Incomplete Responders Research Articles

Stereotactic Body Radiation Therapy for Oligoprogressive Ovarian Cancer Patients Treated During Poly(ADP‐Ribose)‐Polymerase Inhibitor Maintenance: Efficacy and Adverse Events From the Epimetheo Retrospective Study

The aim of this observational, retrospective, multicenter study (Epimetheo) was to analyze the activity and the safety of stereotactic body radiation therapy (SBRT) during poly(ADP-ribose)-polymerase inhibitor (PARPi) maintenance in a series of oligometastatic ovarian cancer (OC) patients. Patients treated with PARPi in maintenance setting received SBRT if oligometastatic progression occurred. Maintenance treatment was continued until the extensive progression of the disease. The primary endpoints of the study were as follows: next systemic treatment change-free survival (NEST-FS) and acute and late toxicity; the secondary endpoints were as follows: the rate of clinical complete response (CR), the 2-year actuarial local control (LC, progression of disease inside SBRT field) rate on "per lesion" basis, the 2-year actuarial progression-free survival, and 2-year overall survival (OS). From April 2018 to September 2023, SBRT was used to treat 74 OC patients with a total of 158 lesions (98 lymph nodes and 60 parenchymal lesions) under PARPi maintenance. Olaparib, niraparib, and rucaparib were administered to 41.9%, 48.6%, and 9.5% of patients, respectively. CR, partial response, stable disease, and progressive disease were observed in 115 (72.8%), 32 (20.3%), 9 (5.7%), and 2 lesions (1.3%), respectively. Severe toxicities were reported in less than 3% of patients. The actuarial median NEST-FS was 10 months, with a range of 6.7-13.3 months. The 12- and 24-month actuarial NEST-FS rates were 44.9% and 31.4%, respectively. The 2-year actuarial LC, progression-free survival, and OS were 68.1%, 22.5%, and 77%, respectively with differences in figures between complete and incomplete responders. The achievement of CR was found to be correlated with an improvement in LC and OS. This study reports the activity and the low toxicity profile of SBRT in association with PARPi in oligometastatic OC patients. A rapid, minimally invasive, and cost-effective treatment such as SBRT may be proposed as a means of prolonging NEST-FS and maintaining an effective treatment regimen involving PARPi.

Molecular differentiation between complete and incomplete responders to neoadjuvant therapy in rectal cancer.

Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer, but only 20-40% of patients completely respond to this treatment. To define the molecular features that are associated with response to nCRT, we generated and collected genomic and transcriptomic data from 712 cancers prior to treatment from our own data and from publicly available data. We found that patients with a complete response have decreased risk of both local recurrence and future metastasis. We identified multiple differences in DNA mutations and transcripts between complete and incomplete responders. Complete responder tumors have a higher tumor mutation burden and more significant co-occurring mutations than the incomplete responder tumors. In addition, mutations in DNA repair genes (across multiple mechanisms of repair) were enriched in complete responders and they also had lower expression of these genes indicating that defective DNA repair is associated with complete response to nCRT. Using logistic regression, we identified three significant predictors of complete response: tumor size, mutations within specific network genes, and the existence of three or more specific co-occurrent mutations. In incompletely responder tumors, abnormal cell-cell interaction and increased cancer associated fibroblasts were associated with recurrence. Additionally, gene expression analysis identified a subset of immune hot tumors with worse outcomes and upregulated of immune checkpoint proteins. Overall, our study provides a comprehensive understanding of the molecular features associated with response to nCRT and the molecular differences in non-responder tumors that later reoccur. This knowledge may provide critical insight for the development of precision therapy for rectal cancer.

Can Pretreatment MRI and Planning CT Radiomics Improve Prediction of Complete Pathological Response in Locally Advanced Rectal Cancer Following Neoadjuvant Treatment?

The treatment response to neoadjuvant chemoradiation (nCRT) differs largely in individuals treated for rectal cancer. In this study, we investigated the role of radiomics to predict the pathological response in locally advanced rectal cancers at different treatment time points: (1) before thestart of any treatment using baseline T2-weighted MRI (T2W-MR) and (2) at the start of radiation treatment using planning CT. Patients on nCRT followed by surgery between June 2017 to December 2019 were included in the study. Histopathological tumour response grading (TRG) was used for classification, and gross tumour volume was defined by the radiation oncologists. Following resampling, 100 and 103 pyradiomic features were extracted from T2W-MR and planning CT images, respectively. Synthetic minority oversampling technique (SMOTE) was used to address class imbalance. Four machine learning classifiers built clinical, radiomic, and merged models. Model performances were evaluated on a held-out test dataset following 3-fold cross-validation using area under the receiver operator characteristic curves (AUC) with bootstrap 95% confidence intervals. One hundred and fiftypatients were included; 58/150 with TRG 1 were classified as complete responders, and rest were incomplete responders (IR). Clinical models performed better (AUC = 0.68) compared to radiomics models (AUC = 0.62). Overall, the clinical + T2W-MR model showed best performance (AUC = 0.72) in predicting the pathological response prior to therapy. Clinical + Planning CT-merged models could only achieve the highest AUC of 0.66. Merging clinical and baseline T2W-MR radiomics enhances predicting pathological response in rectal cancer. Validation in larger cohorts is warranted, especially for watch and wait strategies.

