Patients Experienced Disease Progression Research Articles

Prognostic value of circulating tumor DNA for progression-free survival in patients with locally advanced dMMR/MSI-H colorectal cancer managed without surgery.

256 Background: Immunotherapy has shown the ability to induce a high rate of pathologic and clinical complete response in patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC). The role of circulating tumor DNA (ctDNA) as a prognostic biomarker for survival in patients who receive non-operative management (NOM) is unknown. Among patients enrolled in a phase II trial (NCT04082572) that evaluated the efficacy of pembrolizumab in patients with locally advanced dMMR/MSI-H solid tumors, we evaluated the impact of ctDNA on progression-free survival (PFS) among 12 patients with locally advanced dMMR/MSI-H CRC who received NOM. Methods: ctDNA testing was performed in the CLIA-certified laboratory at MD Anderson using a 70-gene liquid biopsy panel (LBP-70), which used digital sequencing of cell-free DNA. Formalin-fixed paraffin-embedded tumor samples and germline peripheral blood mononuclear cells were profiled using next-generation sequencing. Mutations in ctDNA were considered tumor-specific if they were confirmed with matched tumor tissue profiling. The lower limit of detection of the LBP-70 assay was a mutational variant allele frequency of <0.3%. "ctDNA clearance" and “ctDNA(-)” status were defined as the absence of any detectable tumor-specific mutations in ctDNA. Two-year progression-free survival (PFS) was estimated using Kaplan-Meier techniques and compared with log-rank tests. Results: The median follow-up between the first cycle of pembrolizumab and last radiographic assessment was approximately three years (36.7 mo; range (range 1.2 – 51.0 mo). Forty-nine LBP-70 assays were performed among the 12 patients over the course of treatment with pembrolizumab. The median number of cycles was 16 (range 1 – 16 cycles). Six patients were ctDNA(-) prior to pembrolizumab, all of whom remained ctDNA(-) after. None of these six patients experienced disease progression (PD) at their last follow-up. The other six patients were ctDNA(+) prior to pembrolizumab (median baseline VAF 0.4%, range 0.3%–4.0%). Of these six patients, three experienced ctDNA clearance while receiving pembrolizumab. None of the three patients who cleared ctDNA experienced PD as of their last follow-up. Of the three patients who did not clear ctDNA, two experienced PD in their primary tumor (at two and six months after their first cycle, respectively), while the third patient remains without PD at their last follow-up. The two-year PFS rate was 100% among the nine patients who were ctDNA(-) after pembrolizumab compared to 33% among the three patients who were ctDNA(+) after pembrolizumab (p = 0.03). Conclusions: ctDNA may be a valuable tool for assessing treatment response and improving the ability to tailor organ-sparing, curative strategies to patients with locally advanced dMMR/MSI-H CRC.

The role of sequential PET/CT imaging to predict complete response after definitive chemoradiotherapy for locally advanced squamous cell carcinoma of the anal canal.

12 Background: The standard treatment for locally advanced squamous cell carcinoma of the anal canal (SCCAC) is definitive radiotherapy (RT) with concurrent chemotherapy (CRT), with excellent outcomes. Nevertheless, rates of locoregional failure of 10% to 30% have been reported. Due to the narrow therapeutic window between time-dependent response to RT and prompt salvage surgery, the definition of a surveillance strategy after radical CRT is challenging. In particular the contribution of 18-FDG PET/CT is not clearly established. The purpose of this study was to evaluate the effectiveness of follow-up MR and 18-FDG PET/CT to predict response to CRT in patients with SCCAC. Methods: We analyzed a cohort of consecutive patients who received definitive RT/CRT from January 2019 to February 2024. After completion of therapy, radiologic (rCR) and metabolic complete response (mCR) was assessed with pelvic MR (RECIST v.1.0) and 18-FDG PET/CT at 3 ad 6 months respectively. Local Control (LC) was defined as time from the end of CRT to local failure or last follow-up. Univariate analysis (UVA) was performed to identify variables associated with outcome using the log rank test. Sensitivity and Specificity analysis was performed to assess the correlation between rCR/mCR and LC. Results: A total of 67 patients (median age 67 years, range 44-83) were included. All patients completed RT, and 52 received concurrent CRT. Baseline and surveillance MR and 18-FDG PET/CT were available for 49 patients. After a median follow-up of 28 months, 12 patients experienced disease progression (PD) (10 local; 2 distant), resulting to salvage surgery in 10 cases after biopsy. At 3 years, LC rate was 78%. At UVA, only mCR was correlated with LC (3-year LC 90% versus 59%, p=0,0137; HR 0,01660, IC 95% 0,03-0,84). For prediction of LC, accuracy of mCR at 6 months was 83.7% versus 62.5% for rCR. Specificity/Sensitivity analysis is summarized in the table. Conclusions: 18FDG PET/CT at 6 months may identify patients with a higher likelihood of developing complete tumor regression following CRT. Further data is needed to confirm the appropriate surveillance strategy for patient undergoing CRT in clinical practice. Specificity and sensitivity analysis. Sensitivity Specificity Positive Predictive Value Negative Predictive Value mCR 83.3% 84.0% 92.6% 68.7% rCR 25.0% 70.0% 14.0% 82%

