Citations

Abstract Usually used in emergency settings, bedside sonographic measurement of optic nerve sheath diameter can aid in diagnosing elevated intracranial pressure. We report a case of a 26-year-old male hospitalized for CAR T-cell therapy with Axicabtagene Ciloleucel for treatment of relapsed diffuse large B-cell lymphoma, who developed progressive symptoms of immune effector cell-associated neurotoxicity syndrome. Fundoscopic examination suggested the presence of blurred optic disc margins. Bedside ocular ultrasound revealed wide optic nerve sheath diameters and bulging optic discs bilaterally. The patient had a ventriculostomy placed for monitoring and received treatment with steroids and mannitol, as well as tocilizumab. After 7 days in the ICU, the patient recovered with no evidence of long-term neurological deficits.

Introduction Postural tachycardia syndrome is a form of orthostatic intolerance that often leads to functional impairment. Methods This survey explored functional status and impact of symptoms in adults ( n = 958) ages 18 to 60 (M = 32.63 ± 10.52 years, 96.7% female) with postural tachycardia syndrome. Results Individuals reported an average of 11 daily life activities impacted by postural tachycardia syndrome with high levels of self-perceived disability. Additionally, 93.4% reported some degree of cognitive impairment and falls occurred in 55.3% of participants annually. Despite frequent falls and functional impairment, participants infrequently (26.9%) utilized therapy services. Conclusion Individuals with postural tachycardia syndrome are at an increased risk of experiencing disability and often require assistance with daily activities. Further research is necessary to understand the potential role of therapy in improving function and quality of life.

Abstract There is growing evidence showing that sex disparity in lung cancer risk cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotype from a lung cancer cohort including ~ 47,000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 (OR=0.71, p=4.29x10-8); rs79942605 (OR=2.17, p=2.81x10-8); and rs208908 (OR=0.70, p=4.54x10-8), were identified with different risk effect of lung cancer between men and women. Further eQTL and functional annotation analysis suggested rs208908 affect lung cancer risk through differential regulation of CXADR (Coxsackie Virus And Adenovirus Receptor) gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Introduction: Granulomatosis with polyangiitis (GPA) is a vasculitic process that can cause neurological dysfunction in addition to characteristic sinus and pulmonary manifestations. This case report highlights the spectrum of nervous system manifestations and includes rarely reported autonomic and pituitary involvement. Case Report: A 62-year-old woman presented with orthostatic intolerance, tachycardia, dry mouth, and temperature sensitivity; subsequent autonomic reflex study demonstrated widespread postganglionic sympathetic sudomotor, cardiovagal, and cardiovascular adrenergic impairment reflective of autonomic neuropathy and overall autonomic failure. Additional progressive symptoms included dysarthria, dysphagia, bilateral hearing loss, voice hoarseness, and right-sided facial numbness with multiple cranial neuropathies identified on neurological examination. The diagnosis of central diabetes insipidus was also confirmed. Pachymeningitis was present on brain magnetic resonance imaging. Pathologic review of the dural biopsy specimen revealed necrotizing granulomatous vasculitis consistent with GPA. She was treated with intravenous methylprednisolone and rituximab. Over the next 2 months, she had near-complete resolution of her symptoms with normalization on repeat autonomic testing. Conclusions: This is a unique GPA case presenting with autonomic failure and pituitary dysfunction with conclusive objective findings of autonomic dysfunction. Autonomic dysfunction and other disease manifestations were responsive to immunosuppressive therapy.

Abstract Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P &lt; 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604

Introduction: There are many treatment options for patients who have osteonecrosis of the femoral head (ONFH) and management strategies vary widely both among and within individual countries. Although many researchers have attempted to elucidate the optimal strategies for managing this disease, the lack of large-scale randomized control trials and the lack of agreement on disease staging have curtailed the development of clear-cut guidelines. Materials and Methods: The Association Research Circulation Osseous (ARCO) group sought to address three questions for the management of patients who have ONFH: 1) What imaging studies are most sensitive and specific for the diagnostic evaluation of patients who have ONFH?; 2) What is the best treatment strategy for preventing disease progression in patients who have pre-collapse lesions?; and 3) What is the best treatment strategy for patients who have post-collapse disease? The Patient, Intervention, Comparison, and Outcome (PICO) format was used to formulate the search strategy for each research question. A systematic review will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ARCO participants have been allocated to three groups, each representing one of the PICO questions. After qualitative and quantitative analysis of the data extracted from studies pertaining to each of the three research questions, a set of evidence-based clinical practice guidelines will be proposed for the management of patients who have ONFH. Discussion: It is not always clear which treatment method is optimal for the management of ONFH. Thus, many surgeons have developed and performed various procedures based on patient-specific factors. As there is no consensus on the optimal treatment for various stages of disease, it was clear that developing evidence-based clinical practice guidelines would provide more structure and uniformity to management of these patients. Therefore, the results of this systematic review will lead to the development guidelines that may improve patient-care strategies and result in better outcomes for patients who have ONFH.

PURPOSE To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma. METHODS After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy. RESULTS Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached. CONCLUSION Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.

