Citations

For over a century, scientists reported the disruption of normal nuclear shape and size in cancer. These changes have long been used as tools for diagnosis and staging of malignancies. However, to date, the mechanisms underlying these aberrant nuclear phenotypes and their biological significance remain poorly understood. Using a model of pancreatic ductal adenocarcinoma (PDAC), the major histological subtypes of pancreatic cancer, we found that oncogenic mutant KRAS reduces nuclear size. Transcriptomic and protein expression analysis of mutant KRAS–expressing PDAC cells revealed differential levels of several nuclear envelope–associated genes. Further analysis demonstrated the nuclear lamina protein, Emerin (EMD), acted downstream of KRAS to mediate nuclear size reduction in PDAC. Analysis of human PDAC samples showed that increased EMD expression associates with reduced nuclear size. Finally, in vivo genetic depletion of EMD in a mutant KRAS–driven PDAC model resulted in increased nuclear size and a reduced incidence of poorly differentiated PDAC. Thus, our data provide evidence of a potentially novel mechanism underlying nuclear size regulation and its effect in PDAC carcinogenesis.

Disease response and progression assessment in multiple myeloma (MM) is based on various measurements of monoclonal protein (serum and urine protein electrophoresis, serum free light chain (FLC, and or quantitative immunoglobulins). Currently, the IMWG consensus response criteria require two sequential assessments of any one marker made at any time before confirmation of disease progression and the institution of any new therapy. However, this can be cumbersome in clinical trials. Herein, we hypothesized that if two markers meet the progression criteria simultaneously, a repeat of either will not be necessary for confirmation. We retrospectively studied all sequential patients with myeloma enrolled in clinical trials at Mayo Clinic. We identified 583 episodes of confirmed progression in our study. Among the 583 progression episodes, nearly 70% (sensitivity of the simultaneous criteria) met the two simultaneous variable criteria at the first testing, indicating progression. Conversely, among 413 patients who met progression criteria by two simultaneous values, 98% (specificity of the simultaneous criteria) of patients subsequently had confirmed progression by sequential values. In summary, for patients with two disease burden markers meeting the simultaneous progression criteria, sequential assessment either one for confirmation may not be necessary to determine disease progression.

Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced brown adipose tissue (BAT) thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is dramatically elevated in mice with diet-induced obesity (DIO) and ob/ob mice, as well as in obese humans. In mice fed a high-fat diet, adipocyte TPH2 deficiency improved DIO-induced metabolic complications, enhanced BAT thermogenesis, and increased intestinal energy-harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raised adipose and plasma 5-HT levels, suppressed BAT thermogenesis, and exacerbated obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulated adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 and SREBP1. In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not those of TPH1 , are positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.

BACKGROUND: Patients with lung disease, sleep apnea, and chronic thromboemboli can develop pulmonary hypertension, currently classified as group 3 or 4. Many of these patients also have risk factors for heart failure with preserved ejection fraction (HFpEF), but the optimal approach to identify the disease overlap remains unclear. METHODS: Pretest probability for HFpEF was determined using the HFpEF-ABA (age, body mass index, atrial fibrillation) algorithm among adjudicated group 3 or 4 patients at risk for pulmonary hypertension in the PVDOMICS study (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Patients were stratified by current resting right heart catheterization criteria, and in a separate analysis, stratified only by HFpEF-ABA probability into low (<25%), intermediate, and high (≥75%) HFpEF probability groups. RESULTS: Among 598 patients with group 3 disease, 27% (n=161) had elevated pulmonary capillary wedge pressure (PCWP) with postcapillary pulmonary hypertension even at rest, which was associated with the highest exercise PCWP. However, regardless of this resting PCWP-based classification, a larger subset had intermediate-to-high HFpEF-ABA probabilities (32% [n=197] high and 57% [n=358] intermediate HFpEF probability). High HFpEF probability in group 3 disease was associated with higher resting and dynamic PCWP response to NO, fluid, and exercise ( P <0.0001 for all). These changes were comparable with more traditionally defined HFpEF without pulmonary vascular disease (n=61) but less severe than those with combined precapillary and postcapillary pulmonary hypertension HFpEF (n=31; interaction P =0.006). Increasing HFpEF probability in group 3 disease was associated with worse left heart remodeling, quality of life, 6-minute walk distance, and peak VO 2 ( P <0.0001 for all). Findings were replicated in group 4 disease (n=102). CONCLUSIONS: Quantifying pretest probability for HFpEF in patients with sleep apnea, lung disease, or chronic thromboemboli identifies a progressive gradient for dynamic PCWP abnormalities with worse functional status and quality of life. These subclinical left heart abnormalities are not universally detectable by resting right heart catheterization alone and call for further study of whether strategies to prevent or treat HFpEF might improve functional status in these patients with high risk of occult HFpEF.