Abstract 6414: Molecular differentiation between complete and incomplete responders to neoadjuvant therapy in rectal cancer

Abstract Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer, but only 20-40% of patients completely respond to this treatment. This study aims to identify the molecular features associated with a response to nCRT. We generated and collected genomic and transcriptomic data from 712 cancers prior to treatment from our own data and from publicly available data. A comprehensive integrated analysis was performed. We found that patients with a complete response have decreased risk of both local recurrence and future metastasis. We identified multiple molecular differences between complete and incomplete responders. Complete responders have a higher tumor mutation burden and more significant co-occurring mutations than the incomplete responders. In addition, mutations in DNA repair genes were enriched in complete responders and they also had lower expression of these genes indicating that defective DNA repair is associated with complete response to nCRT. Using logistic regression, we identified three significant predictors of complete response: tumor size, mutations within specific network genes, and the existence of three or more specific co-occurrent mutations. In incompletely responder tumors, abnormal cell-cell interaction and increased cancer associated fibroblasts were associated with recurrence. Additionally, gene expression analysis identified a subset of immune hot tumors with worse outcomes and upregulation of immune checkpoint proteins. Our study directly informs the clinical management of rectal cancer by elucidating the molecular differences between tumors with complete and incomplete responses to neoadjuvant chemoradiotherapy (nCRT), as well as the features of tumors prone to recurrence. We have pinpointed critical molecular markers and clinical indicators—such as tumor size, specific gene mutations, and particular mutation patterns—that are significant predictors of treatment response. These findings offer valuable biomarkers for personalizing treatment strategies. Additionally, the observed mutation enrichment in DNA repair genes among complete responders suggests new avenues for therapeutic innovation. By highlighting the distinct molecular and immune profiles of non-responder tumors at higher recurrence risk, our research supports the advancement of precision oncology approaches, enhancing prognosis and treatment customization in rectal cancer care, ultimately striving to bridge the gap between scientific discovery and clinical application. Citation Format: Fengyuan Huang, M. Chandler McLeod, Regina Kay Irwin, Mary Smithson, Zongliang Yue, Min Gao, Karin M. Hardiman, Zechen Chong. Molecular differentiation between complete and incomplete responders to neoadjuvant therapy in rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6414.

Long-term Efficacy and Safety Following Switch Between Upadacitinib and Adalimumab in Patients with Rheumatoid Arthritis: 5-Year Data from SELECT-COMPARE.

This study aimed to describe the long-term efficacy and safety of upadacitinib and adalimumab through 228weeks following immediate switch to the alternate therapy with a different mechanism of action (MoA) in patients with rheumatoid arthritis (RA) not achieving treatment goals with their initial randomized therapy in the ongoing phase3 SELECT-COMPARE study. Patients with non-response or incomplete response to initially prescribed upadacitinib 15mg once daily or adalimumab 40mg every other week were switched to the alternate therapy by week26. Efficacy was evaluated through 228weeks post-switch using validated outcome measures, including Clinical Disease Activity Index (CDAI) low disease activity (LDA; ≤ 10)/remission (≤ 2.8); 28-joint Disease Activity Score based on C-reactive protein ≤ 3.2/< 2.6; ≥ 20%/50%/70% improvement in American College of Rheumatology (ACR) response criteria; and change from baseline in ACR core components. Data are reported as observed. Safety was assessed by treatment-emergent adverse events (TEAEs) through week264. Of patients initially randomized to upadacitinib and adalimumab, 38.7% and 48.6%, respectively, switched to the alternate therapy by week26. Clinically relevant improvements in all efficacy measures were observed through 228weeks post-switch and were generally similar between groups, with small numeric differences mostly in favor of switching to upadacitinib. CDAI remission was achieved by 32.7% and 28.6% of initial non-responders, and 27.5% and 27.3% of incomplete responders, while CDAI LDA was achieved by 76.9% and 72.9% of non-responders, and 72.5% and 72.7% of incomplete responders switching to upadacitinib and to adalimumab, respectively. TEAE rates were similar between groups, although herpes zoster infection, lymphopenia, and creatine phosphokinase elevation were more frequent when switching to upadacitinib. No new safety signals were identified. Switching to a different MoA may provide long-term benefit to patients with RA not achieving treatment goals with their initial therapy, with acceptable safety profiles. NCT02629159.

