Multi-institutional Cohort Of Patients Research Articles

Development and validation of a unifying pre-treatment decision tool for intracranial and extracranial metastasis-directed radiotherapy.

Though metastasis-directed therapy (MDT) has the potential to improve overall survival (OS), appropriate patient selection remains challenging. We aimed to develop a model predictive of OS to refine patient selection for clinical trials and MDT. We assembled a multi-institutional cohort of patients treated with MDT (stereotactic body radiation therapy, radiosurgery, and whole brain radiation therapy). Candidate variables for recursive partitioning analysis were selected per prior studies: ECOG performance status, time from primary diagnosis, number of additional non-target organ systems involved (NOS), and intracranial metastases. A database of 1,362 patients was assembled with 424 intracranial, 352 lung, and 607 spinal treatments (n=1,383). Treatments were split into training (TC) (70%, n=968) and internal validation (IVC) (30%, n=415) cohorts. The TC had median ECOG of 0 (interquartile range [IQR]: 0-1), NOS of 1 (IQR: 0-1), and OS of 18 months (IQR: 7-35). The resulting model components and weights were: ECOG = 0, 1, and > 1 (0, 1, and 2); 0, 1, and > 1 NOS (0, 1, and 2); and intracranial target (2), with lower scores indicating more favorable OS. The model demonstrated high concordance in the TC (0.72) and IVC (0.72). The score also demonstrated high concordance for each target site (spine, brain, and lung). This pre-treatment decision tool represents a unifying model for both intracranial and extracranial disease and identifies patients with the longest survival after MDT who may benefit most from aggressive local therapy. Carefully selected patients may benefit from MDT even in the presence of intracranial disease, and this model may help guide patient selection for MDT.

Preoperative SARS-CoV-2 infection increases risk of early postoperative cardiovascular complications following noncardiac surgery.

As the coronavirus disease 2019 (COVID-19) pandemic progresses to an endemic phase, a greater number of patients with a history of COVID-19 will undergo surgery. Major adverse cardiovascular and cerebrovascular events (MACE) are the primary contributors to postoperative morbidity and mortality; however, studies assessing the relationship between a previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and postoperative MACE outcomes are limited. Here, we analyzed retrospective data from 457,804 patients within the N3C Data Enclave, the largest national, multi-institutional data set on COVID-19 in the United States. However, 7.4% of patients had a history of COVID-19 before surgery. When comorbidities, age, race, and risk of surgery were controlled, patients with preoperative COVID-19 had an increased risk for 30-day postoperative MACE. MACE risk was influenced by an interplay between COVID-19 disease severity and time between surgery and infection; in those with mild disease, MACE risk was not increased even among those undergoing surgery within 4 wk following infection. In those with moderate disease, risk for postoperative MACE was mitigated 8 wk after infection, whereas patients with severe disease continued to have elevated postoperative MACE risk even after waiting for 8 wk. Being fully vaccinated decreased the risk for postoperative MACE in both patients with no history of COVID-19 and in those with breakthrough COVID-19 infection. Together, our results suggest that a thorough assessment of the severity, vaccination status, and timing of SARS-CoV-2 infection must be a mandatory part of perioperative stratification.NEW & NOTEWORTHY With an increasing proportion of patients undergoing surgery with a prior history of COVID-19, it is crucial to understand the impact of SARS-CoV-2 infection on postoperative cardiovascular/cerebrovascular risk. Our work assesses a large, national, multi-institutional cohort of patients to highlight that COVID-19 infection increases risk for postoperative major adverse cardiovascular and cerebrovascular events (MACE). MACE risk is influenced by an interplay between disease severity and time between infection and surgery, and full vaccination reduces the risk for 30-day postoperative MACE. These results highlight the importance of stratifying time-to-surgery guidelines based on disease severity.

Household income is associated with functional outcomes in a multi-institutional cohort of patients with ischemic stroke and COVID-19

ObjectivesThe COVID-19 pandemic has heightened awareness of health disparities associated with socioeconomic status (SES) across the United States. We examined whether household income is associated with functional outcomes after stroke and COVID-19. Materials and methodsThis was a multi-institutional, retrospective cohort study of consecutively hospitalized patients with SARS-CoV-2 and radiographically confirmed stroke presenting from March through November 2020 to any of five comprehensive stroke centers in metropolitan Chicago, Illinois, USA. Zip-code-derived household income was dichotomized at the Chicago median. Logistic regression was used to examine the relationship between household income and good functional outcome (modified Rankin Scale 0-3 at discharge, after ischemic stroke). ResultsAcross five hospitals, 159 patients were included. Black patients comprised 48.1%, White patients 38.6%, and Hispanic patients 27.7%. Median household income was $46,938 [IQR: $32,460-63,219]. Ischemic stroke occurred in 115 (72.3%) patients (median NIHSS 7, IQR: 0.5-18.5) and hemorrhagic stroke in 37 (23.7%). When controlling for age, sex, severe COVID-19, and NIHSS, patients with ischemic stroke and household income above the Chicago median were more likely to have a good functional outcome at discharge (OR 7.53, 95% CI 1.61 - 45.73; P=0.016). Race/ethnicity were not included in final adjusted models given collinearity with income. ConclusionsIn this multi-institutional study of hospitalized patients with stroke, those residing in higher SES zip codes were more likely to have better functional outcomes, despite controlling for stroke severity and COVID-19 severity. This suggests that area-based SES factors may play a role in outcomes from stroke and COVID-19.

