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Background: TP53-mutated (TP53mut) myeloid neoplasms (MN) have particularly poor survival. Discrepancies in defining TP53mut MN have impact on diagnostic work up, therapeutic decisions, and clinical trial enrolment. Methods: MN cases harboring TP53mut (variant allele frequency, VAF ≥2%) were classified based on bone marrow (BM) and peripheral blood (PB) blast % using the 4th revision of the WHO classification (WHO-4R). Biallelic loss was defined as (i) ≥2 mutations each with VAF ≥2%; (ii) single TP53mut VAF ≥2% plus 17p loss detected on karyotype, FISH, or SNP; or (iii) single TP53mut VAF ≥50%, whereas monoallelic loss was defined as single TP53mut VAF <50% without 17p loss. Primary endpoint was overall survival (OS) from diagnosis. Conditional Inference Trees (CIT) analysis was used to determine the true effect of a predictor. Results: We identified 580 cases including WHO-4R defined acute myeloid leukemia (AML, BM/PB blasts ≥20%, n=219, 37.8%), myelodysplastic syndrome (MDS) with excess blasts-2 (EB-2, BM 10-19% or PB 5%-19%, n=92, 15.9%), MDS with excess blasts-1 (EB-1, BM 5-9% or PB 2-4%, n=75, 12.9%), and the remaining were MDS with low blasts (-LB, BM <5% and PB ≤1%, n=194, 33.4%). Of the 578 cases evaluable for allelic status, 437 (75.6%) and 141 (24.4%) had biallelic and monoallelic TP53 loss, respectively. Higher frequency of biallelic loss was observed with increasing blasts. 63.2%, 73.3%, 78% and 86.3% of cases with MDS-LB, MDS-EB1, MDS-EB2, and AML had bi-allelic TP53 loss (P<0.0001). In a multivariable analysis, WHO-4R categories, VAF ≥10%, and biallelic loss were independent predictors of poor survival. CIT analysis further stratified the cohort into 4 groups with distinct survival: (1) MDS-LB (n=194, 33.4%); (2) MDS-EB1/EB2 and AML with VAF <10% (n=38, 6.6%); (3) MDS-EB1/EB2 with VAF ≥10% (n=149, 25.7%); and (4) AML with VAF ≥10% (n=199, 34.3%). MDS-LB cases could be further stratified based on allelic status and complex karyotype (CK): OS was poor for cases with biallelic TP53 loss and monoallelic TP53mut with CK compared to monoallelic TP53mut without CK, who had the most favorable survival (12.7 vs. 13 vs. 34.8 months, P<0.0001).MDS-EB1/EB2/AML with VAF<10% could also be stratified by CK: MDS-EB1/EB2/AML with VAF<10% cases without CK had the favorable survival compared to their counterparts with CK and MDS-EB1/EB2 with VAF ≥10% cases (26.2 vs. 5.6 vs. 6.3 months, P=0.003).MDS-EB1/EB2 with VAF ≥10% was a homogenous subgroup: Biological characteristics including the proportion of cases with biallelic TP53 loss, CK (P>0.9), monosomal karyotype (MK, P>0.9), del 5q (P=0.6), del 7q (P=0.4), and del 17p (P=0.2) were comparable between MDS-EB1 and -EB2 with VAF ≥10%. Importantly, median OS of MDS-EB1 and EB2 with VAF ≥10% was comparable (9.6 vs. 7.2 months, P=0.12). OS in this group was comparable regardless of the blast %, allelic status, or presence of CK.AML with VAF ≥10% had extremely poor survival: Median OS was 3.9 months. Survival of AML was equally poor irrespective of the mono- or biallelic (3.6 vs. 3.9, P=0.89) and non-CK vs. CK (1.8 vs. 3.9 months, P=0.09). Combined, our model would acknowledge poor survival of 514 (89.1%) cases. In contrast, retrospective application of the 5th edition of the WHO classification (WHO-5) and International Consensus Classification (ICC) would classify only 211 (36.4%) and 468 (80.7%) cases as biallelic/multi-hit TP53mut MN, respectively. Finally, the Harrell's c-index of the proposed model, WHO-5, and ICC was 0.66, 0.571, and 0.617, respectively. Conclusion: We provide evidence for subsequent refinements in classifying MN harboring TP53mut. Our salient findings include: (i) acknowledgement of CK as ‘biallelic equivalent’ in MDS-LB; as well as EB1/EB2/AML with VAF 2 to <10% cases; and (ii) demonstration of poor survival of MDS-EB1 and -EB2 with VAF ≥10% regardless of the allelic status. In conclusion, our proposed model acknowledged poor survival of a higher proportion of cases as TP53mut MN compared to the current models with a higher c- index.

