Citations

Abstract Purpose: DROSHA, DGCR8, and DICER1 regulate miRNA biogenesis and are commonly mutated in cancer. Although DGCR8 and DICER1 germline pathogenic variants (GPV) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported. Experimental Design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts. Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a diagnosis of pineoblastoma (n = 8) or Wilms tumor (n = 1). A somatic second hit in DROSHA was detected in all eight tumors analyzed. All pineoblastoma tumors analyzed were classified as miRNA processing–altered 1 subtype. We estimate the population prevalence of germline DROSHA loss-of-function variants to be 1:3,875 to 1:4,843 but find no evidence for increased adult cancer risk. Conclusions: This is the first report of DROSHA-related tumor predisposition. As pineoblastoma and Wilms tumor are also associated with DICER1 GPVs, our results suggest that the tissues of origin for these tumors are uniquely tolerant of general miRNA loss. The miRNA processing–altered 1 pineoblastoma subtype is associated with older age of diagnosis and better outcomes than other subtypes, suggesting DROSHA GPV status may have important clinical and prognostic significance. We suggest that genetic testing for DROSHA GPVs be considered for patients with pineoblastoma, Wilms tumor, or other DICER1-/DGCR8-related conditions and propose surveillance recommendations through research studies for individuals with DROSHA GPVs.

TPS888 Background: There is currently no Food and Drug Administration (FDA)-approved treatment for intermediate-risk non–muscle-invasive bladder cancer (IR NMIBC), defined by the AUA as recurrence of low-grade (LG) Ta within 1 year, solitary LG Ta >3 cm, multifocal LG Ta, high-grade (HG) Ta (≤3 cm), and/or LG T1. Nadofaragene firadenovec-vncg is the first FDA-approved intravesical nonreplicating gene therapy for the treatment of adult patients with high-risk Bacillus Calmette Guérin (BCG)-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors. In a nonrandomized, multicenter, open-label, repeat-dose, phase 3 study, 53.4% of participants (55/103) with CIS ± HG Ta/T1 achieved complete response 3 months after the first instillation. Nadofaragene firadenovec was well tolerated, with no grade 4/5 study drug-related AEs. Because maintenance treatment with nadofaragene firadenovec following tumor resection may improve clinical outcomes in patients with IR NMIBC, the ABLE-32 open-label randomized study is being conducted to evaluate the efficacy of nadofaragene firadenovec administered every 3 months versus observation in participants with IR NMIBC. Methods: This phase 3 study includes approximately 100 global sites with 454 anticipated participants. Adults diagnosed with new or recurrent IR NMIBC and having undergone transurethral resection of bladder tumor within 60 days prior to randomization are eligible. Participants will be randomly assigned 1:1 to receive nadofaragene firadenovec or continue observation. The nadofaragene firadenovec group will receive quarterly doses unless disease recurs or progresses. The observation group will be followed quarterly and may receive nadofaragene firadenovec if IR NMIBC recurs within 24 months. All participants will be evaluated for recurrence and progression using cytology, cystoscopy, and for-cause biopsy for up to 5 years. The primary endpoint is recurrence-free survival (RFS), from randomization to first documented recurrence, progression, or death. Secondary endpoints include RFS at 12 and 24 months and safety. Exploratory endpoints include effect on potential biomarkers and health-related quality of life. Final results are expected in 2031. Clinical trial information: NCT06510374 .

ZUMA-12 is a multicenter phase 2 study evaluating axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy as part of first-line treatment for high-risk large B-cell lymphoma (LBCL). In the primary efficacy analysis (n = 37; median follow-up, 15.9 months), axi-cel demonstrated a high rate of complete responses (CR; 78%) and a safety profile consistent with prior experience. Here, we assessed updated outcomes from ZUMA-12 in 40 treated patients after ≥3 years of follow-up. Eligible adults underwent leukapheresis, lymphodepleting chemotherapy, and axi-cel infusion (2 × 106 CAR T cells/kg). Investigator-assessed CR, objective response, survival, safety, and CAR T-cell expansion were assessed. The CR rate among response-evaluable patients (n = 37) increased after the primary analysis to 86% (95% confidence interval [CI], 71%-95%), with a 92% objective response rate. After a median follow-up of 47.0 months (range, 37.1-57.8 months), 36-month estimates (95% CI) of duration of response and event-free, progression-free, and overall survival were 81.8% (63.9%-91.4%), 73.0% (55.6%-84.4%), 75.1% (57.5%-86.2%), and 81.1% (64.4%-90.5%), respectively. In total, 4 patients had new malignancies, 2 occurring after the data cutoff of the primary analysis; none were axi-cel–related. Eight patients died on study, 2 of whom died from nonrelapse mortality causes. After long-term follow-up, axi-cel demonstrated a high durable response rate, with no new safety signals after the primary analysis, suggestive of an effective first-line therapy with curative intent in high-risk LBCL. Further assessments are needed to determine its benefit vs standard of care. This trial was registered at clinicaltrials.gov, as NCT03761056.

