Citations

Background: Lytic or malpositioned tunnels may require bone grafting during revision anterior cruciate ligament reconstruction (rACLR) surgery. Patient characteristics and effects of grafting on outcomes after rACLR are not well described. Purpose: To describe preoperative characteristics, intraoperative findings, and 2-year outcomes for patients with rACLR undergoing bone grafting procedures compared with patients with rACLR without grafting. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 1234 patients who underwent rACLR were prospectively enrolled between 2006 and 2011. Baseline revision and 2-year characteristics, surgical technique, pathology, treatment, and patient-reported outcome instruments (International Knee Documentation Committee [IKDC], Knee injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMaster Universities Osteoarthritis Index, and Marx Activity Rating Scale [Marx]) were collected, as well as subsequent surgery information, if applicable. The chi-square and analysis of variance tests were used to compare group characteristics. Results: A total of 159 patients (13%) underwent tunnel grafting—64 (5%) patients underwent 1-stage and 95 (8%) underwent 2-stage grafting. Grafting was isolated to the femur in 31 (2.5%) patients, the tibia in 40 (3%) patients, and combined in 88 patients (7%). Baseline KOOS Quality of Life (QoL) and Marx activity scores were significantly lower in the 2-stage group compared with the no bone grafting group ( P≤ .001). Patients who required 2-stage grafting had more previous ACLRs ( P < .001) and were less likely to have received a bone–patellar tendon–bone or a soft tissue autograft at primary ACLR procedure ( P≤ .021) compared with the no bone grafting group. For current rACLR, patients undergoing either 1-stage or 2-stage bone grafting were more likely to receive a bone–patellar tendon–bone allograft ( P≤ .008) and less likely to receive a soft tissue autograft ( P≤ .003) compared with the no bone grafting group. At 2-year follow-up of 1052 (85%) patients, we found inferior outcomes in the 2-stage bone grafting group (IKDC score = 68; KOOS QoL score = 44; KOOS Sport/Recreation score = 65; and Marx activity score = 3) compared with the no bone grafting group (IKDC score = 77; KOOS QoL score = 63; KOOS Sport/Recreation score = 75; and Marx activity score = 7) ( P≤ .01). The 1-stage bone graft group did not significantly differ compared with the no bone grafting group. Conclusion: Tunnel bone grafting was performed in 13% of our rACLR cohort, with 8% undergoing 2-stage surgery. Patients treated with 2-stage grafting had inferior baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting. Patients treated with 1-stage grafting had similar baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting.

Abstract Context Due to its rare incidence, molecular features of primary aldosteronism (PA) in young adults are largely unknown. Recently developed targeted mutational analysis identified aldosterone-driver somatic mutations in aldosterone-producing lesions, including aldosterone-producing adenomas (APAs), aldosterone-producing nodules (APNs), and aldosterone-producing micronodules, formerly known as aldosterone-producing cell clusters. Objective To investigate histologic and genetic characteristics of lateralized PA in young adults. Methods Formalin-fixed, paraffin-embedded adrenal tissue sections from 74 young patients with lateralized PA (&lt;35 years old) were used for this study. Immunohistochemistry (IHC) for aldosterone synthase (CYP11B2) was performed to define the histopathologic diagnosis. Somatic mutations in aldosterone-producing lesions were further determined by CYP11B2 IHC-guided DNA sequencing. Results Based on the CYP11B2 IHC results, histopathologic classification was made as follows: 48 APAs, 20 APNs, 2 multiple aldosterone-producing nodules (MAPN), 1 double APN, 1 APA with MAPN, and 2 nonfunctioning adenomas (NFAs). Of 45 APAs with successful sequencing, 43 (96%) had somatic mutations, with KCNJ5 mutations being the most common genetic cause of young-onset APA (35/45, 78%). Of 18 APNs with successful sequencing, all of them harbored somatic mutations, with CACNA1D mutations being the most frequent genetic alteration in young-onset APN (8/18, 44%). Multiple CYP11B2-expressing lesions in patients with MAPN showed several aldosterone-driver mutations. No somatic mutations were identified in NFAs. Conclusion APA is the most common histologic feature of lateralized PA in young adults. Somatic KCNJ5 mutations are common in APAs, whereas CACNA1D mutations are often seen in APNs in this young PA population.