EPID-25. THE CLINICAL AND MOLECULAR LANDSCAPE OF GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS

Abstract OBJECTIVE Gliomas in adolescents and young adults (AYA) are commonly treated with a standard chemo-radiation approach. Molecular alterations have not been comprehensively described to date. METHODS We compiled a multi-institutional cohort of patients diagnosed with glioma between 15-39.9 years over 20 years. Molecular analysis, therapeutic data and outcome was collected. For specific alterations, analysis included patients aged 0-39.9 years. RESULTS A total of 1900 patients with 876 AYA gliomas were included. Ongoing analysis reveals genetic alterations in 95% of available tumours. IDH p.R132H was found in 49% of tumours, while non-canonical IDH mutations were found in 7%. Paediatric-type mutations were found in 33% of AYA tumours with IDH-WT GBM accounting for the remaining 11%. The most common paediatric alterations in AYAs included BRAF p.V600E (11%) and FGFR alterations (7%) while BRAF fusions, H3 p.K27M and H3.3 p.G34R were rarely observed (4%, 4% and 1% respectively). BRAF fused tumours with non-canonical binding partners were enriched in AYAs. Analysis of BRAF-V600E gliomas between ages 0-40 revealed increased tendency for malignant tumours in patients > 20 years suggesting malignant transformation possibly due to higher rate of secondary hits. This resulted in worse overall-survival for AYA patients with BRAF-V600E glioma when compared to children under 20 years (p=0.0032). Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma respectively, compared to 14% and 25% for BRAF-V600E and FGFR-altered high grade glioma. In contrast, continuous decline was observed in the IDH-mutant gliomas with 10-year OS of 50% which declined to 29% at 15 years. CONCLUSIONS Gliomas in AYA often have non-canonical alterations that may evade standard molecular analysis. They are enriched for paediatric-type alterations with distinct molecularly-based outcomes. These tumours may respond to targeted inhibitors and would benefit from comprehensive diagnostic and therapeutic approaches.

Genomic Adjusted Radiation Dose (GARD) Predicts Overall Survival and Outperforms AJCC 8th Edition in Prognostication of HPV-Positive Oropharyngeal Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Treatment decision-making in oropharyngeal squamous cell carcinoma (OPSCC) includes clinical stage, HPV status, and smoking history. Despite improvements in staging with separation of HPV positive and negative OPSCC in AJCC 8^th edition (AJCC8), patients are largely treated with a uniform approach, with recent efforts on de-intensification in low-risk patients. We have previously shown, in a pooled analysis, that the genomic adjusted radiation dose (GARD) is predictive of radiation treatment benefit and can be used to guide dose selection. We hypothesize that GARD can be used to predict overall survival (OS) in HPV-positive OPSCC patients treated with radiotherapy (RT). <h3>Materials/Methods</h3> Gene expression profiles were analyzed for 234 formalin-fixed paraffin-embedded samples from HPV-positive OPSCC patients within an international, multi-institutional, prospective/retrospective observational study (Big Data and Models for Personalized Head and Neck Cancer Decision Support (BD2Decide, NCT02832102). GARD, a measure of the biological effect of RT, was calculated for each patient as previously described. In total, 203 patients received definitive treatment (chemoradiation or RT alone), and 31 patients received post-operative RT. Two RT dose fractionations were utilized for definitive cases (70 Gy in 35 fractions or 69.96 Gy in 33 fractions). Median RT dose was 70 Gy (mean 50.88-74) for definitive cases and 66 Gy (range 44-70) for post-operative cases. 29 patients received surgery and adjuvant chemoradiation, 14 received surgery and adjuvant RT, and 19 received RT alone. The median follow up was 46.2 months (95% CI, 41.2 to 50). Cox proportional hazards analyses were performed with GARD as a continuous variable and ROC analyses comparing the performance of GARD with AJCC8. <h3>Results</h3> Despite uniform radiation dose utilization, GARD showed significant heterogeneity (range 30-110), reflecting the underlying genomic differences in the cohort. On multivariate analysis, each unit increase in GARD was associated with an improvement in OS (HR= 0.97, 95% CI 0.94-1.0, p=0.040) compared to AJCC8 (HR=1.96, 95% CI 0.90-4.32, p=0.0952). ROC analysis for GARD at 24 months yielded an AUC of 75.6 (95% CI 61.8-89.4) compared with an AUC of 73.9 (95% CI 56.9-90.9) for AJCC8. GARD ≥64.97 was associated with improved OS (HR=0.29, p=0.005). <h3>Conclusion</h3> In this multi-institutional cohort of patients with HPV-positive OPSCC, GARD predicts OS as a continuous variable and outperforms AJCC8 in prognostication. We propose that GARD, which provides the first opportunity for genomic guided personalization of radiation dose, should be incorporated in the diagnostic workup of HPV-positive OPSCC patients and can be used to guide treatment decision making.

Does Local Failure Following Oligometastasis-Directed SBRT Predict for Widespread Progression and Overall Survival?

