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Abstract Introduction Venetoclax combined with hypomethylating agents (VEN/HMA) is an approved frontline induction therapy for older or unfit patients with acute myeloid leukemia (AML). However, data comparing its efficacy and safety to intensive chemotherapy (IC) in intermediate-risk AML—characterized by molecular and cytogenetic heterogeneity—remain limited. Methods This multicenter, real-world retrospective study analyzed newly diagnosed intermediate-risk AML patients who received either VEN/HMA or IC. We evaluated composite complete remission (CRc) rates, transfusion and infection rates, long-term outcomes including overall survival (OS) and progression-free survival (PFS), and performed subgroup analyses to identify mutation-specific predictors of treatment response. Multivariable Cox regression was used to identify independent prognostic factors. Results A total of 229 intermediate-risk AML patients were included. VEN/HMA achieved a comparable CRc rate to IC (75.3% vs. 63.4%) with lower transfusion needs and fewer infections. Patients harboring FLT3-ITD, DNMT3A, or TET2 mutations showed greater benefit from VEN/HMA, while KIT-mutated patients responded more favorably to IC. Among patients who did not undergo allo-HSCT, VEN/HMA significantly improved 3-year OS (P = 0.001) and PFS (P = 0.008). No significant OS or PFS difference was observed in the allo-HSCT subgroup. In MRD-negative patients without transplant, those treated with VEN/HMA had superior OS compared to IC. Multivariable analysis identified VEN/HMA (HR = 0.613, P = 0.038) and allo-HSCT (HR = 0.11, P = 0.001) as independent predictors of better survival. Conclusions VEN/HMA is a safe and effective induction strategy for intermediate-risk AML, particularly in patients with BCL-2 inhibitor–sensitive mutations (FLT3-ITD, DNMT3A, TET2). These findings support a genotype-guided treatment approach in AML, complementing current risk stratification frameworks and informing individualized induction therapy decisions.

Abstract Introduction Ciltacabtagene autoleucel (cilta-cel) has demonstrated unprecedented response rates and progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM), but a proportion of patients experience early relapse. Identifying these patients is essential to guide future therapeutic strategies, such as enhanced bridging therapy or consolidation, while avoiding overtreatment in those likely to achieve durable disease control. Methods We conducted a multi-center study of patients treated with cilta-cel at 15 U.S. academic centers. Outcomes were evaluated based on high-risk (HR) features, including functional HR disease (FHR; relapse within 18 months of first-line therapy initiation), true extramedullary disease (EMD), traditional HR cytogenetics as defined in CARTITUDE-1 [deletion 17p, t(4;14), t(14;16)], and a 2024 IMS-IMWG-adapted HR definition (deletion 17p; t(4;14) or t(14;16) with gain 1q or deletion 1p; and gain 1q with deletion 1p). Multivariable Cox regression was used to examine the association of HR features (FHR, adapted IMS-IMWG HR, and EMD, individually and collectively) with PFS while adjusting for baseline ferritin, prior BCMA, and ECOG performance status (PS ≥2). Among patients with ≥18 months of follow-up, we evaluated predictors of early relapse (≤18 months post infusion) using logistic regression. Results Our cohort included 598 patients treated with cilta-cel between 5/2022 and 12/2024 who had available data on all HR features. The median age was 65 years (range 33-83), and the median prior lines of therapy (pLOT) was 5 (range: 1-18, 84% with >3 pLOT); 8% had received prior BCMA-directed therapy, and 27% were penta-refractory. Most patients (88%) received bridging therapy and 30% achieved ≥ partial response. In our cohort, 33% (n=195) had FHR, 43% (n=258) had traditional HR cytogenetics, 42% (n=253) had adapted IMS-IMWG HR disease, and 11% (n=64) had EMD. Median follow up was 10.6 months (range 0.4-34.1). Overall response rate (ORR) and complete response (CR) rates were lower in patients with vs without HR features: FHR (ORR: 89% vs 94%, CR: 61% vs 75%), traditional HR (ORR: 90% vs 94%, CR: 65% vs 74%), adapted IMS-IMWG HR (ORR: 91% vs 94%, CR: 64% vs 75%) and EMD (ORR: 77% vs 94%, CR: 61% vs 71%). Corresponding 12-month PFS was also lower in patients with vs without HR features: FHR (55% vs 79%), traditional HR (63% vs 78%), adapted IMS-IMWG HR (61% vs 80%) and EMD (59% vs 73%). ORR, CR rate, and 12-month PFS in patients without any HR features compared to those with ≥1 HR feature were 96% vs 90%, 81% vs 64%, and 83% vs 65%, respectively. In multivariable models, each HR feature (FHR, adapted IMS-IMWG HR, and EMD) was independently associated with inferior PFS after adjusting for baseline ferritin, prior BCMA, and ECOG PS ≥ 2. However, because early relapse cannot always be identified a priori based on traditional risk factors, we sought to identify predictors of relapse