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e15628 Background: Total neoadjuvant therapy (TNT) with cytotoxic chemotherapy and chemoradiation followed by surgical resection is a standard treatment for locally advanced rectal cancer (LARC). In a limited number of LARC patients with deficient mismatch repair (dMMR), treatment with an immune checkpoint inhibitor (ICI) resulted in all patients achieving complete clinical response (cCR) (median follow-up of 29 months) such that radiotherapy and surgery were avoided. These and other data have resulted in the routine use of neoadjuvant ICI for dMMR LARC. Here we report a multicenter series of patients with dMMR LARC treated with neoadjuvant ICI. Methods: Adult patients (N = 21) with dMMR LARC who received neoadjuvant ICI at Mayo Clinic, MD Anderson Cancer Center, Duke University or University of Pittsburgh were identified from the electronic medical record (EMR) and relevant data were abstracted. All patients were staged with pelvic MRI; clinical response was evaluated by repeat pelvic MRI and sigmoidoscopy. Data were summarized using descriptive statistics. This study was approved by the Mayo Clinic IRB. Results: Patients with clinical stage I (n = 2), II (n = 3) or III (n = 15) dMMR LARC were treated with neoadjuvant PD-1 monotherapy (n = 20) or combination (n = 1, ipilimumab+ nivolumab). Median age was 46 years (IQR 39, 65), 15 (71%) were male, 10 (48%) had distal tumors, and 14 had Lynch Syndrome. Median duration of ICI treatment was 7 mos (IQR 6, 12); one patient remains on dostarlimab at data cut-off. Clinical complete response (cCR) was achieved in 11 (52%) patients, partial response (PR) in 7 (33%), stable disease (SD) in 1 (5%), and progressive disease (PD) in 2 (10%) patients. Median time from first dose of ICI to best clinical response was 6 mos (IQR 5, 8) months. All partial or non-responders received salvage TNT with (n = 6) or without (n = 3) surgery. At a median follow up of 19 mos (range 6 to 56), tumor regrowth occurred in 1 patient who was subsequently treated with TNT. Any grade immune-related adverse event occurred in 6 (29%) patients; one grade 3 hepatitis occurred in the patient on Ipi+Nivo (Table1). Conclusions: Neoadjuvant ICI treatment of dMMR LARC resulted in half of treated patients achieving cCR. Careful monitoring is necessary to identify non responders who will require salvage TNT. Patient characteristics and clinical response to ICI. ID Sex Age Stage ICI Response to ICI ID Sex Age Stage ICI Response to ICI 1 M 62 T3N+ Pembro cPR 12 M 37 T3N+ Pembro cCR 2 M 60 T2N0 Pembro cCR 13 M 41 T3N0 Pembro cCR 3 M 80 T2N0 Pembro cPD 14 M 46 T4N+ Pembro cPR 4 M 36 T3N+ Ipi+Nivo cCR 15 M 68 T3N+ Pembro cPR 5 M 57 T3N+ Dostarli cCR 16 M 77 T3N0 Pembro cPR 6 M 39 T3N+ Dostarli cPR 17 M 40 T4Nx Pembro cCR 7 F 44 T2N+ Dostarli cPD 18 F 35 T3N+ Dostarli cCR 8 M 74 T3N+ Pembro cCR 19 M 60 T2N+ Pembro cPR 9 M 43 T3N+ Nivo cCR 20 F 65 T3N+ Pembro cCR 10 F 81 T3N0 Dorstali cPR 21 F 39 T4N+ Dorstali cSD 11 F 32 T2N+ Pembro cCR

