Citations

ABSTRACT Background Symptom management in myeloproliferative neoplasms (MPN) remains challenging despite advancements in disease‐directed therapies. This study assessed the impact of demographic, clinical, laboratory and treatment‐related variables on total symptom scores (TSS) and individual symptom scores in patients with polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Methods A cohort of 553 patients (PV: 200; ET: 190; MF: 163) was identified through a retrospective chart review. Symptom scores, demographic information and clinical variables were captured at the time of the first TSS assessment. Laboratory results within 1 month and treatment information within 90 days prior to the symptom assessment were captured. Univariable linear regression, followed by multivariable regression analyses using a robust variance estimator were performed, with a p value < 0.05 indicating a significant association. Results MF patients experienced the highest symptom burden and fatigue was the most reported symptom across all MPN subtypes. In PV, depression ( β : 10.53; p = 0.001) was associated with a higher TSS whereas older age (−0.17; 0.01) and higher hemoglobin (−1.24; 0.003) were associated with a lower TSS. In ET, depression ( β : 14.19; p < 0.001) was associated with a higher TSS, whereas in MF, depression (12.28; < 0.001) and higher WBC count (0.22; 0.02) were associated with a higher TSS. Depression and non‐White race in PV, depression in ET, and depression, low hemoglobin, and higher WBC count in MF were associated with multiple symptoms. Conclusions Integrating depression screening and management and optimizing hematologic parameters alongside disease‐directed therapy is crucial to improving patient outcomes.

Abstract Molecular profiling reveals that up to 40% of advanced biliary tract cancers (BTCs) harbor actionable genomic alterations amenable to matched targeted therapies. However, conventional trial designs typically evaluate these agents in pretreated populations, resulting in approvals for later-line use. Notably, 25–44% of patients with advanced BTC may become ineligible for treatment after first-line therapy due to disease progression or functional decline, thus the real-world survival outcomes with matched therapies remains poorly characterized. This international collaborative study includes data from Mayo Clinic, Duke Cancer Institute, and National Cancer Center East (Japan), as well as a combined dataset from the SCRUM-Japan GOZILA, MONSTAR-SCREEN-1, and MONSTAR-SCREEN-2 projects. We assessed overall survival (OS) of patients based on the presence of actionable alterations and the receipt of matched therapy. To adjust for confounding, we applied propensity score weighting with inverse probability of treatment and multivariate Cox regression modeling, controlling for age, sex, tumor location, prior resection, and mutational subgroup. Among 1,049 patients that were analyzed, 358 (34.1%) harbored actionable alterations, with 160 (44.7%) receiving matched targeted therapy. The matched group (patients with actionable tumors who received a matched therapy) were significantly associated with longer median OS (23.3 months; 95% CI: 19.5–30.4) compared to the unmatched group (14.7 months; 95% CI: 12.8–17.9) and those with non-actionable tumors (17.1 months; 95% CI: 15.5–18.7; HR 0.57, 95% CI: 0.46–0.71; p < 0.0001). The unmatched group also was associated with the lowest three-year OS rate (13% vs. 35% in matched and 19% in actionable groups, respectively; p<0.0001). On multivariable analysis with patients who received ≥2 lines of therapy, receipt of matched therapy remained an independent predictor of improved OS (HR 0.62; 95% CI 0.43–0.90). These findings support the early integration of targeted therapies in BTC management and underscore the need to overcome systemic barriers to treatment access.

Abstract Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have a propensity to transform to an accelerated or blast phase (MPN-AP/BP). The resulting disease has clinically similar manifestations to Acute Myeloid Leukemia (AML) but worse clinical outcomes. Here we present the first comprehensive description of the transcriptomic characteristics of MPN-AP/BP. Our analysis incorporates data from 261 patients of the BeatAML cohort and 56 MPN-AP/BP patients, 11 of whom had paired samples from before and after transformation. We establish that transformed MPN is a transcriptionally distinct entity from de novo AML and chronic phase MPNs. Genomic pathways traditionally associated with MPN pathogenesis, such as IL2/STAT5 signaling and IL6/JAK/STAT3 signaling were enriched in chronic-phase MPNs but are absent in transformed disease, suggesting JAK2 directed therapy may be less effective in this disease phase. We also discovered that gene expression signatures associated with doxorubicin resistance are highly enriched in transformed MPNs, which may explain the lack of efficacy of standard AML therapies. In addition, we identify that lineage composition at the time of transformation may define distinct subsets of MPN-AP/BP patients, which may assist in the future development of novel treatment strategies.

