Citations

AbstractWilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi‐institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P = .004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event‐free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage‐specific treatment regimens.

PURPOSE Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer. MATERIALS AND METHODS NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; [BF1]) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; [BF2]), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average R2 between treatment hazard ratios for ICE and OS). RESULTS BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated ( R2 = 0.67), but this was not true for BF1 ( R2 = 0.09), BF2 ( R2 = 0.12), or DM ( R2 = 0.18) and OS. CONCLUSION MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.

AbstractObjectiveThe medial temporal lobe (MTL) encodes and recalls memories and can be a predominant site for interictal spikes (IS) in patients with focal epilepsy. It is unclear whether memory deficits are due to IS in the MTL producing a transient decline. Here, we investigated whether IS in the MTL subregions and lateral temporal cortex impact episodic memory encoding and recall.MethodsSeventy‐eight participants undergoing presurgical evaluation for medically refractory focal epilepsy with depth electrodes placed in the temporal lobe participated in a verbal free recall task. IS were manually annotated during the pre‐encoding, encoding, and recall epochs. We examined the effect of IS on word recall using mixed‐effects logistic regression.ResultsIS in the left hippocampus (odds ratio [OR] = .73, 95% confidence interval [CI] = .63–.84, p < .001) and left middle temporal gyrus (OR = .46, 95% CI = .27–.78, p < .05) during word encoding decreased subsequent recall performance. Within the left hippocampus, this effect was specific for area CA1 (OR = .76, 95% CI = .66–.88, p < .01) and dentate gyrus (OR = .74, 95% CI = .62–.89, p < .05). IS in other MTL subregions or inferior and superior temporal gyrus and IS occurring during the prestimulus window did not affect word encoding (p > .05). IS during retrieval in right hippocampal (OR = .22, 95% CI = .08–.63, p = .01) and parahippocampal regions (OR = .24, 95% CI = .07–.8, p < .05) reduced the probability of recalling a word.SignificanceIS in medial and lateral temporal cortex contribute to transient memory decline during verbal episodic memory.

Abstract Pediatric Acute Myeloid Leukemia (AML) with a FLT3 internal tandem duplication (FLT3-ITD) is a challenging disease due to poor outcomes in many patients. The 4-year progression-free survival is still only 31%. Current biomarkers are insufficient to predict why certain patients with FLT3-ITD AML relapse and others do not. The development of prognostic biomarkers in FLT3-ITD pediatric AML may help improve the outcomes and management of these patients. We acquired a panel of 37 diagnostic samples with 18 samples from FLT3-ITD pediatric AML patients with poor outcomes (relapse within 3 years) and 19 from favorable outcome patients that did not exhibit relapse for at least 5 years. Next, we performed FACS to isolate CD34+CD38dim and CD34+CD38+ cells. These two populations were then sequenced using 10x Genomics 3’ end single-cell RNA sequencing (scRNAseq). Using this scRNAseq dataset comprising over 250k single cells, we first investigated if the frequency of specific RNA clusters of AML cells may predict patient outcome. We found 5 clusters had significantly different frequencies between patients with favorable and poor outcomes (p &lt; 0.05). Using these clusters, we performed CIBERSORTx deconvolution on publicly available FLT3-ITD AML bulk RNAseq samples from TCGA (n = 36), BeatAML (n = 47), and the TARGET project (ntrain = 72; ntest = 26) to identify the inferred cluster composition present in each AML patient from these datasets. Next we built LASSO prediction models using the inferred scRNAseq clusters by CIBERSORTx and incorporating clinical features including leukemic blast percentage, bone marrow leukemic blast percentage, and WBC at diagnosis. We found these prediction models to be highly specific as a prognostic biomarker for pediatric AML (p &lt;&lt; 0.01). We were unable to train a model directly using genes from the publicly available bulk RNAseq data for pediatric FLT3-ITD AML, highlighting the relevance of using our deconvolution based biomarker. Between the high (&gt; median) and low (&lt; median) LASSO score groups, there was ~50% difference in the number of patients relapsing after 4 years. When we included this LASSO score in a multivariate cox regression (likelihood ratio p value = 0.007), the LASSO score (HR = 6.8, p = 0.026, CI = 1.26 - 37.28) showed additional predictive ability when including FLT3-ITD allelic ratio (HR = 1.83, p = 0.38, CI = 0.47 - 7.15) and MRD (HR = 3.95, p = 0.021 CI = 0.051 - 0.79). These results demonstrate that incorporating rare AML cell populations into a prognostic biomarker could add substantial clinical information to existing biomarkers. This indicates single-cell derived prognostic models can and should be explored further for pediatric FLT3-ITD AML and demonstrates a platform that could be used for other malignancies, including non-hematologic tumors, to create cell-type biomarkers. Citation Format: Robert Schauner, Zachary Jackson, Nethrie Idippily, Grace Lee, Sheela Karunanithi, Shivaprasaad Manjappa, Tae Hyun Hwang, David Wald. New platform for novel biomarker discovery using single-cell RNA sequencing on pediatric acute myeloid leukemia samples [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 4080.

