Citations

Abstract Background TOPAZ-1 demonstrated durvalumab + gemcitabine and cisplatin (GemCis) superiority over GemCis in first-line treatment of advanced biliary tract cancers. Real-world data from US patients and patients excluded from TOPAZ-1 (patients with autoimmune conditions [AICs] who did not receive immunotherapy) are lacking. We report real-world data for patients with cholangiocarcinoma treated with durvalumab + GemCis. Methods This retrospective, observational study enrolled adult patients diagnosed with cholangiocarcinoma in the US from the International Cholangiocarcinoma Patient Registry (ICPR) treated with first-line durvalumab + GemCis between 2021–2023. De-identified medical records from ICPR were obtained directly from consenting patients/caregivers. Patient demographics and tumor characteristics (primary objective; assessed at initial diagnosis), comorbidities, second-line treatment modalities, median real-world overall survival (mrwOS), and median real-world time to next treatment (mrwTTNT; initiation of first-line treatment and last activity in the database or death) are reported. Results Seventy patients received first-line durvalumab + GemCis: 13 (18.6%) had AIC(s) and 57 (81.4%) did not. Patient demographics, clinical characteristics, and comorbidities are shown (Table). Median (quartile 1–3) time from diagnosis to start of first-line treatment was 1.0 (0.7–1.7) months; median follow-up from first dose of first-line treatment was 7.0 (3.7–12.1) months. The mrwOS (95% CI) was 15.5 (15.1–not evaluable [NE]) months. mrwTTNT (95% CI) was 10.8 (10.4–15.7) months overall and was 20.8 (10.4–NE) months in patients who died without receiving subsequent treatment (censored at date of last activity). Among patients with AIC(s), <5 received second-line therapy (all received chemotherapy alone). Among patients with no AICs, 15 received second-line treatment; 11 (73.3%) received targeted therapy alone and <5 received chemotherapy alone. Conclusions This dataset demonstrates patients with AIC(s) are treated with durvalumab + GemCis in clinical practice. The mrwOS for durvalumab + GemCis in this patient population is consistent with TOPAZ-1 and global real-world studies.

Abstract Background & Objectives Based on the TOPAZ-I study, durvalumab combined with gemcitabine and cisplatin (GemCis) is now supported as a standard of care treatment for cholangiocarcinoma. Patients with extrahepatic cholangiocarcinoma (eCCA) often have underlying autoimmune conditions (AICs) which could restrict immunotherapy use. Treatment patterns in patients with eCCA with AICs and non-autoimmune conditions (NAICs) are reported. Method This retrospective observational analysis of adult patients diagnosed with eCCA in the United States enrolled in the International Cholangiocarcinoma Patient Registry between 2019 and 2023, focused on those treated with durvalumab. The registry contains de-identified data from medical records obtained directly from consenting patients and caregivers. Patients were followed from index date (date of eCCA diagnosis) until the last activity in the database or death. Demographics, clinical characteristics, biomarkers, treatment patterns, and adverse events (AEs) are reported. Results Overall, 135 patients with eCCA were enrolled: 24 (17.8%) had 2:1 AICs and 111 (82.2%) had NAICs. Baseline demographics were comparable between groups: the median (quartile [Q]l-Q3) age at diagnosis was 63.0 (55.0-70.0) years, the mean number of comorbidities in the overall population was 10.1, and 50.4% of patients were female. PD-Ll positivity was noted in 12.6% of patients and HER2 positivity in 10.4%. Of 91 patients with eCCA who received first-line therapy, 34 (37.4%) received GemCis alone, 27 (29.7%) chemotherapy alone (non-GemCis +/- nab-paclitaxel), 9 (9.9%) GemCis plus nab-paclitaxel, 7 (7.7%) durvalumab plus GemCis, 7 (7.7%) durvalumab monotherapy or in combination, and 7 (7.7%) other regimens. Treatment patterns by autoimmune comorbidity status are also reported (Table). Overall, 129 patients (95.6%) had ≥1 AE; fatigue was the most common (71.1%). Conclusion More patients with eCCA received a first-line durvalumab-based regimen post-March 2022 vs the full study period. The use of durvalumab as first-line treatment in this subgroup may suggest that AICs do not restrict its use.