within 18 months of cilta-cel in a subset of patients with ≥18 months of follow-up (N=247; infused by 12/2023). Notably, while FHR (OR=3.04, 95% CI=1.59-5.89) and adapted IMS-IMWG HR (OR=2.07, 95% CI=1.10-3.89) were independently associated with odds of relapse within 18 months, EMD was not (OR=0.90, 95% CI=0.32, 2.40) when accounting for prior BCMA, ECOG PS ≥ 2, and baseline ferritin. We also used a time-varying Cox model to examine each HR feature associated with PFS at two time periods, <18 and ≥18 months, while adjusting for baseline ferritin, ECOG PS, and prior BCMA. We confirmed that FHR and adapted IMS-IMWG HR were both associated with relapse <18 months (HR=2.05, 95% CI=1.48-2.83 and HR=1.56, 95% CI=1.11-2.19) but not in the ≥18-month time period (HR=0.70, 95% CI=0.19-2.59 and HR=0.76, 95% CI=0.24-2.40). The magnitude of the association for EMD with PFS was similar across both time periods (<18 months HR=1.67, 95% CI=1.09-2.57 and ≥18 months HR=2.17, 95% CI=0.45-10.40). Conclusion While cilta-cel leads to high response rates and durable PFS in RRMM, a subset of patients with FHR and adapted IMS-IMWG HR remains at increased risk for early relapse. In this large multi-center cohort, we describe PFS outcomes across high-risk subgroups and identify key predictors of relapse within 18 months of cilta-cel. These findings inform risk-adapted therapeutic strategies and interventional trials, including bridging, consolidation, or maintenance approaches, to improve outcomes in the highest-risk RRMM patients.

Abstract Introduction: BL and DLBCL are the two most common lymphomas associated with HIV infection. Notably, clinical trials often exclude HIV-positive patients and prior retrospective studies often lacked long-term follow-up on overall survival (OS). This has limited our knowledge about the influence of HIV status on survival in BL and DLBCL. Survival outcomes can also vary significantly across ethnic groups, influenced mostly by disparities in healthcare access and socioeconomic status. Additionally, survival rates differ among age groups, which may be attributed to tolerance to intensive chemotherapy and the presence of comorbid medical conditions. Our study primarily focused on comparing OS between HIV-positive and negative patients with DLBCL and BL in the real world. We also examined OS disparities among diverse ethnicities and age groups. Method: Patients diagnosed with DLBCL and BL were identified from the Cerner Health Facts database over five years from 2013 to 2018 using ICD-9 and ICD-10 codes. Within this cohort, individuals with a positive HIV status were identified through specific ICD-9 and ICD-10 codes. Demographic characteristics including age, gender, and ethnicity were collected for all patients, and they were stratified into distinct age groups: <20 years, 20-39 years, 40-59 years, 60-79 years, and 80+ years. OS was calculated for all patients from the time of diagnosis to time of death or hospice discharge. A multivariate cox regression model was employed to adjust for confounding variables. Results: The total number of patients diagnosed with DLBCL and BL was 10,534. Of these patients, 45.3% were female. The ethnic composition included 77% Caucasian, 10.3% African American and 12.7 % from other ethnicities. Among this population, 315 patients were HIV positive. In the cohort of DLBCL patients, 8,275 were HIV negative and 185 were HIV positive. In the cohort of BL patients, 1,944 were HIV negative and 130 were HIV positive. Among patients with DLBCL, HIV positive status had more than two-fold higher mortality rate compared to their HIV negative counterparts (HR=2.1, 95% CI 1.31 to 3.36, p=0.0018). Patients with BL who were HIV positive had no difference in OS in comparison to the HIV negative group (p=0.575). African American patients with DLBCL had almost 40% increased risk of mortality compared to Caucasian patients (HR=1.39, 95% CI 1.05-1.83, p=0.017). African American patients with BL had no difference in OS compared to Caucasian patients (p=0.3). Patients aged 60-79 years were found to have 44% higher risk of mortality compared to 40-59 age group (HR=1.44, 95% CI 1.13-1.83, p=0.0033) and patients aged 80 years or above were found to have more than two-fold higher risk of mortality in the DLBCL cohort (HR=2.16, 95% CI 1.63-2.87, p<0.0001). For patients with BL, those aged 20-39 had half the risk of mortality as compared to the 40-59 age group (HR= 0.50, 95% CI 0.28 - 0.87, p=0.014) whereas patients aged 80 or older had almost three times higher risk of mortality (HR = 2.87, 95% CI 1.81-4.57, p<0.0001). Conclusion: HIV status can significantly influence survival outcomes in patients diagnosed with DLBCL. Early identification of HIV infection, along with the initiation of prompt antiretroviral therapy and the administration of appropriate intensive chemotherapy regimens, is crucial for optimizing treatment outcomes in this patient population. Notably, our study indicates that African American patients exhibit a higher mortality rate compared to their Caucasian counterparts with DLBCL. This could be related to disparities in access to healthcare and treatment resources across different ethnicities. Moreover, it also indicates possible lymphoma biological heterogeneity in various ethnicities. Furthermore, elderly patients demonstrate increased mortality rates likely attributed to a greater prevalence of frailty, indicating the need for innovative less intense regimens for these patients with DLBCL and BL.

