Citations

AbstractPeripheral nerve injury‐induced spinal microglial proliferation plays a pivotal role in neuropathic pain. So far, key intracellular druggable molecules involved in this process are not identified. The nuclear factor of activated T‐cells (NFAT1) is a master regulator of immune cell proliferation. Whether and how NFAT1 modulates spinal microglial proliferation during neuropathic pain remain unknown. Here it is reported that NFAT1 is persistently upregulated in microglia after spinal nerve ligation (SNL), which is regulated by TET2‐mediated DNA demethylation. Global or microglia‐specific deletion of Nfat1 attenuates SNL‐induced pain and decreases excitatory synaptic transmission of lamina II neurons. Furthermore, deletion of Nfat1 decreases microglial proliferation and the expression of multiple microglia‐related genes, such as cytokines, transmembrane signaling receptors, and transcription factors. Particularly, SNL increases the binding of NFAT1 with the promoter of Itgam, Tnf, Il‐1b, and c‐Myc in the spinal cord. Microglia‐specific overexpression of c‐MYC induces pain hypersensitivity and microglial proliferation. Finally, inhibiting NFAT1 and c‐MYC by intrathecal injection of inhibitor or siRNA alleviates SNL‐induced neuropathic pain. Collectively, NFAT1 is a hub transcription factor that regulates microglial proliferation via c‐MYC and guides the expression of the activated microglia genome. Thus, NFAT1 may be an effective target for treating neuropathic pain.

A 70-year-old man with severe valvular cardiomyopathy, permanent atrial fibrillation (AF) with a slow ventricular response, and transient atrioventricular (AV) block, was admitted to our center for severe heart failure and recurrent presyncope. While hospitalized, the coronary computed tomography angiography (CTA) showed huge atriums. We tried His bundle pacing (HBP). HB potential was observed at site A, and the His-ventricular (HV) interval was 68 ms. The duration from the stimulus signal to the onset of paced QRS (S-QRSonset) at site A was 232 ms when pacing at 60 beats per minute (BPM) with the pacing threshold of 2.0 V/0.5 ms. The S-QRSonset was longer than the HV interval and had a notable and progressive prolongation from 252 ms to 456 ms during the pacing at 90 BPM. Then, we pushed another lead a little forward, and the S-QRSonset shortened back to 68 ms, and the paced QRS morphology was the same as the intrinsic QRS morphology with the pacing threshold of 1.5 V/0.5 ms. The progressively prolonged S-QRSonset demonstrated a Wenckebach phenomenon (WP), a well-known electrophysiological characteristic of the AV node (AVN). It is the first time to report an intraoperative AVN-pacing related-WP in a patient with persistent AF. The enlarged atrium might be convenient for capturing the AVN. There are some other potential explanations for this phenomenon. The diameters of atriums decreased significantly, and the symptoms improved after the procedure. This is the first reported case in which we might achieve AVN capture in a patient with persistent AF. Although we ultimately chose HBP for better long-term pacing thresholds, the result of this case suggested that AVN pacing may be possible.

Objective We sought to investigate whether long-term clinical outcomes differ following percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with three-vessel disease (3VD) and lesions in the proximal left anterior descending artery (P-LAD). Methods This post-hoc analysis of the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) Extended Survival study included patients with 3VD who were classified according to the presence or absence of lesions located in the P-LAD. Ten-year all-cause death and 5-year major adverse cardiac or cerebrovascular events (MACCE) were assessed. Results Among 1088 patients with 3VD, 559 (51.4%) had involvement of P-LAD and their 10-year mortality was numerically higher following PCI versus CABG (28.9% vs 21.9%; HR: 1.39, 95% CI 0.99 to 1.95). Although patients without P-LAD lesions had significantly higher 10-year mortality following PCI compared with CABG, there was no evidence of a treatment-by-subgroup interaction (28.8% vs 20.2%; HR: 1.47, 95% CI 1.03 to 2.09, pinteraction=0.837). The incidence of MACCE at 5 years was significantly higher with PCI than CABG, irrespective of involvement of P-LAD (with P-LAD: HR: 1.86, 95% CI 1.36 to 2.55; without P-LAD: HR: 1.54, 95% CI 1.11 to 2.12; pinteraction=0.408). Individualised assessment using the SYNTAX Score II 2020 established that a quarter of patients with P-LAD lesions had significantly higher mortality with PCI than CABG, whereas in the remaining three-quarters CABG had similar mortality. Conclusions Among patients with 3VD, the presence or absence of a P-LAD lesion was not associated with any treatment effect on long-term outcomes following PCI or CABG. Trial registration number SYNTAXES: NCT03417050; SYNTAX: NCT00114972.