AimsThere is a lack of published literature on the diagnostic reproducibility of oesophageal squamous dysplasia using a two‐tiered grading system.Methods and resultsWe identified 75 oesophageal biopsies, which were reviewed by 10 international pathologists twice (1500 total observations) with a > 4‐week washout period. Between rounds, a consensus meeting refining diagnostic criteria was held and an atlas was created to provide illustrations. Overall agreement was fair with kappa of 0.35 and 0.32 in round 1 and 2, respectively. Agreement was moderate to fair for negative for dysplasia (ND) (round 1 = 0.41 and round 2 = 0.34) and poor for indefinite for dysplasia (IND) and low‐grade dysplasia (LGD) (kappa <0.2). Agreement for high‐grade dysplasia (HGD) was good in both rounds (round 1 = 0.64; round 2 = 0.61). In round 1, majority diagnosis (MDx, ≥6 of 10 raters agreeing) was seen in 51 (68%) cases with the majority classified as ND (N = 27) or HGD (N = 18). MDx was rarely achieved for LGD (N = 6). In round 2, MDx was seen in 49 (65%) cases (20 ND, 1 IND, 11 LGD and 17 HGD). Of the 40 cases with MDx for both rounds, 39 were concordant (15 HGD, 6 LGD and 18 ND).ConclusionsOverall agreement among pathologists in diagnosing squamous lesions is fair; however, HGD had good agreement. This study fills an important gap in our knowledge of the inter‐rater variability in the diagnosis of oesophageal squamous dysplasia.

Abstract Background Recently, a model to predict 5-year recurrence-free survival (RFS) and melanoma-specific survival (MSS) after sentinel lymph node biopsy (SLNB) was published. The aim of this study was to validate that model in a large independent international cohort. Methods The database of the Sentinel Lymph Node Working Group (SLNWG) was analysed for patients with malignant melanoma who underwent SLNB. Patients with clinical stage III melanoma, a history of other malignancies, or receiving concomitant systemic therapies during follow-up were excluded. The model’s predictive performance was evaluated using discrimination and calibration metrics in the eligible cohort. Decision curve analysis was performed to assess the clinical value of the model. Results The external validation cohort consisted of 6174 patients of the SLNWG from the USA, Europe, and Israel. A positive sentinel node was found in 788 patients (12.8%). The area under the time-dependent receiver operating characteristic (ROC) curve of the external validation was 0.76 (95% c.i. 0.74 to 0.77) for RFS and 0.79 (95% c.i. 0.76 to 0.81) for MSS. The model was well calibrated, as the observed 5-year survival rates aligned closely with the predicted survival rates (calibration slope of 0.98 for RFS and calibration slope of 0.99 for MSS). The model provided a net benefit versus the ‘treat all’ and ‘treat none’ strategies at the predetermined probability threshold for recurrence of 45%. Conclusion The model demonstrated good performance in a large heterogeneous independent cohort, emphasizing its robustness. Decision curve analysis revealed a clear net benefit of the model over a treat all strategy, highlighting its potential for clinical use.