Background: Continuous single-agent ibrutinib (Ibr) treatment has been associated with extended progression-free survival in patients with Waldenström macroglobulinemia (WM). Previous clinical studies have shown that Ibr dose reductions (DRs) improved or resolved adverse events (AEs) in most patients, while hematologic responses were sustained. However, real-world data on long-term outcomes for patients with WM undergoing Ibr DR in first-line (1L) settings remain limited. Methods: Medicare Fee-for-Service (FFS) medical and pharmacy records were used to identify patients diagnosed with WM who initiated 1L single-agent Ibr (420 mg/day) or 1L Ibr + rituximab from January 1, 2015, to September 30, 2022. Observed patients were enrolled in Medicare FFS ≥12 months before and after 1L treatment initiation and had ≥1 qualifying post-treatment initiation AE of special interest (AESI; both prevalent and incident AEs), as identified via ICD-9-CM or ICD-10-CM diagnosis codes. Ibr DR was defined as a reduction of the starting dose (420 mg/day) following the first AESI during 1L treatment. Patients without an Ibr DR were defined as those who had received Ibr at 420 mg/day during 1L treatment. Patients without an AESI post-Ibr initiation and prior to DR were excluded from the analysis. Demographics, clinical characteristics, time to AESI, duration of therapy (DOT), and time to treatment discontinuation (TTD) were assessed in cohorts with and without DRs. DOT was measured at the date of Ibr treatment initiation through treatment discontinuation (end of 1L treatment). Patients were considered to have discontinued treatment if they received a subsequent systemic therapy after the 1L regimen, had a gap of ≥120 days with no systemic therapy following the last administration, or died while on the 1L regimen. Patients without a discontinuation were censored at the earliest date of end of follow-up or disenrollment. TTD was analyzed using the Kaplan-Meier method. A Cox proportional hazards model adjusted for patient demographics and clinical characteristics was used to identify factors associated with treatment discontinuation. Results: A total of 407 patients with WM were included in the analysis (DR, n=55 [14%]; no DR, n=352 [86%]). Patients in the DR and no DR cohorts, respectively, had similar a median age (78 years vs 77 years), Charlson Comorbidity Index score (3 vs 4), and prevalence of the most common baseline comorbidities: hypertension (67% vs 68%) and cardiovascular conditions (31% vs 28%). The median time between treatment initiation and the occurrence of the first AESI was 89 days versus 76 days, and total Ibr DOT mean ± SD [median] was 786.1 ± 692.6 [661] days versus 454.8 ± 510.4 [279] days (P=0.001) for DR cohort versus no DR cohort. Following DR, patients remained on Ibr for mean ± SD [median] 336.0 ± 422.8 [179] days until the end of 1L therapy. After adjusting for variations in baseline characteristics, patients with a DR had significantly longer TTD post-treatment initiation than those without a DR (median TTD, DR vs no DR: 22.5 months vs 9.3 months; adjusted HR [95% CI], 0.52 [0.37-0.72]). Conclusion: This real-world evidence study suggests that implementing DRs to manage AEs can be a valuable strategy in supporting patients with WM to remain on 1L Ibr longer, thus maintaining beneficial clinical outcomes. These findings are consistent with previous studies, demonstrating that Ibr DRs help to improve tolerability while maintaining treatment efficacy.