e19503 Background: The uptake of BCMA directed ADCs in MM has been hindered by ocular toxicity. Belantamab mafodotin (BM) and MEDI2228 (MEDI) are BCMA directed monoclonal antibodies conjugated to the microtubule inhibitor, monomethyl auristatin F and the alkylator, pyrrolobenzodiazepine, respectively. Differences in the ADCs payload, antibody specificity and linker stability influence ocular toxicity. We investigated the patterns of ocular toxicity and tolerability of BCMA directed ADC therapy. Methods: Retrospective study of MM patients who commenced treatment with a commercial or investigational BCMA directed ADC at the Mayo Clinic between 2019-22. Results: 111 patients were included, the median age was 69 and median follow up 40 months. The median number of prior treatments was 6, 87% of patients were triple class refractory, 50% penta class refractory, 14% had prior BCMA directed therapy and 24% had extraosseous disease. Treatments included BM (n=56, 50%), BM in combination with other MM therapy (n=12, 11%) and MEDI (n=43, 39%). The overall response rate was 30% for BM and 44% for MEDI. The median OS and PFS for BM was 8 and 2 months, the median OS and PFS for MEDI was 11 and 5 months. The median number of ADC cycles was 2.5. Ocular toxicity is summarized in the table 1. Keratopathy was more common with BM (p=0.004). Only 4 MEDI patients developed keratopathy, all grade 1 and associated with dry eyes and/or photophobia. In contrast, 60% of BM patients developed keratopathy (13% grade 3-4 keratopathy). The median time to keratopathy onset was 1 month with BM, and 2.8 with MEDI. The median time until keratopathy was 4.6 months for BM. Loss of best-corrected visual acuity (VA) was significantly more common with BM (p<0.001). The median time to any decline in VA was 1.5 months for BM and 2.3 for MEDI. The median time until VA returned to baseline was 2.4 months for BM and 2.3 for MEDI. The frequency of dose delays for ocular toxicity was comparable between ADCs, as was the number of dose reductions (16% BM vs. 12% MEDI, p=0.5). The most common reasons for treatment discontinuation were progression or death (BM=69%, MEDI=44%) and ocular toxicity (BM=18%, MEDI=30%). Conclusions: Treatment interruptions, dose reductions and drug discontinuation are common with BCMA directed ADC therapy. Further research to optimize the administration schedule of these agents is warranted. BM and MEDI produce distinct patterns of ocular side effects, namely keratopathy and reduced VA with the former, and photophobia and dry eyes with the latter. BM N = 68 MEDI N = 43 p-value 2 Prophylactic steroid eye drops 4 (6%) 28 (68%) <0.001 Prophylactic lubricant eye drops 42 (63%) 33 (80%) 0.051 Max grade keratopathy 0.004 1-2 29 (47%) 4 (19%) 3-4 8 (13%) 0 (0%) VA equal or worse than 20/40 26 (68%) 6 (20%) <0.001 Days of ADC treatment 59 (33, 167) 68 (41, 105) 0.9 Dose delay for ocular toxicity 19 (28%) 8 (19%) 0.2 n (%); Median (IQR); 2 Chisq test; Wilcoxon rank sum.

