Citations

Abstract Anaplastic large cell lymphoma (ALCL) cases were discussed at the 2023 Society of Hematopathology/European Association for Haematopathology workshop held on November 9-11, 2023, in Houston, Texas. This session focused on the clinical and pathologic spectrum of 3 types of ALCL: anaplastic lymphoma kinase (ALK)-positive, ALK-negative, and breast implant associated (BIA). Cases of primary cutaneous ALCL were excluded because they were included in another session. Although the diagnosis of ALCL is often straightforward, the 42 submitted cases encompassed unusual clinical presentations, morphologic variants, and atypical immunophenotypes, exemplifying potential difficulties and challenges in establishing the diagnosis of ALCL. Distinguishing ALCL from CD30-positive peripheral T-cell lymphoma, not otherwise specified, or classic Hodgkin lymphoma was discussed. In patients with a previous history of mycosis fungoides and other T-cell lymphoma/leukemia, the differential diagnosis of a CD30-positive T-cell lymphoma mimicking ALCL (mycosis fungoides transformation vs de novo ALCL) was also discussed. In patients with suspected BIA-ALCL, it is critical to properly handle the periprosthetic fluid when the disease first presents and the capsule at the time of initial capsulectomy to make a correct diagnosis and pathologic staging because a missed diagnosis may lead to disease progression. Comprehensive immunohistochemical analysis; fluorescence in situ hybridization for DUSP22, TP63, or JAK2 rearrangement; assessment of clonality of the T-cell receptor and immunoglobulin genes; and sequencing for mutations were performed as part of the workup of the submitted cases, particularly on ALK-negative ALCL cases, emphasizing the importance of ancillary testing in establishing the diagnosis.

Abstract In recent years, there has been increasing interest in the possible prognostic impact of concomitant medications in patients with cancer treated with immunotherapy combinations. This real‐world analysis aims to evaluate the impact of concomitant medications on survival outcomes in patients with advanced biliary tract cancer (BTCs) treated with cisplatin, gemcitabine and durvalumab (CGD) therapy. The study cohort included patients with a diagnosis of advanced BTCs who were taking concomitant medications for their comorbidities before the start of CGD. The primary objectives were overall survival (OS) and progression‐free survival (PFS). The initial population consisted of 666 patients, who were retrospectively collected from 41 sites in 12 countries. Data on concomitant medications were available for 493 patients. After a median follow‐up of 8.8 months (95% CI: 7.8–9.8), patients who did not take steroids (prednisone >10 mg/day or equivalent) or nonsteroidal anti‐inflammatory drugs (NSAIDs) and opioids, before the start of CGD, had longer OS and PFS in univariate analysis. The multivariate analysis confirmed longer OS for patients who did not take steroids. Patients who did not take steroids had an OS of 14.8 months (95% CI: 13.1–29.1) versus 5.0 months (95% CI: 2.14–11.32) of patients who took prednisone >10 mg/day or equivalent. No differences were reported in terms of overall response rate (ORR), disease control rate (DCR) ( p = 1.0 and p = .16, respectively), and safety profile between the two groups. Our analysis suggests that patients who did not receive steroids before the start of GCD had longer survival and highlighted the relevance of balancing concomitant medications and chemoimmunotherapy.

Abstract Background Cisplatin, gemcitabine, and durvalumab combination is a standard first-line treatment for advanced biliary tract cancer. This study aimed to assess the impact of genetic alterations on outcomes in patients with advanced biliary tract cancer treated with cisplatin, gemcitabine, and durvalumab in real-world clinical practice. Methods Patients with unresectable, locally advanced, or metastatic biliary tract cancer treated with cisplatin and gemcitabine plus durvalumab across 39 centers in 11 countries in Europe, the United States, and Asia were included in this analysis. Results The cohort included 513 patients with advanced biliary tract cancer. The 5 most frequently altered genes were TP53 (22.1%), KRAS (13.7%), CDKN2A/B (13.6%), ARID1A (12.2%), and IDH1 (9.2%). In multivariate analysis, SMAD4 mutations were associated with improved progression-free survival (PFS) (hazard ratio [HR] = 0.49, P = .018) and overall survival (HR = 0.11, P = .023), while TP53 mutations were linked to worse PFS (HR = 1.62, P = .0047) and TERT mutations to worse overall survival (HR = 8.92, P = .0012). No other genomic alterations were statistically associated with outcomes. Subgroup analysis showed that TP53 mutations negatively affected PFS and overall survival in intrahepatic cholangiocarcinoma, while KRAS mutations were associated with poorer PFS in extrahepatic cholangiocarcinoma. No gene alterations were linked to outcomes in gallbladder cancer. Conclusions This large-scale analysis, with comprehensive molecular profiling, supports the positive prognostic impact of SMAD4 mutations for PFS and overall survival and highlights the negative prognostic roles of TP53 (PFS) and TERT (overall survival) mutations, providing valuable insights for personalized treatment strategies in biliary tract cancer.