Abstract Interpretation of the clinical significance of somatic gene variants in cancer remains a major challenge in cancer diagnosis, prognosis and treatment response prediction. We will report on progress and plans of the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG). The CDWG membership consists of over 150 multi-disciplinary experts in cancer biology, oncology, pathology, genetics, genomics and informatics. The mission of the ClinGen Somatic Cancer CDWG is to facilitate the development of data curation guidelines and standards to determine the clinical significance of somatic alterations in cancer, thereby enhancing the usability, dissemination and implementation of cancer somatic changes in the ClinGen resource and other knowledgebases including CIViC, ClinVar, and the Variant Interpretation for Cancer Consortium (VICC) MetaKB. Our goal is to create high-quality assertions of the clinical significance of specific somatic variants in cancer by leveraging the CIViC curation interface, adapting the germline procedures of ClinGen to somatic variant interpretation, and implementing the interoperability standards of the Global Alliance for Genomics and Health (GA4GH). The ClinGen Somatic effort is overseen by the Somatic CDWG and reports progress to the overall ClinGen consortium. There are Somatic Cancer subdomains focused on particular clinically important domains of cancer variant interpretation including three Task Forces (covering Pediatric Cancer, Hematologic Cancer, and Solid Tumors) and a growing number of Somatic Cancer Variant Curation Expert Panels (SC-VCEPs). To improve quality and consistency of clinical interpretations, each candidate somatic cancer VCEP must complete a four step approval process adapted from ClinGen’s work in Germline disease domains. The Somatic CDWG works to ensure that each group is aware of available training materials and detailed standard operating procedures. Each SC-VCEP also coordinates with the ClinGen Cancer Variant Interpretation Committee (CVI) whose goal is to support development of granular specifications for the AMP/ASCO/CAP guidelines for somatic variant interpretation. New SC-VCEPs are anticipated to focus on specific clinically relevant genes, pathways, disease entities, variant classes or treatment modalities. Currently, three SC-VCEPs have begun to work through the four step process (focused on FGFR mutations, NTRK fusions, and FLT3 mutations respectively), and two more SC-VCEPs are in the planning stage (Histone H3 and Ph-like ALL). To date, ClinGen Somatic groups have contributed 619 evidence lines into CIViC from 353 published papers and 21 assertions of clinical significance. Input from the AACR community is critical for the establishment of new SC-VCEPs that address areas of variant interpretation with the greatest need. Citation Format: Jason Saliba, Gordana Raca, Angshumoy Roy, Ian King, Shamini Selvarajah, Xinjie Xu, Rashmi Kanagal-Shamanna, Laveniya Satgunaseelan, David Meredith, Mark Evans, Alanna Church, Panieh Terraf, Yassmine Akkari, Heather E. Williams, Wan-Hsin Lin, Chimene Kesserwan, Deborah I. Ritter, Kilannin Krysiak, Arpad Danos, Alex Wagner, Marilyn M. Li, Dmitriy Sonkin, Jonathan S. Berg, Sharon E. Plon, Heidi L. Rehm, Shashikant Kulkarni, Ramaswamy Govindan, Obi L. Griffith, Malachi Griffith, on behalf of the ClinGen Somatic CDWG. The Clinical Genome Resource (ClinGen) somatic cancer clinical domain working group [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 1192.

This clinical case study describes the velopharyngeal anatomy and physiology in a patient who presented with SATB2-associated syndrome (SAS) and velopharyngeal insufficiency (VPI) in the absence of an overt cleft palate. The clinical presentation, treatment, outcome, and the contribution of anatomical findings from MRI to surgical treatment planning for this rare genetic disorder, SAS, are described. This case study contributes to our current understanding of the anatomy and physiology of the velopharyngeal mechanism in an individual born with SAS and non-cleft VPI. It also details the changes following bilateral buccal myomucosal flaps in this patient.