628 Background: Biliary tract cancers (BTC) are aggressive malignancies with poor survival outcomes and limited treatment options. This study compared the epidemiological and molecular differences of advanced BTC patients through a global collaboration involving the Mayo Clinic and National Cancer Center Hospital East. Methods: We included patients with advanced BTC who underwent comprehensive tumor molecular profiling who received at least 30 days of systemic therapy. Patients were grouped based on specific alterations. Overall survival (OS) was calculated from the start of first-line therapy until death and compared among subgroups using Cox regression models. Results: 332 (36%) out of 932 patients had at least one actionable mutation : somatic BRCA1/2 mutations N=106, FGFR2 fusions N=61, HER2 amplifications N=65, KRAS G12C/D mutations N=46, IDH1 mutations N=38, and TMB >10 mut/Mb N=16. BRCA1/2 -mutated BTC were more commonly found in older Asian males with intrahepatic tumors and often presented with peritoneal and liver metastases upon initial diagnosis. FGFR2 fusions were more prevalent in younger White females with intrahepatic tumors, while HER2 amplifications were mainly seen in Asian females with gallbladder tumors. KRAS mutations were primarily observed in Asian males, and IDH1 mutations were common in White males with intrahepatic tumors, frequently presenting with liver metastasis. Survival outcomes varied significantly based on the alteration type: patients with FGFR2 fusions had the longest median OS (mOS) at 23.3 months (mo) (95%CI 18.4-34.9), followed by those with IDH1 mutations (19.3 mo; 95% CI 17.4-NE) and TMB >10 mut/Mb (17.8 mo; 95% CI 13.6-NE). BRCA mutations had a mOS of 16 mo (95% CI 14.6-19.8), while HER2 amplifications and KRAS mutations had mOS of 15.5 (95% CI 11.9-20.2) and 11.6 mo (95% CI 10.0-20.9), respectively. Conclusions: These findings underscore the heterogeneity in clinical and genomic characteristics among BTC patients, highlighting the importance of tailored therapeutic approaches. Baseline patient characteristics stratified by mutation status. KRAS G12C/D (N=46) BRCA 1/2 (N=106) IDH1 (N=38) HER2 amplification(N=65) FGFR2 fusion(N=61) TMB>10 mut/Mb(N=16) P-value Median Age, year 67 68 64 66 52 73 <0.001 Female, n (%) 19 (41) 34 (32) 18(47) 34 (52) 45(74) 6 (38) <0.001 Race, n (%) <0.001 Asian 31 (67) 97 (92) 13 (34) 51 (79) 10 (16) 6 (38) White 14 (30) 8 (8) 24 (63) 13 (20) 48 (79) 10 (63) Primary tumor location, n (%) <0.001 Intrahepatic 28 (68) 45 (45) 33 (100) 19 (31) 54(95) 10 (67) Extrahepatic 9 (22) 27(27) 0 (0) 10 (16) 2 (4) 4 (27) Gallbladder 4 (10) 28 (28) 0 (0) 32 (53) 1 (2) 1 (7) Sites of Metastasis at diagnosis, n (%) Abdominal Wall / Peritoneal 9 (24) 15 (19) 4(13) 7 (12) 6 (10) 4 (27) 0.309 Bone 33 (92) 70 (90) 26 (87) 2 (3) 9(15) 0 (0) 0.212 Liver 20 (49) 52 (61) 28 (82) 45 (73) 45 (76) 6 (38) 0.001 Lung 26 (70) 65 (82) 22 (69) 36 (58) 27(45) 11 (69) 0.006

556 Background: Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a rare and complex liver cancer with features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), making its management challenging. This study aims to analyze the clinical characteristics, genomic profiles, and treatment outcomes of cHCC-CCA patients in a real-world setting. Methods: We conducted a retrospective analysis of cHCC-CCA patients across three first-line treatment groups: chemotherapy alone(Gemcitabine/Cisplatin, FOLFOX), HCC-directed therapies (atezolizumab/bevacizumab, lenvatinib, nivolumab, durvalumab, sorafenib), and chemoimmunotherapy (Gemcitabine/Cisplatin combined with immunotherapy). This international study, involving Mayo Clinic and the National Cancer Center East (Japan), assessed overall survival (OS) using Kaplan-Meier and Cox regression models. Results: A total of 68 patients were included, with a mean age of 66 years; 74% were male and 66% were White Non-Hispanics. Cirrhosis was present in 74% of patients at diagnosis, and Hepatitis B and C were common etiologies in 57%. Prior primary resection and regional therapies (Transarterial chemoembolization (TACE), Transarterial radioembolization (TARE)) were recorded in 39% and 50% of patients, respectively. Advanced/metastatic disease was present in 52% of the cohort. The distribution of first-line treatments was as follows: 47% received chemotherapy alone, 39% received HCC-directed therapy, and 14% received chemoimmunotherapy. Genomic alterations were detected in 44% patients, with TP53 (28%), ARID1A (25%), and TERT (22%) being the most frequent. The HCC-directed therapy group demonstrated the best overall response rate (52%) and had a median OS of 15.8 months (mo), compared to 11.8 mo for chemotherapy and 4.7 mo for chemoimmunotherapy (p=0.8). Patients who received regional treatments had a longer median OS of 15.8 mo compared to those who did not (10.2 mo) (p=0.4). Conclusions: HCC-directed therapy showed a trend towards better survival outcomes compared to other treatments, though not statistically significant. A considerable proportion of patients had genomic alterations, which may have influenced survival outcomes. Ongoing research with larger cohorts is underway to further elucidate the impact of genomic variations on treatment efficacy and refine therapeutic strategies for this challenging malignancy. Baseline characteristics of patients with combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA). Total(N=68) Mean age at diagnosis, years (SD) 66(6.4) Gender, n (%) Male 50 (74%) Ethnicity, n (%) White, Non-Hispanic 45 (66%) Cirrhosis at diagnosis, n (%) 50 (74%) Etiology of Liver disease, n (%) Viral (Hepatitis B and C) 39 (57%) History of Primary resection, n (%) 27 (39%) Regional treatment, n (%) 34 (50%) Afp, n (%) < 200 23 (64%) ca19_9, n (%) < 50 27 (82%)