Introduction The pathogenic role of somatic non-coding (nc) single nucleotide variants (SNVs) is underexplored in multiple myeloma (MM) and additional characterization of these regions has the potential to provide significant new insights into disease progression. To investigate the role of ncSNVs and their relationship with MM pathogenesis, we have characterized a novel series of WGS from 294 cases of MGUS, SMM, and MM using computational tools optimized to identify functional driver SNVs in these regions. We hypothesize the ncSNVs that co-localize to sites of super-enhancers (SEs) active in plasma cells (PC) are sites of high functional impact SNVs and these mutations lead to the dysregulated expression of genes that should be silent at the terminally differentiated stage of PCs, providing a selective advantage that shapes the fitness of the MM genomic landscape. Methods We analyzed 294 high-coverage matched tumor/normal pairs (80x tumor and 40x normal) derived from 21 MGUS, 86 SMM, 167 NDMM and 40 RRMM. In addition to previously sequenced samples, newly sequenced patients were obtained from NYU Langone Health, Memorial Sloan Kettering Cancer Center, University of Alabama at Birmingham and University of Miami following IRB-approved informed consent. DNA was extracted from CD138+ purified bone marrow plasma cells using standard approaches. We used the MGP1000 (https://github.com/pblaney/mgp1000) to process sequencing data which employs a union-consensus mechanism for determining the final set of variants. We collected enhancer elements (E/SEs) active in GC B-cells, ABC-DLBCL and GBC-DLBCL (Bal, et al. Nature, 2022) and PC specific E/SEs (Loven, et al. Cell 2013). FunSeq2 was used to score ncSNVs. GRAM was used to predict how variants alter TF binding and gene expression in a subset of 6 cases with paired WGS in our series and will expand this analysis on a validation set of 263 NDMM and 93 RRMM cases from University-Hospital Heidelberg enrolled in the GMMG-HD6 clinical trial. Results We identified 1,952,232 high-quality SNVs with 18,199 (0.93%) accumulating in 280 focal sites we termed “mutationally enriched regions” or MERs. To discern SNVs in MERs with the highest potential for imparting a selective advantage, we clustered mutations based on the density of FunSeq2 impact scores which uses reference data contexts on sequence conservation, modification of transcription factor (TF) binding, and gene linkage to regulatory elements and network hubs from pan-cancer studies. We show that MERs are enriched for ncSNVs with high impact scores (mean=2.57) compared to random similarly-sized regions of the genome (Fisher's exact test P<9.7e-12, OR=10.10 [3.88-37.40]). The high impact ncSNVs (hi-ncSNVs) in MERs (n=220) account for 8.09% of all hi-ncSNVs and are present in 46.3% of cases (136/294) with some patients having up to 7. The proportion of cases carrying a MER hi-ncSNVs was similar across disease stages (MGUS=42.9%, SMM=46.5%, MM=40.7%, and RR=47.5%). Analysis of the VAF of MER hi-ncSNVs shows a minor shift towards more clonal versus subclonal mutations (53.6% vs 46.4% VAF>=0.25) suggesting some high impact mutations are acquired in the GC but additional hi-ncSNV are acquired later in PC development, providing evidence that hi-ncSNVs accumulate in MERs throughout disease progression. We mapped these hi-ncSNVs to associated genes then intersected the loci with E/SEs active in GCBs and PCs to determine their functional context. This approach identified 12 genes affected by hi-ncSNVs including the previously identified nc-drivers NEAT1, MIR142, ZCCHC7, and IGLL5 as well as the PC differentiation genes IRF8, BACH2, proliferation genes RHOH, SPRED2, known coding MM drivers CCND1, ZFP36L1, and chr1q genes BTG2 and CROCC. We predicted the effect of ncSNVs on expression through modulation of TF binding at this set of putative nc drivers in MM and identified a trend towards increase in expression of SPRED2, CCND1, NEAT1, and IGLL5 compared to non-mutated cases (P=0.089). We will present data on the validation of this set of genes on a larger set of data derived from the Heidelberg group. Conclusions We identified a set of 12 putative nc driver genes in MM that modify expression and have the potential to significantly alter the pathogenesis of MM by providing a selective survival advantage. We will present the impact of these by clinical stage and on outcome.