Progression-Free Survival Prediction for Locally Advanced Cervical Cancer after Chemoradiotherapy with MRI-based Radiomics

Background and purposeA significant proportion of locally advanced cervical cancer (LACC) patients experience disease progression post-chemoradiotherapy (CRT). Currently existing clinical variables are suboptimal predictors of treatment response. This study reported a radiomics-based model leveraging information extracted from MR T2-weighted image (T2WI) to predict the progression-free survival (PFS) for LACC following CRT. Materials and methodsRadiomics features were extracted from pre-treatment MR T2WI in 105 LACC patients. Following pre-feature selection and a step-forward feature selection method, an optimal feature set was determined with a cox proportional hazard (CPH) model. The PFS predictions were generated through a radiomics-clinical combined model utilized five repeated nested 5-fold cross-validation (5-fold CV). Disease progression risk was stratified into high- and low-risk groups based on the predicted PFS and assessed by Kaplan-Meier analysis. ResultsThe radiomics texture feature extracted from MR T2WI significantly predict PFS in LACC after CRT. In comparison to the model using clinical variables alone, the radiomics-clinical combined model achieves significantly improved performance in testing patient cohort, achieving higher C-Index (0.748 vs 0.655) and AUC (0.798 vs 0.660 for 2-year PFS). Meanwhile, the proposed method significantly differentiated the high- and low-risk patients groups for disease progression (p<0.001). ConclusionAn MR T2WI-based radiomics and clinical combined model provided improved prognostic capabilities in predicting the PFS for LACC patients treated with CRT, outperforming a model using clinical variables alone. The incorporation of MR T2WI-based radiomics is promising in assisting in personalized management in LACC, indicating the potential of MR T2WI radiomics as imaging biomarker.

Long-Term Outcomes in Radioiodine-Resistant Follicular Cell-Derived Thyroid Cancers Treated with [177Lu]Lu-DOTAGA.FAPi Dimer Therapy.

Aim: The study aimed to analyze the long-term outcomes of [177Lu]Lu-DOTAGA.FAPi dimer therapy in individuals diagnosed with radioiodine-resistant (RAI-R) follicular cell-derived thyroid cancer. Materials and Methods: In this retrospective study, 73 patients with RAI-R follicular thyroid carcinoma who had undergone multiple lines of previous treatments were included. Following [68Ga]Ga-DOTA.SA.FAPi positron emission tomography-computed tomography scan, among the 73 patients, 65 received [177Lu]Lu-DOTAGA.FAPi dimer monotherapy with a median activity of 5.5 GBq per cycle at 8-week intervals. The remaining eight patients underwent tandem [177Lu]Lu/[225Ac]Ac-DOTAGA.FAPi dimer therapy, consisting of a median of two cycles of [177Lu]Lu-DOTAGA.FAPi dimer followed by one cycle of [225Ac]Ac-DOTAGA.FAPi dimer, also at 8-week intervals. The primary endpoint included progression-free survival (PFS) and overall survival (OS). Secondary endpoints included PERCIST criteria response assessment and safety assessment according to Common Terminology Criteria for Adverse Events (V5.0). Results: We enrolled 37 female and 36 male patients, with a mean age of 54.3 years (range: 27 - 80 years). The patients received a median cumulative activity of 22.2 GBq (range, 4 GBq-55.5 GBq) of [177Lu]Lu-DOTAGA-FAPi dimer over one to nine cycles, with a median of three cycles. Among 73 patients, 20 died and 16 deaths were due to thyroid cancer. Nineteen patients experienced disease progression, with an estimated median PFS of 29 months [CI 14-34 months]. The estimated median OS was 32 months [CI 21-40 months]. Four patients (5.4%) encountered grade III anemia, primarily linked to bone metastasis in three cases and neck tumor mass bleed in one. Grade III thrombocytopenia occurred in three patients (4%). No grade III renal or hepatotoxicity was observed. Conclusion: In this study, [177Lu]Lu-DOTAGA.FAPi dimer therapy showed promising safety and efficacy in aggressive, radioiodine-resistant thyroid cancer, achieving a median PFS and OS of 29 and 32 months, respectively, with manageable adverse events. Confirmation of our findings is needed from prospective clinical trials comparing [177Lu]Lu-DOTAGA.FAPi dimer therapy to other treatments.

A Phase II Study of Denileukin Diftitox in Patients with Advanced Treatment Refractory Breast Cancer