PURPOSE Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy is used commonly for pediatric Hodgkin lymphoma (pHL) in low- and middle-income countries. The role of radiotherapy (RT) after ABVD in pHL is uncertain. MATERIALS AND METHODS We conducted a systematic review to explore the use of ABVD with or without RT in pHL. Key clinical questions included the number of cycles of ABVD, indications for and dose of RT, and outcomes by risk group. A search was performed in PubMed. Articles reporting survival outcomes by risk group were included. RESULTS Of 97 articles identified in the literature search, nine met inclusion criteria. Chemotherapy consisted of four to six cycles in limited disease and mostly six cycles in advanced disease. Three studies used RT for all patients within a specified risk group. Six studies dictated an adapted RT approach, with 3%-43% of the patients receiving RT for bulky adenopathy, slow early response (SER), and/or incomplete response. Radiation doses ranged between 20 and 36 Gy. The progression-free survival and overall survival at 4-10 years ranged from 84% to 100% and 93%-100% in limited disease and 50%-84.4% and 75%-95.3% in advanced disease, respectively. Studies did not directly assess the impact of certain chemotherapy or RT strategies. Recommendations were made after reviewing outcomes with particular approaches. CONCLUSION Four cycles of ABVD are recommended for limited disease, and six cycles of ABVD are recommended for advanced disease. In both limited and advanced diseases, RT is recommended with a dose of 20-21 Gy only to sites of bulky and/or SER, with a boost of up to 36 Gy to sites of incomplete response. This approach could spare radiation for at least half of the patients with limited disease and one third of advanced disease.

Abstract Objective There is a need to develop a comprehensive, formalized, and globally applicable epilepsy surgery curriculum in order to help standardize the quality of epilepsy surgery practice in the world. Methods The Epilepsy Surgery Educational Task Force of the ILAE developed a competency‐based epilepsy surgery educational curriculum comprised of four domains: Diagnosis, Counseling, Pre‐surgical Work‐up, and Surgical Techniques. To evaluate this educational curriculum, a survey questionnaire consisting of 11 items was sent out for feedback to ILAE and IESS members. The survey questionnaire asked respondents to rate the degree of importance of each competency on a five‐point scale that ranged from “extremely important” to “not at all important” and provided space for free text comments. All competencies that were rated as “slightly important” or “somewhat important” by more than 10% of responders, as well as all free text feedback comments, were fully reviewed, and the final curriculum was adjusted accordingly. Results One hundred and twenty‐two responses ( n = 122) were submitted by the ILAE and IESS communities. Seventy‐one percent (71.9%) of the responses came from neurosurgeons of varied experience and training levels. Ninety‐four percent (94.4%) of responders stated that they “support a curriculum to determine the competency of neurosurgeons participating in the care of people with epilepsy in my country,” and 94.3% confirmed that they “would be interested in taking or would recommend an ILAE course based on these competencies, that would provide an ILAE certificate of completion.” Relevant changes within the curriculum were made based on feedback. Significance The newly developed ILAE comprehensive epilepsy surgery educational curriculum has a high level of support from neurosurgeons and neurologists around the world and shows potential for broad acceptance and implementation.

