Citations

AbstractAn otherwise healthy 4‐week‐old term female of Japanese heritage presented with a 1‐week history of asymptomatic progressive, generalized skin lesions. The lesion morphology, distribution, and dermatopathology result was consistent with Sweet syndrome. The patient was found to have a congenital type H rectovestibular fistula. This case highlights the rare association of rectovestibular fistula in neonatal Sweet syndrome which has only been described in neonates of Japanese heritage.

4099 Background: A+B is standard of care for advanced HCC in the first line setting, although was only evaluated in patients with CP class A liver function in IMbrave150. We sought to determine outcomes of patients in the real-world setting. Methods: We conducted a multi-institution retrospective analysis of patients with HCC who received A+B as first-line systemic therapy between March 2018 and November 2023, at Mayo Clinic and University Hospitals Seidman Cancer Center. Treatment response was evaluated, and progression free survival (PFS) and overall survival (OS) were determined using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazard regression method. Results: Among patients with HCC (n=322), 226, 86, and 10 had CP-A, -B, and -C liver function, while 120, 177, and 25 had ALBI grade 1, 2, and 3 liver function. Median age was 66.5 years, 78.6% were male, and 82.6% were white. Liver disease causes included hepatitis B (5.3%) and C (34.8%), ethanol use (26.1%), and non-alcoholic steatohepatitis (15.5%). Macrovascular invasion was seen in 42.9%, and 30.4% had extrahepatic metastatic disease. Median OS for patients with CP-A5/6 was 21.6 months, B7 (n=49) was 9.1 months, and B8-C12 was 4.7 months ( p<0.0001). Median OS by ALBI grade was 34.9, 11.7, and 4.7 months for grades 1, 2, and 3. Median PFS was 8.9, 6.4, and 2.7 months for CP-A5/6, B7, and B8-C12 ( p<0.0001). Median PFS by ALBI grade was 11.0, 6.4, and 3.7 months for grades 1, 2, and 3 ( p=0.0001). Among patients with CP-A, those with ALBI grade 1 had mOS of 34.9 months versus 14.2 months for those with grade 2. Partial response was seen in 29.2%, 19.8% and 10.0% of patients with CP-A, -B, and -C, while 32.7%, 33.7%, and 40.0% had stable disease. In a univariate analysis, factors predictive of shorter OS included CP-B7 or CP-B8-C12, ALBI grade 2 or 3, hepatitis B, poorer ECOG performance status (PS), macrovascular invasion, non-white race, and lack of prior surgery or embolization. In multivariate analyses, CP score, ALBI grade, hepatitis B, ECOG PS, and macrovascular invasion were significantly associated with survival. There was significant interaction between CP and ALBI grade (Table). Conclusions: A+B remains a viable option in patients with CP-B7 liver function, although benefit is significantly less than those with CP-A. ALBI score has predictive value and can identify two prognostic groups among those with CP-A liver function. [Table: see text]

