Citations

ABSTRACT Background Patients with cancer undergoing cardiac implantable electronic device (CIED) implantation face unique challenges. This study evaluates the outcomes and implications of CIED implantation in this population. Methods Using data from the National Readmission Database (NRD) from 2016 to 2019, we analyzed CIED implantations in patients aged ≥18 years, categorized by cancer status: no cancer, historical cancer, and active cancer. Multivariable logistic and linear regression models assessed associations with in‐hospital, 30‐day, and 90‐day outcomes, adjusting for various patient characteristics. Results A total of 748,957 CIED procedures were analyzed among which 13.3% were in patients with historical cancer and 3.8% with active cancer. Active cancer was linked to higher odds of pacemaker implantation but lower odds for ICD and CRT devices. Patients with active cancer experienced higher index hospitalization mortality (aOR 1.68; 1.50–1.89; p < 0.001), major adverse cardiovascular events (aOR 1.07; 1.02–1.14; p = 0.01), bleeding (aOR 1.36; 1.27–1.46; p < 0.01), and sepsis‐related (aOR 1.31; 1.19–1.44; p < 0.01) complications, with increased readmission rates at 30 (aOR 1.37; 1.30–1.44; p < 0.01) and 90 days (aOR 1.37; 1.31–1.44; p < 0.01) compared to those without cancer. Historical cancer was associated with better outcomes. Key predictors of adverse outcomes included chronic heart failure, kidney disease, cerebrovascular disease, and protein‐calorie malnutrition. Conclusions Patients with active cancer undergoing CIED implantation have an increased risk of in‐hospital complications and readmissions as compared to those without cancer.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.

ABSTRACT Objectives To characterize practice patterns and outcomes in the management of low‐ and intermediate‐grade salivary gland carcinoma prior to the existence of treatment guidelines. Methods Analysis of a registry of patients who underwent parotid and submandibular gland resections for low‐and intermediate‐grade carcinomas between 2010 and 2019. Results Of all 786 patients included in the study, 726 (92%) had preoperative imaging and 653 (83%) had preoperative biopsy. Of the 729 patients with parotid gland cancer, the majority underwent superficial ( n = 384, 53%) or total ( n = 254, 35%) parotidectomy. In patients with facial nerve preservation, total parotidectomy was associated with a significant increase in transient facial weakness (72/177 (41%) vs. 82/311 (26%), RR 0.65, 95% CI 0.50–0.84, p < 0.05) and permanent facial nerve weakness (23/176 (13%) vs. 16/301 (5%), RR 0.41, 95% CI 0.22–0.75, p < 0.05) compared to superficial parotidectomy. Adjuvant radiation therapy ( RT ) was delivered to 285 (36%) patients. The proportion of patients receiving adjuvant RT declined significantly over the time period from 2015 to 2019 compared to 2010 to 2014 at 162/504 (32%) and 123/282 (44%), respectively ( RR 0.74, 95% CI 0.61–0.89, p < 0.05). When comparing the time periods from 2015 to 2019 and 2010 to 2014, there was no significant difference in local control rates ( RR 0.52, 95% CI 0.26–1.04, p = 0.06) or regional control rates ( RR 0.75, 95% CI 0.26–2.13, p = 0.58). Conclusions Management of low‐ and intermediate‐grade salivary cancer from 2010 to 2019 was variable, which is expected given the rarity and heterogeneity of the disease and the lack of treatment guidelines prior to 2021. Most patients with parotid malignancies underwent superficial or total parotidectomy. The extent of parotidectomy had an impact on facial nerve function outcomes. Delivery of adjuvant radiation trended down with time. The data presented here will support dissemination of the guidelines and provide data that could inform future trials. Level of Evidence 2b.

OBJECTIVE The landscape of healthcare policies has undergone significant reforms, with a notable shift toward a patient-centered basis. This change has prioritized the use of metrics reflecting subjective patient-reported outcome measures (PROMs). However, these metrics are often limited, especially in terms of determining clinically relevant changes over time. The concept of the minimal clinically important difference (MCID) has been introduced to address this limitation. In this study, the authors aimed to assess the predictive capability of relative change and its corresponding threshold value, the minimal clinically important relative change (MCIRC), as an alternative to the absolute difference and MCID. METHODS Prospectively collected data from 2006 to 2021 were obtained from the Swedish Spine Registry (Swespine). PROMs included the numeric rating scale (NRS) neck and arm pain scores, the EQ-5D index and EQ visual analog scale (VAS), and the Neck Disability Index (NDI). Anchor-based methods were used to determine MCID and MCIRC. Absolute differences and relative changes were compared in terms of predictive power using the area under the receiver operating characteristic curve (AUC). RESULTS A total of 5323 patients were included. The chosen MCID values were −3 for NRS neck pain, −3 for NRS arm pain, 0.08 for EQ-5D index, 13 for EQ VAS, and −30 for NDI scores. The chosen MCIRC values were −40% for NRS neck pain, −50% for arm pain, 323% for EQ-5D index, 55% for EQ VAS, and −33% for NDI scores. Relative change was superior for NRS neck and arm pain scores and NDI, while absolute difference was superior for EQ-5D and EQ VAS scores. CONCLUSIONS Relative change and its corresponding MCIRC were found to be more appropriate as a surrogate of subjective satisfaction when studying the NRS and NDI scores, whereas absolute difference and MCID was more appropriate when addressing EQ-5D index and EQ VAS scores.