Abstract Marginal zone lymphoma (MZL) is an uncommon non-Hodgkin B-cell lymphoma accounting for 7-10% of lymphoma diagnoses. Extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT) is the most common subtype (61%) of MZL. While the mutational landscape, chromosomal aberrations and transcriptome of nodal and splenic MZL have been extensively evaluated, the mutational landscape of EMZL has only been evaluated in a small number of patients and mainly by targeted sequencing. Consequently, the comprehensive genomic landscape of EMZL remains largely uncharacterized. Herein, we performed whole exome sequencing followed by targeted sequencing of potential tumor driver genes, copy number and/or RNA transcriptome analyses in 165 patients with pretreatment EMZL tumors involving 16 anatomic locations. All samples were collected and underwent expert review as part of the Atlas of Blood Cancer Genomes consortium. The most common anatomic locations were ocular adnexa (OAMZL) (n=35), gastric (n=25, including 6 positive for Helicobacter pylori), salivary glands (n=25), and lungs (n=24). Using common criteria for variant mutation calling and significant focal copy number (CN), we identified 1218 variants (1030 missense and 188 truncation mutations) across 174 genes and 2837 CN focal alterations (1614 copy gains and 1223 copy number losses). Of these genes, 44 and 11 were mutated in >5% and >10% of specimens, respectively. We detected variants identified previously by targeted sequencing in EMZL from different locations (e.g. TNFAIP3 (A20) (12%), TBL1XR1 (13%), SPEN (10%), CARD11 (7%), TET2 (7%) and CREBBP (6%)). We detected mutations in KLF2 (10 mutations in 8 EMZL patients) and PTPRD (7 mutations in 7 EMZL patients) that were previously suggested to be specific for splenic and nodal MZL, respectively. We also detected variants not previously reported in EMZL, including a transcriptional factor ZEB2, LRP1B,and others. The most frequently mutated gene in our study (25% of tumors) was IGLL5. Some mutations were limited to specific locations (e.g. ZEB2 mutations seen exclusively in gastric and salivary gland EMZL), while most were observed across all anatomic locations. There was no association between specific mutations and clonal IGHV, in contrast to previous reports. Using Enrichr tool, we observed enrichment of mutations in genes belonging to the B cell receptor activation, NOTCH signaling, Wnt-beta catenin signaling, NF-kB signaling , PI3K AKT signaling, DNA repair and other pathways. Chromosomal and copy number changes were also commonly observed including previously reported trisomy of chromosomes 3 and 18. Combining DNA mutations and CN alterations, the number of genetic lesions per tumor sample in the 174 mutated genes ranged from 0 to 95, with an average load of 17 lesions per case. RNA sequencing was successful in 159 EMZL tumors from 16 distinct anatomic locations. Unsupervised clustering using all genes with a median log2-normalized gene expression value greater than 5 and a standard deviation greater than 1 (1323 genes) demonstrated that the majority of gastric EMZL with and without H. pylori infections clustered together on 2 dendrograms as did most of the samples of OAMZL. Since the clustering could be forced by organ-specific and not tumor-specific gene expression, we next focused on the expression of the 345 genes from the LM22 matrix that passed our transcriptomic row filtering. Unsupervised clustering resulted in clustering of most gastric EMZL irrespective of H. pylori positivity together in the same dendrogram branch, accompanied by few additional EMZL from other anatomic locations. Most of the EMZL samples from other locations did not show preferential co-clustering together. On comparison of gene expression between gastric and OAMZL, there was enrichment of the B-cell receptor signaling pathway, B-cell activation, B-cell naïve and B-cell memory cells, B-cell proliferation and NF-kB signaling in the latter. Immune microenvironment analysis showed a statistically significant increase in resting mast cells and decrease in M1 macrophages in gastric EMZL and increase in regulatory T cells in salivary EMZL. The broad genomic studies reported here underscore the biological similarity of EMZL across anatomical sites with the potential exceptions of gastric EMZL (regardless of H. Pylori status). These data provide valuable genomic and transcriptomic resources to inform future diagnostic and therapeutic strategies.

