducible and safe minimally invasive procedure for treatment of UTUC. Additional potential advantages of the robot might be a wider implementation of LND with a minimally invasive approach.

BACKGROUND The aim of this study is to evaluate the association between tumor complexity based on RENAL nephrometry score and complications. METHODS We retrospectively identified 2555 patients who underwent RPN for renal cell carcinoma. Major complication was defined as clavien grade≥3. The relationship between baseline demographic, clinical characteristics, perioperative and postoperative outcomes, and tumor complexity were assessed using Chi-square test of independence, Fishers exact and Kruskal Wallis test. An unadjusted and adjusted logistic regression model was used to assess the relationship between major complication and demographic, clinical characteristics, and perioperative outcomes. RESULTS There was a significant relationship between tumor complexity and WIT(p

656 Background: Pathological upstaging to T3a disease may occur following radical (RN) or partial nephrectomy (PN) for patients with T1/T2 renal cell carcinoma (RCC). While a number of studies have demonstrated increased risk of T1/T2 upstaging to pT3a compared to initial staging, a comparison of pathologically upstaged T3a RCC and T3a RCC which was not upstaged has not been performed. We sought to compare survival outcomes and predictors of outcomes in patients who underwent surgical therapy for upstaged T3a RCC versus non-upstaged pT3a RCC. Methods: We conducted a retrospective analysis of a multi-institutional dataset of patients who underwent radical (RN) or partial nephrectomy (PN) with final pathologic stage of pT3a. Patients were classified as being upstaged (US) from cT1 or cT2 or non-upstaged (NUS) with cT3a disease. Primary outcome was Overall Survival (OS)/all-cause mortality (ACM). Secondary outcomes were Cancer-Specific Survival (CSS)/Cancer-Specific Mortality (CSM), and Recurrence-Free survival (PFS)/Recurrence. Multivariable Cox regression analysis (MVA) were conducted for predictors of mortality outcomes and Kaplan Meier Analyses (KMA) were conducted to elucidate survival outcomes comparing US and NUS groups. Results: We analyzed 879 patients [US 691 (cT1 389/cT2 302); NUS 188; median follow-up 48 months). NUS had significantly greater tumor size (9.3 vs. US 7.3 cm, p

OBJECTIVE To develop a structured and objective scoring tool for assessment of robot assisted partial nephrectomy (RAPN): Scoring for Partial Nephrectomy (SPaN). MATERIALS AND METHODS Content development: RAPN was deconstructed into 6 domains by a multi-institutional panel of 10 expert robotic surgeons. Performance on each domain was represented on a Likert scale of 1-5, with specific descriptions of anchors 1, 3 and 5. Content validation: The Delphi methodology was utilized to achieve consensus about the description of each anchor for each domain in terms of appropriateness of the skill assessed, objectiveness, clarity, and unambiguous wording. The content validity index (CVI) of ≥0.75 was set as cut-off for consensus. Reliability: 15 de-identified videos of RAPN were utilized to determine the inter-rater reliability using linearly weighted percent agreement, and Construct validation of SPaN was described in terms of median scores and odds ratios. RESULTS The expert panel reached consensus (CVI ≥ 0.75) after 2 rounds. Consensus was achieved for 36 (67%) statements in the first round and 18 (33%) after the second round. The final six-domain SPaN included: Exposure of the kidney; Identification and dissection of the ureter and gonadal vessels; Dissection of the hilum; Tumor localization and exposure; Clamping and tumor resection; and Renorrhaphy. The linearly weighted percent agreement was > 0.75 for all domains. There was no difference between median scores for any domain between attendings and trainees. CONCLUSION Despite the lack of signification construct validity, SPaN is a structured, reliable and procedure-specific tool that can objectively assesses technical proficiency for RAPN.