3553 Background: Immuno-STATs are modular fusion proteins designed for the selective activation of tumor antigen specific CD8+ T cells. CUE-102, the second Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the Wilms Tumor 1 (WT1) protein, and 4 molecules of reduced affinity human interleukin-2 (IL-2). In preclinical studies CUE-102 binds, activates and expands WT1-specific CD8+ T cells with the potential to enhance anti-tumor immunity in patients with WT1+ cancers. Here we present the results of the dose-finding portion (Part A) of the CUE-102-01 study. Methods: CUE-102-01 is a 2 part phase 1 study. HLA-A*02:01 positive patients with WT1+ advanced colorectal (CRC), gastric (GA) and gastroesophageal junction (GEJ), pancreatic (PDAC) or ovarian (OvCa) tumors refractory to standard therapies were eligible for participation. WT1 status is determined by IHC via central testing. CUE-102 monotherapy was administered intravenously every three weeks in doses ranging from 1 mg/kg to 8 mg/kg following 3+3 design rules with a Bayesian Logistic Regression Model overlay. Dose levels that exhibit an immune or tumor response may be expanded to further characterize activity and toxicity as allowed by safety rules. Results: Dose escalation was successfully completed in 28 patients with CRC (17), PDAC (6), GA/GEJ (3) and OvCa (2). No DLTs were observed. Three dose levels (2, 4 and 8 mg/kg) exhibited evidence of immune activity and were expanded up to 9 patients each for further evaluation. CUE-102 was well-tolerated with > 96% of treatment-related adverse events (TRAEs) grade ≤2. The most common TRAEs, were fatigue, infusion reactions, nausea and vomiting. There were no cases of CRS Grade ≥ 2. Preliminary PK data demonstrate dose dependent increases in exposure across the dose range assessed. Preliminary analysis of patient samples demonstrates selective expansion of WT1-specific CD8+ T cells. Stable disease of ≥ 6 weeks (range 6-36 weeks), as determined by RECIST 1.1, has been observed in 10 of 23 patients (DCR 43.5%). Conclusions: CUE-102 is a novel T cell engager that demonstrates acceptable tolerability, favorable PK, and supportive preliminary PD readouts. No DLTs or drug-related SAEs have been observed in doses up to 8 mg/kg as of the data cut-off. Adverse events have been manageable and consistent with the CUE-102 mechanism of action and underlying disease. Early signs of disease stabilization and anti-tumor activity in late-stage patients are encouraging. Part B is a dose expansion that further evaluates safety, PK/PD, recommended phase 2 dose (RP2D), antitumor efficacy and is currently enrolling patients. Clinical trial information: NCT05360680 .

3077 Background: ATR protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA defects in various cancers. The topoisomerase-I (Top1) inhibitor irinotecan induces DNA damage. The ATR inhibitor BAY1895344 (elimusertib) has demonstrated cytotoxic potential in SCLC and GI cancer xenografts when combined with Top1 inhibitors . Methods: This phase Ia trial assessed elimusertib in combination with irinotecan in adult patients with refractory advanced solid tumors for whom irinotecan can be considered standard care. Patients with previous irinotecan exposure were excluded. Two dosing schedules were used: 1) Biweekly - irinotecan IV (starting at 150 mg/m2) D1 + elimusertib (starting dose 20 mg PO BID) D1,D2 (cycle=14 days); 2) Weekly - irinotecan (starting at 50 mg/m2) IV on D1,8,15 with elimusertib (starting at 20 mg PO daily) on D2,D3,D9,D10 and D16,D17 (cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity. Results: A total of 21 patients were enrolled in dose escalation (N=9 [Biweekly] and N=12 [Weekly], median age 58 and 2 lines of prior therapy. For the Biweekly cohort: 3/3 patients enrolled at dose level (DL) 1 experienced hematologic dose-limiting toxicity (DLT); 6 patients received DL-1 without any DLTs. The weekly regimen escalation comprised of 12 patients: 6 enrolled in DL1 with 2/6 having hematologic DLT and 5/6 unable to complete ≥75% of cycle 1 dosing; 6 enrolled in DL-1 with no DLTs observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized (Table 1). The majority of evaluable patients in both schedules had initial disease control (56% [biweekly] and 67% [weekly]). One confirmed partial response was seen in the biweekly RP2D. Median progression-free survival was 2.1 mo [biweekly] and 2.5 mo [weekly]. PK results will be presented at time of meeting. Conclusions: Both RP2D and MTD of elimusertib in combination with irinotecan were reached for both dosing schedules: irinotecan 150 mg/m2 IV D1 + elimusertib 10 mg BID PO D1,D2 (biweekly) and irinotecan 25 mg/m2 IV on D1 + elimusertib (20 mg PO daily) on D2,D3 (weekly). Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansion but the concept of ATR + topo I combination remains scientifically relevant. Clinical trial information: NCT04514497 . [Table: see text]