ABSTRACT Introduction Etripamil is a fast‐acting intranasally self‐administered calcium‐channel blocker developed for termination of paroxysmal supraventricular tachycardia (PSVT). Prior studies have demonstrated safety and efficacy of etripamil for PSVT termination following an initial medically supervised test dose during sinus rhythm. NODE‐303 is an open‐label, single‐arm study that evaluated etripamil for multiple, at‐home PSVT episodes, without test dose before first use. Methods Patients applied an ECG monitor at symptom onset and self‐administered etripamil (70 mg) if a vagal maneuver was unsuccessful. ECG monitoring occurred for ≥ 1 h following study drug administration. A repeat 70‐mg dose was introduced during the study for symptoms persisting 10 min after the first dose. Safety measures included treatment‐emergent adverse events (TEAEs) and ECG arrhythmia‐surveillance. Efficacy measures were captured for PSVT termination during treatment of each of the multiple episodes. Results 1054 perceived PSVT episodes were etripamil‐treated in 503 of 1116 patients enrolled. TEAEs within 24 h were mostly mild or moderate and localized: 30.2% of patients experienced nasal discomfort, nasal congestion (13.9%), rhinorrhea (13.1%), epistaxis (7.4%). TEAE frequencies decreased across multiple PSVT episodes and were similar for single versus repeat doses. For first PSVT episodes, 70.5% of patients converted to sinus rhythm by 60 min post etripamil (median time to conversion = 18.3 min [14.2–25.6]). Conversion in earlier episodes was consistently predictive of conversion in subsequent episodes. Conclusions Etripamil nasal spray self‐administered in a real‐world setting was well tolerated, effective, and had a consistent safety profile as a single‐ or repeat‐dose regimen across multiple PSVT episodes. Trial Registration: ClinicalTrials.gov NCT04072835

Importance Multiparametric magnetic resonance imaging (MRI), with or without prostate biopsy, has become the standard of care for diagnosing clinically significant prostate cancer. Resource capacity limits widespread adoption. Biparametric MRI, which omits the gadolinium contrast sequence, is a shorter and cheaper alternative offering time-saving capacity gains for health systems globally. Objective To assess whether biparametric MRI is noninferior to multiparametric MRI for diagnosis of clinically significant prostate cancer. Design, Setting, and Participants A prospective, multicenter, within-patient, noninferiority trial of biopsy-naive men from 22 centers (12 countries) with clinical suspicion of prostate cancer (elevated prostate-specific antigen [PSA] level and/or abnormal digital rectal examination findings) from April 2022 to September 2023, with the last follow-up conducted on December 3, 2024. Interventions Participants underwent multiparametric MRI, comprising T2-weighted, diffusion-weighted, and dynamic contrast–enhanced (DCE) sequences. Radiologists reported abbreviated biparametric MRI first (T2-weighted and diffusion-weighted), blinded to the DCE sequence. After unblinding, radiologists reported the full multiparametric MRI. Patients underwent a targeted biopsy with or without systematic biopsy if either biparametric MRI or multiparametric MRI was suggestive of clinically significant prostate cancer. Main outcomes and measures The primary outcome was the proportion of men with clinically significant prostate cancer. Secondary outcomes included the proportion of men with clinically insignificant cancer. The noninferiority margin was 5%. Results Of 555 men recruited, 490 were included for primary outcome analysis. Median age was 65 (IQR, 59-70) years and median PSA level was 5.6 (IQR, 4.4-8.0) ng/mL. The proportion of patients with abnormal digital rectal examination findings was 12.7%. Biparametric MRI was noninferior to multiparametric MRI, detecting clinically significant prostate cancer in 143 of 490 men (29.2%), compared with 145 of 490 men (29.6%) (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points; P = .50). Biparametric MRI detected clinically insignificant cancer in 45 of 490 men (9.2%), compared with 47 of 490 men (9.6%) with the use of multiparametric MRI (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points). Central quality control demonstrated that 99% of scans were of adequate diagnostic quality. Conclusion and relevance In men with suspected prostate cancer, provided image quality is adequate, an abbreviated biparametric MRI scan, with or without targeted biopsy, could become the new standard of care for prostate cancer diagnosis. With approximately 4 million prostate MRIs performed globally annually, adopting biparametric MRI could substantially increase scanner throughput and reduce costs worldwide. Trial registration ClinicalTrials.gov Identifier: NCT04571840

The NCCN Guidelines for Biliary Tract Cancers (BTCs) provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts is convened at least once annually to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. This manuscript focuses on the adjuvant chemotherapy and chemoradiation treatment options for BTCs as well as the systemic treatment recommendations for patients with advanced BTCs.

Abstract Background Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–PA interaction analysis. Methods Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. Results PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81–0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10 − 8 ). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75–0.85), but no significant PA–CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10 − 8 ). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72–0.82). Conclusions In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5 , suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.