Citations

AbstractBackgroundWith increasing molecular analyses of meningiomas, there is a need to harmonize language used to capture clinical data across centers to ensure that molecular alterations are appropriately linked to clinical variables of interest. Here the International Consortium on Meningiomas presents a set of core and supplemental meningioma-specific common data elements (CDEs) to facilitate comparative and pooled analyses.MethodsThe generation of CDEs followed the 4-phase process similar to other National Institute of Neurological Disorders and Stroke (NINDS) CDE projects: discovery, internal validation, external validation, and distribution.ResultsThe CDEs were organized into patient- and tumor-level modules. In total, 17 core CDEs (10 patient level and 7 tumor level) as well as 14 supplemental CDEs (7 patient level and 7 tumor level) were defined and described. These CDEs are now made publicly available for dissemination and adoption.ConclusionsCDEs provide a framework for discussion in the neuro-oncology community that will facilitate data-sharing for collaborative research projects and aid in developing a common language for comparative and pooled analyses. The meningioma-specific CDEs presented here are intended to be dynamic parameters that evolve with time and The Consortium welcomes international feedback for further refinement and implementation of these CDEs.

Abstract Background: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. Methods: We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways. Results: Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N = 137), Cluster 1 cases (N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P < 10−4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (P < 10−6). Conclusions: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways. Impact: This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.

Background: Exploration of cerebrospinal fluid (CSF) amino acids and the impact of dietary intake on central levels may provide a comprehensive understanding of the metabolic component of Alzheimer’s disease. Objective: The objective of this exploratory study was to investigate the effects of two diets with varied nutrient compositions on change in CSF amino acids levels in adults with mild cognitive impairment (MCI) and normal cognition (NC). Secondary objectives were to assess the correlations between the change in CSF amino acids and change in Alzheimer’s disease biomarkers. Methods: In a randomized, parallel, controlled feeding trial, adults (NC, n = 20; MCI, n = 29) consumed a high saturated fat (SFA)/glycemic index (GI) diet [HIGH] or a low SFA/GI diet [LOW] for 4 weeks. Lumbar punctures were performed at baseline and 4 weeks. Results: CSF valine increased and arginine decreased after the HIGH compared to the LOW diet in MCI (ps = 0.03 and 0.04). This pattern was more prominent in MCI versus NC (diet by diagnosis interaction ps = 0.05 and 0.09), as was an increase in isoleucine after the HIGH diet (p = 0.05). Changes in CSF amino acids were correlated with changes in Alzheimer’s disease CSF biomarkers Aβ42, total tau, and p-Tau 181, with distinct patterns in the relationships by diet intervention and cognitive status. Conclusion: Dietary intake affects CSF amino acid levels and the response to diet is differentially affected by cognitive status.

Background: After anterior cruciate ligament (ACL) reconstruction (ACLR), changes in the appearance of the ACL graft can be monitored using magnetic resonance imaging (MRI). Purpose: The purpose of this study was to evaluate and compare the MRI signal intensity (SI) of hamstring and quadriceps tendon grafts during the first postoperative year after ACLR. As a secondary aim, the relationship of SI to clinical and anatomic measurements was analyzed. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 78 patients who underwent ACLR with an autologous graft were reviewed; 55 received hamstring grafts and 23 received quadriceps tendon grafts. At 3 and 9 months postoperatively, 3-T MRI was performed using a dedicated knee coil, and the median SI of the intra-articular ACL graft was measured on sagittal-plane images. Postoperative lateral radiographs were analyzed to determine medial and lateral posterior tibial slope (PTS). Side-to-side difference in anterior knee laxity between injured and uninjured limbs was measured at 6 and 12 months postoperatively. Results: The median SI of quadriceps grafts was significantly greater than hamstring grafts at 3 months after ACLR ( P = .02). Between 3 and 9 months, the median SI of quadriceps grafts decreased ( P < .001), while that of hamstring grafts did not significantly change ( P = .55). The lateral PTS was significantly correlated with median SI measurements at 3 and 9 months such that greater lateral PTS values were associated with greater median SI. The side-to-side difference in anterior knee laxity decreased for the quadriceps group ( P = .04) between 6 and 12 months but did not change for the hamstring group ( P = .88). Conclusion: The median SI of quadriceps grafts significantly decreased on MRI between 3 and 9 months after ACLR, while the median SI of hamstring grafts did not significantly change. The change in MRI appearance of the quadriceps grafts was paralleled by a reduction in anterior knee laxity between 6 and 12 months after surgery. In the absence of standardized imaging techniques and imaging analysis methods, the role of MRI in determining graft maturation, and the implications for progression through rehabilitation to return to sport, remain uncertain.