Abstract Introduction: Incorporation of mammographic density to breast cancer risk models could improve risk stratification to tailor screening and prevention strategies according to risk. However, robust validation of such models in prospective cohort studies is needed to determine their accuracy in identifying women at different risk levels. Methods: We incorporated Breast Imaging and Reporting Data System (BI-RADS) breast density to a literature-based model with questionnaire-based risk factors and a 313-variant polygenic risk score (PRS). The Individualized Coherent Absolute Risk Estimator (iCARE) tool was used to build and validate a 5-year absolute risk model for breast cancer. The model was evaluated for calibration and discrimination in three prospective cohorts of women of European ancestry (1,468 cases, 19,104 controls): US-based Nurses’ Health Study (NHS I and II) and Mayo Mammography Health Study (MMHS); and Sweden-based Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) study. Analyses were done separately for women younger (NHS II, KARMA) and older than 50 years (NHS I, MMHS, KARMA). Improvements in risk stratification were assessed among US non-Hispanic White women aged 50-70 years. Results: For women younger than 50 years, the model with questionnaire-based risk factors, PRS and BI-RADS was well calibrated across risk deciles in NHS II, but overestimated risk at the highest risk decile in KARMA. For women 50 years or older, the model showed good calibration in all studies, with evidence of slight overestimation at the highest risk decile and underestimation at the lowest risk decile. The model with PRS and BI-RADS was well calibrated for women at high-risk in both age groups. Incorporation of BI-RADS to questionnaire-based risk factors and PRS improved risk discrimination: area under the curves (AUC) 67.0% (95% CI: 63.5-70.6%) vs. 65.6% (95% CI: 61.9-69.3%) for models with and without BI-RADS for younger women and 66.1% (95% CI 64.4-67.8%) vs. 65.5% (95% CI: 63.8-67.2%) for older women. The model with BI-RADS identified 18.4% population of non-Hispanic US women 50-70 years old above 3% 5-year risk (used for recommending risk-reducing medication in the US), with 42.4% of future cases expected to occur in this group. Addition of BI-RADS led to the reclassification of ~8.0% of US non-Hispanic White women aged 50-70 years at the high-risk threshold (3% 5-year risk), resulting in identification of 4.2% of additional future cases. Conclusion: Integrating BI-RADS with questionnaire-based risk factors and PRS resulted in improved risk stratification among women of European ancestry, with evidence of slight overestimation of risk for women at elevated risk. Additional validation of the integrated model in diverse populations is needed prior to considering clinical applications. Citation Format: Charlotta V. Mulder, Yon Ho Jee, Xin Yang, Christopher G. Scott, Chi Gao, Amber N. Hurson, Mikael Eriksson, Per Hall, Peter Kraft, Celine M. Vachon, Antonis C. Antoniou, Gretchen Gierach, Montserrat Garcia-Closas, Parichoy Pal Choudhury. Validation of an integrated breast cancer risk model with mammographic density in three prospective cohort studies [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 2256.

9008 Background: Amivantamab, a fully human bispecific antibody targeting epidermal growth factor receptor (EGFR) and MET, is approved for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion after prior platinum-based chemotherapy. Given its bispecific nature, amivantamab is being explored in patients (pts) with primary MET exon 14 skipping mutation (METex14) in the MET-2 cohort of the CHRYSALIS study. Methods: CHRYSALIS (NCT02609776) is an ongoing phase 1 dose escalation/dose expansion study of amivantamab in pts with advanced NSCLC. Pts with primary METex14 whose disease progressed on or who declined current standard of care therapy were treated with amivantamab 1050 mg (pts <80 kg) or 1400 mg (pts ≥80 kg) weekly in cycle 1 and biweekly thereafter. Response was assessed by investigators using RECIST v1.1. Results: As of 2 Dec 2021, 43 pts with METex14 had received amivantamab. Median age was 70 y (range, 43-88), 58% were women, median prior lines of therapy was 2 (range, 0-10) [eg, crizotinib (n=13), capmatinib (n=11), tepotinib (n=5), anti-MET antibody (n=1)], and 23% had history of brain metastases at baseline. In 36 pts with ≥1 postbaseline disease assessment, median duration of follow-up was 5.8 months (range, 0.3-15.8); 6 pts had no prior treatment, 11 had no prior MET inhibitor, and 19 had a prior MET inhibitor. Overall response rate was 33% (50% [3/6] in treatment-naïve pts, 46% [5/11] in pts with no prior MET inhibitor, and 21% [4/19] in pts with prior MET inhibitor therapy). Clinical benefit rate was >54% regardless of prior treatment (Table). Median duration of response (DOR) was not reached (range, 2.1-12.2 months); 67% (8/13) had DOR ≥6 months. Ten of the 12 responders remain on treatment (6.0-14.4 months) with ongoing responses; 2 discontinued after 2 and 12 months, respectively. Safety profile was consistent with previously reported experience of amivantamab (Sabari 2021 JTO 16(3):S108-109). Treatment-related adverse events leading to dose reduction or discontinuation occurred in 3 pts, each. Conclusions: Amivantamab demonstrates anti-tumor activity in primary METex14 NSCLC including after prior MET inhibitor treatment. Enrollment is ongoing and updated data will be shown. Clinical trial information: NCT02609776. [Table: see text]