Background/Objectives: Regulatory T cells (Treg) suppress immunity in the tumor microenvironment, are linked to poor prognosis across breast cancer subtypes, and suppress the cytolytic function of cytotoxic CD8+ T cells. Denileukin diftitox, a diphtheria toxin (DT)/IL-2 fusion protein, targets and depletes Tregs. This Phase II study aimed to assess the safety of denileukin diftitox and its effect on Tregs and tumor growth in patients with advanced breast cancer. Methods: This single-arm Phase II study of denileukin diftitox enrolled patients with refractory stage IV breast cancer. Patients received denileukin diftitox 18 mcg/kg/day IV for Days 1–5 every 21 days for up to six cycles. Toxicity was assessed using CTCAE v3.0 and tumor response was evaluated per RECIST criteria. Blood samples were collected to analyze Tregs by flow cytometry and anti-DT antibodies by ELISA. Results: Fifteen patients with stage IV breast cancer were enrolled. Four patients completed all planned denileukin diftitox infusions and achieved stable disease (27%, 95% CI [0.08, 0.55]). Two patients (13%) discontinued due to toxicity, and nine patients (60%) discontinued due to progressive disease. Eleven patients experienced at least one grade 3 or 4 adverse event. Although there was a general reduction in peripheral blood Tregs, the difference in CD4+CD25+FOXP3+ Tregs levels post-treatment was not statistically significant (p = 0.10). Six patients (40%) achieved 25% reductions in Tregs. A significant increase in anti-DT IgG antibodies was observed post-treatment (p &lt; 0.005). Conclusions: Denileukin diftitox demonstrated moderate toxicity in this advanced breast cancer cohort. Denileukin diftitox modulated regulatory T cells. However, the majority of patients experienced disease progression in the study.

P0481 Real-World Analysis of Disease Progression in Ulcerative Colitis: A Comparative Study Across Diagnostic Eras at a Tertiary IBD Center

Abstract Background Ulcerative colitis (UC) is a chronic condition characterized by a relapsing-remitting course, leading to cumulative systemic damage and disease progression. This progression may include extension of colitis, new extraintestinal manifestations (EIMs), dysplasia/colorectal cancer (CRC), and the need for colectomy. This study aimed to compare disease progression based on the time of diagnosis, to assess the impact of new therapeutic options. Methods Retrospective study at Reina Sofía University Hospital, analyzing all UC patients diagnosed within the past 10 years (2014-2023, cohort B) and a matched cohort diagnosed prior to 2014 (cohort A). Disease progression was defined as the first occurrence of new EIMs, new dysplasia/CRC, need for colectomy, or progression of UC extension. Kaplan-Meier analysis was used to calculate time to progression events. Results Of 643 patients identified, 72 were excluded, leaving 571 for analysis. Among them, 194 (34%) were diagnosed before 2014 and 377(66%) within the last decade (2014-2023). Median age at diagnosis was 39.5 years (IQR 27.3–54.2), and 304 (53.2%) were male. Initial disease extent was: proctitis 147(25.7%), left-sided colitis 203 (35.6%) and pancolitis 191 (33.5%). At diagnosis, 40 (7%) had EIMs. During a median follow-up of 7.1 years (3.7–13.3), 223(39.1%) patients experienced disease progression, including extension of colitis in 57(10%) cases, new EIMs in 114 (20%), colectomy in 46 (8.1%), and dysplasia/CRC in 56(9.8%). Patients diagnosed within the last decade showed a shorter time to progression compared to those diagnosed prior to 2014 (log-rank test, p&amp;lt;0.0001). This trend was also observed for new EIMs (p=0.01), dysplasia/CRC (p&amp;lt;0.0001), and disease extension (p=0.014) (Figure 1B-E). However, no significant difference was found in time to colectomy between groups (p=0.31) (Figure 1F). First maintenance therapy was mesalazine in 366(97.9%) of patients diagnosed within the last decade compared to those diagnosed previously 178(96.7%). Corticosteroids were used at some point in 379(69.4%), median number of corticosteroid courses of 2(1-4). Advanced therapy during follow-up was prescribed in 94(24.9%) of patients diagnosed in the last decade compared to 66(34%) of those diagnosed previously, p=0.022. However, time to advanced therapy prescription was significantly shorter in patients with recent diagnosis (log-rank test p=0.014) (Figure 1A) Conclusion A substantial proportion of patients with UC experienced disease progression within a follow-up period of less than 10 years. Despite the availability and earlier use of advanced therapeutic options, disease progression was observed to occur sooner in patients diagnosed within the last decade, compared to those diagnosed before 2014.

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone Induction in Newly Diagnosed Myeloma: Analysis of the MIDAS Trial.

In patients with transplant-eligible newly diagnosed multiple myeloma, induction therapy with a quadruplet regimen prior to autologous transplant is the standard of care. The phase III IFM2020-02-MIDAS study (NCT04934475) assessed a minimal residual disease (MRD)-driven consolidation and maintenance strategy following induction with isatuximab, carfilzomib, lenalidomide, and dexamethasone (IsaKRD). Here, we report safety and efficacy outcomes of six 28-day cycles of IsaKRD. Between December 2021 and July 2023, 791 patients were enrolled across 72 centers. The median age was 59 years; 13% had ISS-stage III, 5% had R-ISS-stage III, and 8% had high-risk cytogenetics (IFM Linear Predictor cytogenetic score >1). Overall, 96% (N=757) of patients completed induction. The median CD34+ cell yield was 7 × 106/Kg, with 94% of patients able to proceed with a potential tandem transplant. The best overall response rate was 95%. In the intent-to-treat population, 91% achieved a very good partial response or better after induction, with MRD-negativity rates of 63% at 10-5 and 47% at 10-6. MRD-negativity rates differed across ISS stages and cytogenetic subgroups. During induction, 7 patients experienced disease progression, and 5 died due to disease progression (N=1), cardiac events (N=2), or other causes (N=2). The most common grade 3/4 adverse events were neutropenia (25%), thrombocytopenia (5%), and infections (7%); only 13% of patients reported any grade peripheral neuropathy. IsaKRD induction yielded deep responses and high MRD-negativity rates while ensuring successful stem cell collection, with no new safety signals. Continued follow-up of this ongoing study is required to confirm these findings.

