Citations

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

Abstract Castleman disease (CD) describes a group of rare lymphoproliferative disorders that exhibit a wide range of symptomatology and degree of lymphadenopathy, particularly across the 2 forms of CD with unknown etiology, unicentric CD (UCD), and human herpesvirus-8–negative/idiopathic multicentric CD (iMCD). Whereas UCD cases typically present with localized lymphadenopathy and mild symptoms, iMCD involves multicentric lymphadenopathy and cytokine storm–driven symptoms with 3 recognized clinical phenotypes. Increasingly, there are anecdotal reports of cases that do not fit into this framework, but these cases have not been systematically described. Herein, we use the ACCELERATE natural history registry to characterize the spectrum of CD based on disease features, symptomatology, and severity. Our results characterize a cohort of 179 CD cases, which were reviewed and confirmed by an expert panel of clinicians and hematopathologists. We show that patients with CD present on a continuous spectrum of clinical phenotypes, and we describe oligocentric CD (OligoCD), an intermediate phenotype that does not fit the criteria for UCD or iMCD. These cases tend to have “oligocentric” lymphadenopathy (median [interquartile range] regions of lymphadenopathy, 3.0 [2.0-4.0]) in a regional pattern and exhibit a mild clinical phenotype that is more similar to UCD than iMCD. We also show that patients with OligoCD are inconsistently categorized as UCD vs iMCD, highlighting the need for this characterization. Future data collected through ACCELERATE may further elucidate the natural history and risk profile of these patients.

Abstract Metastasis accounts for the overwhelming majority of cancer deaths. In prostate cancer and many other solid tumors, progression to metastasis is associated with drastically reduced survival outcomes, yet the mechanisms behind this progression remain largely unknown. ATPase family AAA domain containing 2 (ATAD2) is an epigenetic reader of acetylated histones that is overexpressed in multiple cancer types and usually associated with poor patient outcomes. However, the functional role of ATAD2 in cancer progression and metastasis has been relatively understudied. Here, we employ genetically engineered mouse models of prostate cancer bone metastasis, as well as multiple independent human cohorts, to show that ATAD2 is highly enriched in bone metastasis compared with primary tumors and significantly associated with the development of metastasis. We show that ATAD2 expression is associated with MYC pathway activation in patient datasets and that, at least in a subset of tumors, MYC and ATAD2 can regulate each other’s expression. Using functional studies on mouse bone metastatic cell lines and innovative organ-on-a-chip bone invasion assays, we establish a functional role for ATAD2 inhibition in reducing prostate cancer metastasis and growth in bone. Implications: Our study highlights ATAD2 as a driver of prostate cancer progression and metastasis and suggests it may constitute a promising novel therapeutic target.

Esophageal squamous cell carcinoma (ESCC) remains a significant global health challenge, being the sixth leading cause of cancer mortality with pronounced geographic variability. The incidence rates range from 125 per 100,000 in northern China to 1–1.5 per 100,000 in the United States, driven by environmental and lifestyle factors such as tobacco and alcohol use, dietary habits, and pollution. Major modifiable risk factors include tobacco and alcohol consumption, with a synergistic risk increase when combined. Nonmodifiable risk factors include previous diagnoses of head and neck squamous cell carcinoma (H&N SCC), achalasia, and prior radiotherapy. Prevention strategies must be tailored to specific regional burdens to efficiently allocate medical and financial resources. Gastrointestinal endoscopy is crucial in reducing ESCC burden through early detection and characterization of neoplastic changes, such as high‐grade dysplasia. Early diagnosis significantly improves survival rates, while endoscopic resection of noninvasive dysplasia can prevent ESCC onset, reducing treatment burden for advanced disease. Postresection surveillance can detect high‐risk metachronous lesions. Despite these benefits, endoscopic prevention faces challenges, including the lack of high‐level evidence supporting its efficacy, opportunity costs, the need for specialized training and techniques, and the requirement for advanced technology investments. This Position Statement from the World Endoscopy Organization (WEO) aims to address these challenges, supplying recommendations for the exploitation of endoscopic resources regarding the possible role of screening, quality, and training for the detection, characterization, resection, and surveillance of ESCC.