12003 Background: AIMSS are common and frequently lead to early discontinuation of adjuvant AI therapy. Single nucleotide polymorphisms (SNPs) in candidate genes have been associated with AIMSS and AI discontinuation. The primary objective of E1Z11 was to validate previously identified associations between 10 specific SNPs in candidate genes and AI discontinuation due to AIMSS in a community-based, racially diverse cohort. Methods: Postmenopausal women with hormone receptor-positive stage I-III breast cancer enrolled onto a prospective multi-site cohort study, the majority through the NCI Community Oncology Research Program (NCORP). Participants received anastrozole 1 mg oral daily, and completed patient-reported outcomes (PROs) at baseline, 3, 6, 9, and 12 months. AIMSS was defined as >20% increase in Stanford Health Assessment Questionnaire (HAQ) score over baseline occurring within 1 year of AI therapy. We projected 40% would develop AIMSS and 25% would discontinue AI treatment within 1 year, informing a planned enrollment of 1000 women with a fixed number per strata (600 Caucasian, 200 African-American [AA] & 200 Asian) to provide 80% power to detect an effect size of 1.5-4. SNPs include ESR1 (rs2234693, rs2347868, rs9340835), CYP19A1 (rs1062033, rs4646), TCL1A (rs11849538, rs2369049, rs7158782, rs7159713), and HTR2A (rs2296972). Hardy-Weinberg equilibrium (HWE) was evaluated within each racial subset. SNP genotypes were coded as additive effects on the log odds ratio by coding as 0, 1 or 2 for the count of the minor allele. A Cochran-Armitage trend test was used with a 1-sided alpha of 0.0025 (Bonferroni correction for 10 tests). Results: We enrolled 999 evaluable women (616 Caucasian, 184 AA, 199 Asian). Genotyping was successful in 974 (98%). AIMSS developed in 43%, and AI therapy was discontinued in 12% within 1 year. While more AA and Asians developed AIMSS compared to Caucasians (48% vs 38%, p=0.017; 50% vs 38%, p=0.004), AI discontinuation rates were similar across racial groups. HWE was satisfied for all SNPs at the 5% alpha level, except for TCL1A/rs11849538 (p=0.002) in the AA cohort. None of the 10 SNPs were significantly associated with AI discontinuation or development of AIMSS in the overall population, or in any of the 3 cohorts. Conclusions: Although AIMSS were more common in AA and Asians, AI discontinuation rates were similar in the 3 cohorts. We were unable to prospectively validate 10 SNPs in 4 genes previously associated with AI discontinuation due to AIMSS. Future analyses will include other predictors of AIMSS, PROs, and additional genetic markers for the entire cohort and by race. Support: NCI UG1CA189828, UG1CA233196, UG1CA233277, UG1CA233320, UG1CA233178, UG1CA233160, UG1CA232760, UG1CA233341, UG1CA233329, U10CA180821, UG1CA189821, UG1CA189830, U10CA180888, UG1CA189859, UG1CA189863, UG1CA189971. Clinical trial information: NCT01824836.

7541 Background: FT516 is an investigational, NK cell cancer immunotherapy derived from a clonal master iPSC line. FT516 is engineered with a novel hnCD16 Fc receptor, demonstrated preclinically to maximize antibody-dependent cellular cytotoxicity (Zhu et al. Blood 2020). FT516 can be mass produced and made available off-the-shelf for broad pt access and multi-dose administration. Methods: This is a Phase I trial of FT516 combined with rituximab (R) in pts with R/R BCL. Treatment consists of 2 cycles, each with 3 days lympho-conditioning (fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 ) and 1 dose of R followed by 3 weekly infusions of FT516 (planned doses 30-900 million/dose) with IL-2 (6 MIU after each FT516 dose). The primary objective is to identify the incidence of dose-limiting toxicity (DLT)/dose cohort and the recommended Phase II dose using a standard 3+3 design. Additional objectives include safety, tolerability, preliminary activity, pharmacokinetics, and immunogenicity. Results: Six pts (5 DLBCL, 1 FL, median age 65.5 y) have completed (5) or discontinued (1) study treatment after the DLT period (data cutoff 9 Dec 2020): 2 received 30 million cells/dose, 3 received 90 million cells/dose, and 1 received 300 million cells/dose. All pts received > 1 prior R-containing regimen, and median number of prior therapies was 3 (range 2-6), including CAR-T in 3 pts. FT516 was primarily administered in the outpatient setting. No FT516-related Grade ≥3 adverse events (AEs) or serious AEs, and no events of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) of any grade were reported. DLT (Grade 4 neutrophil count decreased, not recovered to baseline by D29) was reported in the first pt at 30 million cells/dose and R dosing of 375 mg/m 2 weekly x 4/cycle, resulting in modification of R dosing to once/cycle; no DLTs were observed with modified R dosing. Most common all grade AEs in ≥3 pts: fatigue (4 pts) and decreased appetite, nausea, neutrophil count decreased, and headache (3 pts each). Grade ≥3 AEs in ≥2 pts: neutrophil count decreased (3 pts) and febrile neutropenia and platelet count decreased (2 pts each); none considered related to FT516. Host anti-product B- or T-cell immunogenicity was not observed. Three of 4 pts treated at ≥90 million cells/dose achieved objective response (2 complete responses [CRs] and 1 partial response). Conclusions: Administration of up to 6 doses of FT516 cells, including up to 300 million cells/dose, appears to be safe and tolerable, without CRS, ICANS, or GvHD. Activity was observed, including CRs, in heavily pretreated pts. Dose escalation is ongoing. Updated clinical and translational data will be presented. Clinical trial information: NCT04023071.