Objectives: Cervical esophageal cancer (CEC) is an uncommon malignancy accounting for <5% of all esophageal carcinomas. Treatment of CEC varies and is adapted from established regimens used for squamous cell carcinoma (SCC) or the lower esophageal and head and neck. The present systematic review and guidelines are intended to assist treatment decision making for patients with CEC based on the available evidence. Methods: Using the Population, Intervention, Comparator, Outcome, Timing, and Study Design (PICOTS) framework, the evidence regarding treatment outcomes was assessed using Cochrane and PRISMA 2020 methodology. Eligible studies included prospective Phase II to III trials and retrospective analyses published between January 1, 2013 and February 23, 2024 in the Ovid Medline database. These references were assessed through the American Radium Society (ARS) Appropriate Use Criteria (AUC) methodology. A systematic review PRISMA 2020 checklist confirmed the completion of essential elements. RAND-UCLA consensus methodology was used by the expert panel to rate the appropriateness of the treatment options. Results: ARS AUC recommendations include (1) larynx preservation using endoscopic resection (EMR or ESD) alone for the typical case with pT1a cN0 cM0 CEC, (2) definitive CRT for the typical case with cT1bN0M0 in patients who cannot undergo endoscopic resection, (3) larynx-preserving using definitive CRT (with or without induction chemotherapy) for the typical case with nonmetastatic locally advanced CEC (advanced T-stage tumors or involved lymph nodes), with surgery reserved for those patients with incomplete response or locoregional recurrence. Conclusions: This ARS AUC summary provides guidelines for the management of SCC of the cervical esophagus provides based on available evidence. Topics that warrant further investigation include optimization of (1) patient selection; (2) multimodality therapies including chemotherapy, immunotherapy, and targeted agents; (3) radiation dose, schedule, and treatment volume; and (4) supportive care for patients with CEC. Ongoing trials continue to improve outcomes for patients with CEC.

Purpose: The aim of this study was to investigate whether successful surgical management of velopharyngeal insufficiency (VPI) aids in the remediation of compensatory misarticulation errors (CMAs) among children with VPI and CMAs. Method: Fourteen participants with VPI and use of CMAs from a larger study were included in this retrospective cohort study. The mean age at the time of preoperative evaluation was 8.9 years ( SD = 1.1). Perceptual ratings of hypernasality, phonetic transcription, and anatomic measurements from magnetic resonance imaging were performed by raters blinded to the participants' medical and surgical history. The mean percentage of CMAs produced on the American English Sentence Sample was calculated. The Wilcoxon signed-ranks test was used to compare the change in CMA use pre- and postoperatively. During the study period, 71% ( n = 10) of participants received speech therapy. Results: Nine participants had resolved hypernasality after surgery, and five had persistent hypernasality. Among those with resolved hypernasality, the mean percentage of CMAs significantly decreased from 14.6% preoperatively to 1.1% postoperatively ( p = .028). For participants with persistent hypernasality, the mean percentage of CMAs decreased from 27.6% to 22%; this change was not significant ( p = .586). Conclusions: Correction of VPI may aid in the remediation of CMAs as participants have more normal anatomy to achieve velopharyngeal closure. These findings suggest correction of VPI may reduce the amount of speech therapy needed to treat CMAs.