11562 Background: Afami-cel is an autologous, HLA-A*02-restricted, specific peptide enhanced affinity receptor, T-cell therapy engineered to target MAGE-A4+ solid tumors. The pivotal, 2-cohort, single-arm, Phase 2, SPEARHEAD-1 trial (NCT04044768) with afami-cel met its primary endpoint based on Cohort 1 data. As of September 1, 2021, in 47 patients (pts) with metastatic synovial sarcoma (SyS) or myxoid/round cell liposarcoma (MRCLS), the overall response rate (ORR) per independent review was 34% with encouraging durability (Van Tine, et al. Paper 30: CTOS 2021; Virtual). To identify potential stratification factors for response and assess whether response is a proxy for progression-free survival (PFS), we present pooled analyses using data from the prior Phase 1 trial (NCT03132922) and Cohort 1 of the SPEARHEAD-1 trial. Methods: Eligible pts (16–75 years) were HLA-A*02+ with MAGE-A4+ tumors. Pts received afami-cel after lymphodepleting chemotherapy. The pooled analyses evaluated ORR per RECIST v1.1 by investigator review, stratified by 7 factors, and safety. Results: In the pooled data, 69 pts received afami-cel (2.12–9.99×109 transduced T-cells) and were evaluable for response (Phase 1, n = 18; Phase 2, n = 51); all expressed one eligible HLA-A*02 allele. Median (range) for: age was 42 years (19–76), number of prior lines of therapy was 2 (1–12), and tumor MAGE-A4 H-score was 230 (60–300). Median (range) H-score was higher in SyS (256 [60–300]) than in MRCLS (180 [112–230]). The pooled investigator-assessed ORR was 36.2% (40.7% in SyS; 10.0% in MRCLS). Responses occurred across a wide MAGE-A4 H-score range (134–300). Median (range) duration of response was 52 weeks (8.29–75.14). Response rate was higher in the 59 pts with SyS: with ≤2 vs ≥3 prior lines of therapy (55.2% vs 26.7%), baseline target lesion sum of longest diameters <10cm vs ≥10cm (53.1% vs 25.9%), MAGE-A4 H-score ≥200 vs <200 (46.3% vs 27.8%), without vs with bridging therapy (48.6% vs 29.2%), who were female vs male (46.4% vs 35.5%), aged ≥40 vs <40 years (45.7% vs 33.3%), and from North America vs Europe (42.6% vs 33.3%). In responders vs non-responders with SyS, respectively, median PFS was 58.3 vs 11. 0 weeks (log-rank p-value <0.0001); the probability of being progression-free at 24 weeks was 0.8 vs 0.2. The pooled benefit:risk profile of afami-cel was similar to that in the SPEARHEAD-1 trial (Van Tine, et al. Paper 30: CTOS 2021; Virtual.). Conclusions: We show that baseline tumor burden, prior systemic treatment history, and MAGE-A4 tumor expression levels are potential factors associated with response to afami-cel, although their true predictive value for response status awaits confirmation. Our findings will inform the ongoing clinical development of afami-cel in sarcoma, especially for prognostic studies with PFS or overall survival endpoints. Clinical trial information: NCT04044768, NCT03132922.

11016 Background: Stress Management and Resiliency Training (SMART) is a validated resilience training program designed to reduce stress, improve emotional resilience, and decrease burnout. The prevalence of burnout among practicing oncologists is as high as 40%, but unknown among oncology trainees. We implemented a virtual format of the SMART program to the Hematology/Oncology fellowship at Mayo Clinic to assess the feasibility of such a delivery, measure baseline rates of burnout in this group, and to investigate if a virtual method of delivery is as effective as in-person delivery as described in the literature. Methods: The SMART project was a mixed-methods, prospective, single arm clinical trial. Hematology/Oncology Fellows at Mayo Clinic were invited to participate. Four one-hour training sessions were conducted virtually. Fellows were given access to SMART online video modules and a book which supported the content covered during virtual training, a companion resilience mobile app, and a paperback mindfulness journal. Stress, burnout, and emotional resilience were measured at baseline and three months post-intervention using the Perceived Stress Scale (PSS), Maslach Burnout Inventory (MBI), and Connor-Davidson Resilience Scale (CD-RISC2). Changes in mean scores on the PSS, MBI, and CD-RISC2 were assessed using the Wilcoxon signed-rank test. Program feedback and feasibility data were obtained during a virtual focus group. Audio transcripts from the focus group were codified for thematic analysis and verified by intercoder triangulation. A 6-month assessment will be due in March 2022. Results: 26 of 50 fellows invited participated in our study. At baseline, 24% of participants had measurable burnout and 92% had moderate to high stress. At 3-months, the number of participants with moderate to high stress decreased to 71%, while rates of burnout remained unchanged. The PSS demonstrated a decrease in mean stress (-10.9%, p = 0.005), while the MBI demonstrated decreased emotional exhaustion (MBI-EE -6.01%, p = 0.04), an improved sense of personal achievement (MBI-PA 28.1%, p < 0.001), but slightly worse feelings of depersonalization (MBI-DP 16.46%, p = 0.05). The CD-RISC2 suggested no change in global emotional resilience (-0.71%, p = 0.82). Thematic analysis of the focus group data revealed that participants overwhelmingly found the program beneficial (83% of all responses), 20% indicated improved stress, and 15% indicated improved work performance. Conclusions: Oncology fellows in this study had lower rates of burnout compared to practicing oncologists. Virtual implementation of the SMART program is feasible and resulted in improvements in stress and prevented worsened burnout. Outcomes were comparable to previously published studies conducted in-person. Focus group participants found the training beneficial, reported lower stress, and improved work performance.

