Citations

Abstract Background: The dysregulation of polycomb repressive complex 2 (PRC2) promotes tumorigenesis and progression. Two therapeutic agents targeting enhancer of zeste homolog (EZH) 2 or EZH1/2, the catalytic subunits of PRC2, have been approved in several cancer types. HH2853 is a novel selective EZH1/2 dual inhibitor, which has demonstrated superior anti-tumor efficacy to tazemetostat (EZH2 inhibitor approved by FDA) in various preclinical models. Methods: This is a first-in-human, open-label, multi-center, phase (Ph) I/II study of HH2853 in patients (pts) with relapsed/refractory (r/r) non-Hodgkin lymphomas (NHLs) or advanced solid tumors. HH2853 was administered orally twice daily (BID) on a continuous 28-day treatment cycle. Ph I consist of two parts: dose escalation part adopting accelerated titration followed by a Bayesian optimal interval design and dose extension part. Dose limiting toxicity (DLT) was evaluated during the 1st cycle in dose escalation. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of HH2853 were explored in this Ph I study. Results: As of Oct 19, 2022, a total of 57 pts, including 50 pts with solid tumors and 7 pts with r/r follicular lymphoma (FL), were enrolled from 12 sites in China and the US. Twenty-five (43.9%) pts received ≥3 lines of prior systemic therapies. Six dose levels(50 mg, 100 mg, 200 mg, 400 mg, 600 mg and 800 mg)were evaluated. DLTs were observed in 2 of 8 DLT evaluable pts at 800 mg: one grade 3 platelet count decreased and one grade 3 diarrhea. A conclusive maximal tolerated dose was not reached. The most common treatment-related adverse events (TRAE) were diarrhea (45.6%), blood bilirubin increased (35.1%), white blood cell count (WBC) decreased (26.3%), platelet count decreased (26.3%), rash (24.6%) and anemia (22.8%). The most common ≥grade 3 TRAEs included anemia (8.8%), platelet count decreased (7.0%), WBC decreased (5.3%) and diarrhea (5.3%). TRAEs leading to dose interruption or reduction were reported in 17.5% and 8.8% pts respectively. No TRAE led to dose discontinuation or death. PK data indicated dose-related increase in exposure from 50 to 600 mg. PD data showed a significant inhibition (maximum reached >90%) of H3K27me3 in granulocytes and monocytes at 400-800 mg. Tumor responses were observed in 7 pts from 200 to 800 mg in multiple tumor types, including complete response in 1 patient with FL, partial response in 3 pts with epithelioid sarcoma, 2 pts with FL and 1 patient with malignant rhabdoid tumor of pancreas. Conclusions: This first-in-human study of HH2853 showed a manageable safety profile and promising anti-tumor activity in multiple tumor types, supporting further exploration in NHLs and solid tumors after recommended Ph II dose is determined.Clinical trial information: NCT04390737 Citation Format: Zhengfu Fan, Jin Wang, Meiyu Fang, Johnston Patrick, Tun Han, David Sommerhalder, Jifang Gong, Jilong Yang, Yun Yang, Javier Munoz, Yuqin Song, Zhiming Li, Xian'an Li, Qiuying Ma, Jinming Han, Lin Shen, Jun Zhu. Preliminary results from the Phase I part of a first-in-human Phase I/II study of HH2853, an EZH1/2 inhibitor, in patients with relapsed/refractory non-Hodgkin lymphomas or advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT105.

Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

AbstractBackgroundMechanical accuracy should be verified before implementing a proton stereotactic radiosurgery (SRS) program. Linear accelerator (Linac)‐based SRS systems often use electronic portal imaging devices (EPIDs) to verify beam isocentricity. Because proton therapy systems do not have EPID, beam isocentricity tests of proton SRS may still rely on films, which are not efficient.PurposeTo validate that our proton SRS system meets mechanical precision requirements and to present an efficient method to evaluate the couch and gantry's rotational isocentricity for our proton SRS system.MethodsA dedicated applicator to hold brass aperture for proton SRS system was designed. The mechanical precision of the system was tested using a metal ball and film for 11 combinations of gantry and couch angles. A more efficient quality assurance (QA) procedure was developed, which used a scintillator device to replace the film. The couch rotational isocentricity tests were performed using orthogonal kV x‐rays with the couch rotated isocentrically to five positions (0°, 315°, 270°, 225°, and 180°). At each couch position, the distance between the metal ball in kV images and the imaging isocenter was measured. The gantry isocentricity tests were performed using a cone‐shaped scintillator and proton beams at five gantry angles (0°, 45°, 90°, 135°, and 180°), and the isocenter position and the distance of each beam path to the isocenter were obtained. Daily QA procedure was performed for 1 month to test the robustness and reproducibility of the procedure.ResultsThe gantry and couch rotational isocentricity exhibited sub‐mm precision, with most measurements within ±0.5 mm. The 1‐month QA results showed that the procedure was robust and highly reproducible to within ±0.2 mm. The gantry isocentricity test using the cone‐shaped scintillator was accurate and sensitive to variations of ±0.2 mm. The QA procedure was efficient enough to be completed within 30 min. The 1‐month isocentricity position variations were within 0.5 mm, which demonstrating that the overall proton SRS system was stable and precise.ConclusionThe proton SRS Winston–Lutz QA procedure using a cone‐shaped scintillator was efficient and robust. We were able to verify radiation delivery could be performed with sub‐mm mechanical precision.