ObjectiveThe objective was to determine the mortality rate as well as the causes and predictors of death in antiphospholipid antibody (aPL)–positive patients with and without antiphospholipid syndrome (APS) classification.MethodsThe inclusion criterion for the multicenter international Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) registry is positive aPLs according to the Revised Sapporo Classification Criteria tested within one year before enrollment. Patients are observed every 12 ± 3 months with clinical data and blood collection. For this prospective analysis, we first analyzed the causes of death for patients reported as “deceased.” Secondly, we analyzed risk factors for death using the adjusted Cox proportional hazards model and calculated survival probability using the Kaplan‐Meier model based on different age groups.ResultsOf 967 patients, 43 (5%) were deceased after a median follow‐up of 5.3 years. Based on the univariate analysis, deceased patients, compared to living patients, were more likely to be older and have a history of arterial thrombosis, catastrophic APS, concomitant systemic autoimmune diseases (SAIDs), and baseline cardiovascular disease (CVD) risk factors. Based on the Cox proportional hazards model adjusted for age and for each of the strongest predictors of death, arterial thrombosis (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.50–5.76), concomitant SAIDs (HR 2.97, 95% 1.56–5.63), and baseline any CVD risk factor (HR 2.43, 95% CI 1.05–5.71) were significantly associated with mortality.ConclusionIn our cohort of persistently aPL‐positive patients, the mortality rate was 5% after a median follow‐up of five years and was highest for patients ≥60 years old at registry entry. History of arterial thrombosis, concomitant SAIDs, and baseline any CVD risk factor independently predicted future death.

OBJECTIVE Spinal cord cavernous malformations (SCCMs) are rare vascular malformations with a capricious prognosis. Given the eloquent nature of the spinal cord, considerable surgical morbidity may be encountered. Therefore, conservative management has emerged as a valid alternative, especially for incidental lesions diagnosed on ubiquitous imaging. The aim of this systematic review and meta-analysis was to evaluate the safety and efficacy of surgical versus conservative management of SCCMs. METHODS Following PRISMA guidelines, this study included articles published in full-text form comparing the outcomes following conservative and surgical management of SCCMs. Collected variables included the total number of patients, spine level, resection, myelotomy, follow-up duration, bleeding, motor weakness, pain, bladder and/or bowel dysfunction, and neurological improvement or deterioration after discharge. The primary outcome of interest was long-term functional outcome. RESULTS Eleven articles comprising 515 patients were included, of whom 343 (66.6%) underwent resection and 172 (33.4%) were managed conservatively. Patients who underwent surgery were more likely to have preoperative motor deficits, hemorrhagic episodes, and bladder and/or bowel dysfunction, indicating increased disease severity. Resection was associated with significantly improved long-term functional outcomes (OR 3.27, 95% CI 1.72–6.24) compared with conservative management. There was no significant difference between the two groups regarding odds of long-term clinical deterioration (OR 1.03, 95% CI 0.35–3.03). However, the risk of hemorrhagic episodes during follow-up was higher in the conservative group (17.3%) compared with the surgical group (1.69%). The odds of hemorrhage during follow-up were lower in the surgical group, although not statistically significant (OR 0.24, 95% CI 0.05–1.05). CONCLUSIONS This study highlights that while surgical management of SCCMs is associated with better long-term functional outcomes and reduced risk of recurrent hemorrhage, treatment decisions must be carefully tailored to the individual patient, particularly given the potential risks associated with surgery. Conservative management, although less invasive, carries a nonnegligible risk of hemorrhage during follow-up, warranting close monitoring. These findings parallel management strategies used for brainstem cavernomas, for which surgery is reserved for cases with low surgical risk and worsening neurological symptoms. However, the limitations of current data, including selection bias and heterogeneity in reporting, emphasize the need for a multi-institutional registry to better define the natural history of SCCMs and inform future management strategies.

Introduction: Cerebral Amyloid Angiopathy (CAA) is caused by the progressive deposition of β-amyloid in the walls of small to medium-sized cerebral vessels. Although seizures represent a debilitating manifestation of CAA, little is known about their prevalence or associated factors. We aim to fill this gap by determining the prevalence of seizures in CAA and identify factors associated with an increased risk of seizures. Methods: We identified consecutive patients with CAA, evaluated within the Mayo Clinic health system between January 2010 and December 2023 using the ICD-10 code. Data on demographics and comorbidities were compared between those with and without seizures using the chi-square test for categorical variables and independent samples t-test for continuous variables. Odds ratios (OR) were estimated after adjusting for age, sex, and race in multivariable logistic regression. Results: We included 1,914 patients with CAA with a mean age of 75.4 ± 8.6 years, of whom 52.3% were female and 87.5% were white. Seizures were observed in 347 patients (18.1%). Individuals with seizures were significantly younger (mean age 67.7 ± 9.1 vs. 77.2 ± 7.5 years, p < 0.001). Multivariable modeling identified alcohol abuse (OR 1.92, 95% CI 1.03-3.56, p=0.04), diabetes mellitus (OR 2.14, 95% CI 1.13-4.06, p=0.02), hypertension (OR 1.79, 95% CI 1.33 - 2.41, p= <0.001), liver disease (OR 1.75, 95% CI 1.14-2.69, p=0.01), and ischemic stroke (OR 1.33, 95% CI 1.01-1.74, p=0.04) as independently associated with an increased risk of seizures. Conclusion: We found that seizures affect nearly one in five patients with CAA. Also, comorbidities such as alcohol abuse, diabetes mellitus, hypertension, liver disease, and ischemic stroke were found to be significantly associated with an increased risk of seizures. Longitudinal studies are warranted to confirm these risk factors, some of which may be modifiable.