Abstract Objective In patients with focal drug‐resistant epilepsy (DRE), resective epilepsy surgery correlates with high rates of remission. However, in cases where the epileptic region is deemed surgically inaccessible, or when it involves a complex network, stereoelectroencephalography‐guided radiofrequency thermocoagulation (SEEG‐RFTC) might be an alternative therapeutic strategy. However, most of the available evidence is limited to small observational studies. An updated meta‐analysis is warranted to provide a comprehensive assessment of SEEG‐RFTC in patients with DRE. Methods Databases were searched until September 9, 2023 to identify published studies reporting on the effectiveness of SEEG‐RFTC in patients with DRE. The primary outcomes of interest were the 1‐year seizure‐freedom rate and response rate (50% seizure frequency decrease from baseline). These outcomes were pooled using the inverse variance and a random‐effects model. Results We screened 182 articles and included 16 retrospective cohort studies. A total of 437 unique patients from 12 nonoverlapping cohorts were analyzed for seizure and complication outcomes. The pooled seizure‐free rate after 1 year was 37.8% (95% confidence interval [CI] = 24.7%–50.8%), whereas the seizure response rate after 1 year was 69.7% (95% CI = 52.7%–86.7%). There was high heterogeneity among the included studies. Subgroup analysis revealed that patients with nodular heterotopia achieved higher rates of seizure freedom (57.1%, 95% CI = 38.8%–75.5%) compared to those with cortical dysplasia (CD) and magnetic resonance imaging‐negative conditions. Furthermore, hippocampal sclerosis patients exhibited higher seizure freedom rates (66.7%, 95% CI = 49.8%–83.5%) than those with CD (12.0%, 95% CI = .0%–24.7%). Significance SEEG‐RFTC might be an effective therapeutic option for seizure control in patients with DRE who undergo SEEG for DRE workup. The role of SEEG‐RFTC as a potential adjunct therapy to laser interstitial thermal therapy or surgical resection should be explored. This study highlights the need for well‐designed clinical trials to compare SEEG‐guided RFTC with other therapeutic modalities.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Introduction Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, with a high 5-year survival rate of approximately 98%. Despite advances in diagnosis and treatment, up to 20% of patients experience recurrence, adversely affecting their quality of life. Predictive models have been developed to assess recurrence risk and guide clinical decision-making, but these models often face limitations such as retrospective design, lack of diversity in study populations and absence of external validation. The primary aim is to externally validate existing predictive models for DTC recurrence using prospective data from a diverse Latin American cohort. The secondary aim is to explore opportunities for model recalibration to improve their performance in our population. Methods and analysis The CaTaLiNA study is a multicentre prospective observational study conducted across 10 hospitals in five Latin American countries, including Ecuador, Peru, Uruguay and Mexico. Patients aged 18 years or older receiving treatment for DTC, such as the first thyroid surgery, active surveillance or radiofrequency ablation will be included. Recruitment will occur from November 2023 to June 2025, with follow-up extending until June 2028. Data collection will include baseline clinical, surgical and histological characteristics, treatment details and follow-up outcomes. Statistical analysis will follow the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis guidelines, using imputation strategies for missing data and evaluating calibration and discrimination of the prediction models. Calibration measures include the ratio of expected and observed events, calibration slope and calibration plot, while discrimination will be assessed using the C-index and area under the receiver operating characteristic curve. Ethics and dissemination This study protocol was approved by Comité de Ética de Investigación en Seres Humanos de la Universidad San Francisco de Quito USFQ ‘CEISH-USFQ’ APO-010–2023-CEIHS-USFQ Oficio No. 161-2023-CA-23030M-CEISH-USFQ. Results will be disseminated via peer-reviewed publications.