OBJECTIVE To analyse whether selective arterial clamping (SAC) and off-clamp (OC) techniques during robot-assisted partial nephrectomy (RPN) are associated with a renal functional benefit in patients with Stage 3-5 chronic kidney disease (CKD). PATIENTS AND METHODS The change in estimated glomerular filtration rate (eGFR) over time was compared between 462 patients with baseline CKD 3-5 that underwent RPN with main arterial clamping (MAC) (n = 375, 81.2%), SAC (n = 48, 10.4%) or OC (n = 39, 8.4%) using a multivariable linear mixed-effects model. All follow-up eGFRs, including baseline and follow-up between 3 and 24 months, were included in the model for analysis. The median follow-up was 12.0 months (interquartile range 6.7-16.5; range 3.0-24.0 months). RESULTS In the multivariable linear mixed-effects model adjusting for characteristics including tumour size and the R.E.N.A.L. (Radius; Exophytic/Endophytic; Nearness; Anterior/Posterior; Location) Nephrometry Score, the change in eGFR over time was not significantly different between SAC and MAC RPN (β = -1.20, 95% confidence interval [CI] -5.45, 3.06; P = 0.582) and OC and MAC RPN (β = -1.57, 95% CI -5.21, 2.08; P = 0.400). Only 20 (15 MAC, two SAC, three OC) patients overall had progression of their CKD stage at last follow-up. The mean ischaemia time was 17 min for MAC and 15 min for SAC. There was no benefit to SAC or OC in terms of blood loss, perioperative complications, length of stay, or surgical margins. CONCLUSION SAC and OC techniques during RPN were not associated with benefit in preservation of eGFR in patients with baseline CKD.

Objectives: To evaluate the feasibility of postoperative day 1 (POD1) discharge after robotic partial nephrectomy (RPN) and to determine whether a protocol targeting a shorter length of stay (LOS) ...

Objective To determine the safety and efficacy of performing partial nephrectomy (PN) on patients with high nephrometry score tumors. Patients and methods We used a prospectively maintained multi-institutional kidney cancer database to identify 144 patients with R.E.N.A.L. nephrometry score ≥10 who underwent PN for a cT1-cT2 renal mass. Baseline demographics and clinical characteristics, tumor characteristics, perioperative, and pathological outcomes were analyzed and reported. Trifecta achievement, defined by warm ischemia time Results Baseline median eGFR was 84.57 ml/min/1.73 m2, with 119 (84.39%) patients having normal baseline kidney function. The median clinical tumor size was 4.95 cm, with 74 (51.75%) being completely endophytic and 58 (41.73%) located on the hilum. The median ischemia time was 20 minutes. Median estimated blood loss was 150 ml. Twelve patients (8.33%) had intraoperative complications. No patient had a conversion to open surgery. Postoperative, perioperative, and major complication rate were 10.42%, 17.3%, and 2.34% respectively. Thirty-six patients (37.89%) developed postoperative acute kidney injury and 28 (20.90%) developed new-onset CKD at a median follow-up of 6 months. Eight patients (5.56%) had a positive surgical margin. Trifecta was achieved in 89 (61.81%) patients. There was no significant difference in baseline, clinical, and tumor characteristics between those that achieved trifecta and in those where trifecta was not. Pathologic tumor stage was the only factor significantly associated with trifecta achievement (P = 0.025). Conclusion In treating complex renal tumors, PN should be performed when possible. Although this remains a challenging procedure, with experience and appropriate case selection, the trifecta outcome can be achieved in a significant number of patients with high renal score lesions.

Introduction: As the prevalence of obesity increases worldwide, an increasing proportion of surgical candidates have an elevated body mass index (BMI), with associated metabolic syndrome. ...

Purpose of review Robotic-assisted laparoscopic retroperitoneal lymph node dissection (R-RPLND) is gaining acceptance as an alternative to open and laparoscopic RPLND for the treatment of testicular cancer. We discuss the current state of R-RPLND and summarize the latest relevant literature regarding the feasibility of this operation. Recent findings R-RPLND has been utilized effectively for both treatment of high-risk, clinical stage I testicular cancer as well as in the postchemotherapy setting. The feasibility of R-RPLND has been established with complication rates comparable to open RPLND and with decreased postoperative hospital stay and blood loss. Summary As R-RPLND continues to evolve and experience grows in high-volume centers, more information will be gained regarding long-term oncologic outcomes. Ultimately, head-to-head trials comparing R-RPLND to open RPLND will be needed to determine the role of R-RPLND in the treatment of testicular cancer.