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Importance High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. Objective To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). Design, Setting, and Participants The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (<60 years vs ≥60 years) and disease duration (<6 months vs ≥6 months). Interventions A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. Main Outcomes and Measures The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. Results A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). Conclusions and Relevance Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Importance Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. Objective To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Design, Setting, and Participants Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Intervention Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Main Outcomes and Measures Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Results Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (<60 years or ≥60 years) and disease duration (recent [<6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P >.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months ( P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). Conclusions and Relevance One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Introduction: The treatment of older patients with advanced stage classical Hodgkin lymphoma (cHL) is challenging and outcomes remain poor compared to younger patients (pts). A subgroup analysis of older pts (aged ≥ 60 years) enrolled in the SWOG S1826 study showed the Nivolumab-AVD regimen was better tolerated and improved progression free survival (PFS) compared to concurrent brentuximab vedotin-AVD (Bv-AVD). The sequential administration of Bv before and after AVD chemotherapy (seq Bv-AVD-Bv) is a commonly used approach to minimize the toxicity of Bv-AVD in older pts based on the tolerability and efficacy shown in a phase II study (Evens, et al. J Clin Oncol 2018). There is limited data on clinical outcomes with seq Bv-AVD-Bv in the real-world setting. We report our multicenter study of sequential Bv-AVD-Bv administration in older patients with cHL. Methods: This retrospective study included a total of 40 older pts with cHL treated with sequential Bv-AVD-Bv in 6 cancer centers. Descriptive statistics were used to depict patient demographics and disease characteristics prior to treatment initiation. Responses to therapy were assessed using the Lugano criteria. Response evaluable patients were those who received at least one cycle of chemotherapy with AVD. PFS and overall survival (OS) were estimated using log-rank testing with the Kaplan Meier curves. Results: The majority (n=23, 57.2%) of patients were male; median age was 72.5 years (range, 57-86 years); 10 (25%) pts were Hispanic, and 18 (45%) pts were Caucasian; performance status by ECOG was 0-2 in 33 (82.5%) pts. In terms of disease characteristics 19 (47.5%) pts had cHL NOS, 10 (25%) had nodular sclerosing subtype; stage III/IV in 35 (87.5%), stage II in 5 (12.5%) pts; B- symptoms in 21 (52.5%); extranodal disease in 19 (47.5%), with bone marrow involvement in 10 (25%) pts. Among the 38 response-evaluable patients the ORR and CR rates were 97.4% and 71.1%, respectively. Bv dose reductions or interruptions were reported in 14 (35.9%) pts. Treatment discontinuation (Td) occurred in 16 (40%) pts. The most common any grade adverse events were hematological toxicities (HT) in 28 (70%) pts and peripheral neuropathy in 24 (60%) pts. Forty-five percent of patients experienced grade 3 or higher HT. The overall incidence of grade 2 or higher peripheral neuropathy was 15%. The main reasons for treatment discontinuation were toxicity (n=9) and disease progression (n=4). During treatment, 1 (2.5%) pt reported loss of basic activities of daily living (ADLs) and 5 (12.5%) had loss of instrumental ADLs (iADLs). G-CSF prophylaxis was used in most (n=33, 82.5%) pts. At a median follow up of 25.7 months (range, 2.6 - 58.9) the 2 years PFS was 62.6% (95% CI: 46.1-79.1) and the 2 years OS was 83.3% (95% CI: 67-99.6). On univariate analysis, the median PFS correlated with the depth of response (CR: not reached; PR: 11.4 months; SD/PD: 3.9 months; P=0.0001); and with treatment discontinuation (No Td: not reached; Td: 21.6 months; P=0.007). There was no correlation between age, sex, institution, B- symptoms, bone marrow involvement, ADL/iADLs, or disease stage with treatment discontinuation. Conclusion: Sequential Bv-AVD-Bv in older patients with cHL can help minimize the toxicity associated with the concurrent administration of Bv-AVD. This sequential approach has shown comparable efficacy in real-word setting as seen in clinical trials. Our findings suggest seq Bv-AVD-Bv remains a feasible option for older fit patients with cHL outside clinical trials. Further randomized studies in older cHL pts are needed.

Introduction: Thoracic aortic aneurysms (TAA) are a significant health concern, with the true prevalence likely underestimated due to undiagnosed cases. Outcomes in TAA are influenced by factors like age, sex, and comorbidities such as hypertension. This study examines mortality trends and disparities associated with TAA in US adults. Methodology: This study analyzed death certificates from 1999 to 2020 using the CDC WONDER Database to identify TAA-related deaths in individuals aged 25 and older using ICD-10 codes I71.1 and I71.2. Age-adjusted mortality rates (AAMRs) per 1 000 000 and annual percent changes (APCs) were calculated and stratified by year, sex, age group, race/ethnicity, region, and urbanization status. Results: Between 1999 and 2020, 47 136 TAA-related deaths were reported among US adults. The AAMR decreased from 16.2 to 8.2 per 1 000 000, with a significant decline from 1999 to 2013 (APC: −5.00; 95% CI: −5.54 to −4.54; P<0.001). Older adults had the highest AAMRs at 44.6 per 1 000 000. Men had higher AAMRs than women (11.2 vs. 9). AAMRs were highest among non-Hispanic (NH) Black (11), followed by NH White (10.3), NH Asian or Pacific Islander (9.5), NH American Indian or Alaska Native (7.8), and Hispanic (5.2) populations. Nonmetropolitan areas had higher AAMRs than metropolitan areas (11 vs. 9.8). Conclusions: The analysis showed a significant decline in TAA mortality since 1999, with recent stabilization. However, disparities persist, with higher AAMRs among men, older adults, NH Black adults, and nonmetropolitan residents, highlighting the need for targeted and equitable interventions.