Analysis of 41 cases of myocardial infarction in children with coronary artery lesion after Kawasaki disease

Objective: To analyze the clinical characteristics,diagnosis and treatment of pediatric myocardial infarction (MI) patients with coronary artery lesions (CAL) after Kawasaki disease (KD). Methods: Clinical data including baseline characteristics, KD and CAL information, clinical symptoms at MI onset, electrocardiogram (ECG) and imaging findings, MI treatment, and clinical outcomes of 41 MI patients with CAL after KD admitted to the Children's Hospital of Fudan University from January 2017 to August 2024 were analyzed retrospectively. Results: (1) Demographic characteristics: a total of 41 patients were included (36 males and 5 females). The age at MI was 4.6 (2.3, 5.7) years, and time from KD onset to MI was 397 (50, 1 095) d. (2) Treatment of acute KD: only 15 patients (37%) received standard initial treatment within 10 days of KD onset with intravenous immunoglobulin 2 g/kg. The other 26 cases (63%) received non-standard treatment or no treatment. (3) Treatment of CAL before MI: the time from KD onset to CAL was 14 (10, 116) d, with CAL not identified before MI onset in 15 patients. Among the 26 cases diagnosed with CAL prior to MI, 9 cases received only single or dual antiplatelet drug, of which 7 cases received oral dipyridamole. The remaining 16 cases received antiplatelet drug combined with warfarin, but only 1 case achieved the target international standardized ratio of 1.5-2.5. Out of all 41 cases, only 1 case (2%) received standard antithrombotic treatment before MI onset. (4) Clinical symptoms of MI: at MI onset, 32 patients presented with different clinical symptoms, with typical MI symptoms such as chest tightness, chest pain, precordial discomfort in 18 cases, and cardiopulmonary arrest accompanied by syncope or convulsions in 10 cases. Other non-specific symptoms included abdominal pain, nausea, vomiting and pallor. Nine patients were asymptomatic and were found to have silent MI on follow-up. (5) ECG and imaging findings: ECG showed ST-T changes in 33 cases, and abnormal Q waves, and arrhythmias in the remaining patients; echocardiography indicated coronary artery aneurysm with thrombosis in 27 cases, reduced left ventricular ejection fraction in 18 cases, abnormal wall motion in 15 cases, and ventricular aneurysm in 3 cases. Thirty-seven patients underwent coronary angiography and (or) multi-slice spiral CT angiography, with 39 occluded vessels and 3 severe stenosis (≥75%), all of which were caused by giant aneurism with thrombus formation. (6) Treatment of MI: of the 32 patients with acute MI, 9 patients received successful cardiopulmonary resuscitation, 7 patients received intravenous thrombolysis, and 1 patient underwent percutaneous coronary balloon angioplasty. All of these patients received dual antiplatelet drugs and low-molecular-weight heparin at therapeutic doses following MI treatment. Sixteen patients received coronary artery bypass graft (CABG) treatment, all of which were successful. (7) Outcomes: the follow-up time was 994 (215, 1 832) d. Thirty-one patients showed improvement, 5 patients experienced disease progression or no change, 1 patient died, and 4 patients were lost to follow-up. Conclusions: MI in children with CAL after KD often occurs within 1 year after the onset of KD. MI can present with atypical clinical symptoms in children. CABG is the main treatment option in children severe CAL after KD who developed MI.

Factors associated with first-to-second-line attrition among patients with metastatic breast cancer in the real world.

Estimating patient attrition across lines of treatment (i.e. the probability that upon treatment failure the patient will not be able to receive a subsequent treatment) may be a valuable tool for optimizing treatment sequencing. We sought to describe the first-to-second-line attrition rate and factors associated with attrition in a real-world cohort of patients with metastatic breast cancer. The Gruppo Italiano Mammella (GIM)14/BIO-META (NCT02284581) is an ongoing, ambispective observational multicenter study enrolling patients with metastatic breast cancer receiving first-line therapy. In patients experiencing disease progression, attrition was defined as no further anticancer treatment and death within 6 months from the end of first-line therapy. The attrition rate from the first-to-second line was studied by descriptive analyses and univariate and multivariable logistic models were used to explore potentially predictive factors. From January 2000 to December 2021, 3109 patients with metastatic breast cancer were enrolled in the GIM14/BIO-META study. Among them, 2498 patients experienced first-line treatment failure. Overall, first-to-second line attrition was 9.0% (95% confidence interval 7.9% to 10.1%), with similar attrition for patients with hormone receptor-positive/HER2-negative (8.5%) and HER2-positive (7.1%) breast cancer. Patients with triple-negative disease experienced the highest attrition (13.0%). Age, menopausal status, disease-free interval from primary tumor diagnosis, type of metastatic spread, and tumor subtype independently predicted first-to-second-line attrition. These findings could inform treatment decisions and guide clinical research on treatment sequencing. For instance, patients with the lowest risk of attrition may be the ideal candidates for trials exploring de-escalated first-line regimens, followed by more aggressive treatments upon progression.