<h3>Purpose/Objective(s)</h3> The potential of oligometastasis (OM)-directed therapy to translate to survival benefit has been shown in randomized trials, but typically in small or histology-specific cohorts (i.e., prostate or NSCLC). We investigated the impact of local control (LC) on widespread progression (WSP) and overall survival (OS) in a large, multi-institutional cohort of patients across heterogeneous histologies treated with SBRT to OMs. <h3>Materials/Methods</h3> Patients treated at 6 international centers from 2007 – 2016 were retrospectively reviewed and included if they had 1) five or fewer lesions, 2) no history of brain metastases, 3) curative treatment for primary disease, and 4) SBRT to all known OMs at initial presentation. The relationship between LC at certain time points and OS and WSP (>5 active/untreated lesions) were explored using Cox and Fine-Gray regression models. The relative strength of association between LC and dosimetric predictors was analyzed with competing risk regression using death as a competing risk. <h3>Results</h3> In total, 1033 patients treated to 1700 OMs were analyzed. The median follow up was 24.1 mo (range: 0.3-104.7). Most patients (57.1%) had solitary OM, 24.0% had 2 OMs, 10.3% had 3 OMs, and 8.6% had 4-5 OMs. The most common histologies were NSCLC (25.2%), colorectal (22.8%), prostate (12.8%), and breast (8.1%). The median prescription dose was 48 Gy (range: 10-60) in a median of 5 fractions (range: 1-15). Median OS was 44.2 mo. Cumulative incidence of local failure at 6m, 1y, 2y and 3y was 3.3%, 10.0%, 19.6% and 23.9% respectively. As detailed below, patients who fail locally in any or all SBRT-targeted OMs have significantly increased risk of WSP and death compared to those with no failure. These risks may be greater with shorter duration of LC. Patients who failed in only a subset of treated OMs and those who failed in all OMs did not have significantly different WSP and OS outcomes. Minimum BED to the GTV or ITV was most predictive of LC when compared to prescription dose, PTV Dmin, and PTV Dmax, across a range of simulated a/b ratios. <h3>Conclusion</h3> This large multi-institutional series demonstrates that duration of LC in SBRT-targeted OMs translates strongly to WSP and OS outcomes in an all or nothing manner, where failure in a subset of treated OMs appears no different in risk compared to failing in all OMs. This highlights the importance of maximizing LC to each OM in this treatment paradigm, where GTV or ITV Dmin may be a key dosimetric parameter.

Efficiency Effectiveness Gap of Durvalumab in Locally Advanced Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Following results of the PACIFIC trial, definitive chemoradiation with one year of adjuvant durvalumab became the standard of care for patients with stage III NSCLC. Using a multi-institutional cohort of patients across the Veterans Health Administration, we recently showed that this treatment was effective in a real-world setting. While veterans receiving chemoradiation and adjuvant durvalumab had significant improvement in both PFS and OS compared to veterans who received chemoradiation alone, their OS was significantly worse than the patients in the PACIFIC trial. Veterans had a shorter median treatment duration and higher discontinuation of treatment secondary to toxicity, suggesting inferior overall treatment tolerance. Adherence and toxicity rates are often worse in real-world patients compared to clinical trial cohorts and no studies have evaluated the optimal duration of adjuvant durvalumab to maximize treatment adherence and effectiveness while minimizing treatment-related toxicities. We sought to determine predictors for early treatment discontinuation and examine the influence of durvalumab treatment duration on oncologic outcomes. <h3>Materials/Methods</h3> We identified patients with stage III NSCLC treated with definitive chemoradiation and at least one dose of adjuvant durvalumab from November 2017 to April 2021 in the United States Veterans Affairs system. Duvalumab infusion dates and reasons for early discontinuation of therapy were determined manually by chart review. Predictors of early durvalumab discontinuation were evaluated with Cox proportional hazards regression. The effect of differing durations of treatment (up to 6, 9, and 12 months) on PFS and OS were compared with a marginal structural model simulating a three-arm randomized controlled trial. In sensitivity analyses, we used time-dependent Cox modeling to assess the effect of cumulative durvalumab duration on PFS/OS and adjusted for reasons for early discontinuation. <h3>Results</h3> A cohort of 1,006 patients with stage III NSCLC were included in our analysis. The median duration of durvalumab treatment was 7 months (interquartile range 2.8 – 11.5) and only 31% of patients completed the intended course. The most common reasons for early discontinuation were tumor progression (22%), immune-related adverse events (15%), and nonimmune-related toxicity (6.0%). Furthermore, older age was associated with an increased risk of early treatment discontinuation. Marginal structural models showed an equivalent PFS for 9 months versus 12 months of durvalumab treatment and inferior PFS for 6 months versus 12 months. Finally, sensitivity analyses with time-dependent Cox modeling suggested equivalence of shorter durations of therapy for PFS. <h3>Conclusion</h3> These data suggest that de-escalation of durvalumab treatment duration may be possible while not compromising cancer control. Prospective randomized studies are needed to further evaluate this important clinical question.

Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts

Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.

Fascial dehiscence after radical cystectomy: Is abdominal exploration mandatory?