11504 Background: Pazopanib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity in advanced soft tissue sarcoma. ARST1321 was a phase II study designed to compare the near complete pathologic response rate (≥ 90% necrosis) following preoperative chemoradiation +/- pazopanib in children and adults with intermediate/high risk chemotherapy-sensitive body wall/extremity NRSTS. Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary analysis of the study, we now report the outcome data for this cohort. Methods: ARST1321 was a jointly designed COG and NRG Oncology study open to enrollment July 2014-October 2018. Eligible adult (≥18 years) and pediatric (< 18 years) patients with newly-diagnosed unresected body wall/extremity NRSTS were enrolled into the Chemotherapy Cohort (> 5 cm, FNCLCC grade 2/3, protocol-designated chemotherapy-sensitive histology). Following a dose-finding phase, patients were randomized to receive (Regimen A) or not receive (Regimen B) pazopanib (< 18 years: 350 mg/m2/day; ≥ 18 years: 600 mg/day) in combination with ifosfamide (7.5 gm/m2/cycle) and doxorubicin (75 mg/m2/cycle) + 45 Gy preoperative RT followed by primary resection at week 13, then further chemotherapy to week 25. Results: Eighty-five eligible patients were enrolled in the Chemotherapy Cohort and randomized to receive or not receive pazopanib. Median age 22.1 years (range: 5.7-64.2 years); 30 patients < 18 years. Most common histologies were synovial sarcoma (n = 42) and undifferentiated pleomorphic sarcoma (n = 19). As of December 31, 2021, at a median survivor follow-up of 3.3 years (range: 0.1 – 5.8 years), the 3-year event-free survival (EFS) for all patients in the intent-to-treat analysis was 52.5% (95% CI: 34.8%-70.2%) for Regimen A and 50.6% (32%-69.2%) for Regimen B (p = 0.8677); 3-year overall survival (OS) was 75.7% (59.7%-91.7%) for Regimen A and 65.4% (48.1%-82.7%) for Regimen B (p = 0.1919). Conclusions: Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib to preoperative chemoradiation in children and adults with intermediate/high risk body wall/extremity NRSTS, outcomes were not statistically significantly different between the two regimens. Pathologic response could be a TKI-related phenomenon and may not be a good surrogate marker of outcome in future studies. Clinical trial information: NCT02180867.

4146 Background: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse models. Defactinib is a highly potent oral FAK inhibitor shown to have a tolerable safety profile. We evaluated the safety and recommended phase 2 dose (RP2D) of defactinib in combination with pembrolizumab and gemcitabine for PDAC patients. Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In 3x3 dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a RP2D. In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had treatment response or stable disease (SD) on standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and post-treatment tumor biopsies were performed to evaluate changes in tumor immunity. Results: The triple drug combination was well-tolerated with no dose-limiting toxicities. Among 17 treated patients with refractory PDAC, the disease control rate (DCR) was 58.8% with one partial response (PR) and nine SDs and the median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 9.1 months, respectively. Among the evaluable patients in the maintenance cohort, DCR was 63.6% with one PR and six SD. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS were 5.0 months and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated, had promising preliminary efficacy, and showed increased infiltrative T lymphocytes in post-treatment tumor biopsies. Incorporation of a more potent chemotherapy backbone should be considered to achieve better clinical response in future trial design. Clinical trial information: NCT02546531.