OBJECTIVES: To analyze the outcomes of patients in whom cortical (outer) renorrhaphy (CR) was omitted during robotic partial nephrectomy (RPN). METHODS: We analyzed 1453 patients undergoing RPN, from 2006 to 2018, within a large multi-institutional database. Patients having surgery for bilateral tumors (n = 73) were excluded. CR and no-CR groups were compared in terms of operative and ischemia time, estimated blood loss (EBL), complications, surgical margins, hospital stay, change in estimated glomerular filtration rate (eGFR), and need of angioembolization. Inverse probability of treatment weighting with Firth correction for center code was performed to account for selection bias. RESULTS: CR was omitted in 120 patients (8.7%); 1260 (91.3%) patients underwent both inner layer and CR. There was no difference in intraoperative complications (7.4% CR; 8.9% no-CR group; P = .6), postoperative major complications (1% and 2.8% in CR and no-CR groups, respectively; P = .2), or median drop in eGFR (7.3 vs 10.4 mL/min/m2). The no-CR group had a higher incidence of minor complications (26.7% vs 5.5% in CR group; P < .001). EBL was 100 mL (IQR 50-200) in both groups (P = .6). Angioembolization was needed in 0.7% patients in CR vs 1.4% in no-CR group (P = .4). Additionally, there was no difference in median operative time (168 vs 162 min; P = .2) or ischemia time (18 vs 17 min; P = .7). CONCLUSION: In selected patients with renal masses, single layer renorrhaphy does not significantly improve operative time, ischemia time, or eGFR after RPN. There is a higher incidence of minor complications, but not major perioperative complications after no-CR technique.

Background: The role of race on functional outcomes after robotic partial nephrectomy (RPN) is still a matter of debate. We aimed to evaluate the clinical and pathologic characteristics of African American (AA) and Caucasian patients who underwent RPN and analyzed the association between race and functional outcomes. Methods: Data was obtained from a multi-institutional database of patients who underwent RPN in 6 institutions in the USA. We identified 999 patients with complete clinical data. Sixty-three patients (6.3%) were AA, and each patient was matched (1:3) to Caucasian patients by age at surgery, gender, Charlson Comorbidity Index (CCI) and renal score. Bivariate and multivariate logistic regression analyses were used to evaluate predictors of acute kidney injury (AKI). Kaplan-Meier method and multivariable semiparametric Cox regression analyses were performed to assess prevalence and predictors of significant eGFR reduction during follow-up. Results: Overall, 252 patients were included. AA were more likely to have hypertension (58.7% vs. 35.4%, P=0.001), even after 1:3 match. Overall 42 patients (16.7%) developed AKI after surgery and 35 patients (13.9%) developed significant eGFR reduction between 3 and 15 months after RAPN. On multivariate analysis, AA race did not emerge as a significant factor for predicting AKI (OR 1.10, P=0.8). On Cox multivariable analysis, only AKI was found to be associated with significant eGFR reduction between 3 and 15 months after RAPN (HR 2.49, P=0.019). Conclusions: Although African American patients were more likely to have hypertension, renal function outcomes of robotic partial nephrectomies were not significantly different when stratified by race. However, future studies with larger cohorts are necessary to validate these findings.