Abstract Menopausal users of hormone replacement therapy (HRT) are at increased breast cancer risk and decreased colorectal cancer (CRC) risk compared with individuals who have never used HRT, but these opposing associations may differ by familial risk of breast cancer and CRC. We harmonized data from 3 cohorts and generated separate breast cancer and CRC familial risk scores based on cancer family history. We defined moderate or strong family history as a risk score of 0.4 or higher, where 0.4 was equivalent to a 50-year-old woman with 1 parent diagnosed with either breast cancer or CRC at 55 years of age. Of 24 486 women assessed, 1243 and 405 were diagnosed with incident breast cancer and CRC, respectively. For breast cancer, menopausal HRT ever use versus never use hazard ratios were 1.27 (95% CI = 1.11 to 1.45) for a breast cancer familial risk score below 0.4 and 1.01 (95% CI = 0.82 to 1.25) for a breast cancer familial risk score of 0.4 or higher (Pdifference = .08). For CRC, menopausal HRT hazard ratios were 0.63 (95% CI = 0.50 to 0.78) for a CRC familial risk score below 0.4 and 1.21 (95% CI = 0.73 to 2.00) for a CRC familial risk score of 0.4 or higher (Pdifference = .03). Associations with menopausal HRT use that apply to the general population may not hold for women at moderate or strong familial risk of these cancers.

Background and Objective Rehabilitation therapy plays an important role in treating physical and functional impairments observed in individuals undergoing hematopoietic stem cell transplants (HSCT). This study assessed the rehabilitation practices implemented in the HSCT population internationally. Materials and Methods A 48-question online survey comprising questions soliciting information regarding patient characteristics, therapy details (timing, indication, and administering providers), outcome measures, and precautions were developed by an international group of cancer rehabilitation physicians. As reported by European registries, surveys were administered to personnel providing care to patients receiving HSCT at cancer centers, which comprised the top 10% of HSCT volume. In addition, emails were sent to National Medical Societies and registries in the Latin America, Asia, and Pacific regions. Results Forty-three institutions from 18 countries responded to the survey. Half of the centers provided referrals for rehabilitation therapy at the time of admission. Referrals were provided for functional decline (84.5%), risk of falls (53.3%), and discharge planning (42.2%). Rehabilitation therapies were administered by physical therapists (93.0%), occupational therapists (34.9%), therapy aides (14.0%), and speech-language pathologists (11.6%). Approximately 95% of the surveyed centers used objective functional measures such as sit-to-stand (46.5%), grip strength (46.5%), and 6-min walk/gait speed (both 34.9%). The blood counts were monitored to determine the appropriateness of the therapy modalities. Conclusion Rehabilitation practices varied internationally; however, most centers provided skilled therapy during hospitalization for HSCT, utilized objective and patient-reported outcomes, and monitored blood counts to determine the safety of administering therapy.

Objective To characterise the changing trends in the pharmacological management of SLE in the USA between 2007 and 2023 as new treatment options emerged. Methods In a retrospective cohort study using data from OptumLabs Data Warehouse, we characterised the annual prevalent (ie, all) and incident (ie, new) use of antimalarials, glucocorticoids and immunosuppressive medications among patients with SLE from 2007 to 2023 and assessed for changing trends over time. Results We identified 19 122 adults with SLE; they were 51.2 (SD 16.1) years of age, 89% were female, 61.3% were White, 18.5% were Black and 13.1% were Hispanic. The proportion of prevalent users of antimalarials has decreased from 79.4% in 2007 to 77.2% in 2023 (p=0.0055), while the proportion of incident users fluctuated between a lowest 5.8% in 2021 and a highest 8.1% in 2008 (p=0.008). The proportion of prevalent users of glucocorticoids increased from 64.6% in 2007 to 66.7% in 2023 (p=0.0132), as did the proportion of incident users (12.4% in 2007 to 21.7% in 2023; p<0.0001). The use of cyclophosphamide (2.0% in 2007 to 0.4% in 2023, p<0.0001) has decreased; the use of mycophenolate mofetil (7.7% in 2007 to 10.3% in 2023, p<0.0001), rituximab (1.4% in 2007 to 2.1% in 2023, p<0.0001) and belimumab (0.8% in 2011 to 6.1% in 2023, p=0.0001) has increased. Conclusions Despite increasing availability of alternative treatment options, patients with SLE in the USA increasingly rely on glucocorticoid-based therapy. Efforts to improve the use of antimalarials and steroid-sparing immunosuppressants are needed.