Survival and toxicity outcomes of hypofractionated conformal radiotherapy compared to conventionally fractionated radiotherapy in the treatment of diffuse intrinsic pontine gliomas.

Diffuse intrinsic pontine gliomas are associated with dismal survival outcomes. Conventional fractionation radiation to a dose of 60Gy is the standard of treatment. This retrospective review aims to compare survival and toxicity outcomes of patients treated with conventional fractionation (CF) and hypofractionation (HF) radiotherapy. Treatment-naïve diffuse intrinsic pontine glioma patients undergoing radical radiation were analyzed. CF was delivered to a dose of 50-60Gy in 25-30 fractions, while HF was delivered as 38-40Gy in 12-15 fractions. All patients were planned via the volumetric modulated arc therapy (VMAT) technique. A total of 64 patients were eligible for analysis. The median age of presentation was 10years. Motor deficit was the most common presenting complaint in 51.6% of the patients, with a median symptom duration of 2months. The pons was the most frequent site of disease epicenter in 71.8% of the patients. After a median follow-up of 9.45months (range 0.23-72.63months), 23 patients died, and 28 patients experienced disease progression. The unadjusted hazard ratio (HR) for death in patients treated with HF as compared to CF was 1.330 (95% CI 0.522-3.386) (p-value 0.550, by Cox regression analysis). The median OS for the entire cohort was 13.9months, while it was 9.7months (95% CI 5.65-13.74) and 15.1months (95% CI 9.02-21.18) (p-value = 0.547) with CF and HF, respectively. On multivariate analysis, disease epicenter in the pons was the only significant factor associated with PFS. Hypofractionation was associated with a significantly higher aspiration rate and Ryle's tube requirement (p-value 0.027). Hypofractionated radiation can be considered for diffuse intrinsic pontine glioma with optimum supportive care.

Organ-specific response to [177Lu]DOTATATE peptide receptor radionuclide therapy (PRRT) assessed by sequential [68Ga]DOTATOC PET/CT in patients with metastatic small intestine neuroendocrine tumors.

To evaluate organ-specific response to [177Lu]DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) in patients with small intestine neuroendocrine tumor (SiNET) through [68Ga]DOTATOC PET/CT, and to analyze tumor uptake and functional volume variations at different metastatic sites in relation to disease progression during clinical follow-up after treatment. A retrospective analysis was conducted on 33 metastatic patients. PET/CT were performed pre-treatment (PET0), mid-treatment after two PRRT cycles (PET2), and post-treatment (PET4). SUVmax and somatostatin receptor-expressing tumor volume (SRETV) were measured in liver, lymph node, peritoneum/mesentery, and bone metastases. Liver metastases showed significant reduction in both SUVmax and SRETV from PET0 to PET4, with early response evident after two PRRT cycles. Nodal lesions exhibited a delayed response, with significant reductions at PET4. Peritoneal and bone metastases showed a continuous decline in SUVmax, but no significant changes in SRETV. Objective response rates were highest in liver metastases after treatment completion with lesser responses in nodal, peritoneal, and bone lesions. At a median follow-up of 24.3 months, 70% of patients experienced disease progression, while 30% did not. Liver metastases showed no significant changes in SUVmax or SRETV regardless of progression. Conversely, in non-progressing patients, peritoneal/mesenteric lesions showed a significant reduction in SUVmax, with unchanged SRETV, and nodal metastases exhibited reduced SRETV. Bone lesions in non-progressing patients showed significant decreases in both SUVmax and SRETV. [177Lu]DOTATATE PRRT effectively reduces tumor functional activity in patients with SiNETs, with organ-specific responses highlighting the need for personalized treatment strategies to optimize efficacy and minimize toxicity.

Glutathione peroxidase 4 overexpression induces anomalous subdiffusion and impairs glioblastoma cell growth

Glioblastoma tumors are the most common and aggressive adult central nervous system malignancy. Nearly all patients experience disease progression, which significantly contributes to disease mortality. Recently, it has been suggested that recurrent tumors may be characterized by a ferroptosis-prone phenotype with a significant decrease in glutathione peroxidase 4 (GPx4) expression. This led to the hypothesis that GPx4 expression negatively influences GBM cell growth. This study utilizes a doxycycline inducible GPx4 overexpression model to test this hypothesis. Consistently, the overexpression of GPx4 significantly impairs cell growth and colony formation while also causing an accumulation of cells in G1/G0 phase of the cell cycle. From a biophysical perspective, GPx4 overexpressing cells have significantly greater surface area, increased Young’s modulus, and experience anomalous sub-diffusion as opposed to normal diffusion associated with Brownian motion. Moreover, analysis of patient derived GBM cells reveal that cell growth rates, plating efficiency, and Young’s modulus are all inversely proportional to GPx4 expression. Therefore, GPx4 appears to be a biophysical regulator of GBM cell growth that warrants further mechanistic investigation in its role in GBM progression.

Sequential Endoluminal Doxorubicin and Gemcitabine Alternating Weekly with Sequential Mitomycin and Docetaxel for Recurrent Non-Muscle Invasive Urothelial Carcinoma.