Abstract Introduction Penile augmentation or penis enlargement surgery refers to any technique aimed at enhancing penile length or girth. These male enhancement surgical techniques can increase total penile length, either flaccid or erect, while others add to the penile shaft’s girth and/or glans size. Proposed strategies include physical methods such as various penile exercises, mechanical traction devices, and medical therapy, while surgical interventions include cosmetic and phallic reconstructive techniques and use of fillers, sleeves, grafts, and flaps to augment penile size. Objectives The International Consultation on Sexual Medicine (ICSM) consensus statements provide evidence-based recommendations and aim to guide a clinical framework in penile aesthetic and augmentation. Methods A comprehensive literature search was conducted to identify published literature relevant to penile augmentation or enhancement. Preliminary consensus was presented to the delegates attending the 5th ICSM meeting, and feedback was incorporated into the final document. Results Twenty new recommendations are provided with corresponding levels of evidence and grades of recommendation. Conclusions Due to the controversies and lack of longer-term data regarding penile augmentation and cosmetic procedures, comprehensive assessments and careful patient counseling weighing the pros and cons, as well as potential complications, are mandatory before embarking on any treatment. Surgeons should be experienced in anatomy and various surgical techniques, and it is important to individualize surgical options based on patient condition(s) and needs, surgeon expertise, and local resources.

Abstract Introduction There is no ideal treatment for Peyronie’s Disease (PD) since every patient has different needs with varying perceived risks versus benefits of individual treatment options, coupled with the degree of impact relating to PD on sexual function and beyond. Objectives The 5th International Consultation on Sexual Medicine (ICSM) guideline on PD provides an update to the previous ICSM with an aim to provide a clinical framework and best-evidenced consensus recommendations to assist clinicians in managing PD. Methodology Available literature was reviewed, and a modified Delphi consensus was undertaken by leading sexual medicine experts to achieve a set of Quality of Evidence and strength of recommendations. This guideline was developed as an authoritative best-evidenced consensus incorporating state-of-the-art knowledge and contemporary literature. Results A total of thirty-one recommendations were made on PD guidelines. New updates to the 4th ICSM on PD have been made in definition, pathophysiology, and treatment strategies. The presence of penile pain with erection could occur in the chronic phase due to torque or stretch on the penile scar and surrounding tissue. Oral therapy works best during the acute phase and should be provided concurrently with other treatment modalities. Penile traction therapy can reduce penile deformity as monotherapy or may be offered as part of a multimodal therapy approach. There is no convincing evidence supporting cellular-based therapy. The type of plication procedure used depends on the surgeon and patient preference, although excision of the tunica followed by plication may have a higher complication rate. There is currently no ideal graft, and graft contracture can occur postoperatively. Adjunctive procedures such as penile modeling, tunical plication, plaque incision/excision and grafting can be performed when penile deformity and/or penile curvature persist following penile prosthesis implantation. Conclusions The management of PD should be individualized based on the patient’s needs and preferences while balancing the benefits and risks of each treatment option.