260 Background: NGS to identify HRR mutations (mut) is indicated in advanced prostate cancer (aPC); samples for testing may be tissue or plasma. In a large real-world (RW) database, we determined concordance between plasma ctDNA and primary tumor tissue (PT) and/or metastatic tissue (MT) for BRCA1, BRCA2, and ATM mut in PC patients (pts) who received both LB and tissue NGS any time during standard of care (SOC) management. The study objective was to assess the utility of LB to detect actionable mut in these HRR genes and demonstrate the utility of combined LB and tissue testing. Methods: We examined de-identified data from pts who had NGS using both Tempus xF (105 genes-LB) and Tempus xT (648 genes-tissue) during SOC for aPC. Analyses included 1) PT and LB and 2) MT and LB. The results from the pts’ earliest PT or MT and earliest LB were used for paired analyses. The prevalence of a pathogenic/likely pathogenic germline and/or somatic mut in BRCA1, BRCA2, or ATM was reported as N (%), 95% CI. The sensitivity of the LB to identify observed HRR mut in tissue was also reported as N (%), 95% CI. Concordance between pairs was evaluated by Cohen’s kappa statistic with 95% CI. Results: HRR results are show for 1074 PC pts who had NGS performed on PT and LB and 451 PC pts with NGS on both MT and LB. In the PT and LB analysis, HRR mut were found in 6.2% (95% CI: 4.9%-7.9%) of LB and 8.8% (95% CI: 7.2%-11%) of PT. The sensitivity of LB to detect HRR mut in the PT was 53% (95% CI: 43%-64%). Cohen’s kappa statistic was 0.59, 95% CI=0.50-0.68, between PT and LB. In the MT and LB analysis, HRR mut were found in 10% (95% CI 7.8%-14%) of LB and 10% (7.6%-13%) of MT. The sensitivity of LB to detect HRR mut in the MT was 70% (95% CI: 54%-82%). Cohen’s kappa statistic was 0.65, 95% CI=0.54-0.77, between MT and LB. Conclusions: In this large RW dataset, plasma ctDNA-based analysis of BRCA1, BRCA2, and ATM mut showed greater concordance between LB and MT than LB and PT, and may be used as an initial tool for HRR mut detection. When LB results are negative, further exploration with tissue-based testing may identify HRR mut to guide clinical decisions. [Table: see text]

AbstractObjectiveTo dissect the kinetic defects of acetylcholine receptor (AChR) γ subunit variant in an incomplete form of the Escobar syndrome without pterygium and compare it with those of a variant of corresponding residue in the AChR ε subunit in a congenital myasthenic syndrome (CMS).MethodsWhole exome sequencing, α‐bungarotoxin binding assay, single channel patch‐clamp recordings, and maximum likelihood analysis of channel kinetics.ResultsWe identified compound heterozygous variants in AChR γ and ε subunits in three Escobar syndrome (1–3) and three CMS patients (4–6), respectively. Each Escobar syndrome patient carries γP121R along with γV221Afs*44 in patients 1 and 2, and γY63* in patient 3. Three CMS patients share εP121T along with εR20W, εG‐8R, and εY15H in patients 4, 5, and 6, respectively. Surface expressions of γP121R‐ and εP121T‐AChR were 80% and 138% of the corresponding wild‐type AChR, whereas εR20W, εG‐8R, and εY15H reduced receptor expression to 27%, 35%, and 30% of wild‐type εAChR, respectively. γV221Afs*44 and γY63* are null variants. Thus, γP121R and εP121T determine the phenotype. γP121R and εP121T shorten channel opening burst duration to 28% and 18% of corresponding wild‐type AChR by reducing the channel gating equilibrium constant 44‐ and 63‐fold, respectively.InterpretationSimilar impairment of channel gating efficiency of a corresponding P121 residue in the acetylcholine‐binding site of the AChR γ and ε subunits causes Escobar syndrome without pterygium and fast‐channel CMS, respectively, suggesting that therapy for the fast‐channel CMS will benefit Escobar syndrome.