Background: After first-line treatment failure, patients with non-muscle invasive urothelial carcinoma (NMIUC) are recommended to undergo radical cystectomy. However, those unable to pursue radical surgery or desiring bladder preservation require effective salvage therapies. Multi-agent treatment regimens are particularly useful for targeting the complex resistance mechanisms of recurrent UC. Herein, we report a regimen of sequential doxorubicin and gemcitabine alternating weekly with sequential docetaxel and mitomycin (Quad Chemo) for patients with recurrent high-risk NMIUC. Materials and Methods: We retrospectively identified all patients sequentially treated with 50 mg of doxorubicin followed by 1000 mg of gemcitabine alternating weekly with sequential 37.5 mg of docetaxel followed by 40 mg mitomycin-C between 2007-2024. Induction consisted of 8 weekly treatments, and, if disease-free, patients were initiated on monthly maintenance treatments for 2 years. Results: In total, 29 patients (39 treated units; 26 lower urinary tract, 13 upper urinary tract) with high-grade NMIUC were included in the final analysis. The cohort had high-risk features with a median of three prior induction therapies and with 38 (97%) units presented with either biopsy-proven CIS or presumed CIS in the context of high-grade urine cytology in the absence of tumorous lesions. There were 26 recurrences during follow-up, 17 in the lower tract and 9 in the upper tract. Among all of the treated units, the complete response rate was 80%, and 1- and 2-year recurrence-free survival was 60% and 43%, respectively. In total, 10 patients experienced disease progression yielding a 5-year progression-free survival of 57%. Five patients ultimately died due to bladder cancer yielding a 5-year cancer-specific survival of 83%. A total of 19 (66%) patients reported side effects during treatment, and 7 (24%) stopped treatment secondary to side effects. Conclusions: In a high-risk heavily pre-treated cohort, Quad Chemo rescued a significant portion of patients with recurrent NMIUC from disease relapse. However, progression events were considerable in the long term. Further prospective evaluation of this treatment regimen is warranted.

Larotrectinib for Newly Diagnosed Infantile Fibrosarcoma and Other Pediatric NTRK Fusion-Positive Solid Tumors (Children's Oncology Group ADVL1823).

The TRK inhibitor larotrectinib is US Food and Drug Administration approved for NTRK fusion-positive solid tumors that lack a satisfactory alternative or have progressed after treatment but has not been systematically studied as a frontline therapy with a defined duration of treatment. ADVL1823 evaluated larotrectinib in patients with newly diagnosed NTRK fusion-positive solid tumors with response-adapted duration of therapy and local control. Patients received larotrectinib twice daily in 28-day cycles for a predefined duration of treatment, ranging from 6 to 26 cycles depending on response to therapy and surgical resectability. The primary end point was the objective response rate (ORR) within six cycles in patients with infantile fibrosarcoma (IFS); patients with other histologic diagnoses were analyzed in a separate cohort. Secondary objectives included event-free survival (EFS) and overall survival (OS). Thirty-three patients were enrolled: 18 with IFS and 15 with other solid tumors. The ORR within six cycles was 94% (17/18; 95% adjusted CI, 72.7 to 98.6) among children with IFS and 60% (9/15; 95% CI, 32.3 to 83.7) among children with other solid tumors. Six percent (2/33; 95% CI, 0.7 to 22.2) patients developed progressive disease while on therapy. Two-year EFS and OS among these groups were 82.2% (95% CI, 54.3 to 93.9) and 93.8% (95% CI, 63.2 to 99.1) for IFS and 80% (95% CI, 50.0 to 93.1) and 93.3% (95% CI, 61.3 to 99.0) for other solid tumors, respectively. Patients undergoing surgical resection of their tumor had prolonged EFS, with only 1 of 16 such patients experiencing disease progression. Four of 33 patients had dose-limiting toxicities. Larotrectinib is highly active in patients with newly diagnosed NTRK fusion-positive solid tumors. Larotrectinib should be a frontline option for patients with IFS and other NTRK fusion-positive solid tumors. Local control with surgical resection remains important in the treatment of patients with IFS.

Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-mutant, metastatic non-small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum-based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837). Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS. Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients. Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Machine-learning methodologies to predict disease progression in chronic hepatitis B in Africa.

Little is known about the determinants of disease progression among African patients with chronic HBV infection. We used machine-learning models with longitudinal data to establish predictive algorithms in a well-characterized cohort of Ethiopian HBV-infected patients without baseline liver fibrosis. Disease progression was defined as an increase in liver stiffness to >7.9kPa or initiation of treatment based on meeting the eligibility criteria. Twenty-four of 551 patients (4.4%) experienced disease progression after a median follow-up time of 69 months. A random forest model based on a combination of available laboratory tests (standard hematology and biochemistry) demonstrated the best predictive properties with the AUROC ranging from 0.82 to 0.88. We conclude that combined metrics based on simple and available laboratory tests had good predictive properties and should be explored further in larger HBV cohorts.