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. NCT04539964; August 31, 2020.

Factors associated with immunological non-response after ART initiation: a retrospective observational cohort study

BackgroundAmong people living with HIV (PLHIV) on antiretroviral therapy (ART), the mortality of immunological non-responders (INRs) is higher than that of immunological responders (IRs). However, factors associated with immunological non-response following ART are not well documented.MethodsWe obtained data for HIV patients from the National Free Antiretroviral Treatment Program database in China. Patients were grouped into IRs (CD4 cell count ≥ 350 cells/μl after 24 months’ treatment), immunological incomplete responders (ICRs) (200–350 cells/μl) and INRs (< 200 cells/μl). Multivariable logistic regression was used to assess factors associated with immunological non-response.ResultsA total of 3900 PLHIV were included, among whom 2309 (59.2%) were IRs, 1206 (30.9%) ICRs and 385 (9.9%) INRs. In multivariable analysis, immunological non-response was associated with being male (2.07, 1.39–3.09), older age [40–49 years (vs. 18–29 years): 2.05, 1.29–3.25; 50–59 years: 4.04, 2.33-7.00; ≥ 60 years: 5.51, 2.84–10.67], HBV co-infection (1.63, 1.14–2.34), HCV co-infection (2.01, 1.01–4.02), lower CD4 + T cell count [50–200 cells/μl (vs. 200–350 cells/μl): 40.20, 16.83–96.01; < 50 cells/μl: 215.67, 85.62-543.26] and lower CD4/CD8 ratio (2.93, 1.98–4.34) at baseline. Compared with patients treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) based regimens, those receiving protease inhibitors (PIs) based regimens were less likely to be INRs (0.47, 0.26–0.82).ConclusionsWe found a sizable immunological non-response rate among HIV-infected patients. Being male, older age, coinfection with HBV and HCV, lower CD4 + T cell count and lower CD4/CD8 ratio are risk factors of immunological non-response, whereas PIs-based regimens is a protective factor.

Short-term response to anti-VEGF as indicator of visual prognosis in refractory age-related macular degeneration.

Some patients with neovascular age-related macular degeneration (nAMD) respond insufficiently to anti-VEGF treatment despite maximal monthly intravitreal injections. Their short-term response between injections was investigated for extent and visual prognosis. Monocentric retrospective observational study. 45 eyes from 41 patients with refractory nAMD (who previously received at least 12 months of anti-VEGF treatment), evaluated by optical coherence tomography (OCT) in between monthly anti-VEGF injections. The fluid profile on OCT was evaluated before, 1 week after, and 1 month after an intravitreal injection, using central retinal thickness (CRT), manual measurements, and fluid specific volumetric measurements performed by an automated algorithm based on artificial intelligence. A significant improvement was found at week 1 in terms of CRT (p < 0.0001), intraretinal (IRF) (p = 0.007), subretinal fluid (SRF) (p < 0.0001), and pigment epithelium detachment (PED) volume (p < 0.0001). Volumetric fluid measures revealed a >50% reduction at week 1 for both IRF and SRF for approximately two-thirds of eyes. Poorer short-term response was associated with larger exudative fluid amounts (IRF + SRF) (p = 0.003), larger PED (p = 0.007), lower visual acuity (p = 0.004) and less anatomic changes at treatment initiation (p < 0.0001). Univariate and multivariate analysis revealed that visual outcomes 4 and 5 years later was significantly worse with weaker short-term responsiveness (p = 0.005), with the presence of atrophy (p = 0.01) and larger PED volumes (p = 0.002). Incomplete responders to anti-VEGF showed a significant short-term response, identifiable at 1 week after injection, with rapid recurrence at 1 month. Weaker short-term responsiveness at 1 week was associated with poorer long term visual prognosis. These patients may need adjuvant treatment to improve their prognosis.

Comparison of Study Designs for Primary Phase III Trials for Omalizumab Versus Dupilumab for Patients With Chronic Spontaneous Urticaria