BackgroundFascial dehiscence after radical cystectomy may have serious clinical implications. To optimize its management, we sought to describe accompanying intraabdominal findings of post-cystectomy dehiscence repair and determine whether a thorough intraabdominal exploration during its operation is mandatory.MethodsWe retrospectively reviewed a multi-institutional cohort of patients who underwent open radical cystectomy between 2005 and 2020. Patients who underwent exploratory surgery due to fascial dehiscence within 30 days post-cystectomy were included in the analysis. Data collected included demographic characteristics, the clinical presentation of dehiscence, associated laboratory findings, imaging results, surgical parameters, operative findings, and clinical implications. Potential predictors of accompanying intraabdominal complications were investigated.ResultsOf 1301 consecutive patients that underwent cystectomy, 27 (2%) had dehiscence repair during a median of 7 days post-surgery. Seven patients (26%) had accompanying intraabdominal pathologies, including urine leaks, a fecal leak, and an internal hernia in 5 (19%), 1 (4%), and 1 (4%) patients, respectively. Accompanying intraabdominal findings were associated with longer hospital stay [20 (IQR 17, 23) vs. 41 (IQR 29, 47) days, P = 0.03] and later dehiscence identification (postoperative day 7 [IQR 5, 9] vs. 10 [IQR 6, 15], P = 0.03). However, the rate of post-exploration complications was similar in both groups. A history of ischemic heart disease was the only predictor for accompanying intraabdominal pathologies (67% vs. 24%; P = 0.02).ConclusionsA substantial proportion of patients undergoing post-cystectomy fascial dehiscence repair may have unrecognized accompanying surgical complications without prior clinical suspicion. While cardiovascular disease is a risk factor for accompanying findings, meticulous abdominal inspection is imperative in all patients during dehiscence repair. Identification and repair during the surgical intervention may prevent further adverse, possibly life-threatening consequences with minimal risk for iatrogenic injury.

Abstract 1722: Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer (NSCLC)

Abstract The rapid clinical expansion of immune checkpoint blockers (ICB) has transformed the therapeutic arsenal for non-small cell lung cancer (NSCLC). However, only a relatively small fraction of patients benefits from these treatments and those who respond can develop acquired resistance. This underlines the need to identify factors or biomarkers associated with treatment sensitivity and resistance to guide clinical decisions. It has been proposed that elevated levels of tumor infiltrating lymphocytes (TIL) in the tumor microenvironment could be associated with favorable clinical outcomes after treatment with ICB. However, few studies have explored this relationship and they used semi-quantitative scoring methods and/or analyzed small tumor areas. Here, we used multiplexed quantitative immunofluorescence (QIF) panels to study major TIL subsets (DAPI, CK, CD4, CD8 and CD20) and T-cell exhaustion markers (DAPI, CD3, LAG-3, PD-1, TIM-3) in full-face baseline whole-tumor slides from a large multi-institutional patient cohort (n=179). The analysis of numerous fields of view per case allowed us to examine the spatial distribution of immune cells and spatial immune heterogeneity. Our results demonstrate that CD8+ effector T-cells are the largest TIL subpopulation and that they are preferentially located in the stromal compartment. We also show that tertiary lymphoid structures have limited association with survival and their detection depends on the size of the tissue area analyzed. Additionally, higher levels of baseline CD8+ T-cells in the stroma were significantly associated with better survival in PD-L1 positive patients but not in PD-L1 negative. To validate these results, we used whole-exome sequencing to analyze the TCR-burden in an independent cohort of ICI-treated NSCLC patients. Increased expression of the exhaustion markers LAG-3 and TIM-3 in CD3 positive T-cells was associated with reduced survival. Finally, we used a novel multiparametric heterogeneity metric termed Rao’s quadratic entropy that enabled us to measure the spatial immune heterogeneity and was associated with worse survival. In summary, we quantitatively measured the density, functional properties, and spatial distribution of major TIL subsets in a large cohort of NSCLC patients treated with ICB. Our results highlight the prominent role of TILs in NSCLC and their potential role as a biomarker. These results could be easily translated into the clinic and used to guide optimal treatment options. Citation Format: Miguel Lopez de Rodas Gregorio, Venkata Nagineni, Arvind Ravi, Ila J. Datar, Mari Mino-Kenudson, German Corredor, Cristian Barrera, Lindsey Behlman, David L. Rimm, Roy S. Herbst, Anant Madabhushi, Jonathan W. Riess, Vamsidhar Velcheti, Matthew Hellmann, Justin F. Gainor, Kurt A. Schalper. Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1722.

LGG-41. The clinical and molecular landscape of gliomas in adolescents and young adults