Abstract B048: Microfluidic isolation of immune cell-derived extracellular vesicles in head and neck cancer patients on immune-checkpoint blockade

Abstract Background: Immune-checkpoint blockade (ICB), with or without chemotherapy, is the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). However, only a minority of patients get clinical benefit from it. The combined expression of PD-L1 in a tumor section is currently the only biomarker approved for response prediction. Yet, its invasive nature and suboptimal predictive performance underscores the need for new, non- invasive surrogates of immune activity in patients undergoing ICB. Extracellular vesicles (EVs) carry key molecules critical for cell-cell communication and have the potential to be used as a non-invasive, real-time biomarker of systemic immune activity, essential for success in ICB- based therapy. Methods: We used a multichannel, microfluidic device that employs an immune- affinity approach, ‘herringbone chip’ (EVHB-Chip), to retrospectively isolate EVs from twelve HNSCC patients before and after the first cycle of ICB. One mL of plasma was used per patient per time point. For each patient, two devices were serially used, with each sample continuously following through each chip in a non-destructive manner—the first device aimed to isolate B cell EVs (antibodies against CD19 and CD20). The second device was optimized to capture T cell EVs (against CD274/PD-L1). Digital-droplet PCR was performed after EVs were isolated to detect the RNA transcripts in the EV cargo. Serial sampling was performed for six out of the twelve patients. Response assessment was conducted via RECIST1.1 criteria or clinical evaluation. Results: Most of our cohort was male 7/12 (57%) and had oral cavity 4/12 (33%) or oropharynx 4/12 (33%) tumors. Additionally, 11/12 (91%) patients received ICB monotherapy. Most of the cohort had a PD-L1 ≤ 1 (7/12; 58%), 7/12 patients experienced disease progression (PD), 4/12 experienced stable disease (SD), and one patient had a partial response (PR). Most of the RNA signal in pre-ICB samples was obtained from CD20 (12/12; 100%), followed by CD45 (10/12; 83%), CD19 (9/12; 75%), and CD274/PD-L1 (5/12; 41%). No difference was found in the RNA signal pre-ICB between responders and non-responders (p=0.1). For the patients with serial sampling available, the signal from CD274/PD-L1 increased after one infusion of ICB in 4/6 patients and remained negative in one. A trend towards a high amount of T cell-derived EVs was observed for the entire cohort (p=0.07; p=0.08) when comparing the amount of RNA via our EV marker (GAPDH, ACTB) between T and B cell devices. Patients with higher than 11.4/mL copies of CD19 (median value for the cohort) in the pre-ICB plasma sample tended to have a higher overall survival (HR 0.26, 95% CI: 0.06-1.13; p-value: 0.05) and progression-free survival (HR 0.28, 95% CI: 0.07-1.16; p-value: 0.06). Conclusion: The EVHB-Chip allowed for the detection and profiling of T and B cell-derived EVs in pre-ICB plasma samples of HNSCC patients undergoing ICB in this pilot cohort. Higher CD19 signal pre-ICB could potentially impact response and survival outcomes in ICB-based therapies. Citation Format: Andrew R. Levy, Daniel A Ruiz Torres, Uma Paithankar, Raheel Ahmad, Daniel C Rabe, Daniel L Faden, Shannon L Stott. Microfluidic isolation of immune cell-derived extracellular vesicles in head and neck cancer patients on immune-checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B048.

Abstract B020: A blood-based multi-omics test for early evaluation of lymphoma treatment effectiveness

Abstract Introduction: The standard clinical assessment for treatment response of lymphoma currently relies on periodic functional imaging examinations. In this prospective study, we utilized a blood-based multi-omics test, SeekInClarity, to evaluate treatment response and predict patient outcomes in the major types of lymphoma. Methods: 116 patients with various lymphoma subtypes were recruited from two clinical centers: The First Affiliated Hospital of Zhengzhou University and Sun Yat-sen University Cancer Center. Blood samples were collected at pre- treatment (baseline) and after two cycles of treatment (landmark) for SeekInClarity analysis, which integrated shallow whole-genome sequencing (sWGS) data of circulating-free DNA (cfDNA), including copy number aberrations (CNA) and fragment size (FS), with seven protein markers. The molecular tumor burden (MTB) score was calculated with SeekInClarity to assess the therapeutic efficacy of patients. Results: At 95.2% specificity, cancer signals were detected in 74.1% (86/116) of patients at baseline. Higher MTB scores were associated with advanced tumor stages, with MTB+ ratios of 31.8%, 63.6%, 84.6%, and 91.2% for stage I, II, III, and IV, respectively. After two cycles of treatment, patients with MTB+ status exhibited significantly poorer progression-free survival (PFS) (HR: 0.13, 95% CI, 0.05-0.33, P &amp;lt; 0.001) and overall survival (OS) (HR: 0.24, 95% CI, 0.06-0.97, P &amp;lt; 0.05) compared to MTB- patients. These trends were consistent across stages, subtypes, and treatment regimens. Traditional biomarkers, lactate dehydrogenase (LDH) and β2-microglobulin (B2M), showed no OS difference between high and low expression groups. The disease progression (PD) rate was 5.2 times higher in the MTB+ group (41.5%) than in the MTB- group (8.0%, P &amp;lt; 0.001), outperforming LDH (1.1 times, 20.7% vs 18.1%, P = 0.15) and B2M (3.1 times, 43.8% vs 14.0%, P = 0.02). All 116 patients, except four with stable disease, were classified as partial or complete response based on imaging at the landmark analysis. However, 13 patients experienced disease progression within six months after treatment. Notably, six (46.2%) were identified earlier through MTB reduction at the landmark. Greater MTB reduction at landmark associated with better OS (P&amp;lt;0.05). Multivariate Cox regression analysis confirmed MTB reduction at landmark as an independent prognostic indicator for PFS, with low reduction indicating a significant increase in disease progression (HR: 0.11, 95% CI: 0.03-0.42, P &amp;lt; 0.001), while other clinical parameters were not significant. Conclusions: This study confirms the clinical utility of SeekInClarity in evaluating lymphoma treatment responses. Reductions in MTB during treatment are associated with patient survival and can predict therapeutic outcomes. Furthermore, post-treatment MTB status after two cycles is an independent prognostic indicator for both PFS and OS. Citation Format: Mao Mao, Wang Xin hua, Li Zhi ming, Chang Yu, Li Shi yong, Wu Wei, Chang Fang yuan, Chang Yin yin, Zhu Dan dan, Zhang Ming zhi. A blood-based multi-omics test for early evaluation of lymphoma treatment effectiveness [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B020.