10009 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients, age 1-21 years, with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms based on genetic alterations detected in their tumor. Arm C evaluated the EZH2 inhibitor tazemetostat in patients whose tumors harbored EZH2 hotspot mutations or SMARCB1 or SMARCA4 loss by immunohistochemistry. Methods: Tazemetostat 1200 mg/m2/dose PO BID was administered to the first 13 patients; after study amendment due to second malignancy noted in the pediatric phase 1 trial, the dose for patients with non-CNS tumors was reduced to 520 mg/m2/dose PO BID. Patients were treated for 28-day cycles until PD or intolerable toxicity (max 26 cycles); response assessments occurred every 2-3 cycles. Primary and secondary endpoints were ORR and PFS, respectively. Results: Twenty eligible and evaluable patients (median age 5 years; range 1-21) were enrolled between Nov 2017 and Sept 2020. SMARCB1 loss was detected in 16/20 (80%) tumors: atypical teratoid rhabdoid tumor (ATRT, n = 8), malignant rhabdoid tumor (MRT, n = 4), epithelioid sarcoma (ES, n = 2), renal medullary carcinoma (RMC, n = 1) and hepatocellular carcinoma (HCC, n = 1). EZH2 mutations were identified in 3/20 (15%) tumors: Ewing sarcoma (n = 2), ependymoma (n = 1). One patient with Langerhans cell histiocytosis (LCH) had SMARCA4 loss. Centrally reviewed, one objective response (PR) was observed (LCH [SMARCA4], 26 cycles at 1200 mg/m2/dose BID). Five other patients had a best response of stable disease (ES [SMARCB1], 26 cycles, 520 mg/m2/dose BID; ATRT [SMARCB1], 13 cycles,1200 mg/m2/dose BID; RMC [SMARCB1], 12 cycles, 520 mg/m2/dose BID; ES [SMARCB1], 9 cycles,1200 mg/m2/dose BID; ATRT [SMARCB1], 6 cycles, 1200 mg/m2/dose BID). No other patients received > 2 cycles. Six-month PFS was 35% (95% CI 15.7%, 55.2%); OS was 45% (95% CI 23.1%, 64.7%). Treatment-related adverse events were consistent with AEs previously reported with tazemetostat, including anemia, thrombocytopenia, elevated LFTs, abdominal pain, dyspnea, infection, and intracranial hemorrhage. Three patients had bromide elevations. Conclusions: In this cohort of children with relapsed tumors harboring EZH2 mutations or loss of SMARCB1 or SMARCA4, tazemetostat did not produce significant objective responses (ORR: 5%, 90% CI 1%, 20%). However, we observed prolonged stable disease of > 6 months (range: 6-26 cycles) in 33% of patients across different histologic diagnoses, including two patients who received the full two years of study therapysuggesting a potential effect of tazemetostat on disease stabilization. Future studies will incorporate tazemetostat in combination with chemotherapy or immunologic agents for patients with these aggressive and difficult to treat tumors. Clinical trial information: NCT03213665.