To prospectively compare standard and valve-less insufflation systems on pneumoperitoneum-related complications in robotic-assisted laparoscopic partial nephrectomy. A prospective randomized controlled trial was conducted during a 1.5-year period to compare insufflation-related complications in partial nephrectomy surgery by a single surgeon. Thirty-one patients were recruited for each group: AirSeal insufflation system at 12 mmHg (AIS12), AirSeal at 15 mmHg (AIS15), and conventional insufflation system at 15 mmHg (CIS). Primary outcome assessed was rate of subcutaneous emphysema. Secondary outcomes included rates of pneumothorax, pneumomediastinum, shoulder pain scores, overall pain scores, pain medication usage, insufflation time, recovery room time, length of hospital stay and impact of surgical approach. Predictors for subcutaneous emphysema were assessed with univariate and multivariate logistic models. 93 patients with similar baseline characteristics were randomized into the three insufflation groups. Incidence of subcutaneous emphysema was lower in the AIS12 group compared to CIS (19% vs 48%, p = 0.03,). Mean pain score was less for AIS12 compared to CIS at 12 h (3.1 vs 4.4, p = 0.03). Shoulder pain was less in AIS12 and AIS15 groups compared to CIS at 8 h (AIS12 vs CIS: 0.6 vs 1.6, p = 0.01, AIS15 vs CIS: 0.6 vs 1.6, p = 0.02), and between AIS12 as compared to CIS at 12 h (0.4 vs 1.4, p = 0.003) postoperatively. There was no difference between morphine equivalent use, insufflation time, recovery room time, and length of hospital stay. Multivariable regression analysis showed AirSeal at 12 mmHg and the transperitoneal approach to be the only significant predictors for lower risk of developing subcutaneous emphysema (p 0.001). Compared to standard insufflation, AirSeal insufflation at 12 mmHg was associated with reduced risk of developing subcutaneous emphysema in robotic partial nephrectomy. Furthermore, shoulder pain was reduced in both AirSeal groups compared to standard insufflation. The retroperitoneal approach increases the risk of developing subcutaneous emphysema.

OBJECTIVES To compare peri-operative outcomes after robot-assisted partial nephrectomy (RAPN) for cT2a (7 to

Objectives To analyze the outcomes of robot-assisted partial nephrectomy (RAPN) in patients with a solitary kidney in a large multi-institutional database. Patients and Methods A total of 2755 patients in the Vattikuti Collective Quality Initiative database underwent RAPN by 22 surgeons at 14 centers in nine 9 countries. Out of these patients, 74 underwent RAPN in solitary kidney between 2007 and 2016. A retrospective analysis of the functional and oncological outcomes was performed. Trifecta was defined as a warm ischemia time of less than 20 minutes, negative surgical margins, and no complications intraoperatively or within 3 months of follow up. Results All 74 patients underwent RAPN successfully with one conversion to radical nephrectomy. The median (interquartile range [IQR]) operative time was 180 (142-230) minutes. Early unclamping was used in 11 (14.9%) cases, while zero ischemia was used in 12 (16.2%) cases. Trifecta outcomes were achieved in 38/66 (57.6%) of the patients. Median (IQR) ischemia time was 15.5 (8.75-20.0) minutes for the entire cohort. Overall complication rate was 24.1% and the rate of Clavien-Dindo ≤2 complications was 16.3%. Positive surgical margins were present in four cases (5.4%). Median (IQR) follow-up was 10.5 (2.12-24.0) months. The median drop in estimated glomerular filtration rate at three months was 7.0 ml/min/1.72m2 (11.01%). Conclusion Our findings suggest that RAPN is a safe and effective treatment option for select renal tumors in solitary kidneys in terms of a trifecta of negative surgical margins, warm ischemia time less than 20 minutes, and low operative and perioperative morbidity. This article is protected by copyright. All rights reserved.

Retroperitoneal lymph node dissection (RPLND) can been employed as primary treatment for stage I non-seminomatous germ cell tumor (NSGCT) as well as for treatment of post-chemotherapy masses. Open RPLND (O-RPLND) has long been the standard approach for lymphadenectomy, but is associated with significant morbidity. Laparoscopic RPLND (L-RPLND) was developed to mitigate the morbidity associated with O-RPLND, but is a technically challenging procedure requiring significant experience with laparoscopic dissection and suturing to remove lymph nodes behind the great vessels and to control vascular injury. Robotic RPLND (R-RPLND) has gained traction in recent years as an alternative to both O-RPLND and L-RPLND. With superior instrument dexterity and better visualization compared to L-RPLND, and with decreased morbidity, compared to O-RPLND, R-RPLND can be performed safely and effectively. With the latest advances in robotic technology, one can perform a full bilateral dissection without needing to reposition the patient or redock the robot. R-RPLND has been applied for both primary treatment as well as in patients with post-chemotherapy residual abdominal masses.