Abstract Objective β-Catenin–mutated hepatocellular adenomas (HCAs) carry an increased malignant transformation risk and are screened by interpreting glutamine synthetase (GS) and β-catenin by immunohistochemistry (IHC). Our study aims to assess GS and β-catenin interpretation guidelines for applicability and reproducibility in predicting high-risk HCA and other relevant molecular alterations. Methods Hematoxylin and eosin (H&E), β-catenin, GS, and CD34 stains from 75 HCAs were interpreted by three pathologists using Method A (GS interpretation: negative, perivenular patchy, map-like, diffuse, and indeterminate) and Method B criteria (similar GS interpretation scheme based on a recent publication, with and without CD34 expression patterns). Ease of application and interpretation confidence level were assessed. High-risk IHC was defined as nuclear β-catenin and/or diffuse homogeneous GS. Molecular testing was performed on a subset of HCAs and controls. Results There were 57 resections and 18 biopsy specimens examined. Methods A and B (GS only) were rated as easy to apply, with high interpretation confidence (≥90% using both methods). Consensus rate was comparable in biopsy specimens (100% for both methods) and resections (88% for Method A, 93% for Method B). While the same cases were stratified into high-risk GS categories using both systems, clinically significant genetic alterations (TERT promoter, EGFR, MTOR, and TP53) were identified in 25% of cases stratified as not high risk by IHC. Conclusions Both methods have a similar ease of application and level of interpretation confidence, and they also detected β-catenin mutations as expected. Other relevant molecular alterations associated with risk of neoplastic progression and/or bleeding were detected in 25% of HCAs with the non-high-risk IHC phenotype, suggesting the value of molecular testing in this subset.

Importance The introduction of immune checkpoint inhibitor (ICI) therapy has improved cancer outcomes but at the cost of adverse events, mainly related to the immune system. Cardiovascular (CV) toxic effects, and especially myocarditis, are of particular concern and are the subject of this position statement by the International Cardio-Oncology Society with representation of experts from oncology, hematology, and cardiology. Observations CV toxic effects of ICI therapies include inflammation-associated diseases, such as myocarditis, pericarditis, and vasculitis, as well as the aggravation of chronic inflammatory conditions, such as atherosclerosis with acute ischemic complications (myocardial infarction and stroke). Patients taking ICI therapies can also develop cardiac dysfunction, stress-induced cardiomyopathy (Takotsubo or apical ballooning syndrome), and heart failure without inflammatory cell infiltration of the myocardium. Atrial and ventricular arrhythmias can emerge in the setting of a systemic inflammatory milieu, myocarditis, or ischemia. Of all potential CV adverse effects, myocarditis remains of highest concern, although fatality rates have declined over time with a broadening spectrum of presentations ranging from troponin elevation of uncertain significance to smoldering, nonsevere, and severe or fulminant myocarditis. Conclusions and Relevance Concerns for myocarditis continue to dominate the spectrum of CV toxic effects in patients receiving ICI therapy. Recommendations for management vary according to severity. Multidisciplinary collaborations remain key for managing acute toxic effects and future cancer treatment decisions, including ICI rechallenge. Ischemic heart disease constitutes the main differential diagnosis in these patients, while pericarditis can be concomitantly present, and atrial and ventricular arrhythmias can also complicate the clinical picture. Several gaps in knowledge are identified and require further research.

Abstract PURPOSE Age over 40 years is commonly regarded as a “high risk” feature and potential indication for adjuvant chemoradiotherapy for patients with lower grade glioma in most clinical practice guidelines. However, these recommendations are based on retrospective observations and their subsequent incorporation into legacy clinical trials. It is unclear whether age remains a relevant prognostic factor in the molecular era. METHODS The Prospective Gliomas Research [PROGRES] Database contains individual patient-level data from 11 prospective clinical trials or observational registries, including seven international trials from the RTOG, EORTC, or Alliance cooperative groups. We determined the association of age with progression-free survival (PFS) in low grade or anaplastic glioma, stratified by isocitrate dehydrogenase (IDH1/2) status. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] Database). RESULTS We identified 1,619 and 1,271 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH-wildtype tumors were more common in patients >40 years (38% vs, 5%, odds ratio: 11.3 [95%CI 6.5 – 19.7]). Age was associated with PFS in IDH-wildtype (5-year PFS: 6% vs, 24%, P =.003) but not in IDH-mutant glioma (60% vs, 59%, P = 0.22, P value of interaction <.001). In IDH-wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% vs, 28%), EGFR amplification (41% vs, 15%), and chromosome +7/-10 alteration (57% vs, 25%). Age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone in IDH-mutant glioma. CONCLUSION Older age is a putative surrogate for IDH-wildtype status, but was not an independent predictor of progression in IDH-mutant lower grade glioma and did not predict benefit from chemoradiotherapy. In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.