Introduction: Epcoritamab (Epcor) is a novel subcutaneous CD3xCD20 bispecific antibody (bsAb) that is currently approved as monotherapy for the treatment of adults with relapsed or refractory (R/R) large B-cell lymphoma after ≥2 systemic therapies. The combination of Epcor with standard treatment regimens has been shown to be safe and efficacious; Epcor in combination with gemcitabine and oxaliplatin (Epcor+GemOx) has provided deep and durable responses with favorable survival outcomes in a transplant-ineligible R/R diffuse large B-cell lymphoma (DLBCL) patient (pt) population, of which 99% were from the US and Europe (EPCORE NHL-2; NCT04663347). Another CD3xCD20 bsAb, intravenous glofitamab, has been studied in combination with gemcitabine and oxaliplatin (Glofi+GemOx) in the randomized STARGLO trial (NCT04408638) and demonstrated benefit over rituximab plus GemOx (R-GemOx), despite not demonstrating superiority over R-GemOx in patients from the US and Europe. In the absence of head-to-head data, this study used matching-adjusted indirect comparisons (MAICs) to assess the comparative efficacy of Epcor+GemOx vs R-GemOx and vs Glofi+GemOx. Methods: Individual pt-level data from EPCORE NHL-2 arm 5 and aggregated data from pts in each of the STARGLO arms were used to conduct an MAIC. Logistic propensity score models were used to weight Epcor+GemOx-treated pts to create matched cohorts with the R-GemOx and Glofi+GemOx arms separately. Weighting was conducted based on the distribution of baseline characteristics and prognostic factors such as age, sex, Eastern Cooperative Oncology Group performance status, previous therapies, and primary refractory status. Overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS) were compared for Epcor+GemOx vs R-GemOx, and vs Glofi+GemOx. Results: A total of 103 pts treated with Epcor+GemOx (median follow-up: 13.2 months) were compared to 91 pts treated with R-GemOx and 183 pts treated with Glofi+GemOx (median follow-up: 20.7 months), although differences in median follow-up time limited comparisons of longer-term survival outcomes. Match-adjustment mitigated differences in baseline characteristics across the 3 cohorts. After adjustment, Epcor+GemOx demonstrated a significant 44.8% advantage in ORR over R-GemOx (85.4% vs 40.7%), with a 110% increase in the likelihood of achieving a response (odds ratio [OR] 2.1; 95% CI 1.6-2.8; P<0.0001). Epcor+GemOx also demonstrated a significant 43.2% advantage in CR rate over R-GemOx (68.5% vs 25.3%), with a 170% increase in the likelihood of achieving a CR (OR 2.7; 95% CI 1.8-4.1; P<0.0001). With the current follow-up, Epcor+GemOx demonstrated superior PFS vs R-GemOx (hazard ratio [HR] 0.37; 95% CI 0.22-0.63; P<0.001), corresponding to a 63% reduction in the risk of progression. Median OS was not reached [NR] for Epcor+GemOx vs 13.9 months for R-GemOx, corresponding to a 43% reduction in the risk of mortality (HR 0.57 [95% CI 0.33-0.98]; P=0.04). After adjustment, Epcor+GemOx demonstrated a significant 15% advantage in ORR over Glofi+GemOx (83.3% vs 68.3%), with a 20% increase in the likelihood of achieving a response (OR 1.2; 95% CI 1.0-1.4; P=0.021). Epcor+GemOx demonstrated a trend toward higher CR rate than Glofi+GemOx (66.8% vs 58.5%; OR 1.1; 95% CI 0.90-1.5; P=0.277). Adjusted median PFS and OS for Epcor+GemOx, with limited follow-up and substantial censoring, was 12.9 months and NR, respectively. For Glofi+GemOx with longer follow-up, PFS and OS were 13.8 months and 25.6 months, respectively. Conclusions: Results show significantly superior efficacy for all outcomes with Epcor+GemOx vs R-GemOx from STARGLO. Epcor+GemOx also provided superior ORR and a trend toward higher CR rates vs Glofi+GemOx, indicating potential for better long-term efficacy outcomes. The Epcor+GemOx survival data are still maturing given shorter follow-up time, preventing a robust comparison of survival vs Glofi+GemOx. Findings support the efficacy of Epcor+GemOx as an alternative therapeutic regimen in transplant-ineligible patients with R/R DLBCL.