Background: Hepatocellular carcinoma (HCC) is a prevalent liver cancer with poor prognosis, often linked to hepatitis B (HBV) and C (HCV) infections. This meta-analysis evaluates the efficacy of immunotherapy in HCC, particularly in cases arising from viral hepatitis. Methods: In adherence to PRISMA Statement 2020 guidelines, the immunotherapeutic outcomes comprised objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Data were analyzed from randomized controlled trials up to April 2024 using the fixed-effects models in R (V.4.3.3.) and RevMan (Cochrane). Results: This study included 9 trials with 5316 patients. The ORR was slightly higher in the viral group at 27.93% compared to 24.07% in the non-viral group, though this difference was not significant (p = 0.15). Viral HCC patients exhibited a median PFS of 7.3 months (IQR: 6.2–8.4) compared to 5.8 months (IQR: 5.48–6.13) in non-viral patients, a significant improvement (p = 0.005). Similarly, median OS was longer in the viral group at 16.8 months (IQR: 12.99–20.61) versus 15.2 months (IQR: 13.25–17.15) for non-viral HCC, which was also significant (p < 0.0001). The median OS for viral HCC was 16.8 months (IQR: 14.11–19.49 months), with HBV patients experiencing slightly higher survival at 17.15 months (IQR: 14.3–20 months) compared to 16.8 months (IQR: 12.99–20.61 months) for HCV patients; this difference was not statistically significant (p = 0.89). Conclusions: Immunotherapy shows potential in treating HCC, with significantly better outcomes in viral HCC, particularly HBV-associated cases. The heterogeneity highlights the need for personalized treatment approaches based on the viral background of HCC patients. Further research should aim to optimize these therapies to improve survival rates.

Background: Pulsatile perfusion is a developing technique that attempts to mimic the natural pulsatile flow of blood during cardiopulmonary bypass (CBP). Purpose: Our meta-analysis was done to evaluate the effects of pulsatile perfusion in CPB compared to non-pulsatile on hospital stay, ICU stay, and intubation time. Methods: Randomized control trials that evaluated the implementation of pulsatile perfusion during CPB were identified by a literature search of the following databases (PubMed, Web of Science, Scopus, Central, and Embase) up to February 2024. Results: Our search yielded 33 trials with 3174 patients, the analysis showed that pulsatile perfusion led to a significant decrease in hospital stay [MD = -1.38, 95% CI (-2.51, -0.25), P = 0.016], ICU stay [MD = -0.47, 95% CI (-0.82, -0.13), P = 0.007], intubation time [MD = -3.73, 95% CI (-5.42, -2.04), P < 0.001]. However, no significant difference between the two regimens was detected in the adult subgroup when we performed sungroup analysis based on the age for hospital stay and ICU stay outcomes [MD = -0.31, 95% CI (-0.95, 0.33), P = 0.334] and [MD = -3.73, 95% CI (-5.42, -2.04), P < 0.001] respectively. Conclusion: Pulsatile perfusion showed positive effects on hospital stay, ICU stay, and intubation time. However, there was no difference between the two methods on hospital and ICU stay in the adult’s subgroup. Also, the outcomes showed significant heterogeneity, which requires more robust RCTs to be conducted to increase the quality and the certainty of evidence.

Background: Hypertensive heart disease (HHD) poses a growing public health concern. Global data reveal a concerning rise in HHD prevalence, deaths, and disability-adjusted life years (DALYs) between 1990 and 2019. The Framingham Study highlights that hypertension is linked to approximately one-quarter of heart failure cases. This association is even stronger among older adults, in whom hypertension is responsible for up to 68% of heart failure cases. Methods: This study analyzed death certificates within the CDC WONDER database for patients in the United States from 1999 to 2020. We identified deaths among individuals aged 25 years and older caused by HHD and CHF using the International Classification of Diseases, Tenth Revision (ICD-10) code I11.0. Age-adjusted mortality rates (AAMRs) per 1,000,000 individuals and annual percent change (APC) were computed and categorized based on year, gender, race/ethnicity, and urbanization status. Results: Between 1999 and 2020, a total of 302,270 deaths were reported in patients due to HHD with CHF. Overall, AAMR increased from 37.3 to 134.9 per 1,000,000 population between 1999 and 2020, with a significant decrease from 1999 to 2004 (APC: -7.91; 95% CI: -20.16 to -1.04), followed by a significant increase from 2004 to 2007 (APC: 42.47; 95% CI: 21.27 to 55.62), a slight decrease from 2007 to 2014 (APC: -0.9; 95% CI: -9.38 to 2.39), and finally a steep increase from 2014 to 2020 (APC: 14.22; 95% CI: 10.87 to 20.84). Gender-based analysis revealed that men had slightly higher AAMRs than women (Men: 63.1; 95% CI: 62.8 to 63.5 vs. Women: 60.7; 95% CI: 60.5 to 61). Moreover, AAMRs were highest among non-Hispanic African Americans (109.6; 95% CI: 108.6 to 110.6), followed by non-Hispanic American Indian or Alaska Natives (66.6; 95% CI: 63.1 to 70.1), non-Hispanic Whites (58.5; 95% CI: 58.2 to 58.7), Hispanics (53.7; 95% CI: 52.9 to 54.5), and non-Hispanic Asian or Pacific Islanders (39; 95% CI: 38–39.9). In addition, non-metropolitan areas had higher AAMRs than metropolitan areas (non-metropolitan: 65.7; 95% CI: 65.2 to 66.3 vs. metropolitan: 62.1; 95% CI: 61.8 to 62.3) (Figure 1). Conclusions: Despite an initial decline, mortality from combined HHD and CHF has risen significantly since 1999. Notably, mortality was most pronounced among men, non-Hispanic African Americans, and individuals residing in non-metropolitan areas.