3076 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA abnormalities in various cancers. The topoisomerase-I (Top1) inhibitor topotecan induces DNA damage. The ATR inhibitor BAY 1895344 (elimusertib) has demonstrated cytotoxic potential in small cell lung cancer and gastrointestinal cancer xenografts when combined with Top1 inhibitors . Methods: This is phase Ia study of elimusertib combined with topotecan in adult patients with refractory advanced solid tumors for whom topotecan can be considered as part of standard care. Patients with previous topotecan exposure were excluded. The study combination was assessed starting at Topotecan 1 mg/m2 IV (D1-D5) plus elimusertib 20 mg BID (D2, D5) (Cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination. Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity of the combinations. Results: Eight patients were treated in dose escalation. Participants were a median of 63 years old and had received 2 median lines of previous therapy. The initial two patients enrolled into dose level (DL) 1 had dose-limiting toxicities with one of patient experiencing respiratory failure and cardiac arrest in setting of pancytopenia related to study drug. Six patients were subsequently enrolled in and received DL-1 (elimusertib decreased from 20 mg BID to 20 mg Daily) and no DLTs were observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized in Table. Disease control rate was 43% among evaluation patient including one unconfirmed partial response. Median progression-free survival in the RP2D cohort was 3.45 months. PK studies are in process and results will be presented at time of meeting. Conclusions: RP2D and MTD was established for elimusertib in combination with Topotecan: Topotecan 1 mg/m2 IV [D1-D5] plus elimusertib 20 mg Daily [D2, D5] every 3 weeks. Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansions cohorts but the concept of ATR + topo I inhibition remains relevant. Clinical trial information: NCT04514497 . [Table: see text]

AbstractINTRODUCTIONCorticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker‐confirmed AD in CBS.METHODSA cohort of eighteen CBS patients (8 amyloid beta [Aβ]+; 10 Aβ−) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal–Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake.RESULTSCBS Aβ+ group showed a reduced Aβ42/40 ratio, with elevated phosphorylated tau (p‐tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aβ− group only showed elevated NfL concentration compared to CU. Both p‐tau181 and GFAP were able to differentiate CBS Aβ− from CBS Aβ+ and showed positive associations with Aβ and tau PET uptake.DISCUSSIONThis study supports use of plasma p‐tau181 and GFAP to detect AD in CBS. NfL shows potential as a non‐specific disease biomarker of CBS regardless of underlying pathology.Highlights Plasma phosphorylated tau (p‐tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aβ)− from CBS Aβ+. Plasma neurofilament light concentrations are elevated in CBS Aβ− and Aβ+ compared to controls. Plasma p‐tau181 and GFAP concentrations were associated with Aβ and tau positron emission tomography (PET) uptake. Aβ42/40 ratio showed a negative correlation with Aβ PET uptake.

Abstract Background Stepwise functional connectivity (SFC) detects whole‐brain functional couplings of a selected region of interest at increasing link‐step topological distances. Objective This study applied SFC to test the hypothesis that stepwise architecture propagating from the disease epicenter would shape patterns of brain atrophy in patients with progressive supranuclear palsy–Richardson's syndrome (PSP‐RS). Methods Thirty‐six patients with PSP‐RS and 44 age‐matched healthy control subjects underwent brain magnetic resonance imaging on a 3‐T scanner. The disease epicenter was defined as the peak of atrophy observed in an independent cohort of 13 cases with postmortem confirmation of PSP pathology and used as seed region for SFC analysis. First, we explored SFC rearrangements in patients with PSP‐RS, as compared with age‐matched control subjects. Subsequently, we tested SFC architecture propagating from the disease epicenter as a determinant of brain atrophy distribution. Results The disease epicenter was identified in the left midbrain tegmental region. Compared with age‐matched control subjects, patients with PSP‐RS showed progressively widespread decreased SFC of the midbrain with striatal and cerebellar regions through direct connections and sensorimotor cortical regions through indirect connections. A correlation was found between average link‐step distance from the left midbrain in healthy subjects and brain volumes in patients with PSP‐RS ( r = 0.38, P < 0.001). Conclusions This study provides comprehensive insights into the topology of functional network rearrangements in PSP‐RS and demonstrates that the brain architectural topology, as described by SFC propagating from the disease epicenter, shapes the pattern of atrophic changes in PSP‐RS. Our findings support the view of a network‐based pathology propagation in this primary tauopathy. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