Abstract 4117032: Investigating the natural history and risk factors underlying deterioration in early-stage hypertrophic cardiomyopathy: findings from SOLENOID

Background: Understanding the natural history and factors contributing to heterogeneous outcomes in patients with early-stage hypertrophic cardiomyopathy (HCM) is crucial to improving patient management. Aim: Utilizing a real-world data cohort spanning multiple centers, we described the natural history of early-stage HCM patients and identified risk factors for disease progression. Methods: SOLENOID is an observational study conducted in five academic centers (two in France, UK, Spain and the US). Inclusion criteria were patients with confirmed HCM seen between 2010 and 2022 in NYHA class I, or in “early stage” NYHA class II (defined by an NT-pro BNP&lt;300 pg/ml, resting or provoked LVOT&lt;50 mmHg, LAVi&lt;35 ml/m2, E/e’&lt;14, without a history of atrial fibrillation (AF), and not on HCM-specific therapy). The endpoint was a composite of NYHA class worsening, new onset of AF and cardiovascular hospitalization. To identify risk factors, univariate analyses were conducted in each center, and then aggregated through a meta-analysis. Results: A total of 1044 patients were included with a median follow-up of 3.9 years (IQR 1.5-7.0). The mean age was 53±16 years, with 30% females and 42% of NYHA I were treated with beta-blockers. Genetic tests in 57% of patients revealed mutations, primarily in MYBPC3 (29%) and MYH7 (12%). During follow-up, the composite endpoint has an incidence of 27% and 41% at 3 and 5 years. The main contributor was NYHA class worsening with an incidence of 24% and 35% at 3 and 5 years. AF at inclusion (log-HR=1.56, p&lt;0.001), baseline level of NT-proBNP (log-HR=0.75, p&lt;0.001) and age at inclusion (log-HR=0.24, p=0.005) were the main predictors of the composite endpoint. Conclusion: Nearly 30% of the early-stage HCM patients experienced disease progression within a 3 year follow-up period, highlighting a medical unmet need. Further studies are needed to assess whether the population characterized by elevated NT-proBNP, or pre-existing AF at inclusion, may benefit from more intensive surveillance and, in future HCM-specific therapy.

EXTH-77. INFANT-TYPE HEMISPHERIC GLIOMAS WITH INITIAL RESPONSE FOLLOWED BY RESISTANCE ON TARGETED AGENTS

Abstract Pediatric-type Diffuse High Grade Gliomas (pHGG) are a rare brain tumor with high mortality and need for more effective treatment options. pHGG’s make up only about 10% of CNS tumors but are responsible for a majority of the deaths. Infant-type Hemispheric Gliomas are a subtype of pHGG with tyrosine kinase alterations in genes such as ROS1, ALK, MET, and NTRK1-3. Despite advances in categorization and targeted therapies, the natural history of patients with infant HGG treated with targeted therapy over time needs to be better characterized, including the durability of objective responses. We present a retrospective case series involving two patients diagnosed with Infant-type Hemispheric Gliomas at Arkansas Children’s Hospital from 2022-2024. Each diagnosis was determined based on histology, targeted tumor sequencing, and methylation profiling. Both patients were initially treated with primary surgical resection and systemic chemotherapy. Each patient experienced disease progression. Actionable pathogenic mutations were identified in both patients (a MET alteration in patient 1 who was then started on Cabozantinib, an ALK fusion in patient 2 subsequently treated with Lorlatinib) with an objective disease response in both patients. In both cases, further relapse occurred while on targeted inhibition. Relapse specimen was not available for patient 1, but for patient 2, recurrent tumor sequencing revealed similar genetics from the diagnostic specimen except for a MET copy number gain suggesting the mechanism of resistance in this patient. Infant-type Hemispheric Gliomas with targetable alterations can show meaningful responses to pathway inhibition. Relapse after initial response may warrant additional surgical sample to identify new alterations which can lead to changes in therapy. Larger prospective cohorts are needed to study targeted agents in this population, and early integration during radiation or after initial diagnosis may be needed.