Autologous stem cell transplantation (ASCT) in AL amyloidosis effectively produces a high overall hematological response rate, complete response rate, and durable remissions. However, it is a high-dose chemotherapy-based therapy with high morbidity which can be offered only to a subset of AL amyloidosis patients who are considered fit for this therapy. Transplant-related mortality (TRM) in AL amyloidosis has decreased over the past three decades due to improvement in patient selection. New therapeutic options question the utilization of ASCT. A model to predict TRM can improve the decision-making process, patient selection and further reduce TRM. AL amyloidosis patients (n=1718) from 9 centers globally, transplanted in the years 2003-2020 were included. Pre-ASCT variables of interest were assessed for association with Day-100 all-cause mortality, including age at ASCT (≥ 60 years), sex, light chain isotype, ECOG performance status (ECOG PS; 0, 1 and 2/3), the difference between involved and uninvolved light chains (dFLC; ≥180 mg/L), N-terminal prohormone of B natriuretic peptide (NT-proBNP; ≥1800 pg/mL) or B-type natriuretic peptide (BNP; ≥400 pg/mL), left ventricle ejection fraction (LVEF, &lt;50%), interventricular septum (&gt;16 mm), corrected diffusing capacity for carbon monoxide (cDLCO; ≤65% of predicted), forced expiratory volume in one second (FEV1; ≤65% of predicted), serum albumin (&lt;2.5 g/dL), estimated glomerular filtration rate (eGFR; &lt;30 mL/min/m2), alkaline phosphatase (&gt;X2 upper limit of normal), and systolic blood pressure (&lt;100 mmHg). Troponins could not be included in our modeling given the multitude of assays used across institutions and periods that could not be reconciled. A random forest (RF) classifier with 10-fold cross-validation was used to assist in variable selection. The final model variables were selected based on statistical performance and clinical relevance. The model was fitted using logistic regression. The median age at ASCT was 58, and 40% of patients were women. The most frequently involved organs were the kidneys (69%) and the heart (52%). Mayo 2004 stages I and II were collectively present in 83% of patients. Day-100 TRM occurred in 75 patients (4.4%) with the 3 main causes being shock (n=27), cardiac arrhythmia (n=26), and organ failure (n=22). Age at ASCT, sex, and light chain isotype were not predictors of Day-100 TRM. Across the other pre-ASCT variables, adverse features were present from 6.9% (LVEF &lt;50%) to 25.8% (dFLC ≥180 mg/L) of patients. Ten factors were associated with Day-100 TRM on univariate analysis. The odds ratio of these variables ranged from 1.6 to 10.2. RF classifier using all these variables identified a model with an area under the curve (AUC) of 0.72±0.12. Using the importance hierarchy function to refine the model selection, a 4-variable model [NT-proBNP/BNP ≥1800/400 pg/mL, serum albumin &lt;2.5 g/dL, ECOG PS 1 or 2/3, and systolic blood pressure &lt;100 mmHg] was built with an AUC of 0.70±0.12. Based on logistic regression coefficients, ECOG PS 2/3 was assigned two points, while other adverse predictors were assigned 1-point each (model score range 0-5). We then applied the model scoring to our study population. Score distribution was as follows: 0 (n=431, 25.1% of patients), 1 (n=688,40.1%), 2 (n=413, 24.0%), and 3 and above (n=186, 10.8%). Day-100 TRM rates were 0.46%, 3.2%, 5.8%, and 14.5% for 0, 1, 2, and ≥3 points, respectively. The respective rates for the years 2003-2011 were 1.1%, 3.3%, 6.4%, and 19.2%, while for the years 2012-2020 0%, 3.1%, 5.2%, and 8.4%. We developed a simple clinical tool to predict the Day-100 TRM risk in AL patients undergoing ASCT. This tool will allow more informed decision making weighing the individual benefits and risks of ASCT compared to other therapies.