OBJECTIVE: Gliomas in adolescents and young adults (AYA) are commonly treated with a standard chemo-radiation approach based on data from adults. The clinical impact of paediatric-type alterations in these tumours is unknown. METHODS: We compiled a multi-institutional cohort of patients diagnosed with glioma between 15-39.9 years over 20 years. Complete molecular analysis, therapeutic data and outcome was collected. For specific alterations, analysis included patients aged 0-39.9 years. RESULTS: A total of 1900 patients with 876 AYA gliomas were included. Ongoing analysis reveals genetic alterations in 95% of available tumours. IDH-mutant tumours account for only 53%, while paediatric-type mutations were found in 35% of AYA tumours with IDH-WT GBM accounting for the remaining 12%. The most common paediatric alterations in AYAs included BRAF p.V600E (11%) and FGFR alterations (6%) while BRAF fusions, H3 p.K27M and H3.3 p.G34R were rarely observed (4%, 4% and 1% respectively). BRAF fused tumours with non-canonical binding partners were enriched in AYAs. Analysis of BRAF-V600E gliomas between ages 0-40 revealed increased tendency for malignant tumours in patients >20 years suggesting malignant transformation possibly due to higher rate of secondary hits including TP53, CDKN2A and ATRX mutations. This resulted in worse overall-survival for AYA patients with BRAF-V600E glioma when compared to children under 20 years (p=0.0032). Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma respectively, compared to 14% and 25% for BRAF-V600E and FGFR-altered high grade glioma. In contrast, continuous decline was observed in the IDH-mutant gliomas with 10-year OS of 50% which declined to 29% at 15 years. CONCLUSIONS: Gliomas in AYA are enriched for paediatric-type alterations with distinct molecularly-based outcomes. As these tumours carry different outcomes than childhood glioma and may respond to targeted inhibitors, AYA gliomas would benefit from comprehensive diagnostic and therapeutic approaches.

Lingual Mucosal Graft Ureteroplasty for Long Proximal Ureteral Stricture: 6 Years of Experience with 41 Cases

BackgroundManagement of a long proximal ureteral stricture is challenging. Lingual mucosal graft ureteroplasty (LMGU) is a novel minimally invasive technique for ureteral reconstruction that avoids the morbidity of bowel interposition or autotransplantation. ObjectiveTo evaluate the long-term effectiveness of LMGU for managing long, complex proximal ureteral strictures in a multi-institutional cohort of patients. Design, setting, and participantsThis retrospective study involved data for 41 patients treated with LMGU at three centers between June 2015 and January 2021. Surgical procedureLMGU was performed using either an onlay ureteroplasty in which the diseased ureter was incised ventrally and repaired with a lingual mucosal graft (LMG) to widen the ureteral lumen, or an augmented anastomotic technique in which the obliterated segment of the ureter was excised and reanastomosed primarily on dorsal side, and an LMG was placed on the ventral side. MeasurementsPre-, intra-, and postoperative variables and outcomes were assessed. A descriptive statistical analysis was performed. Results and limitationsOf 41patients, 40 were operated with laparoscopic procedures and one with a robot. Twenty-four (59%) patients underwent an onlay ureteroplasty, and 17 (41%) underwent an augmented anastomotic ureteroplasty. The reconstructed ureter was wrapped with omentum in 90% of cases. The median (range) stricture length was 4.8 cm (2.0–8.0), operative time was 166 min (98–306), and estimated blood loss was 65 ml (15–220). No open conversions and intraoperative complications occurred. At a median follow-up of 35 mo (range 13–80), the overall success rate was 97.6% (40/41). ConclusionsLMGU is a safe, feasible, and effective long-term technique for managing long, complex proximal ureteral strictures. Patient summaryWe reported a novel technique for long proximal complex ureteral strictures using an onlay lingual mucosal graft (LMG). Our 6-yr outcomes demonstrate that onlay LMG ureteroplasty is a safe, feasible, and effective long-term procedure for ureteral reconstruction.

PD58-11 IMPACT OF PRE-OPERATIVE KIDNEY FUNCTION ON SURVIVAL OUTCOMES IN UPPER TRACT UROTHELIAL CARCINOMA: ANALYSIS OF THE ROBUUST REGISTRY

PD58-11 IMPACT OF PRE-OPERATIVE KIDNEY FUNCTION ON SURVIVAL OUTCOMES IN UPPER TRACT UROTHELIAL CARCINOMA: ANALYSIS OF THE ROBUUST REGISTRY

PD18-02 EXTERNAL VALIDATION OF THE ASSURE MODEL TO PREDICT ONCOLOGICAL OUTCOMES AFTER RESECTION OF HIGH-RISK RENAL CELL CARCINOMAS