Introduction: Epcoritamab, a novel subcutaneously administered CD3xCD20 bispecific antibody (bsAb) being developed as a core therapy across several lymphoma subtypes, is currently approved for the treatment of adults with different types of R/R LBCL after ≥2 systemic therapies. The combination of epcoritamab with standard treatments has been shown to be safe and efficacious; epcoritamab in combination with gemcitabine and oxaliplatin (Epcor+GemOx) has provided deep and durable responses with favorable survival benefits in a transplant-ineligible R/R DLBCL study population, of which 99% was from the United States and Europe (EPCORE NHL-2; NCT04663347). The rituximab plus gemcitabine and oxaliplatin (R-GemOx) regimen has been a widely used treatment for patients with R/R DLBCL ineligible for transplant, albeit with suboptimal efficacy outcomes. In the absence of direct comparisons of these regimens, this study assessed the comparative efficacy of Epcor+GemOx vs R-GemOx in patients with R/R DLBCL ineligible for transplant. Methods: Individual patient-level data (IPD) from EPCORE NHL-2 arm 5 were compared to 2 sources of clinical practice data for patients with R/R DLBCL treated with R-GemOx: published data from Cazalles et al (2021) and IPD from the US-based COTA electronic health record database. The Cazalles study reports the results of a large retrospective analysis of patients with R/R DLBCL treated in 2 academic centers in France. The COTA database includes de-identified IPD with demographic and clinical information from numerous academic and community clinical sites in the US. For the comparison to Cazalles, logistic propensity score models were used to weight the Epcor+GemOx cohort to create match-adjusted distributions of baseline characteristics with the R-GemOx cohort in Cazalles. For the comparison to COTA, inverse probability of treatment weighting was employed to balance covariates between the Epcor+GemOx and R-GemOx cohorts. Analyses were restricted to chimeric antigen receptor T-cell therapy (CAR T)-naive patients from EPCORE NHL-2, as the comparator cohorts did not include patients treated with CAR T. Overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS) were compared for Epcor+GemOx vs R-GemOx. Results: A total of 74 patients treated with Epcor+GemOx (median follow-up: 13.2 months) were compared to 196 R-GemOx-treated patients from Cazalles et al (median follow-up: 22 months). After match-adjustment, Epcor+GemOx (ORR 86.8%) demonstrated significantly higher ORR, corresponding to a 48.5% advantage over R-GemOx (ORR 38.3%) with an odds ratio (OR) of 2.3 (95% CI 1.8-2.9; P<0.0001). Adjusted CR rate was also significantly higher with Epcor+GemOx vs R-GemOx (71.2% vs 32.7%; 38.6% difference; OR 2.2 [95% CI 1.6-3.0]; P<0.0001). Median PFS was significantly longer with Epcor+GemOx (26.7 months) vs R-GemOx (4.8 months; hazard ratio [HR] 0.38 [95% CI 0.22-0.67]; P<0.001). Median OS was not reached (NR) for Epcor+GemOx vs 10.0 months with R-GemOx (HR 0.54 [95% CI 0.29-1.0]; P=0.05), corresponding overall to a 62% reduction in the risk of a progression event and a 46% reduction in the risk of mortality with Epcor+GemOx vs R-GemOx. A total of 72 patients were treated with R-GemOx in COTA (median follow-up: 7.5 months) and compared to 74 Epcor+GemOx patients. After adjustment, ORR was significantly higher with Epcor+GemOx vs R-GemOx (88.5% vs 35.6%; OR 2.5 [95% CI 1.8-3.4]; P<0.0001). Adjusted CR rate was also significantly higher with Epcor+GemOx (63.9% vs 10.2%; OR 6.3 [95% CI 3.1-12.7]; P<0.0001). Adjusted median PFS was significantly longer with Epcor+GemOx (11.2 months) vs R-GemOx (2.4 months; HR 0.23 [95% CI 0.15-0.36]; P<0.0001). Adjusted median OS was also significantly longer with Epcor+GemOx (21.6 vs 8.3 months; HR 0.47 [95% CI 0.30-0.74]; P=0.002), corresponding overall to a 77% reduction in the risk of a progression event and a 53% reduction in the risk of mortality with Epcor+GemOx vs R-GemOx. Conclusions: In this indirect treatment comparison analysis,Epcor+GemOx provided significantly superior efficacy benefits in terms of ORR, CR, PFS, and OS vs standard-of-care R-GemOx. While subject to the limitations of comparisons outside of controlled trials, findings indicate the compelling efficacy of Epcor+GemOx as a novel therapeutic option for transplant-ineligible patients with R/R DLBCL.