2068 Background: There is a lack of effective therapy for recurrent high-grade meningiomas who relapsed after prior radiation therapy (RT). ETCTN 10186 is a phase I/II study to evaluate the feasibility and preliminary clinical efficacy of combining reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab for recurrent high-grade meningiomas. The preliminary results from the phase I portion are reported here. Methods: Recurrent grade II-III meningioma patients were treated with radiosurgery plus nivolumab with or without ipilimumab. Key eligibility criteria include age ≥ 18 years; ECOG score ≤ 2; tumor diameter 1-5 cm; prior radiation dose ≤ 70 Gy; normal organ function; no active autoimmunity. During the phase I portion, eligible patients were treated according to treatment-escalation schema following the modified 3+3 design (Table 1). The maximum tolerated combination (MTC) will be the regimen at which ≤ 1/6 patients experience dose-limiting toxicity (DLT) within 8 weeks of the start of study therapy. During the phase II portion, a total of 24 evaluable patients will be enrolled at the MTC using Simon’s MiniMax two-stage design. The primary endpoint of the phase I portion is to determine the MTC. Objective radiological responses (ORRs) are defined as per the Macdonald criteria. One cycle of immunotherapy is defined as 4 weeks of nivolumab with or without concurrent ipilimumab. Results: From 7/2019 to 3/2021, 13 patients were enrolled in the phase I, including 6 with regimen A and 7 with regimen B (Table). The median prior RT dose was 56 Gy (18-70) at a median interval of 2.8 years (1.3-13.3). There was no DLT in either cohort, so regimen B was deemed the MTC. The median cycles of immunotherapy completed were not significantly different between cohort A and B (11 vs. 6, p = 0.41, respectively). Three cohort A patients and 2 cohort B patients completed all planned doses of immunotherapy. Most patients stopped due to progression, and only one cohort B patient stopped due to treatment-related toxicity (grade 3 hypophysitis and encephalitis after 6 cycles of immunotherapy). After a median follow-up of 11.1 months, there have been 5 progressions and 4 deaths. The 6 month-PFS and 12 month-PFS rates are 62% and 54%, respectively. Two ORRs have been reported by institutional assessment, and central radiology review is ongoing and will be reported. Conclusions: Reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab are well tolerated for radiation-relapsed high-grade meningiomas. Phase II study of regimen B is currently enrolling. Clinical trial information: NCT03604978. [Table: see text]

AbstractSeizure is one of the manifestations of central nervous system inflammatory demyelinating diseases, which mainly include multiple sclerosis (MS), aquaporin 4 antibody‐positive neuromyelitis optica spectrum disorder (AQP4‐NMOSD), and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD). Acute symptomatic seizures secondary to MS/AQP4‐NMOSD/MOGAD occur in the acute phase of the diseases, and are more frequent in MOGAD. In contrast, recurrent nonprovoked seizures, mainly attributed to autoimmune‐associated epilepsy, occur in the nonacute phase of the diseases. Seizures in MS/AQP4‐NMOSD/MOGAD mostly have a focal onset. MS patients with concomitant systemic infections, earlier onset, and greater disease activity are more likely to have seizures, whereas factors such as greater MS severity, the presence of status epilepticus, and cortical damage indicate a greater risk of developing epilepsy. In MOGAD, cerebral cortical encephalitis and acute disseminated encephalomyelitis (ADEM)‐like phenotypes (predominately ADEM and multiphasic disseminated encephalomyelitis) indicate a greater seizure risk. Multiple relapses with ADEM‐like phenotypes predict epilepsy in pediatrics with MOGAD. Pathophysiologically, acute symptomatic seizures in MS are associated with neuronal hyperexcitability secondary to inflammation and demyelination. Chronic epilepsy in MS is largely due to gliosis, neuronal dysfunction, and synaptic abnormalities. The mainstay of treatment for seizures secondary to MS/AQP4‐NMOSD/MOGAD consists of immunotherapy along with antiseizure medications. This critical review discusses the most‐updated evidence on epidemiology, clinical correlates, and inflammatory mechanisms underlying seizures and epilepsy in MS/AQP4‐NMOSD/MOGAD. Treatment cautions including drug‐drug interactions and the impact of treatments on the diseases are outlined. We also highlight pitfalls and challenges in managing such patients and future research perspectives to address unsolved questions.