You have accessJournal of UrologyCME1 May 2022PD18-02 EXTERNAL VALIDATION OF THE ASSURE MODEL TO PREDICT ONCOLOGICAL OUTCOMES AFTER RESECTION OF HIGH-RISK RENAL CELL CARCINOMAS Zine-Eddine Khene, Alessandro Larcher, Jean-Christophe Bernhard, Nicolas Doumerc, Romain Boissier, Idir Ouzaid, Philippe Barthelemy, Morgan Roupret, Francesco Montorsi, Pierre Bigot, and Karim Bensalah Zine-Eddine KheneZine-Eddine Khene More articles by this author , Alessandro LarcherAlessandro Larcher More articles by this author , Jean-Christophe BernhardJean-Christophe Bernhard More articles by this author , Nicolas DoumercNicolas Doumerc More articles by this author , Romain BoissierRomain Boissier More articles by this author , Idir OuzaidIdir Ouzaid More articles by this author , Philippe BarthelemyPhilippe Barthelemy More articles by this author , Morgan RoupretMorgan Roupret More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Pierre BigotPierre Bigot More articles by this author , and Karim BensalahKarim Bensalah More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002556.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A prognostic model based on the population of the ASSURE phase III trial has recently been described. The ASSURE model stratifies patients into risk groups to predict survival after surgical resection of intermediate and high-risk localized kidney cancer. Our objective was to validate the ASSURE model in a large independent multi-institutional cohort of patients treated in a “real life” setting outside of a clinical trial. METHODS: Data of patients from ten institutions who underwent radical or partial nephrectomy for a non-metastatic RCC between 2013 and 2019 were analyzed. We exclusively focused on patients with pT1b and ISUP 3-4, pT2, pT3, pT4, and N1 (i.e., those classified as intermediate and high risk according to the ASSURE model). The performance of the ASSURE model was evaluated in terms of discrimination and calibration. In addition, decision curve analysis (DCA) was used to determine whether the clinical value of the new model increased the net benefit over a realistic range of threshold probabilities. Finally, DCA of the ASSURE model was compared with that of older UCLA Integrated Staging System (UISS) and Leibovich 2018 score. RESULTS: 1372 patients were included in the analysis. Median age was 64 years (IQR 55-72). Median tumor size was 6.5 cm (IQR 5-9). The majority of tumors were clear cell RCCs (77%), of high ISUP grade (72% of grade 3 and 4), with 45% exhibiting tumor necrosis and 5% harboring nodal involvement. Median follow up was 54 months (IQR 32-75). Regarding disease-free survival, the ASSURE model showed modest discrimination (65%), miscalibration and poor net benefit compared with UCLA Integrated Staging System (UISS) and Leibovich 2018 models. Similarly, the ability of the ASSURE model to predict overall survival was poor in terms of discrimination (63%), with an overestimation on calibration plots and a modest net benefit for probability threshold between 10-40%. CONCLUSIONS: The ASSURE model is the last reported prognostic model that evaluates survival after surgical resection of a non-metastatic renal cell carcinoma. An improvement of patient classification was not clearly established when compared with available models, and implementation of this model in this setting still needs to be clarified. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e342 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zine-Eddine Khene More articles by this author Alessandro Larcher More articles by this author Jean-Christophe Bernhard More articles by this author Nicolas Doumerc More articles by this author Romain Boissier More articles by this author Idir Ouzaid More articles by this author Philippe Barthelemy More articles by this author Morgan Roupret More articles by this author Francesco Montorsi More articles by this author Pierre Bigot More articles by this author Karim Bensalah More articles by this author Expand All Advertisement PDF DownloadLoading ...

Multiinstitutional Evaluation of the Liver Surface Nodularity Score on CT for Staging Liver Fibrosis and Predicting Liver-Related Events in Patients With Hepatitis C.

BACKGROUND. In single-institution multireader studies, the liver surface nodularity (LSN) score accurately detects advanced liver fibrosis and cirrhosis and predicts liver decompensation in patients with chronic liver disease (CLD) from hepatitis C virus (HCV). OBJECTIVE. The purpose of this study was to assess the diagnostic performance of the LSN score alone and in combination with the (FIB-4; fibrosis index based on four factors) to detect advanced fibrosis and cirrhosis and to predict future liver-related events in a multiinstitutional cohort of patients with CLD from HCV. METHODS. This retrospective study included 40 consecutive patients, from each of five academic medical centers, with CLD from HCV who underwent nontargeted liver biopsy within 6 months before or after abdominal CT. Clinical data were recorded in a secure web-based database. A single central reader measured LSN scores using software. Diagnostic performance for detecting liver fibrosis stage was determined. Multivariable models were constructed to predict baseline liver decompensation and future liver-related events. RESULTS. After exclusions, the study included 191 patients (67 women, 124 men; mean age, 54 years) with fibrosis stages of F0-F1 (n = 37), F2 (n = 44), F3 (n = 46), and F4 (n = 64). Mean LSN score increased with higher stages (F0-F1, 2.26 ± 0.44; F2, 2.35 ± 0.37; F3, 2.42 ± 0.38; F4, 3.19 ± 0.89; p < .001). The AUC of LSN score alone was 0.87 for detecting advanced fibrosis (≥ F3) and 0.89 for detecting cirrhosis (F4), increasing to 0.92 and 0.94, respectively, when combined with FIB-4 scores (both p = .005). Combined scores at optimal cutoff points yielded sensitivity of 75% and specificity of 82% for advanced fibrosis, and sensitivity of 84% and specificity of 85% for cirrhosis. In multivariable models, LSN score was the strongest predictor of baseline liver decompensation (odds ratio, 14.28 per 1-unit increase; p < .001) and future liver-related events (hazard ratio, 2.87 per 1-unit increase; p = .03). CONCLUSION. In a multiinstitutional cohort of patients with CLD from HCV, LSN score alone and in combination with FIB-4 score exhibited strong diagnostic performance in detecting advanced fibrosis and cirrhosis. LSN score also predicted future liver-related events. CLINICAL IMPACT. The LSN score warrants a role in clinical practice as a quantitative marker for detecting advanced liver fibrosis, compensated cirrhosis, and decompensated cirrhosis and for predicting future liver-related events in patients with CLD from HCV.