Background: Randomized controlled trials (RCTs) evaluating the efficacy of platelet-rich plasma (PRP) for the management of lateral epicondylitis (LE) have been characterized by substantial variability in reported outcomes. The source of this heterogeneity is uncertain. Purpose: To determine the effect of estimated platelet concentration on the efficacy of PRP for the management of LE. Study Design: Systematic review and meta-analysis; Level of evidence, 2. Methods: All RCTs evaluating the efficacy of PRP in managing LE were identified. RCTs were classified according to whether the study documented a platelet concentration factor of PRP representing a greater than 3-fold increase over whole blood or a supraphysiological platelet dose (high-dose vs low-dose PRP). The primary outcome was the mean difference (MD) in the visual analog scale (VAS) score at latest follow-up. Random-effects and mixed-effects meta-analyses were performed, and meta-regression was used to evaluate whether differences in outcomes after treatment with PRP could be explained by differences in the concentration of PRP used. Results: Overall, 13 RCTs with a total of 791 patients were included in this analysis, with 5 that utilized low-dose PRP and 8 that used high-dose PRP. Meta-analysis of VAS scores reported by studies that used high-dose PRP resulted in an MD of −1.31 (95% CI, −1.87 to −0.75) in favor of PRP over all alternative treatment strategies ( P < .001). Meta-analysis of VAS scores reported by studies that used low-dose PRP resulted in an MD of 0.08 (95% CI, −0.51 to 0.68), suggesting no difference in the effect between PRP and all alternative treatment strategies ( P = .79). The platelet concentration factor of PRP used in each RCT was found to be strongly predictive of the VAS score at final follow-up in meta-regression ( P < .001), with 58.5% of the heterogeneity in the outcomes of PRP between studies explained by the platelet concentration factor alone. Conclusion: The platelet concentration of PRP may play a significant role in the outcomes of patients with LE. A direct linear relationship was observed between the platelet concentration factor of PRP used and the magnitude of patient-reported symptom relief after the management of LE with PRP. Clinicians should ensure a supraphysiological platelet concentration when preparing PRP for the management of LE.

ABSTRACTBackgroundThe carbon‐13 spirulina gastric emptying breath test (GEBT) is approved to identify delayed, but not accelerated, gastric emptying (GE). We compared the utility of the GEBT to scintigraphy for diagnosing abnormal GE in patients with diabetes mellitus.MethodsTwenty‐eight patients with diabetes ate a 230‐kcal test meal labeled with technetium 99 m and 13C‐spirulina, after which 10 scintigraphic images and breath samples (baseline, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min) were collected on 2 occasions 1 week apart. We assessed the accuracy of 13C‐spirulina GEBT excretion rate (percent dose multiplied by 1000 [kPCD] min−1) values to predict scintigraphic half‐life and distinguish between normal, delayed, and accelerated GE and the intraindividual reproducibility of the GEBT.Key ResultsScintigraphy revealed normal, delayed, and accelerated GE, respectively, in 17 (30%), 29 (52%), and 10 (18%) test results. GE T½ values measured with scintigraphy and GEBT were highly concordant within individuals; the intraindividual reproducibility was 34% (scintigraphy) and 15% (GEBT). Compared to current criteria, the kPCD150 (150 min) and kPCD180 values provided equally sensitive (90%) and more specific (81% vs. 67%) approach for distinguishing between delayed versus normal/accelerated GE. A new metric (kPCD60–kPCD15 min) was 90% sensitive and 83% specific for distinguishing between accelerated versus normal/delayed GE. These findings were used to create nomograms and an algorithm for interpreting GEBT results.Conclusions and InferencesAmong patients with poorly controlled diabetes, the 13C‐spirulina GEBT can accurately and precisely assess GE and effectively distinguish between normal, delayed, and accelerated GE.