Objectives To determine the risk of COVID-19 transmission during minimally invasive surgical (MIS) procedures METHODS: Surgical society statements regarding the risk of COVID transmission during MIS procedures were reviewed. In addition, the available literature on COVID-19 and other viral transmission in CO2 pneumoperitoneum, as well as the presence of virus in the plume created by electrocautery during MIS was reviewed. The society recommendations were compared to the available literature on the topic to create our review and recommendations to mitigate COVID-19 transmission. Results The recommendations promulgated by various surgical societies evolved over time as more information became available on COVID-19 transmission. Review of the available literature on the presence of COVID-19 in CO2 pneumoperitoneum was inconclusive. There is no clear evidence of the presence of COVID-19 in plume created by electrocautery. Technologies to reduce CO2 pneumoperitoneum release into the operating room as well as filter viral particles are available and should reduce the exposure risk to operating room personnel. Conclusion There is no clear evidence of COVID-19 virus in the CO2 used during MIS procedures or in the plume created by electrocautery. Until the presence or absence of COVID-19 viral particles has been clearly established, measures to mitigate CO2 and surgical cautery plume release into the operating room should be performed. Further study on the presence of COVID-19 in MIS pneumoperitoneum and cautery plume is needed.

BACKGROUND Recent evidence suggests that the "oldest old" patients might benefit of partial nephrectomy (PN), but decision-making for this subset of patients is still controversial. Aim of this study is to compare outcomes of robotic partial (RPN) or radical nephrectomy (RRN) for large renal masses in patients older than 65 years. METHODS We identified 417≥65 years old patients who underwent RRN or RPN for cT1b or ≥cT2 renal mass at 17 high volume centers. Propensity score match analysis was performed adjusting for age, ASA≥3, pre-operative eGFR, and clinical tumor size. Predictors of complications, functional and oncological outcomes were evaluated in multivariable logistic and Cox regression models. RESULTS After propensity score analysis, 73 patients in the RPN group were matched with 74 in the RRN group. R.E.N.A.L. Score (9.6±1.7 vs. 8.6±1.7; P

Robotic-assisted partial nephrectomy (RAPN) continues to gain popularity in the setting of nephron-sparing surgery for small renal masses. Although the recent introduction of technological advancements has allowed for expanded roles for RAPN, the optimal techniques and approaches to the procedure remain controversial.Of recent interest has been the role of warm ischemia time and its impact on postoperative renal function. Available studies suggest that although warm ischemia time remains an independent and modifiable risk factor for postoperative renal function, the role for 'zero ischemia' RAPN is still unclear. Recent studies on complex and/or larger tumors have demonstrated the feasibility of the procedure with comparable short-term outcomes to the open approach. Although these results should currently be considered experimental, they do shed light on the growing role for RAPN. Surgeon comfort and tumor location remain important factors when determining a retroperitoneal or transperitoneal approach. Available research demonstrates shorter operative times, length of stay and potentially lower costs to the retroperitoneal approach.Robotic-assisted partial nephrectomy remains an evolving procedure. Although recent literature suggests the feasibility of new and novel techniques, variable approaches and expanded indications, prospective, long-term follow-up data are needed before a consensus can be reached.

Importance Planning complex operations such as robotic-assisted partial nephrectomy requires surgeons to review 2-dimensional computed tomography or magnetic resonance images to understand 3-dimensional (3-D), patient-specific anatomy. Objective To determine surgical outcomes for robotic-assisted partial nephrectomy when surgeons reviewed 3-D virtual reality (VR) models during operative planning. Design, Setting, and Participants A single-blind randomized clinical trial was performed. Ninety-two patients undergoing robotic-assisted partial nephrectomy performed by 1 of 11 surgeons at 6 large teaching hospitals were prospectively enrolled and randomized. Enrollment and data collection occurred from October 2017 through December 2018, and data analysis was performed from December 2018 through March 2019. Interventions Patients were assigned to either a control group undergoing usual preoperative planning with computed tomography and/or magnetic resonance imaging only or an intervention group where imaging was supplemented with a 3-D VR model. This model was viewed on the surgeon’s smartphone in regular 3-D format and in VR using a VR headset. Main Outcomes and Measures The primary outcome measure was operative time. It was hypothesized that the operations performed using the 3-D VR models would have shorter operative time than those performed without the models. Secondary outcomes included clamp time, estimated blood loss, and length of hospital stay. Results Ninety-two patients (58 men [63%]) with a mean (SD) age of 60.9 (11.6) years were analyzed. The analysis included 48 patients randomized to the control group and 44 randomized to the intervention group. When controlling for case complexity and other covariates, patients whose surgical planning involved 3-D VR models showed differences in operative time (odds ratio [OR], 1.00; 95% CI, 0.37-2.70; estimated OR, 2.47), estimated blood loss (OR, 1.98; 95% CI, 1.04-3.78; estimated OR, 4.56), clamp time (OR, 1.60; 95% CI, 0.79-3.23; estimated OR, 11.22), and length of hospital stay (OR, 2.86; 95% CI, 1.59-5.14; estimated OR, 5.43). Estimated ORs were calculated using the parameter estimates from the generalized estimating equation model. Referent group values for each covariate and the corresponding nephrometry score were summed across the covariates and nephrometry score, and the sum was exponentiated to obtain the OR. A mean of the estimated OR weighted by sample size for each nephrometry score strata was then calculated. Conclusions and Relevance This large, randomized clinical trial demonstrated that patients whose surgical planning involved 3-D VR models had reduced operative time, estimated blood loss, clamp time, and length of hospital stay. Trial Registration ClinicalTrials.gov identifiers (1 registration per site):NCT03334344,NCT03421418,NCT03534206,NCT03542565,NCT03556943, andNCT03666104