Abstract Faciobrachial dystonic seizures (FBDS), paroxysmal dizziness spells, and thermal sensory attacks are highly frequent and stereotypic phenomena experienced in leucine‐rich glioma inactivated 1 (LGI1)‐antibody encephalitis. This study aims to describe the electrophysiologic mechanism underlying these pathognomonic symptoms. LGI1‐antibody encephalitis patients with active symptoms were enrolled from two separate centers in South Korea and the United States. Patients were evaluated with simultaneous magnetoencephalography (306 channels) and electroencephalography. Regional alterations in neuronal excitability represented by interictal epileptiform discharges were present in the faciobrachial area of the motor cortex, insula, and somatosensory cortex, somatotopically aligned with each of the ictal semiologies observed in patients. FBDS and other LGI1‐antibody encephalitis‐specific spells localized to cortical regions neuroanatomically corresponding to ictal semiologies: the faciobrachial homunculus (FBDS), insular cortex (paroxysmal dizziness spells), and somatosensory cortex (thermal sensory attacks). Our findings support the ictal hypothesis underlying these unique phenomena.

Abstract Study Objectives This study examined whether basal electromyographic (EMG) amplitude during sleep is altered in patients with isolated REM sleep behavior disorder (iRBD) and its relationship to disease progression, as well as changes across the sleep cycle. Methods Baseline polysomnograms collected from 95 iRBD patients (15 converters, 80 non-converters) and matched 24 controls were analyzed. EMG amplitude was calculated from submentalis recordings across all sleep stages using 3-s mini-epochs, with REM sleep further classified as REM sleep without atonia (RWA) and non-RWA (RA) according to the presence of “any” RWA events. Kaplan–Meier analysis assessed phenoconversion risk, and EMG amplitude was compared between early and late sleep cycles within each group. Results Group comparisons with post-hoc adjustment showed that EMG amplitude in RA and RWA was higher in non-converters than controls (adj-p < .001), while converters showed further increases of EMG amplitude in N2 and N3 (adj-p < .045). RA amplitude was higher in converters than non-converters (adj-p = .02). Increased EMG amplitude in N2, N3, and RA was associated with higher phenoconversion risk (p < .05). EMG amplitude remained stable between early and late cycles during RA in both iRBD and controls. In contrast, iRBD patients showed a significant decrease in EMG amplitude during late cycles in N2 (p < .009). Conclusions Elevated basal EMG amplitude during both REM and NREM sleep in iRBD patients shows potential as a prognostic marker, indicating muscle tone dysregulation beyond REM atonia loss and underscoring the need to consider broader sleep stages in iRBD evaluation. Statement of Significance This study provides compelling evidence that increased basal electromyographic amplitude during both REM and NREM sleep in isolated REM sleep behavior disorder (iRBD) patients serves as a marker of prodromal alpha-synucleinopathy. By showing that electromyographic abnormalities extend beyond discrete REM events to affect global muscle tone, our findings challenge the conventional view that iRBD pathophysiology is limited to REM-specific activity. Furthermore, the predictive value of these changes appears linked to muscle tone regulation across the sleep–wake cycle. These insights not only deepen our understanding of iRBD pathophysiology but also underscore the potential for refining diagnostic criteria.

ABSTRACT Real time, chronic electrochemical detection of neurotransmitters will provide a positive step in the treatment and understanding of neurological disease. However, current electrodes using carbon fibers (CF) fail to perform chronically. While diamond‐based coatings show promise in improving their longevity, achieving a uniform layer of such coatings on CFs is challenging, and the electrodes often lose sensitivity after coating. In this work, a complete and uniform boron‐doped nanocrystalline material grown in a diamond reactor (B‐NCD) was developed to coat CF microelectrodes for neurochemical sensing. The coating was characterized electrically, optically, mechanically, and chemically. The B‐NCD coated CF electrodes were able to detect phasic dopamine at a sensitivity comparable to the most widely used alternatives (uncoated and PEDOT:Nafion coated CFs). During biofouling testing, the B‐NCD coated CF electrodes demonstrated better stability than uncoated CFs and comparable performance to PEDOT:Nafion coated CFs. Moreover, B‐NCD exhibited no signs of degradation during consecutive FSCV applications, while uncoated and PEDOT:Nafion coated CF electrodes degraded significantly over time. Furthermore, the B‐NCD coating supported the survival and development of neurons and astrocytes in vitro, exhibited excellent adhesion and durability during mechanical bending testing, and enabled successful in vivo recording of phasic dopamine release in the rat brain. Overall, B‐NCD coated CFs present as an ideal candidate for chronic, flexible neural implantable electrodes for long‐term neurochemical monitoring.

Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged on H3K27ac-marked epigenetic suppression of the serine glycine one carbon (SGOC) metabolism pathway, including the key enzymes PHGDH and PSAT1. Knockdown of PSAT1 was sufficient to replicate synergy with single-agent inhibition of either BET or mTOR. Our results tie together epigenetic regulation, metabolism, and apoptosis induction as key therapeutic targets for further exploration in this underserved disease.

Abstract Introduction: Individuals with cancer may be at higher risk of atrial fibrillation (AF). However, sufficient data are lacking in AF risk among breast cancer survivors, especially for the mid-to long-term risk of AF and the impact of cancer treatment on this association. We aimed to investigate the risk of incident AF in women diagnosed with breast cancer and evaluate the association by length of follow-up and breast cancer treatment. Methods: Using the Korean Health Insurance Service database, we studied 96,476 women who were diagnosed with breast cancer (aged≥20 years) without prior history of AF and breast cancer and underwent breast cancer surgery between January 2007 and December 2013. They were matched 1:3 to a cancer-free population (n=289,428) based on birth year and sex and were followed to the end of 2018. Using ICD-10 codes (I48.0 to I48.4, I.48.9), AF was defined when it was a discharge diagnosis or was verified more than twice in an outpatient clinic. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of AF associated with breast cancer relative to the cancer-free population, adjusting for age, income, and comorbidities including diabetes, hypertension and hyperlipidemia. Results: During a median follow-up of 6.8 years, AF developed in 2,105 women with breast cancer (3.2 per 1,000 person-years). Mean age at baseline among participants was 49.6 years. Having breast cancer was associated with increased risk of AF (HR, 2.04; 95% CI, 1.93-2.15). This association was stronger for women aged <50 years (HR, 3.98; 95% CI, 3.59-4.40). When we repeated analyses with lag periods of two years to explore the possibility of reverse causation and mid-to long-term risk of AF (n=91,370), the association was largely attenuated but remained significant (HR, 1.18; 95% CI, 1.09-1.28 for total women and HR, 1.60; 95% CI, 1.38-1.86 for women aged <50 years). However, no increased risk of AF was observed in women with breast cancer aged >65 years. Compared with no use of anthracyclines and taxanes, respectively, ever use of anthracyclines and taxanes was associated with increased risk of AF after further adjusting for other cancer treatment modalities including use of trastuzumab, radiotherapy, and endocrine treatment (HR, 1.25; 95% CI, 1.12-1.40 and HR, 1.37; 95% CI, 1.23-1.53, respectively). This association persisted only among women with breast cancer ever treated with anthracyclines when analysis was limited to those with two year-lag periods (HR, 1.23; 95% CI, 1.04-1.45). Conclusions: In this large-scale nationwide cohort study in South Korea, women with breast cancer had an elevated risk of incident AF, especially for women with breast cancer younger than 50 years, regardless of the length of follow-up. Our findings also suggest that cardiotoxic side effects of cancer treatment such as use of anthracyclines might increase both short-term and mid-to long-term risk of AF among women with breast cancer. Citation Format: Yong-Moon ("Mark") Park, Wonyoung Jung, Yohwan Yeo, Sang Hyun Park, Ronda Henry-Tillman, Hong Seok Lee, Tasneem Z. Naqvi, Kyungdo Han, Dong Wook Shin. Risk of atrial fibrillation among women diagnosed with breast cancer [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 3214.