Introduction&#x0D; Omalizumab is currently the only biologic approved and recommended as second-line treatment for patients with chronic spontaneous urticaria (CSU). However, clinical trial programs are underway for other biologic treatments such as dupilumab. Given head-to-head trials will not be conducted, consideration of study design may be important.&#x0D; Methods&#x0D; Comparison of participants, interventions, outcomes, and results for phase III primary efficacy clinical trials for omalizumab versus dupilumab for patients with CSU. The omalizumab trials were ASTERIA I/II (NCT01287117 and NCT01292473) and the dupilumab trial was LIBERTY-CSU CUPID (NCT04180488) that consisted of Study A, B, and C.&#x0D; Results&#x0D; Participants in ASTERIA I/II were 12 to 75 years with a diagnosis of CSU refractory to H1 antihistamines. Participants in LIBERTY-CSU CUPID were 6 to 80 years (Study A and C) or 12 to 80 years (Study B) with a diagnosis of CSU refractory to H1 antihistamines, and Urticaria Activity Score (UAS)7≥16 and Itch Severity Score (ISS)7≥8 during the 7 days before randomization; Study A and C included participants who were omalizumab naïve and Study B included intolerant or incomplete responders to omalizumab. For ASTERIA I and II, the interventions were placebo or omalizumab (75mg, 150mg, 300mg) every 4 weeks for 24 and 12 weeks, respectively. For LIBERY-CSU CUPID, the interventions were placebo or dupilumab (200mg or 300mg, weight based) every 2 weeks for 24 weeks. The primary efficacy outcome for ASTERIA I/II was change from baseline in ISS7 at Week 12. The primary efficacy outcome for LIBERTY-CSU CUPID was change from baseline in ISS7 at Week 24. For the ASTERIA I primary outcome, the change from baseline in ISS7 at Week 12 was -3.6 for placebo and -6.5, -6.7, and ‑9.4 for omalizumab 75mg, 150mg, and 300mg, respectively. For the ASTERIA II primary outcome, the change from baseline in ISS7 at Week 12 was -5.1 for placebo and ‑5.9, ‑8.1, and ‑9.8 for omalizumab 75mg, 150mg, and 300mg, respectively. For the LIBERTY-CSU CUPID Study A primary outcome, the change from baseline in ISS7 at Week 24 was ‑6.0 for placebo and -10.2 for dupilumab. The LIBERTY-CSU CUPID Study B was stopped due to futility based on a pre-specified interim analysis.&#x0D; Conclusion&#x0D; Comparing study designs for primary clinical trials for omalizumab and dupilumab for patients with CSU will aid in the comparative analysis and clinical evaluation of final trial results.&#x0D; Funding: ASTERIA I/II were funded by Genentech Inc. and Novartis Pharma AG.

Systemic Therapies for HER2-Positive Advanced Breast Cancer.

Despite recent advances, HER2-positive advanced breast cancer (ABC) remains a largely incurable disease, with resistance to conventional anti-HER2 drugs ultimately unavoidable for all but a small minority of patients who achieve an enduring remission and possibly cure. Over the past two decades, significant advances in our understanding of the underlying molecular mechanisms of HER2-driven oncogenesis have translated into pharmaceutical advances, with the developing of increasingly sophisticated therapies directed against HER2. These include novel, more potent selective HER2 tyrosine kinase inhibitors (TKIs); new anti-HER2 antibody-drug conjugates; and dual epitope targeting antibodies, with more advanced pharmacological properties and higher affinity. With the introduction of adjuvant T-DM1 for incomplete responders to neoadjuvant therapy, fewer patients are relapsing, but for those who do relapse, disease that may be resistant to standard first- and second-line therapies requires new approaches. Furthermore, the risk of CNS relapse has not been abrogated by current (neo)adjuvant strategies; therefore, current research efforts are being directed towards this challenging site of metastatic disease. In this article, we review the currently available clinical data informing the effective management of HER2-positive breast cancer beyond standard first-line therapy with pertuzumab, trastuzumab, and taxanes, and the management of relapse in patients who have already been exposed to both these agents and T-DM1 for early breast cancer (EBC). We additionally discuss novel anti-HER2 targeted agents and combinations in clinical trials, which may be integrated into standard treatment paradigms in the future.

Comparison of Study Designs for Primary Phase III Trials for Omalizumab Versus Dupilumab for Patients With Chronic Spontaneous Urticaria