Hilar tumors pose unique challenges during partial nephrectomy. We present the characteristics and outcomes of 263 patients with hilar tumors undergoing robot-assisted partial nephrectomy (RPN) in the largest series to date. Perioperative, pathologic, functional, and oncological outcomes were compared between 1467 (84.8%) patients with a non-hilar tumor and 263 (15.2%) patients with a hilar tumor undergoing RPN. Variables were compared in univariable (unadjusted) analysis and using multivariable linear, logistic, poisson, cox proportional hazards and linear mixed effects regression models adjusting for tumor diameter and RENAL Nephrometry score. Hilar tumors were larger (3.7 vs. 3.0 cm, p

When performing robotic nephron-sparing surgery (NSS) for renal tumors, either a transperitoneal approach or retroperitoneal approach can be utilized. The operative technique for robotic retroperitoneal partial nephrectomy (RPPN) is discussed and a matched-paired analysis comparing both RPPN and transperitoneal partial nephrectomy (TPPN) at a single institution is discussed.A retrospective review over a 10-year period (2006-2016) was performed for all patients who underwent robotic partial nephrectomy. A total of 281 patients underwent RPPN and 263 patients underwent TPPN. A matched-paired analysis was performed on 166 pairs of patients and the outcomes reviewed.Operative time (p 0.001) and estimated blood loss (p 0.001) were significantly less in the RPPN group compared to the TPPN group. No differences (p 0.05) were seen with regard to complexity of cases, warm ischemia time, tumor pathology, positive margin rates, complications, or kidney function post-operatively.Robotic RPPN and TPPN can both be used for NSS with good results. RPPN, when used appropriately, can lead to shorter operative times, less blood loss and equivalent oncologic and post-operative outcomes. Surgeon comfort and expertise will help determine which approach to use.

Following partial nephrectomy (PN), it is important to prevent any deterioration in estimated glomerular filtration rate (eGFR). At present there are no evidence-based recommendations on when a nephrology consultation should be requested and how to adjust postoperative management when the risk of renal function decline is high. In an effort to address this void, we used our previously published nomogram to define risk groups for a significant decline in eGFR at 3-15 mo after PN. We used the nomogram-derived probability as the independent variable for the classification and regression tree and identified four risk groups: low (0-10%), intermediate (10-21%), high (21-65%), and very high (65-100%). Overall, 336 (34%), 386 (39%), 243 (24%), and 34 (4%) patients fell in the low, intermediate, high, and very high risk groups, respectively. The rates of significant eGFR decline across the low, intermediate, high, and very high risk groups were 4%, 14%, 29%, and 79%. With the low risk category as a reference, the hazard ratio for eGFR decline was 3.21 (95% confidence interval [CI] 1.83-5.64) for the intermediate, 7.80 (95% CI 4.52-13.48) for the high, and 27.24 (95% CI 13.8-53.8) for the very high risk group (all p

INTRODUCTION AND OBJECTIVES:The technique of renal reconstruction after robotic partial nephrectomy (RPN) is a modifiable factor with a possible impact on ischemia time, postoperative bleeding, ren...