Abstract The ATM inhibitor AZD1390 disrupts cellular responses to ionizing radiation (IR) and is a potent radiosensitizer being tested in clinical trials. Here, we evaluated, the effects of AZD1390 on radiation sensitivity and DNA damage repair pathways in glioblastoma (GBM) cells and patient derived xenografts (PDXs). AZD1390 (30 nM and higher) suppressed IR (5 Gy)-induced phosphorylation of ATM-Serine1981 and downstream phosphorylation sites on Kap1, Chk2 and H2AX in U251 cells and multiple PDXs. Consistent with enhanced DNA damage, AZD1390 increased IR induced G2/M arrest in U251 (80.6% with AZD1390/IR vs. 64.6% with IR, p= 0.01), GBM43 (61.9% vs. 25.7%, p= 0.01) and GBM39 (40.9% vs. 25.4%, p= 0.01). Moreover, in a clonogenic survival assay, AZD1390 sensitized U251 cells to 5 Gy IR (0.24% survival with AZD1390/IR vs. 2.3% with IR alone, p=0.01). In a reporter-based analysis of DNA repair capacity, ATM inhibition resulted in a 40 to 60% reduction in homologous recombination (HR) and modest but significant decrease in micro-homology mediated end joining (MMEJ) and gap fill-in synthesis in U251 cells but had no effect on non-homologous end joining, translesion synthesis, nucleotide or base excision repair pathways. Comparing effects of AZD1390 on repair in GBM14 (TP53-wt) and GBM43 (TP53-mutant), similar results were observed except that decreased MMEJ was seen only in GBM43 (0.03± 0.01% vs. 0.07± 0.01% in control, p=0.002). Intriguingly, RAD51 knockdown (to disrupt HR) sensitized U251 and GBM43 but not GBM14. The efficacy of AZD1390 ± IR was studied in vivo in 10 PDXs. IR was delivered to orthotopic tumors using opposed lateral 225 kVp beams. AZD1390 (20 mg/kg PO) was given just prior to each radiation dose (2 Gy x 5 fractions). AZD1390 monotherapy was mostly ineffective, IR alone was reasonably efficacious with an average 1.8 ± 0.1-fold-increase in survival relative to sham radiation (survival ratio) across all 10 models. IR/AZD1390 treatment resulted in significant survival extension relative to IR alone in 6 of 10 models. Analysis of the survival benefit of combination therapy compared to IR alone across the entire cohort of PDXs was statistically marginal (average survival ratio 2.3± 0.3 vs. 1.8 ± 0.1 with IR, p=0.08). However, when stratified by TP53 status, combination therapy was significantly more effective than IR (mean survival ratio 2.3 ± 0.1 vs. 1.6 ± 0.2 with IR alone, p=0.02) in TP53-mutant PDXs, where all 5 models benefited. In contrast, TP53-wt group had no benefit (mean survival ratio 2.2 ± 0.5 vs. 2.0 ± 0.2, p=0.61), GBM39 was only TP53-wt PDX that benefited from the combination. In conclusion, AZD1390 is an effective radio-sensitizer that causes disruption in HR and potentially other DNA repair pathways. Interestingly, in vivo radiosensitizing effects are mostly restricted to TP53-mutant GBM PDXs. Understandingmechanism of resistance in the context of different TP53 backgrounds remains an important future direction. Citation Format: Shiv K. Gupta, Jiajia Chen, Daniel J. Laverty, Surabhi Talele, Brett L. Carlson, Ann C. Mladek Tuma, Danielle Burgenske, Gaspar J. Kitange, Petra Hamerlik, Zachary D. Nagel, Stephen T. Durant, William F. Elmquist, Jann N. Sarkaria. AZD1390 radio-sensitizes p53-mutant GBM via disrupting homology directed DNA repair [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 2598.