3051 Background: Clonal hematopoiesis (CH), characterized by the presence of somatic mutations in blood cells, can be found in cancer-related genes when sequencing tumor tissue or plasma samples. Inability to distinguish somatic, tumor-derived mutations from CHm can lead to inaccurate treatment decisions. In this prospective study, we confirmed potential CHm in solid tumors by sequencing and analysis of paired matched normal (PMN) specimens. Methods: We prospectively enrolled 56 patients diagnosed with advanced cancer, including lung (16), colorectal (13), breast (10), gastric (7), ovarian (2), pancreatic (2), liver (2), cervix (1), uterine (1), fallopian tube (1), and perihilar bile duct (1). Targeted next-generation sequencing using a 523 gene panel was performed on paired formalin-fixed paraffin-embedded (FFPE) and circulating tumor DNA (ctDNA) samples. Additionally, whole exome sequencing was performed on PMN buffy coat samples. Analysis of all three specimens was performed to classify somatic mutations as tumor-derived or CHm. Results: We identified 21 potential CHm within the FFPE and ctDNA samples of 13 patients (23.2% of the cohort) with lung (7), breast (2), liver (2), colorectal (1), and gastric (1) cancers. CHm were further confirmed when present in buffy coat samples. The VAF of CHm in FFPE and ctDNA samples exhibited a wide range, spanning from 0.85% to 38.4%, with 7 of those identified at <2% VAF. For these same aberrations, VAF in buffy coat samples ranged from 1.6% to 48%, with seven mutations exhibiting VAF levels <5%. Four of these CHm were classified as oncogenic or likely oncogenic. Four CHm, including an oncogenic TP53 mutation, were identified in the oldest patient (75 years old, lung cancer), while an oncogenic DNMT3A mutation was detected in the youngest patient (42 years old, breast cancer). Both had a 30-year history of smoking. Conclusions: Our findings identified somatic CHm in a substantial subset (23.2%) of solid tumors, with four identified as oncogenic or likely oncogenic mutations. The broad spectrum of VAFs for CHm suggests that using VAF as a cut-off to exclude likely CHm may be unreliable. The low VAF CHm found in matched normal specimens indicates low-pass sequencing may not detect critical CHm, even in paired analysis. The diverse age range of patients with CHm (42 to 75 years old) suggests that CHm are not restricted to older populations, and that additional factors, such as smoking history, may play a role. These findings underscore the importance of incorporating routine PMN buffy coat sequencing into clinical practice, to identify somatic CHm that can impact personalized cancer treatment strategies.

Aim: The six-minute walk test (6MWT) is a common measure of functional capacity in patients with heart failure (HF). Primary clinical study end points in cardiomyopathy (CM) trials, including transthyretin-mediated amyloidosis with CM (ATTR-CM), are often limited to hospitalization and mortality. Objective: To investigate the relationship between the 6MWT and hospitalization or mortality in CM, including ATTR-CM. Method: A PRISMA-guided systematic literature review was conducted using search terms for CM, 6MWT, hospitalization and mortality. Results: Forty-one studies were identified that reported 6MWT data and hospitalization or mortality data for patients with CM. The data suggest that a greater 6MWT distance is associated with a reduced risk of hospitalization or mortality in CM. Conclusion: The 6MWT is an accepted alternative end point in CM trials, including ATTR-CM.