6061 Background: PDS0101 is a T cell stimulating immunotherapy (therapeutic vaccine) targeting HPV16. The combination of PDS0101 + pembrolizumab (5 cycles) has shown durable clinical responses in HPV-positive recurrent/metastatic HNSCC. MC200710 is a window of opportunity study in patients with HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC). This prospective phase II trial utilized 2 cycles of neoadjuvant PDS0101 aloneor in combination with pembrolizumab prior to surgical resection or chemoradiotherapy (CRT). Herein, we report the initial results, including primary endpoint of ctDNA response. Methods: Between June 2022 and September 2024, 20 patients (10 per Arm) with locally advanced HPV+ OPSCC were enrolled in a sequential alternating design. Arm A received 2 cycles of PDS0101 and Arm B received 2 cycles of PDS0101 and pembrolizumab with all patients undergoing subsequent surgery or CRT. Assessments were done at baseline, post cycle 1, and post cycle 2 (prior to surgery or CRT). The coprimary endpoint of ctDNA response was defined as a ≥50% decline in ctDNA post cycle 2 compared to baseline as quantified using NavDx (TTMV fragments/mL). Radiologic objective response rate (ORR) was assessed as per RECIST 1.1. Toxicity through the neoadjuvant period was assessed using CTCAE criteria and recurrence rates following surgery or CRT are reported. Results: Patients were similar between arms: male 90%, median age 61 years, cT1/T2 70%, cN1 65%, and no smoking history 65%. All patients completed both cycles of therapy with 13 (65%) undergoing primary operative management and 7 CRT (35%). The most common toxicity was injection site reaction 85% grade 1, 15% grade 2, 0% grade 3, consistent with prior studies. One patient experienced grade 2 pneumonitis during the neoadjuvant window (Arm B). There was one grade 3 toxicity (5%) possibly attributable to study intervention with one patient experiencing transient hepatitis requiring hospitalization (Arm A). Zero of 10 patients in Arm A had a ≥50% decline in ctDNA from baseline while 5 of 10 patients (50%) met this primary endpoint in ARM B (p=0.03). After Cycle 2, based on RECIST 1.1, no Arm A patients had a partial response (PR), with 7 having stable disease (SD); Arm B had 2 patients with PR and 8 with SD. With median follow up of 6 months, 2 patients in Arm A recurred and 0 patients in Arm B. Conclusions: The combination of PDS0101 and pembrolizumab met the trial’s primary endpoint of ctDNA response and shows promise for further evaluation. ctDNA can be used to assess early response and future studies could use ctDNA to adapt neoadjuvant therapy. Based on these findings, a neoadjuvant dose optimization study in HPV16+ oropharyngeal carcinoma is warranted and evaluation of PDS0101 and pembrolizumab in comparison to pembrolizumab alone. Clinical trial information: NCT05232851 .

e13575 Background: Cellular therapies continue to expand in diversity, complexity, and financial impact leading clinicians and administrators to seek innovative care options. The paradigm of late has been to move to an outpatient treatment model. However, centers may not find this model to be the safest option for their patients. This pilot project aims to use established outpatient resources to reduce hospital length of stay (LOS) for patients receiving ciltacabtagene autoleucel in an inpatient setting. Methods: Chart review was conducted for 42 patients treated for incidence of CRS, days to onset, LOS, readmissions, and hospital expenses and charges. The cohort showed an 83% incidence of CRS with a mean onset of 7 days. 71% of CRS was limited to Grade 1. The mean LOS was 10.8 days and the readmission rate was 21%. Financial modeling estimated overall cost reduction to range from $13,000 to $20,000 per patient for a LOS of 3 days. A pilot project to reduce LOS was developed with inclusion/exclusion criteria prioritizing patient safety and likelihood of remaining in the outpatient setting. A workflow for administering one dose of tocilizumab for Grade 1 CRS in the outpatient setting was also established to counterbalance readmissions. The goal of the pilot is to reduce the overall LOS from 10 days to 3 days while maintaining readmission rates and comparable charge to reimbursement ratios on net operating income. Results: In the first five months, 25 patients were screened for eligibility. 60% were deemed eligible and 66% of those were discharged after three days. No patients discharged after a minimum admission were readmitted within three days. Current data suggests the readmission rate within 30 days is higher than baseline at 40%. The overall LOS of patients enrolled in the pilot upon infusion was six days. Patients successfully remaining on the pilot have a 60% reduction in LOS. There have been no major safety events. Conclusions: We identified that select patients could be managed in the outpatient setting after a minimum three-midnight hospital admission. A pilot project was developed using our comprehensive care model coupled with a minimum LOS of 3 days. After discharge, patients are followed daily in our outpatient clinic using in-person visits and remote patient monitoring. To counterbalance readmissions, Grade 1 CRS has been treated in the outpatient clinic including administration of tocilizumab. Early data indicates that the workflow is reducing LOS by 60% under patient selection criteria capturing approximately 60% of patients. While readmissions in the first three days post discharge have been parried, there is opportunity to further reduce readmissions in the first 30 days following CAR-T infusion. We anticipate the pilot will reduce costs without negatively impacting reimbursement or readmissions.