The literature describing psychological interventions for co-occurring obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) is limited. Acceptance and Commitment Therapy (ACT) is a transdiagnostic intervention that targets functionally avoidant behavior underlying both OCD and PTSD. The current case report describes how an ACT-informed approach to treatment was implemented over 14 sessions to treat co-occurring OCD and PTSD in a 9-months postpartum adult woman. The patient was initially referred to psychotherapy by her psychiatrist and showed high motivation to engage in treatment. This case presentation outlines how the intervention targeted core ACT processes while also incorporating components from both exposure and response prevention (ERP) and cognitive processing therapy (CPT) to address the patient’s presenting concerns. Measurements of OCD and PTSD symptom severity, as well as of depressive and anxiety symptoms, over the course of treatment are included. Health-related comorbidities, psychiatric medications, and implications are discussed.

Abstract Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate malignancy. We describe the largest cohort of IMT patients to date, aiming to further characterize this rare, poorly understood tumor. This is a multi‐institutional review of IMT patients ≤39 years, from 2000 to 2018, at 18 hospitals in the Pediatric Surgical Oncology Research Collaborative. One hundred and eighty‐two patients were identified with median age of 11 years. Thirty‐three percent of tumors were thoracic in origin. Presenting signs/symptoms included pain (29%), respiratory symptoms (25%) and constitutional symptoms (20%). Median tumor size was 3.9 cm. Anaplastic lymphoma kinase (ALK) overexpression was identified in 53% of patients. Seven percent of patients had distant disease at diagnosis. Ninety‐one percent of patients underwent resection: 14% received neoadjuvant treatment and 22% adjuvant treatment. Twelve percent of patients received an ALK inhibitor. Sixty‐six percent of surgical patients had complete resection, with 20% positive microscopic margins and 14% gross residual disease. Approximately 40% had en bloc resection of involved organs. Median follow‐up time was 36 months. Overall 5‐year survival was 95% and 5‐year event‐free survival was 80%. Predictors of recurrence included respiratory symptoms, tumor size and distant disease. Gross or microscopic margins were not associated with recurrence, suggesting that aggressive attempts at resection may not be warranted.

AbstractGraft‐versus‐hostdisease (GVHD) following liver transplantation (LT) is rare but can lead tosignificant mortality. The leading cause of death following GVHD diagnosis isinfectious complications. However, there is a lack of clear descriptions concerning infection and antimicrobial management patterns. Our study aims toprovide the focused details of all infectious complications of acute GVHDfollowing LT. We retrospectively reviewed all adult LT recipients with acute GVHD at Mayo Clinic's Transplant Centers from January 1, 2010, to December 31, 2021. Detailed characteristics of infection in each case were described. Among 4,585 LTs performed during this period, 12 (0.3%) patients developed acuteGVHD. The median time from transplantation to GVHD diagnosis was 49.0 days [IQR 31.5–99.0]. Ten (83.3%) patients developed severe infections leading tomortality. The most common cause of infection was nosocomial bacteremia fromenteric bacteria such as vancomycin‐resistant enterococci and gram‐negative bacilli. Other infections included breakthrough invasive fungal infections,cytomegalovirus (CMV) reactivation, and Clostridioides difficile colitis. Antimicrobial prophylaxis strategies in most cases were based on the degree of neutropenia—these include levofloxacin for bacterial prophylaxis, nebulized pentamidine for Pneumocystis jiroveci pneumonia prophylaxis, posaconazole for invasive fungal prophylaxis, and valganciclovir based on CMVstatus. All GVHD patients with severe infections succumbed to thesecomplications. Ourstudy reiterates that despite prophylaxis, infectious complications in GVHDfollowing LT are common and lead to exceptionally high mortality. Individualizedantimicrobial treatment, prophylaxis and monitoring strategies remain a criticalcomponent of GVHD management. Further study to optimize these practices isrequired. image