Introduction&#x0D; Omalizumab is currently the only biologic approved and recommended as second-line treatment for patients with chronic spontaneous urticaria (CSU). However, clinical trial programs are underway for other biologic treatments such as dupilumab. Given head-to-head trials will not be conducted, consideration of study design may be important.&#x0D; Methods&#x0D; Comparison of participants, interventions, outcomes, and results for phase III primary efficacy clinical trials for omalizumab versus dupilumab for patients with CSU. The omalizumab trials were ASTERIA I/II (NCT01287117 and NCT01292473) and the dupilumab trial was LIBERTY-CSU CUPID (NCT04180488) that consisted of Study A, B, and C.&#x0D; Results&#x0D; Participants in ASTERIA I/II were 12 to 75 years with a diagnosis of CSU refractory to H1 antihistamines. Participants in LIBERTY-CSU CUPID were 6 to 80 years (Study A and C) or 12 to 80 years (Study B) with a diagnosis of CSU refractory to H1 antihistamines, and Urticaria Activity Score (UAS)7≥16 and Itch Severity Score (ISS)7≥8 during the 7 days before randomization; Study A and C included participants who were omalizumab naïve and Study B included intolerant or incomplete responders to omalizumab. For ASTERIA I and II, the interventions were placebo or omalizumab (75mg, 150mg, 300mg) every 4 weeks for 24 and 12 weeks, respectively. For LIBERY-CSU CUPID, the interventions were placebo or dupilumab (200mg or 300mg, weight based) every 2 weeks for 24 weeks. The primary efficacy outcome for ASTERIA I/II was change from baseline in ISS7 at Week 12. The primary efficacy outcome for LIBERTY-CSU CUPID was change from baseline in ISS7 at Week 24. For the ASTERIA I primary outcome, the change from baseline in ISS7 at Week 12 was -3.6 for placebo and -6.5, -6.7, and ‑9.4 for omalizumab 75mg, 150mg, and 300mg, respectively. For the ASTERIA II primary outcome, the change from baseline in ISS7 at Week 12 was -5.1 for placebo and ‑5.9, ‑8.1, and ‑9.8 for omalizumab 75mg, 150mg, and 300mg, respectively. For the LIBERTY-CSU CUPID Study A primary outcome, the change from baseline in ISS7 at Week 24 was ‑6.0 for placebo and -10.2 for dupilumab. The LIBERTY-CSU CUPID Study B was stopped due to futility based on a pre-specified interim analysis.&#x0D; Conclusion&#x0D; Comparing study designs for primary clinical trials for omalizumab and dupilumab for patients with CSU will aid in the comparative analysis and clinical evaluation of final trial results.

Use of social media for the improvement of safety knowledge and awareness among Saudi Arabian phlebotomists.

The purpose of this study is to investigate the use of social media for the improvement of safety knowledge and awareness among phlebotomists. As this study was intended to arrive at specific conclusions using empirical evidence, a deductive quantitative cross-sectional online survey design was adopted. A total of 521 phlebotomists participated in the survey, and 86 incomplete responders were removed, resulting in a final sample of 435 considered in this study. T-tests and ANOVA were used to analyze the data. A total of 41.6% stated that social media was very effective, and 31.5% stated that it was somewhat effective in improving safety knowledge and awareness. in addition, this study revealed no major differences between male and female participants (p > 0.05) with respect to the effectiveness of social media. However, statistically significant differences (p < 0.05) among the age groups were identified in relation to the effectiveness of social media and the intention to use it in the future. Social media applications are effective for knowledge dissemination among healthcare professionals.

Automating Patient-Reported Outcome Measures Following Hand Surgery

The purpose of this study was to assess the overall response rate of patients receiving electronic patient-reported outcome measures (ePROMs) following hand surgery and to determine the patient characteristics associated with responding. A Health Insurance Portability and Accountability Act-compliant, web-based system was developed to automatically distribute ePROMs to patients undergoing hand surgery at five institutions with 22 surgeons. Patients who were at least 18 years old were eligible. The PROMs used were the visual analog scale (VAS) for pain and the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH). After surgery, ePROMs along with a satisfaction questionnaire were electronically sent three, six, 12, 24, and 52 weeks after surgery. A total of 6458 patients were eligible. Of these, 80% were enrolled voluntarily. Among these, 70% completed ePROMs for at least one postoperative time point, whereas 30% did not complete any. Among responders, 28% completed all five time points, whereas 72% completed four or fewer time points. Incomplete responders were more likely to be insured by workers' compensation when compared to complete responders. Incomplete responders exhibited higher baseline QuickDASH scores and similar baseline VAS compared to complete responders. During the follow-up, incomplete responders demonstrated worse VAS and QuickDASH scores at all time points. Finally, in comparison with complete responders, incomplete responders were less likely to be satisfied with their surgery at all time points. This study demonstrates that automated email-based ePROM systems may be an effective method for survey distribution. Particularly for simple, outpatient surgeries, this study illustrates the potential for clinical use of the data obtained from these systems. Patient-reported outcome measures continue to have an expanding role in health care with the rise of valued-based systems. Electronic PROMs are a relatively unexplored medium that may offer a viable alternative to more effectively collecting these valuable patient metrics.

Real-World Use and Predictors of Response to Disopyramide in Patients with Obstructive Hypertrophic Cardiomyopathy.