536 Background: The prognosis of advanced BTC remains poor. Although targeted agents have expanded late-line options, many patients (pts) become ineligible for these therapies after progressing on first-line treatment. Herein, we examined the real-world impact of targeted therapy on survival in advanced BTC. Methods: In this international collaborative study between the Mayo Clinic (US) and the National Cancer Center East (Japan), we included pts with advanced BTC with comprehensive tumor molecular profiling who had received at least 30 days of systemic therapy. Pts were categorized into 3 groups: 1) non-actionable, 2) pts with alterations who received matched targeted therapy at any point during their treatment (matched group), and 3) those with mutations who did not receive matched therapy (unmatched group). OS was calculated from the start date of first-line therapy until death and compared among three subgroups using Cox regression models. Results: Of 932 pts, 366 (39.3%) had an actionable alteration, and 135 of these received matched therapy. 566 (61.7%) did not have an actionable alteration (Table). The most common alterations were somatic BRCA1/2 (N=106, 11.4%), HER2 amplification (N=65, 7%), FGFR2 fusion (N=61, 6.5%), KRAS G12C/D (N=46, 4.9%), and IDH1 (N=38, 4.1%). 78.7% of FGFR2 fusions were found in Caucasian pts, whereas BRCA1/2 (97.5%), HER2 (78.5%), and KRAS G12C/D (67.4%) alterations were more prevalent in Asian pts. The median OS was significantly longer in the matched group (21.4 months; 95% CI 18.4-27.9) compared to the unmatched group (14.6 months; 95% CI 12.8-17.6) and the non-actionable group (17.2 months; 95% CI 15.5-19.0). The 36-month OS rate was 33% in the matched group vs. 7% in the unmatched group (p < 0.0001). After adjusting for age, gender, prior surgical resection, primary tumor location, and country of origin, matched targeted therapy remained a strong independent predictor for improved OS (HR 0.61; 95% CI 0.48-0.79). Conclusions: These real-world findings suggest that matched targeted therapies significantly improve survival in advanced BTC, underscoring the need to incorporate them earlier in the treatment course and address barriers to treatment access. The regional prevalence of actionable alterations should also be considered when developing new targeted therapies. Patient baseline characteristics stratified by actionable alterations and targeted therapy. Non-actionable(N=566) Unmatched group(N=231) Matched group(N=135) Site, n (%) Japan 409 (72%) 166 (72%) 50 (37%) US 157 (28%) 65 (28%) 85 (63%) Age at Dx > 65, n (%) 324 (57%) 122 (53%) 54 (40%) Female, n (%) 235 (42%) 92 (40%) 77 (57%) Primary tumor location (category), n (%) Intrahepatic 217 (43%) 115 (55%) 99 (76%) Extrahepatic 150 (30%) 39 (19%) 17 (13%) Gallbladder 142 (28%) 54 (26%) 14 (11%) Prior surgical resection, n (%) 220 (42%) 74 (34%) 48 (37%)