INTRODUCTION: The performance of a high quality esophagogastroduodenoscopy (EGD) is dependent on the mucosal cleanliness. Recently, the Polprep: Effective Assessment of Cleanliness in EGD (PEACE) scale was created to assess the degree of mucosal cleanliness during EGD. The aim of this study was to validate this scoring system in a cohort of international endoscopists. METHODS: In total, 39 EGD videos, with different degrees of mucosal cleanliness were retrieved from a previously conducted prospective trial. All experts rated the cleanliness of the mucosa on each video using the PEACE scale. To evaluate agreement of all scores (0–3), intraclass correlation coefficient 2.1 was used. The agreement on adequate (scores 2 and 3) and inadequate (scores 0 and 1) cleanliness was assessed using kappa values. RESULTS: Videos evaluating esophagus, stomach, and duodenum cleanliness were reviewed by 16 endoscopists. The PEACE scores demonstrated good agreement (intraclass correlation coefficient 0.82, 95% CI 0.75–0.89), especially for esophagus (0.84; 95% CI 0.71–0.95) and stomach (0.81; 95% CI 0.69–0.91), while agreement was moderate for the duodenum (0.69; 95% CI 0.51–0.87). The agreement was similar between Eastern (0.86; 95% CI 0.79–0.92) and Western experts (0.80; 95% CI 0.72–0.88). Similarly, agreement regarding adequate cleanliness was comparable between Eastern (0.70; 95% CI 0.55–0.85) and Western (0.74; 95% CI 0.64–0.84) endoscopists being overall 0.75 (95% CI 0.65–0.85). DISCUSSION: The PEACE scoring system is a simple and reliable scale to assess the cleanliness during EGD. The score is now validated among international experts with high concordance, justifying its use in clinical practice.

Background: Nationally, many ASCVD patients fail to achieve an LDL-C <70 mg/dL, and uptake of both statin and non-statin therapies is low. The degree to which this varies across health systems is less clear. Methods: A cross sectional analysis was performed where lipid levels and lipid lowering therapies (LLT) were assessed using electronic health record data in patients with a previous diagnosis of ASCVD. The data was obtained across 14 US healthcare systems between 1/1/2021-12/31/2022. Proportions of patients with an active prescription of any statin, high intensity statin, ezetimibe, PCSK9i, and combination therapy (two or more agents) within 395 days of the most recent LDL-C value (index date) was evaluated overall and by participating site. Additionally, the proportion of patients with an LDL-C <70 mg/dL at the index date was also assessed. Results: Across 14 health systems, 1,118,623 patients with ASCVD were identified (median 61,840 per health system, range 8,161-182,315). Overall, 675,776 (60.4%) had an LDL-C level in the past year (range 39.1% - 70.8%). Of those with a lipid level, achievement of LDL-C <70 mg/dL ranged from 34.6-47.2%. In total, 42.6% were on any statin, 20.1% were on a high intensity statin, 4.3% on ezetimibe, and 1.2% on a PCSK9i. Only 2.9% were on combination therapy of a statin with ezetimibe or a PCSK9i. Variability was seen across health systems in utilization of each of these therapies, however even in the highest performing health systems, LLT uptake and achievement of LDL-C < 70mg/dL remained low ( Figure). Conclusion: Variability in utilization of LLT in ASCVD patients between health systems suggests that system-level factors may impact achieving guideline-based LDL-C goals. Despite the variability, the highest proportion of patients achieving an LDL-C <70mg/dL remained under 50% indicating the need for aggressive implementation efforts.

Abstract Therapy-related myeloid neoplasm (t-MN), characterized by its association with prior exposure to cytotoxic therapy, remains poorly understood and is a major impediment to long-term survival even in the era of novel targeted therapies due to its aggressive nature and treatment resistance. Previously, cytotoxic therapy–induced genomic changes in hematopoietic stem cells were considered sine qua non in pathogenesis; however, recent research demonstrates a complex interaction between acquired and hereditary genetic predispositions, along with a profoundly senescent bone marrow (BM) microenvironment. We review emerging data on t-MN risk factors and explore the intricate interplay among clonal hematopoiesis, genetic predisposition, and the abnormal BM microenvironment. Significance: t-MN represents a poorly understood blood cancer with extremely poor survival and no effective therapies. We provide a comprehensive review of recent preclinical research highlighting complex interaction among emerging therapies, hereditary and acquired genetic factors, and BM microenvironment. Understanding the risk factors associated with t-MN is crucial for clinicians, molecular pathologists, and cancer biologists to anticipate and potentially reduce its incidence in the future. Moreover, better understanding of the molecular pathogenesis of t-MN may enable preemptive screening and even intervention in high-risk patients.