Purpose: Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. In previous studies, we and others have described the functional influence of plasminogen activator inhibitor-1 (PAI1) in bladder cancer development. While polymorphisms in PAI1 have been associated with increased risk and worsened prognosis in some cancers, the mutational status of PAI1 in human bladder tumors has not been well defined. Methods: In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. Results: Sequencing analyses identified two clinically relevant 3′ untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1 (rs7242; rs1050813). Somatic SNP rs7242 was present in human BCa cohorts (overall incidence of 72%; 62% in Caucasians and 72% in Asians). In contrast, the overall incidence of germline SNP rs1050813 was 18% (39% in Caucasians and 6% in Asians). Furthermore, Caucasian patients with at least one of the described SNPs had worse recurrence-free survival and overall survival (p = 0.03 and p = 0.03, respectively). In vitro functional studies demonstrated that SNP rs7242 increased the anti-apoptotic effect of PAI1, and SNP rs1050813 was related to a loss of contact inhibition associated with cellular proliferation when compared to wild type. Conclusion: Further investigation of the prevalence and potential downstream influence of these SNPs in bladder cancer is warranted.

Objective: Chronic nonspecific low back pain (CNLBP) is a serious medical and social problem resulting in functional decline and decreased work ability. Tuina, a form of manual therapy, has been sparsely used to treat patients with CNLBP. To systematically assess the efficacy and safety of Tuina for patients with CNLBP. Methods: Multiple English and Chinese literature databases were searched until September 2022 for randomized controlled trials (RCTs) of Tuina in the treatment of CNLBP. The methodological quality was assessed using the Cochrane Collaboration’s tool, and certainty of the evidence was determined with the online Grading of Recommendations, Assessment, Development and Evaluation tool. Results: Fifteen RCTs with 1390 patients were included. Tuina demonstrated a significant effect on pain (SMD: −0.82; 95% CI −1.12 to −0.53; P < .001; I 2 = 81%) and physical function (SMD: −0.91; 95% CI −1.55 to −0.27; P = .005; I 2 = 90%) when compared to control. However, Tuina resulted in no significant improvement for quality of life (QoL) (SMD: 0.58; 95% CI −0.04 to 1.21; P = .07; I 2 = 73%;) compared to control. The Grading of Recommendations, Assessment, Development and Evaluation evidence quality was determined to be low level for pain relief, physical function, and QoL measurements. Only six studies reported adverse events; none were serious. Conclusion: Tuina might be an effective and safe strategy for treating CNLBP in terms of pain and physical function, but not for QoL. The study results should be interpreted with caution for their low-level evidence. More multicenter, large-scale RCTs with a rigorous design are required to further confirm our findings.

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we aimed to assess survival and safety in ZUMA-1 after 5 years of follow-up. Eligible adults with refractory LBCL (diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma) received lymphodepleting chemotherapy followed by axi-cel infusion targeted at 2×106 cells/kg. Investigator-assessed response, updated survival, safety, and pharmacokinetic outcomes were assessed in treated patients. The objective response rate in the 101 treated patients was 83% (58% complete response rate), and with a median follow-up of 63.1 months, responses were ongoing at data cutoff in 31%. Median overall survival (OS) was 25.8 months and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91%. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. ClinicalTrials.gov, number NCT02348216

Importance Numerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction. Objective To determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk. Design, Setting, and Participants Case-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry. Exposures Two APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype. Main Outcomes and Measures The primary outcome was AD case-control status, and secondary outcomes included age at AD onset. Results Stage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In ε3/ε4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P = 6.0 × 10 −6 ) and was associated with a reported younger age at AD onset (β, −5.87 years; 95% CI, −8.35 to −3.4 years; P = 3.4 × 10 −6 ). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P = .04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P = .051). Association with earlier AD onset was replicated in stage 2 (β, −5.23 years; 95% CI, −9.58 to −0.87 years; P = .02) and stage 3 (β, −10.15 years; 95% CI, −15.66 to −4.64 years; P = 4.0 × 10 −4 ). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H. Conclusions and Relevance In this exploratory analysis, the APOE ε3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the ε3/ε4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.