Citations

Abstract Atrial fibrillation (AF) is increasingly diagnosed early, close to its first occurrence due to: (i) increased public awareness with self-screening; (ii) health care initiatives including population screening and opportunistic case finding; and (iii) increased use and surveillance of implantable cardiac devices. At its onset, AF is often low burden, and cardiovascular co-morbidities may be absent or at an early stage. Thus, the management of recent-onset AF has become an issue of growing importance. Professional guidelines have traditionally focused on anticoagulant thromboprophylaxis, generally recommending a cautious approach to rhythm control, and priority has been given to rate control to alleviate symptoms. In recent guidelines, the importance of managing lifestyle and co-morbidities has increased. The AF-SCREEN collaboration proposes that a vigorous approach to active management of recent-onset AF may be warranted. This includes addressing co-morbidities and promoting healthy lifestyles to prevent the emergence or progression of AF and associated cardiovascular disease, as well as the initiation of active rhythm control ± anticoagulation to prevent AF-related morbidity and mortality, including stroke and heart failure (HF). Intuitively, intervention early after AF onset would be beneficial since lifestyle and co-morbidity management, plus rhythm control and anticoagulation, are important contributors to improved outcomes in patients with established AF, but robust evidence is lacking for recent-onset AF. There is a delicate balance between achieving favourable outcomes such as preventing strokes, HF and AF progression vs the complications and potential adverse effects of interventions. Given the serious long-term consequences, innovative approaches are necessary to determine the value and risks of initiating active therapy very early in the course of AF. More data are needed to guide the best management of recent-onset AF, bearing AF burden in mind. Long-term studies using large national databases linked to electronic medical records and rhythm monitoring devices offer excellent opportunities. Shorter-term studies focusing on reducing AF burden to slow AF progression and studies focusing on outcomes such as HF could be used in both randomized clinical trials and observational cohort studies.

Black patients with metastatic prostate cancer have higher mortality rates compared to non-Hispanic White patients. There are no data on outcomes with [177Lu]Lu-PSMA-617 (LuPSMA) across racial groups. We evaluated the association between race and outcomes with LuPSMA in a multi-institutional cohort of consecutive patients with mCRPC treated with LuPSMA. The primary outcomes were PSA-50 rate, PSA-progression-free survival (PSA-PFS), and overall survival (OS). Statistical models were adjusted for age, number of prior therapies, sites of metastases, and baseline PSA. A total of 654 patients were included; 593 (91%) were White, 45 (7%) were Black and 16 (2%) were another non-Black minority (NBM). There were no statistically significant differences in PSA-50 rates, PSA-PFS and OS between the groups. Black and White patients treated with LuPSMA had similar clinical outcomes; efforts are needed to ensure Black and NBM patients have equal access to life prolonging therapies to narrow disparities in outcomes.

Background: Periarticular local infiltration analgesia has become an important mainstay of multimodal analgesia after elective total hip arthroplasty (THA). However, the role of novel motor-sparing fascial plane blocks—with or without periarticular local infiltration analgesia—has not been fully elucidated for patients undergoing THA. The authors conducted a network meta-analysis evaluating the relative analgesic effectiveness of motor-sparing fascial plane blocks (quadratus lumborum, erector spinae, and pericapsular nerve group blocks) and periarticular local infiltration analgesia for adult patients undergoing THA. Methods: Randomized trials examining single-injection quadratus lumborum, erector spinae, or pericapsular nerve group blocks, or periarticular local infiltration analgesia, for THA were sought. The primary outcome was area under the curve (AUC) rest pain scores during the period from 0 to 24 h. Secondary outcomes included rest pain scores at 0, 6, 12, and 24 h; postoperative function at 6, 12, and 24 h; analgesic consumption at 0 to 24 h; incidence of opioid-related side effects; and incidence of block-related complications. Network meta-analysis was performed using a frequentist approach. Results: A total of 44 trials (3,579 patients) evaluating the quadratus lumborum block, erector spinae block, pericapsular nerve group block, or periarticular local infiltration analgesia for THA were considered. Network meta-analysis was used to derive the probability of each intervention being the most effective as compared to the others (P score). For AUC 0 to 24 h rest pain, periarticular local infiltration analgesia was the most effective intervention, as demonstrated by a P score of 89%. For postoperative analgesic consumption, the quadratus lumborum block was the most effective intervention, with a P score of 88%. This was followed by the pericapsular nerve group block (74%), the erector spinae block (38%), and periarticular local infiltration analgesia (42%). Conclusions: Periarticular local infiltration analgesia alone provides the most consistent improvements in postoperative rest pain, analgesic consumption, and functional recovery after THA. The addition of a quadratus lumborum block or pericapsular nerve group block to periarticular local infiltration may further improve analgesic outcomes.