7006 Background: Measurable residual disease (MRD) prior to allogeneic hematopoietic cell transplantation (alloHCT) is associated with increased relapse and death in patients with acute myeloid leukemia (AML) in cytomorphological complete remission (CR). We recently demonstrated AML MRD detected in pre-alloHCT blood by DNA-sequencing was associated with increased relapse and decreased overall survival in patients randomized to reduced intensity conditioning (RIC) versus myeloablative conditioning (MAC). The clinical utility of such ultra-deep next-generation sequencing (NGS-MRD) had not yet been reported in a large multi-center cohort. Methods: Patients aged 18 or older who underwent first alloHCT between 2013-2017 for AML in first CR (CR1), reported to be FLT3, NPM1, IDH1, IDH2 and/or Kit mutated at diagnosis, with a pre-conditioning remission blood sample available in the CIBMTR biobank were eligible for this study. Ultra-deep anchored multiplex PCR-based NGS-MRD for the above mutations was performed on 500ng gDNA with error-corrected variant calling as previously described. The pre-specified statistical analysis plan was registered on OSF. Results: Of 457 patients with a sample available, 448 had sufficient clinical annotation and DNA for analysis. 147 of these 448 patients (33%) experienced relapse at a median of 5.6 months post-alloHCT. NGS-MRD was positive in 129 pre-alloHCT patient samples (29%), averaging 1.35 mutation(s)/patient (range: 1-4). 173 mutations were detected with a median VAF of 0.18% (range: 0.0054-62%), most frequently FLT3-ITD (n = 43 patients), NPM1 (n = 48), and IDH2 (n = 46). Testing positive by NGS-MRD prior to alloHCT was associated with a 3yr RFS of 36% (95% CI: 28-45%) compared with 56% (51-62%) in those testing negative (p < 0.001). Detection of NPM1 and/or FLT3-ITD mutations prior to alloHCT was associated with a 3yr relapse probability of 55% (43-67%) and RFS of 26% (16-37%). NGS-MRD impact was modified by conditioning intensity: positive patients receiving RIC/NMA had the highest relapse of 57% at 3yr, testing negative followed by RIC/NMA had the same relapse rate at 3yr (35%) as those who tested positive but received MAC (p < 0.001). At three years, those positive for FLT3-ITD and/or NPM1 mutations prior to RIC/NMA alloHCT had a relapse probability of 67% (50-83%) with a RFS of 19% (8-33%). HR for relapse if NGS-MRD positive pre-alloHCT in CR1 was 2.3 (p < 0.001, 95% CI 1.6-3.1) when adjusting for conditioning intensity and age group. Conclusions: In this largest cohort of NGS-MRD testing prior to alloHCT for AML reported to date, we confirm the ability to identify patients in CR1 but at high-risk of subsequent relapse. This evidence provides the foundation for future precision medicine approaches to reduce post-transplant AML relapse.

6530 Background: Only a small fraction of patients with cancer participate in treatment trials. Patients identifying as members of racial and ethnic minority groups are consistently underrepresented in these trials. A recent systematic review reported that patients, regardless of race and ethnicity, are willing to enroll in trials if asked to participate by their treating clinician. Prospective and longitudinal data and metrics at the site- and clinician-level are necessary to understand whether patients are equitably considered for clinical trials. Methods: ASCO and Association of Community Cancer Centers (ACCC) developed a self-assessment for trial sites to record and gauge the number of patients across races and ethnicities screened, offered, and enrolled into clinical trials. Research sites, from across the US, were recruited through an open call to apply to participate in the ASCO-ACCC Pilot Project. There were 65 sites assigned to this pilot study, which tested the feasibility and utility of the site assessment. Sites were asked to enter 2019 and 2020 aggregate data for each step along the clinical trial enrollment continuum by select races and ethnicities (Black, Hispanic/Latinx, White) and overall. Results: 62 of 65 sites completed the study and represented a range of settings and practice types (61% academic, 26% hospital/health system, 13% independent). Only 2 sites (3%) were able to provide the data requested at each enrollment step in the assessment (table). Sites that collected the data did not do so routinely (table) and most had to compile data through multiple sources and/or manual extraction (40-100% across enrollment steps). Sites with missing data reported they did not collect data at all (36-64% across enrollment steps), did not collect data in a systematic way (0-29% across enrollment steps), or stated it would be too burdensome to manually review charts to extract data (12-29% across enrollment steps). Conclusions: Data collection and routine evaluation of participation metrics, by race and ethnicity, are necessary to assess and monitor equity and diversity in clinical trials. Most sites in this study did not collect, or routinely collect, data for screening, offering, and consenting patients to clinical trials. Without these data, sites are unable to evaluate and monitor whether their patients have equitable access to clinical trials or establish strategies to address any inequities. ASCO and ACCC will continue to partner with sites to better understand their processes and the feasibility of collecting such data in a systematic and automated way, such as through electronic health record systems. [Table: see text]