ROS1 is a proto-oncogene that encodes the receptor tyrosine kinase ROS1, which can be aberrantly activated by gene rearrangement to drive tumor cell proliferation, survival, and metastasis. In non-small cell lung cancer (NSCLC), ROS1 rearrangements are detected in 1% to 3% of patients; at the time of diagnosis, 20% to 30% of these patients present with accompanying central nervous system (CNS) metastases. The tyrosine kinase inhibitors (TKIs) crizotinib, entrectinib, lorlatinib and repotrectinib have been used to treat ROS1-positive patients, but have been limited by the emergence of ROS1 resistance mutations, progression of disease in the CNS, or treatment-related adverse events (AEs) associated with off-target kinase inhibition. Novel ROS1 inhibitor NUV-520 (NVL-520) was designed to address these challenges. Across a panel of 335 wild-type kinases, NUV-520 (NVL-520) was highly selective for ROS1; it only inhibited one kinase, ALK, by >50% within 10-fold of its IC50 for ROS1. In recombinant enzyme assays, NUV-520 (NVL-520) inhibited the kinase activity of ROS1 and ROS1 G2032R with Kiapp < 10 nM in the presence of 1 mM ATP. The activity of NUV-520 (NVL-520) against the G2032R mutation is notable. G2032R, referred to as the solvent front mutation, is a frequent acquired resistance mutation to crizotinib and confers resistance to entrectinib and lorlatinib. NUV-520 (NVL-520) also selectively inhibited ROS1 in cells. It inhibited the growth of Ba/F3 cells driven by expression of the CD74-ROS1 fusion with either wild-type kinase domain or drug-resistance mutations G2032R, D2033N, S1986F, or L2026M at IC50 values < 10 nM and with selectivity over structurally related tropomyosin receptor kinase B (TRKB). Avoiding TRKB inhibition is preferred, as TRKB-related CNS adverse events have been reported for CNS-active dual TRK/ROS1 inhibitors entrectinib and repotrectinib. In vivo, NUV-520 (NVL-520) induced regression at well-tolerated doses in patient-derived xenograft (PDX) models of SDC4-ROS1 and CD74-ROS1 G2032R. Furthermore, NUV-520 (NVL-520) was active in a mouse orthotopic brain model of CD74-ROS1 G2032R, reducing tumor size and prolonging survival. In conclusion, NUV-520 (NVL-520) offers a distinct preclinical profile; it is a brain-penetrant and TRKB-sparing small-molecule inhibitor of ROS1 with activity against the frequent drug-resistance mutation G2032R, as well as D2033N, S1986F, and L2026M. Citation Format: Henry E. Pelish, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Joshua C. Horan. NUV-520 (NVL-520) is a brain-penetrant and highly selective ROS1 inhibitor with antitumor activity against the G2032R solvent front mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1465.