BACKGROUND AND OBJECTIVES: It remains unclear whether decompressive craniectomy (DC) is beneficial in patients who suffer symptomatic intracerebral hemorrhage (sICH) after acute ischemic stroke (AIS). We sought to study the effect of DC on functional outcomes in patients with sICH after AIS who underwent mechanical thrombectomy (MT). METHODS: Patients with AIS from anterior circulation large vessel occlusion who underwent MT and subsequently developed sICH were identified from the Stroke Thrombectomy and Aneurysm Registry database. The primary outcome was acceptable 90-day functional neurological outcome, defined as modified Rankin scale (mRS) 0-3. Multivariable logistic regression and propensity-score matching were used to identify and quantify risk factors. RESULTS: Of 464 patients identified with sICH after AIS after MT, 97 patients (20.9%) underwent DC. Patients who underwent DC were more likely to be female ( P < .001), younger ( P < .001), have a measured medical comorbidity, have higher baseline mRS ( P = .02), and have higher-grade hemorrhages ( P = .01). At 90 days, 14% of patients had the primary outcome of mRS 0-3 and 56% had died. The primary outcome was observed in 11 patients who underwent DC (11%) and 55 (15%) of those without DC (odds ratio [OR] 0.7, 95% CI 0.4-1.4, P = .40). DC did not affect mRS shift at 90 days ( P = .10) but was associated with lower mortality (OR 0.5, 95% CI 0.3-0.8, P = .01). Multivariable analysis demonstrated that DC decreased the odds of primary outcome (adjusted OR 0.2, 95% CI 0.02-0.9, P = .045), but did not affect mortality ( P = .94), mRS shift ( P = .50), or length of stay ( P = .90). Propensity-matched analysis similarly demonstrated that non-DC patients were more likely to achieve the primary outcome (24% vs 8%, P = .045). CONCLUSION: In patients with sICH after AIS after MT, those selected for DC had less favorable outcomes and similar rates of mortality at 90 days.

Abstract Background and Aims Visceral pain is a cardinal symptom of many disorders affecting the gut. Modulators of gamma-aminobutyric acid (GABA) such as benzodiazepines may attenuate colonic pain but the specific contribution of peripheral GABAA receptors remains unclear as these agents have prominent central effects. Methods Using medicinal chemistry optimization of the benzodiazepine scaffold, we developed a novel and potent benzodiazepine-based positive allosteric modulator (PAM) of GABAA receptors, Li633, with no significant central nervous system (CNS) penetration. Results The locomotor activity of rats placed in an open field was unchanged with Li633 at doses up to 30 mg/kg, confirming its lack of a CNS effect. LI-633 produced robust potentiation of GABA-induced inward current, with EC50 values ranging from 8 nM (α5β2γ2) to 128 nM (α3β2γ2). In vitro electrophysiological studies confirmed its ability to reduce excitability of human dorsal root ganglion (DRG) neurons. LI-633 potentiated muscimol-induced GABAergic currents in rat DRG neurons in a dose-dependent manner, with an EC 50 of 70.4 nM. In vivo, LI-633 significantly attenuated visceral hypersensitivity and pain behavior in a rat model of irritable bowel syndrome (IBS) and functional dyspepsia (FD). In the IBS model, administration of the drug also resulted in decreased excitability of colon-specific DRG neurons and significantly reduced the colonic afferent response to balloon distention as measured by recordings of neural activity in dorsal ganglia rootlets. Conclusions These findings highlight the potential of targeting peripheral GABAA receptors for pain management in IBS and other disorders associated with visceral hypersensitivity.