DOP74 Comparative effectiveness of vedolizumab and ustekinumab in Crohn’s Disease patients who failed anti-TNF treatment: Interrogating 1019 patients from the UK IBD BioResource

Abstract Background Ustekinumab (UST) and vedolizumab (VDZ) are widely used to treat patients with Crohn’s disease (CD). However, limited data exist regarding comparative effectiveness of these agents for patients with CD who have failed anti-TNF treatment. We aimed to compare the efficacy of UST and VDZ utilizing the largest cohort of CD patients who failed anti-TNF in real world clinical practice. Methods We conducted a retrospective cohort analysis using data retrieved from the UK IBD BioResource, capturing 34,148 subjects. We identified patients with CD, who failed anti-TNF and were subsequently treated with UST or VDZ as second or third-line therapy. Inverse probability of treatment weighting (IPTW) was used to balance groups using a propensity score-weighting approach accounting for baseline patient or disease related characteristics. Persistence on therapy with clinician assessment of treatment success, without the need for treatment change or surgery was used to estimate the response to treatment. We compared treatment survival curves before and after IPTW and used a log rank test for differences between groups Results 654 CD patients received VDZ, either as second line (51%) or third line (49%) therapy. 365 patients received UST, 52% as a second line and 48% as a third line therapy. All patients received either infliximab or adalimumab as first and/or second biologic therapy. Baseline characteristics are detailed in table 1. Following IPTW, variables were well balanced. Patients receiving VDZ showed similar rates of treatment success compared to UST as second- and third-line biologic agent after anti TNF failure (before IPTW adjustment, log rank p 0.241; after IPTW, log rank p 0.154). Outcomes for UST were similar between 2nd and 3rd line usage (p 0.81), but outcomes for VDZ were significantly worse when used 3rd line compared to 2nd line (p &amp;lt;0.0001).Subgroup analysis of unadjusted survival data showed significantly better outcomes for patients with ileal disease distributiontreated with UST compared to VDZ (p=0.043) but no significant differences in outcomes for subgroups with colonic or ileocolonic disease.We estimate persistence on UST and VDZ to be 67%, 54%, 49% and 49% at 1, 2, 3 and 5 years respectively. Conclusion Using data from a multi-institutional cohort of patients with CD with larger number of participants and longer follow-up than previous cohorts, we demonstrate no difference between UST and VDZ used as second and/or third line biologic therapy, after anti-TNF failure. Subgroup analysis reveals some patient characteristics predictive of differential treatment response.

Prognostic significance of extent of venous tumor thrombus in patients with non-metastatic renal cell carcinoma: Results from a Canadian multi-institutional collaborative.

The prognostic significance of level of venous tumor thrombus (VTT) extension in patients with non-metastatic renal cell carcinoma (RCC) has been controversial. The aim of this study was to examine the prognostic significance of VTT extent in patients who underwent surgery for non-metastatic RCC. The Canadian Kidney Cancer information system database was used to identify patients who underwent surgery for non-metastatic RCC and VTT from January 2011 to December 2019. Association between VTT level and recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) was examined. Univariable and multivariable analyses were performed to estimate predictors of survival. Out of 6,340 patients during the study period, 228 patients (3.6%) had VTT. VTT was level 0 in 84 (37%), level I to II in 112 (49%), and level III to IV in 33 (14%) patients as per the Mayo Clinic classification. Median age was 65.4 years (interquartile range [IQR] 57.6-72.2) and 169 (74.1%) were male. After a median follow-up of 21.2 months, VTT level did not significantly impact the RFS, CSS, or OS. For VTT level 0, I to II, and III to IV, there was no significant difference in estimated 5-year RFS (31%, 23%, and 30.5%; P > 0.05), CSS (70%, 69%, and 55%; P > 0.05) and OS (64%, 66%, and 50%; P > 0.05). Adjusting for known prognostic factors, thrombus level was not associated with risk of recurrence or death. In a large, multi-institutional cohort of patients undergoing surgery for non-metastatic RCC with tumor thrombus, thrombus extent was not independently associated with recurrence or death.

A multi-institutional validation study of prognostic nomograms for retroperitoneal sarcoma.

Prognostic nomograms for patients undergoing resection of retroperitoneal sarcoma (RPS) include the Sarculator and Memorial Sloan Kettering (MSK) sarcoma nomograms. We sought to validate the Sarculator and MSK nomograms within a large, modern multi-institutional cohort of patients with primary RPS undergoing resection. Patients who underwent resection of primary RPS between 2000 and 2017 across nine high-volume US institutions were identified. Predicted 7-year disease-free (DFS) and overall survival (OS) and 4-, 8-, and 12-year disease-specific survival (DSS) were calculated from the Sarculator and MSK nomograms, respectively. Nomogram-predicted survival probabilities were stratified in quintiles and compared in calibration plots to observed survival outcomes assessed by Kaplan-Meier estimates. Discriminative ability of nomograms was quantified by Harrell's concordance index (C-index). Five hundred and two patients underwent resection of primary RPS. Histologies included leiomyosarcoma (30%), dedifferentiated liposarcoma (23%), and well-differentiated liposarcoma (15%). Median tumor size was 14.0 cm (interquartile range [IQR], 8.5-21.0 cm). Tumor grade distribution was: Grade 1 (27%), Grade 2 (17%), and Grade 3 (56%). Median DFS was 31.5 months; 7-year DFS was 29%. Median OS was 93.8 months; 7-year OS was 51%. C-indices for 7-year DFS, and OS by the Sarculator nomogram were 0.65 (95% confidence interval [CI]: 0.62-0.69) and 0.69 (95%CI: 0.65-0.73); plots demonstrated good calibration for predicting 7-year outcomes. The C-index for 4-, 8-, and 12-year DSS by the MSK nomogram was 0.71 (95%CI: 0.67-0.75); plots demonstrated similarly good calibration ability. In a diverse, modern validation cohort of patients with resected primary RPS, both Sarculator and MSK nomograms demonstrated good prognostic ability, supporting their ongoing adoption into clinical practice.