ALK is a proto-oncogene that encodes the receptor tyrosine kinase ALK, which can be aberrantly activated by gene rearrangement or point mutation to drive tumor cell proliferation, survival, and metastasis. In advanced non-small cell lung cancer (NSCLC), ALK rearrangements are detected in about 4% of patients; at the time of diagnosis, 30% to 40% of these patients present with accompanying central nervous system (CNS) metastases. Brain-penetrant tyrosine kinase inhibitors (TKIs) alectinib, brigatinib, ceritinib, and lorlatinib are FDA-approved treatments for ALK-positive NSCLC; however, durability of response to these treatments has been limited in many cases by the emergence of mutations in ALK that confer resistance. A major resistance mutation to alectinib, brigatinib, and ceritinib is the ALK G1202R solvent front mutation. Although patients with tumors harboring the ALK G1202R mutation have responded to lorlatinib, many have subsequently relapsed by emergence of ALK compound mutations, such as G1202R/L1196M and G1202R/G1269A. Novel ALK inhibitor NUV-655 (NVL-655) was designed for broader coverage of ALK resistance mutations, activity in the CNS, and selectivity over structurally related tropomyosin receptor kinase B (TRKB). Avoiding TRKB inhibition is preferred, as CNS adverse events associated with TRKB inhibition have been reported for brain-penetrant TKIs. In recombinant enzyme assays, NUV-655 (NVL-655) inhibited the kinase activity of ALK and ALK G1202R/L1196M with Kiapp < 5 nM in the presence of 1 mM ATP and with selectivity over TRKB. Across a panel of 335 wild-type kinases, NUV-655 (NVL-655) inhibited only 5 other kinases by >50% within 10-fold of its IC50 for ALK. NUV-655 (NVL-655) also selectively inhibited ALK in cells. It inhibited the growth of Ba/F3 cells driven by expression of EML4-ALK variant 1 (v1) with either wild-type kinase domain or drug-resistance mutations G1202R, G1202R/L1196M, or G1202R/G1269A at IC50 values < 10 nM and with selectivity over TRKB. In vivo, NUV-655 (NVL-655) induced regression at well-tolerated doses in a Ba/F3 EML4-ALKv1 G1202R/L1196M xenograft model. Furthermore, NUV-655 (NVL-655) demonstrated brain penetrance in rodent pharmacokinetic studies. In conclusion, NUV-655 (NVL-655) offers a preclinical profile that addresses a medical need for ALK-positive NSCLC patients; it is a brain-penetrant and TRKB-sparing small-molecule inhibitor of ALK with activity against the solvent front drug-resistance mutations G1202R, G1202R/L1196M, and G1202R/G1269A. Citation Format: Henry E. Pelish, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Joshua C. Horan. NUV-655 (NVL-655) is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1468.

The formation of the d-homocyclopamine ring system in IPI-926 is the key step in its semisynthesis and proceeds via a chemoselective cyclopropanation followed by a stereoselective acid-catalyzed carbocation rearrangement. In order to perform large-scale cyclopropanation reactions, we developed new iodomethylzinc bis(aryl)phosphate reagents that were found to be both effective and safe. These soluble reagents can be prepared under mild conditions and are stable during the course of the reaction. Importantly, they have favorable energetics relative to other cyclopropanating agents such as EtZnCH2I. Herein, we describe the process optimization studies that led to successful large-scale production of the d-homocyclopamine core necessary for IPI-926.

Background In recent years, novel technologies have been implemented in order to improve the surgical outcomes of robot-assisted partial nephrectomy (RAPN). Intraoperative administration of indocyanine green (ICG) has been proposed to assess kidney perfusion intraoperatively. Objective To confirm, on a large scale, the effectiveness of near-infrared fluorescence ICG–guided RAPN in leading the surgeon strategy and to provide hints to the use of this tool. Design, setting, and participants The Transatlantic Robotic Nephron-sparing Surgery (TRoNeS) study group collected data from 737 patients subjected to RAPN between 2010 and 2016 at three tertiary care referral centers. Of them, 318 had complete demographic and clinical data, and underwent ICG-guided RAPN for clinically localized kidney cancer. Surgical procedure Patients were subjected to RAPN with intraoperative intravenous ICG injection. Measurements Optimal surgical outcomes, defined according to both the margin, ischemia, and complication (MIC), and the trifecta score, were assessed. Results and limitations A total of 194 (61%) patients were male and 124 (39%) were female. The median patient age was 61 yr and median preoperative tumor size was 30 mm. Median operative time, estimated blood loss, and warm ischemia time were, respectively, 162 min, 100 ml, and 17 min. In total, 228 (71.7%) and 254 (79.9%) individuals, respectively, were selected as optimal surgical patients defined according to MIC and trifecta. The univariate and multivariable logistic regression models showed that tumor complexity nephrometry scores were independent predictors of both trifecta and MIC. The main limitation of this study is the lack of a control group. Conclusions We report the largest population of patients who underwent ICG-guided RAPN. Intraprocedural ICG administration represents a useful tool where the vascular anatomy is challenging, and it could be implemented to maximize the adoption of RAPN. Patient summary We demonstrated that indocyanine green (ICG) is a reliable tool for guiding the surgeon strategy during robot-assisted partial nephrectomy. ICG may help in procedure tailoring, especially in cases with challenging vascularization or impaired renal function.