Background: Although disopyramide has been widely used to reduce left ventricular outflow obstruction (LVOTO) and to improve symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM), its use in real world as well as patient characteristics associated with a positive treatment response are still unclear. Methods: From 1980 to 2021, 1527 patients with HCM were evaluated and 372 (23%) had a LVOTO with active follow-up. The efficacy and safety of disopyramide were assessed systematically during 12 months (2-, 6-, and 12-month visits). Responders were patients with a final NYHA = I and a LVOTO < 30 mmHg; incomplete responders were those patients with NYHA > I and a LVOTO < 30 mmHg; and non-responders were symptomatic patients with no change in functional class NYHA and a LVOT gradient > 30 mmHg. Results: Two-hundred-fifty-four (66%) patients were in functional class NYHA I/II and 118 (34%) in NYHA III/IV. A total of 118/372 (32%, 55 ± 16 years) underwent disopyramide therapy. Twenty-eight (24%) patients responded to therapy, 39 (33%) were incomplete responders, and 51 (43%) did not respond. Responder were mainly patients in functional NYHA class I/II (24/28, 86%), whereas incomplete responders and non-responders were more often in functional NYHA class III/IV (50/54 (93%)). An independent predictor of response to disopyramide treatment was the presence of NYHA I/II at the initiation of therapy (HR 1.5 (95% CI 1.1-4.5), p = 0.03). No major life-threatening arrhythmic events or syncope occurred, despite 19 (16%) patients showing reduced QTc from baseline, 19 (16%) having no difference, while 80 (69%) patients had prolonged QTc interval. Thirty-one (26%) patients experienced side effects, in particular, 29 of the anticholinergic type. Conclusions: Disopyramide was underused in oHCM but effective in reducing LVOTO gradients and symptoms in slightly symptomatic patients with less severe disease phenotype with a safe pro-arrhythmic profile.

Abstract 1062: A comprehensive CRISPR-enabled functional genomics profiling platform in acute myeloid leukemia (AML): Pilot study and validation of Fx Heme

Abstract AML is the most common acute leukemia in adults over 50 years of age. Current therapeutic approaches are focused on high or low dose chemotherapy in the front line setting, with use of molecularly targeted agents in unfit patients or the relapsed/refractory setting. However, routine genomic profiling for common molecular lesions (e.g. FLT3 mutation) incompletely stratifies the target patient population, and more personalized and comprehensive approaches could be of significant clinical benefit. To this end, we have developed an in vitro functional genomics platform for the systematic characterization of gene dependency on drug targets using CRISPR/Cas9 technology. Methods: Retrospective pre-therapy samples were obtained for a cohort of AML patients who subsequently went onto therapy with a combination of the tyrosine kinase inhibitor sorafenib plus chemotherapy (e.g. GCLAM). Unsorted primary tumor cells from these samples were transduced with lentivirus harboring Cas9 enzyme and an sgRNA library. This customized sgRNA library (Fx Heme) was designed to inhibit expression of genes encoding the targets of all FDA-approved oncology drugs, as well as internal positive and negative references. Transduced cells were harvested at multiple timepoints, and sgRNA distribution was assessed by amplicon sequencing of DNA barcodes. Changes in barcode abundance were quantitated and aggregated to calculate gene-level phenotype scores, enabling identification of gene dependencies. Dependency on targets of sorafenib was compared to clinical outcome (complete response (CR) without minimal residual disease (MRD), incomplete response, CR with MRD, or refractory) following treatment with sorafenib plus chemotherapy. Results: Among the 22 AML patients analyzed, 14 reached CR and 8 were classified as incomplete responders (refractory or MRD). Gene dependency on sorafenib targets including FLT3, KIT, PDGFR, and all RAF isoforms was frequently observed (12/22 cases). Among cases indicating any sorafenib target gene dependency, 5/12 (42%) demonstrated dependence on 2 or more sorafenib target genes. Overall, Fx Heme achieved 78.6% sensitivity, 87.5% specificity, and 91.7% PPV for prediction of observed clinical outcome. In contrast, stratification based on FLT3 mutation (internal tandem duplication or tyrosine kinase domain mutation) demonstrated 64.3% sensitivity, 50% specificity, 69.2% PPV. In summary, our results establish feasibility of CRISPR-based Fx Heme comprehensive functional genomic profiling for AML precision medicine, and validate this approach in a retrospective study cohort. Functional genomics may contribute to more effective personalization of AML treatment by uncovering drug target dependencies not readily identified by conventional genomic profiling, in an unbiased, comprehensive and patient-specific fashion. Citation Format: Stephane Corbel, Karl Hodel, Kathleen Tran, Maci Meyers, Jing Tong, Michele Baltay, Peter Kilfeather, Yali Li, Christian Schmedt, Srinath Sampath, Srihari Sampath. A comprehensive CRISPR-enabled functional genomics profiling platform in acute myeloid leukemia (AML): Pilot study and validation of Fx Heme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1062.

A Proposal to Differentiate ACO, Asthma and COPD in Vietnam.