Background: Outcomes after arthroscopic rotator cuff repair (RCR) are frequently measured through clinically significant outcomes (CSOs) such as the minimal clinically important difference, the substantial clinical benefit, and the Patient Acceptable Symptom State. Global achievement of CSOs is challenging to predict. Purpose: To determine if unsupervised machine learning can identify distinct patient subgroups based on CSO achievement after elective arthroscopic RCR. Study Design: Case-control study; Level of evidence, 3. Methods: A prospectively collected database was analyzed to identify patients who underwent elective arthroscopic RCR from 2015 to 2017. Tear dimensions were measured on magnetic resonance imaging utilizing a validated technique. CSO achievements on the American Shoulder and Elbow Surgeons, the Single Assessment Numeric Evaluation, and the Constant-Murley subjective score at 2-year follow-up were calculated. An unsupervised random forest algorithm was utilized to develop and internally validate patient subgroups with significantly different rates of CSO achievement. Patient subgroup membership, along with a total of 30 demographic and clinical variables, as well as preoperative patient-reported outcomes, were incorporated into a stepwise multivariable logistic regression to identify factors predictive of optimal CSO achievement. Results: A total of 346 patients (192 male; mean ± SD age, 57.2 ± 9.1 years; body mass index, 30.1 ± 5.4 kg/m 2 ) were eligible for inclusion and followed for a mean of 3.8 years (range, 2.0-6.2 years) Of these, a total of 333 patients were partitioned by the random forest algorithm into 2 subgroups (stability, 0.16; connectivity: 180.8; Dunn: 0.16; silhouette: 0.05), with 176 patients in the optimal achievement subgroup and 157 patients in the suboptimal achievement subgroup. The 2 subgroups differed significantly (all P ≤ .004) in the likelihood of achievement of all CSOs. Stepwise multivariable logistic regression identified an increase of 1 mm in tear size in the sagittal dimension beyond 1.9 cm to predict a 10% increase in the probability of suboptimal achievement. Additional risk factors for suboptimal CSO achievement included increasing number of tendons involved (odds ratio [OR], 14.07; 95% CI, 4.50-44.02; P < .001), subscapularis involvement (OR, 8.67; 95% CI, 2.45-30.71; P = .01), and increased preoperative CMS score (OR, 1.11; 95% CI, 1.04-1.18; P = .001). Protective factors included performance of a subpectoral biceps tenodesis compared with biceps tenotomy (OR, 0.22; 95% CI, 0.05-0.92; P = .03). Conclusion: Clinically meaningful subgroups were uncovered using an unsupervised machine learning algorithm in patients undergoing arthroscopic RCR. Tear size, number of tendons involved, and subscapularis involvement were significant and additive predictors of suboptimal CSO achievement at 2-year minimum follow-up. Treatment of concurrent biceps pathology with tenodesis conferred 78% increased likelihood of CSO achievement compared with tenotomy.

ABSTRACT Background Over the years, prognostic indexes have been developed to help clinicians stratify patients with biliary tract cancers (BTC) into risk groups. This study aims to identify a new prognostic index for patients with BTC treated with cisplatin, gemcitabine and durvalumab (CGD) in the first‐line setting. Patients and Methods The study population consisted of patients with BTC from 11 Eastern and Western Countries. Using multivariate analysis for overall survival (OS), we identified 5 baseline statistically significant variables: stage, carcinoembryonic antigen (CEA) levels, albumin levels, gamma glutamyl transferase (GGT) levels, neutrophil‐to‐lymphocyte ratio (NLR). Metastatic disease is a prognostic factor with a superior weight considering the HR of 3.62, while all the others can be considered prognostic factors with equivalent weight as the HRs are quite similar (HRs between 1.55 and 1.92). Based on these reasons, we developed a prognostic model called the MAGIC‐D index by assigning a score of 2 for metastatic disease, and a score of 1 for CEA increased levels, albumin decreased levels, GGT increased levels, NLR ≥ 3. Patients were stratified into three risk groups as follows: low‐risk group (Score from 0 to 2), intermediate‐risk group (Score from 3 to 4) and high‐risk group (Score from 5 to 6). At the first data cutoff (April 2024), these data were available for 319 patients that composed the training cohort used for the analysis. At the second data cutoff (May 2025), 79 patients were further enrolled and composed the validation cohort. Results Median progression‐free survival was 11.7 months in low‐risk group (20.7%), 8.7 months in intermediate‐risk group (46.4%) and 5.4 months in high‐risk group (32.9%) [low‐risk hazard ratio (HR): 0.27, intermediate‐risk HR: 0.55, high‐risk HR: 1, p < 0.0001]. Median OS was 18.4 months in low‐risk group,15.9 months in intermediate‐risk group and 7.8 months in high‐risk group (low‐risk HR: 0.17, intermediate‐risk HR: 0.43, high‐risk HR: 1, p < 0.0001). There was no difference in overall response rate (low‐risk: 31.8%, intermediate‐risk: 36.5% and high‐risk: 25.7%; p = 0.0718), while disease control rate was significantly different across the three risk groups (low‐risk: 83.3%, intermediate‐risk: 70.9% and high‐risk: 60.9%; p < 0.0001) as well as the rate of patients receiving a second‐line therapy (low‐risk: 54.5%, intermediate‐risk: 48.6% and high‐risk: 25.7%; p = 0.0061). Finally, the prognostic role in terms of OS and PFS of the MAGIC‐D index was confirmed in a validation cohort of 79 patients. Conclusion The MAGIC‐D index is an easy‐to‐use tool able to stratify patients with BTC with different prognoses undergoing first‐line therapy with CGD.