Abstract We performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 years with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had Eastern Cooperative Oncology Group performance status (PS) 0-2, and 12% had documented loss of ≥1 activity of daily living (ADL). Medical comorbidities were assessed by the Cumulative Illness Rating Scale–Geriatric (CIRS-G), where n = 44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; hazard ratio [HR] 2.13, P = .007) and overall survival (OS; HR 2.52, P = .02). Most patients (n = 203, 83%) received conventional chemotherapy regimens, including doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P = .0007) and OS (HR 0.31, P = .0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, P = .63; OS HR 0.73, P = .55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥10 (28% vs 12%, P = .016) or documented geriatric syndrome (28% vs 13%, P = .02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, P = .02) and higher mortality from causes other than disease or treatment with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.

AbstractGlioblastoma multiforme (GBM) is one of the most aggressive malignant brain tumors and urgently requires the development of new therapeutic strategies. In this study, an innovative hybrid in vitro vascularized GBM‐on‐a‐chip model is presented as a strategic integration of microfluidics and 3D bioprinting technologies. The system can recreate the compartmentalized brain tumor microenvironment, comprising the functional blood brain barrier (BBB) and the adjacent 3D perivascular tumor niche, by selectively mimicking physiological shear stress and cell–cell, cell–matrix mechanical interaction. The GBM‐on‐a‐chip model was evaluated under simulated microgravity (µG) condition as a form of mechanical unloading showing a significant cell morphological and mechanotransduction response thereby indicating that gravitational forces play an important role in glioblastoma mechanical regulation. The proposed GBM‐on‐a‐chip represents a meaningful biological tool for further research in cancer mechanobiology and pre‐clinical approach in brain tumor therapy.

PURPOSE This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte–associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348 ). PATIENTS AND METHODS Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. RESULTS A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. CONCLUSION All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.

Abstract Background FGFR2 fusions occur in ~15% of patients (pts) with iCCA, a rare cancer with a poor prognosis. Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, has shown activity across tumor types, including iCCA, in a phase 1 study. The pivotal phase 2 FOENIX-CCA2 trial (NCT02052778) is evaluating futibatinib in iCCA harboring FGFR2 fusions/rearrangements. Here, we report the first efficacy, safety, and quality of life (QoL) data for the complete FOENIX-CCA2 population. Methods Eligible pts had unresectable/metastatic iCCA with an FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; excluding FGFR inhibitors). Pts received futibatinib 20 mg QD until PD/intolerability. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central review (target ORR: 20%). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and patient-reported outcomes (PROs). Subgroup analyses were performed by pt characteristic and molecular alteration. Results Among 103 pts (56% female), 53% had received ≥2 prior tx. FGFR2 fusions were present in 78% (23% had FGFR2-BICC1 fusions) and FGFR2 rearrangements in 22%. At data cutoff (Oct 1, 2020), 72 pts (70%) had discontinued tx. The study met its primary objective with a confirmed ORR of 41.7% (43/103). Responses were durable, with a median (m) DOR of 9.7 mo and 72% of responses ≥6 mo. DCR was 82.5%. mPFS was 9.0 mo; mOS was 21.7 mo, with a 12-mo OS rate of 72%. ORR was consistent across pt demographic subgroups (≥65 y: 65.2%; 2 prior tx: 38.7%). Common tx-related AEs (TRAEs) were hyperphosphatemia (85%), alopecia (33%), and dry mouth (30%). The most frequent grade 3 TRAE, hyperphosphatemia (30%), resolved with adequate management (median 7 d). Retinal disorders (all grade 1-2) were reported in 8% of pts. TRAEs were managed with dosing interruptions (50%)/reductions (54%); 2 pts discontinued tx due to TRAEs. No tx-related deaths occurred. ORRs were consistent in pts with dosing interruptions (40.2%) or reductions (46.8%). PROs were stable through 11.0 mo of tx. In exploratory biomarker analyses, ORR was consistent in pts with FGFR2 fusions (43.8%) and other FGFR2 rearrangements (34.8%) and in pts with BICC1 (41.7%) and non-BICC1 (44.6%) fusion partners. Notably, no obvious differences in ORR were observed in pts with co-occurring genetic alterations, including TP53 comutations (ORR, 38.5% [5/13]). Additional biomarker data will be presented. Conclusions Futibatinib resulted in frequent, durable objective responses in pts with iCCA harboring FGFR2 fusion/rearrangements, regardless of pt baseline characteristic, molecular alteration, or comutation. AEs were manageable with dosing modifications that did not impact response. QoL was maintained. Citation Format: Lipika Goyal, Funda Meric-Bernstam, Antoine Hollebecque, Chigusa Morizane, Juan W. Valle, Thomas B. Karasic, Thomas A. Abrams, Robin Kate Kelley, Philippe Cassier, Junji Furuse, Heinz-Josef Klümpen, Heung-Moon Chang, Li-Tzong Chen, Yoshito Komatsu, Kunihiro Masuda, Daniel Ahn, Yaohua He, Nital Soni, Karim A. Benhadji, John A. Bridgewater. Primary results of phase 2 FOENIX-CCA2: The irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements [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 CT010.