In low- and middle-income countries, such as Vietnam, the population is exposed to multiple risks, leading to frequent allergic asthma, COPD and their overlap (ACO). We aimed to differentiate asthma and COPD, so that recommended treatments can be applied. We hypothesized that during life, the cumulative exposure to noxious particles increases the relative prevalence of COPD, while due to immuno-senescence, the prevalence of allergic asthma decreases with age. Among 568 patients with chronic respiratory symptoms, five phenotypes were defined, based on responsiveness to a bronchodilator (BD), diffusion capacity and cumulative smoking. Then the relative prevalence of each phenotype was related with age. the smoker BD irreversible patients were considered "COPD", while the full BD responders and non-smoking BD incomplete responders were "asthmatics". The other patients were ACO, distributed as "like-COPD" or "like-asthma", based on decreased or normal diffusion capacity. The relative prevalence of asthma, COPD and ACO were 26, 42 and 32% (18% "like-asthma", 14% "like-COPD"). Vietnamese patients with chronic respiratory symptoms were considered as falling into asthma or COPD groups, based on cumulative smoking, spirometry with reversibility and diffusion capacity. The relative prevalence of asthma and COPD were 44 and 56%, respectively, most of which did not require corticosteroids.

P004 Addition of an oral expiratory positive pressure valve (EPAP) to an oral appliance therapy device can resolve obstructive sleep aponea (OSA)

Abstract Background Mandibular advancement splints (MAS) provide effective therapy for many people with OSA. However, in ~50% of cases, MAS alone does not fully resolve OSA. A single-night study showed that ~45% of people with incompletely treated OSA with MAS alone had resolution (apnoea-hypopnea index [AHI]&amp;lt;10 events/h) with the addition of an oral expiratory positive airway pressure (EPAP) valve. This study aimed to determine the safety, tolerability, and longer-term efficacy of oral EPAP valve plus MAS in incomplete responders to MAS alone. Methods Seven people with OSA (AHI=26±13events/h) not fully resolved with MAS alone (AHI&amp;gt;10events/h) were recruited. In-laboratory polysomnography with MAS plus oral EPAP was performed on night 1. Participants then used MAS+EPAP at home for 30-days and completed weekly questionnaires to assess safety, tolerability, and next-morning sleepiness (Karolinska sleepiness scale, KSS). Impact on daytime sleepiness (Epworth sleepiness scale, ESS) was assessed at night 1 and 30. A final at-home WatchPAT study was performed at night 30. Results OSA was successfully treated (AHI&amp;lt;10events/h) in 4/7 participants during the night 1 in-laboratory study (MAS alone vs. MAS+ EPAP 13±2 vs. 7±2events/h). Five had treatment success by night 30 (6±3events/h). Daytime sleepiness (ESS) did not change after 30 days of MAS+EPAP although next-morning sleepiness tended to reduce ( KSS 4.4±1.9 vs. 3.3±1.5, p=0.047 n=7). Oral EPAP was generally well-tolerated with no major side effects reported. Discussion Oral EPAP may be an effective treatment addition for some people with OSA who have an incomplete therapeutic response to MAS alone.

Convolutional Neural Network Classification of Pretreatment Biopsies of Rectal Adenocarcinoma Predicts Complete Clinical Response to Short-Course Radiation and Consolidation Chemotherapy

<h3>Purpose/Objective(s)</h3> Nonoperative treatment of rectal cancer (RCa) with short course radiation (SCRT) (25 Gy in 5 fractions) followed by chemotherapy results in high treatment efficacy while maintaining rectal function. Identifying patients likely to experience a complete response to nonoperative management could prevent overtreatment with chemotherapy and reduce the risk of metastatic progression for incomplete responders. We constructed a convolutional neural network (CNN) classifier of pre-treatment histopathological images to identify patients who will experience a complete response to SCRT and consolidation chemotherapy. <h3>Materials/Methods</h3> Image files of hematoxylin and eosin-stained pre-treatment rectal adenocarcinoma biopsies (n=15) were acquired using the Zeiss microscopy software suite. Files were segmented using grid tools in the ZEN software package. Grid images comprised largely of whitespace were manually removed. Grid images were exported to .jpeg format, preserving micron scale pixel resolution. This analysis utilized 32 .jpeg images belonging to complete responders and 37 .jpeg images belonging to partial responders as the basis for data augmentation to generate a more robust training cohort. We employed the architecture and weights of the well-known VGG16 model with fine tuning of the later layers of the model during training. Regularization, dropout, and early stopping were implemented to prevent overfitting. <h3>Results</h3> Utilizing the VGG16 model with frozen nodal weights resulted in poor classification accuracy and failure to improve via monitoring loss function (training accuracy: 0.3152, validation accuracy: 0.33). Unfreezing, or pruning, after the 7th layer of the VGG16 model and allowing fine tuning of the transferred architecture improved this approach. Later network architectural layers are hypothesized to represent the most sophisticated image features. When nodal weights in VGG16's later layers were allowed to be updated based on training from histopathological slide images the classifiers accuracy improved (training accuracy: 0.9457, validation accuracy: 0.944). Further, loss function was reliably minimized (Epoch 10 validation set binary cross-entropy loss: 0.610, Epoch 50 validation set binary cross-entropy loss: 0.0648). <h3>Conclusion</h3> This is the first study to utilize imaging features extracted by a CNN to predict biological behavior or responsiveness to therapy in rectal cancer. We demonstrated that a transfer learning and layer pruning approach outperforms classical transfer learning utilizing previously deeply trained architectures. While future studies to refine and validate this CNN classifier are warranted, deep learning methods can play a role in preventing overtreatment vs metastatic progression in patients receiving SCRT for RCa.