LBA4005 Background: To date, no phase 3 clinical trial has demonstrated an overall survival (OS) benefit in patients with locally advanced pancreatic adenocarcinoma (LA-PAC). TTFields are electric fields that disrupt cancer cell division. TTFields therapy is approved for glioblastoma, pleural mesothelioma, and metastatic non-small cell lung cancer. A phase 2 trial in PAC demonstrated the safety and preliminary efficacy of TTFields therapy with gemcitabine with or without nab-paclitaxel. We report final data from PANOVA-3 (NCT03377491), the largest global, phase 3, randomized, open-label trial in LA-PAC to date. Methods: Adult patients with newly diagnosed unresectable LA-PAC were randomized 1:1 to receive TTFields therapy (150 kHz) with gemcitabine/nab-paclitaxel (GnP) or GnP. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), local PFS, objective response rate (ORR), and pain-free survival. Distant PFS (metastases beyond the pancreas and regional lymph nodes) was assessed post hoc. Survival data were compared using the Kaplan-Meier method and a log-rank test. Results: 571 patients were randomized. Baseline characteristics were generally well balanced between the study arms. OS was significantly longer with TTFields/GnP than with GnP (median 16.2 [95% CI: 15.0, 18.0] vs 14.2 months [95% CI: 12.8, 15.4]; HR 0.82 [95% CI: 0.68, 0.99], p=0.039). One-year survival rate was also significantly improved with TTFields/GnP vs GnP (68.1% [95% CI: 62.0-73.5] vs 60.2% [95% CI: 54.2-65.7], p=0.029). There was no significant difference in PFS or local PFS between arms. Pain-free survival was significantly longer with TTFields/GnP vs GnP (median 15.2 [95% CI: 10.3, 22.8] vs 9.1 months [95% CI: 7.4, 12.7]; HR 0.74 [95% CI: 0.56, 0.97], p=0.027). Post-hoc analysis showed significant distant PFS benefit (median 13.9 [95% CI: 12.2, 16.8] vs 11.5 months [95% CI: 10.4, 12.9], HR 0.74 [95% CI: 0.57, 0.96], p=0.022) with TTFields/GnP vs GnP. ORR was similar between arms (36.1% [95% CI: 30.0, 42.4] vs 30.0% [95% CI: 24.3, 36.2], p=0.094). 97.8% and 98.9% of patients who received TTFields/GnP and GnP, respectively, had adverse events (AEs) and 88.6% and 84.3% had grade ≥3 AEs. The most frequent grade ≥3 AEs were neutropenia (47.8% and 47.6%) and anemia (21.9% and 22.3). 81% of patients receiving TTFields/GnP had device-related AEs, mostly grade 1/2 skin AEs, e.g., dermatitis (27.7%), rash (17.5%), and pruritus (15.0%); grade 3 and grade 4 device-related AEs occurred in 9.1% and 0.4% of patients, respectively. Conclusions: PANOVA-3 is the largest phase 3 trial exclusively performed in patients with LA-PAC and the first to show a statistically significant OS benefit. With no additive systemic toxicity and a statistically significant pain-free survival benefit, TTFields therapy is a potential new standard treatment for LA-PAC. Clinical trial information: NCT03377491 .

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45–1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28–2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35–5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53–20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18–0.88]; P interaction =0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

CARTITUDE-1 evaluated ciltacabtagene autoleucel (cilta-cel) in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM). We describe overall survival (OS), ≥5-year progression-free outcomes, associated biomarkers, and safety, with a median study follow-up of 61.3 months. For the 97 treated patients, median OS was 60.7 months (95% CI, 41.9 to not estimable). One third (32/97) of patients remain alive and progression-free for ≥5 years after a single cilta-cel infusion, without maintenance treatment. Twelve of these patients treated at a single center underwent serial minimal residual disease (MRD) and positron emission tomography-computed tomography assessments, and all (100%) were MRD-negative (at least 10 −5 threshold) and imaging-negative at year 5 or later after cilta-cel. Baseline characteristics, including the presence of high-risk cytogenetics and extramedullary disease, were generally comparable for the 32 patients who were progression-free for ≥5 years versus patients who had progressive disease by year 5. A trend of lower baseline tumor burden, higher fraction of naïve T-cells in the cilta-cel drug product, higher T cell-to-neutrophil ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio were associated with ≥5-year progression-free status. The safety profile of cilta-cel remained consistent with previous reports. To our knowledge, our data provide the first evidence that cilta-cel is potentially curative in patients with RRMM.