Risk factors associated with positive surgical margins' location at radical cystectomy and their impact on bladder cancer survival.

To evaluate the risk factors associated with positive surgical margins' (PSMs) location and their impact on disease-specific survival (DSS) in patients with bladder cancer (BCa) undergoing radical cystectomy (RC). We analyzed a large multi-institutional cohort of patients treated with upfront RC for non-metastatic (cT1-4aN0M0) BCa. Multivariable binomial logistic regression analyses were used to assess the risk of PSMs at RC for each location after adjusting for clinicopathological covariates. The Kaplan-Meier method was used to estimate DSS stratified by margins' status and location. Log-rank statistics and Cox' regression models were used to determine significance. A total of 1058 patients were included and 108 (10.2%) patients had PSMs. PSMs were located at soft-tissue, ureter(s), and urethra in 57 (5.4%), 30 (2.8%) and 21 (2.0%) patients, respectively. At multivariable analysis, soft-tissue PSMs were independently associated with pathological stage T4 (pT4) (Odds ratio (OR) 6.20, p < 0.001) and lymph-node metastases (OR 1.86, p = 0.04). Concomitant carcinoma-in-situ (CIS) was an independent risk factor for ureteric PSMs (OR 6.31, p = 0.003). Finally, urethral PSMs were independently correlated with pT4-stage (OR 5.10, p = 0.01). The estimated 3-years DSS rates were 58.2%, 32.4%, 50.1%, and 40.3% for negative SMs, soft-tissue-, ureteric- and urethral PSMs, respectively (log-rank; p < 0.001). PSMs' location represents distinct risk factors' patterns. Concomitant CIS was associated with ureteric PSMs. Urethral and soft-tissue PSM showed worse DSS rates. Our results suggest that clinical decision-making paradigms on adjuvant treatment and surveillance might be adapted based on PSM and their location.

Peri-operative morbidity and mortality in a modern series of patients treated with cytoreductive nephrectomy (CN) at five centers.

268 Background: For metastatic renal cell cancer (mRCC) patients considering cytoreductive nephrectomy (CN), perioperative morbidity is important to discuss but few contemporary multi-institutional data are available. The objective of this study is to describe factors associated with perioperative outcomes in a modern multi-institutional cohort of patients treated with cytoreductive nephrectomy. Methods: Data for perioperative complications was recorded for patients treated with CN at 5 centers from 2005-2019. Postoperative complications within 90 days were categorized using Clavien- Dindo system. Univariate and multivariable analysis was used to evaluate for associations with complications and 90-day mortality. Factors evaluated included receipt of pre-surgical systemic therapy, ECOG performance status (PS), Charlson comorbidity index (CCI), concurrent IVC thrombectomy, age, and surgical approach (open vs. laparoscopic/robotic). Results: Perioperative outcomes were evaluated in 937 consecutive patients treated with CN at 5 institutions from 2005-2019. Median age at surgery was 61 years (IQR 53-68) and median tumor diameter was 9.8cm (IQR 7-12).Venous thrombus was present in 406/937 (43.3%) patients overall including 65/406 (16%) patients for whom IVC thrombus extended above the hepatic veins. Open and laparoscopic/robotic approach was used in 715 (76.3%) and 290 (23.4%) patients. The median ECOG PS was 1 (IQR 0-1) and median CCI was 1 (IQR 0-2). Pre-surgical systemic therapy was given to 243 (25.9%) patients prior to CN. The median length of hospital stay was 5 days (IQR 4-7) and 429 (34.6%) received blood transfusion. Median length of stay was 3.0 (IQR 2-4) for laparoscopic/robotic approach and 6 days (IQR 4-8) for patients with IVC thrombectomy. Hospital readmission within 30 days was identified in 112 (9.0%) patients. A total of 93/937 (9.9%) patients had major (≥Clavien 3) complications identified within 90 days postoperatively. On multivariable analysis, IVC thrombectomy was associated with higher risk of major complications OR 1.95 (95% CI 1.2-3.1), p = 0.006. Pre-surgical systemic therapy, ECOG PS, CCI, age and surgical approach were not associated with major complications (p = 0.09-0.85). Perioperative mortality was 12/937 (1.3%) at 30 days and 51/937 (6.7%) at 90 days. After multivariable analysis, pre-surgical systemic therapy, ECOG PS, CCI, age, and IVC thrombectomy were not associated with perioperative mortality (p = 0.1-0.85). Conclusions: Cytoreductive nephrectomy is associated with major complications for 10% of patients and 1% mortality at 30 days. Pre-surgical systemic therapy was not associated with increased risk of complications or mortality.