Outcomes Associated with Total Neoadjuvant Therapy (TNT) with Non-Operative Intent for Rectal Adenocarcinoma

<h3>Purpose/Objective(s)</h3> To evaluate surgery- and permanent ostomy-free survival in patients treated with total neoadjuvant therapy (TNT) with intent for non-operative management of rectal adenocarcinoma. <h3>Materials/Methods</h3> A retrospective review was conducted of patients treated with TNT for stage II-IV rectal adenocarcinoma (n=45) at our institution between 2013-2021. All patients received radiation with concurrent capecitabine or 5-fluorouracil and additional chemotherapy, either prior to or following chemoradiation (CRT), with intent for non-operative management. Clinical complete response rates were determined based on post-treatment MRI or endoscopy. Kaplan-Meier method was utilized to estimate the 1- and 2-year surgery- and permanent ostomy-free survivals. Cox regression analysis was used to evaluate associations between surgery- and permanent ostomy-free survivals and various factors of interest, including patient and tumor characteristics and clinical response. Institutional results on patient outcomes treated from 2013-2018 (n=28) has been reported previously, which have been updated with more patients and longer-term follow-up. <h3>Results</h3> 45 patients were identified with a median follow up of 28 months. 66.7% (n=30) achieved a clinical complete response (cCR). 17 patients (37.8%) underwent surgical resection while only 13.3% (n=4) of patients who achieved a cCR ultimately required surgery. 2 clinical incomplete responders did not have surgery; one patient refused APR and has been stable on maintenance chemotherapy, and one patient continued on surveillance and failed distantly. At 12 months, permanent ostomy free survival was 90.8% and 80.3% at 24 months. Surgery free survival was 76.9% and 65.7%, at 12 and 24 months, respectively. On Cox regression multivariate analysis, 6-month, but not 1-month, post treatment endoscopy was associated with surgery free survival (p=0.006) and permanent ostomy free survival (p=0.033). <h3>Conclusion</h3> Our institutional results support evidence that TNT may be a non-surgical option for select patients with rectal adenocarcinoma. 6-month, but not 1-month post treatment endoscopy was associated with surgery- and permanent ostomy-free survival suggesting continued tumor regression after 1 month. This is consistent with National Comprehensive Cancer Network (NCCN) guidelines to restage rectal cancer patients after at least 8 weeks following RT. Identification of reliable predictors of tumor regression after TNT for patient treatment planning is warranted.

Efficacy and Safety of Bezafibrate Alone or in Combination with Ursodeoxycholic Acid in Primary Biliary Cholangitis: Systematic Review and Meta-Analysis.

Bezafibrate (BZF) alone or in combination with ursodeoxycholic acid (UDCA) has been used to slow disease progression in patients with primary biliary cholangitis (PBC). We performed a systematic review and meta-analysis to assess the efficacy and harms of BZF monotherapy or combination therapy. We performed a systematic search of PubMed, EMBASE, Cochrane Library, Scopus, ClinicalTrials.gov, and WHO ICTRP from inception until January 2020, for randomized controlled clinical trials assessing BZF + UDCA versus UDCA monotherapy or BZF monotherapy versus UDCA monotherapy in PBC patients. Additionally, we systematically evaluated data on harms using seven observational studies. Pooled effect estimates were calculated for the outcomes of interest. The certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). We identified 7 randomized controlled trials with a total of 279 participants. Comparing BZF + UDCA to UDCA alone, a clinically significant improvement was observed in serum ALP with a mean difference (MD) of - 159.04 U/L (95% CI - 186.45 to - 131.62) and a reduction in gamma-glutamyltransferase (GGT) (MD - 106.94IU/L; 95% CI - 151.99 to - 61.89), but not in total bilirubin (TB) or IgM levels. A statistically significant reduction in ALP levels was also noticed with BZF monotherapy compared to UDCA monotherapy. The effect of BZF + UDCA versus UDCA on mortality remains unclear. Across 5 observational studies including 106 patients, one death was reported due to advanced liver disease in an incomplete responder getting treatment with BZF + UDCA. Analysis of observational studies demonstrated improvement in pruritus intensity with BZF. Use of BZF alone or in combination with UDCA improved liver biochemistries in patients with PBC, but its effect on mortality, liver-related complications or quality of life remains unknown.