Real-world Cohort Research Articles

Real-world effectiveness of inactivated vaccine on COVID-19 patients with comorbidities.

Patients with underlying diseases do not respond adequately to vaccines. Thus, continued research on the effects of vaccination in patients with comorbidities is crucial to evaluate the necessity of vaccination in this population. This study assessed the protective effects of inactivated vaccines on the severity and prognosis of COVID-19 in patients with comorbidities. A real-world retrospective cohort study was conducted from April 7, 2022, to June 6, 2022, at the Fudan University Pudong Medical Center. The collected data included demographic characteristics, symptoms, clinical severity, and outcomes of the COVID-19 patients. A total of 3,996 indigenous confirmed cases and asymptomatic infections with the Omicron variant were enrolled. Of these, 1322 (33.1%) patients had chronic comorbidities. Compared to others, COVID-19 patients with comorbidities were older, had lower vaccination rates, longer days of nucleic acid conversion and hospitalization, and a higher incidence of severe-critical illness and composite endpoint. Multivariable analyses suggested that in the comorbidity group, two-dose- (odds ratio [OR] 0.38, 95% CI 0.24-0.60; OR 0.20, 95% CI 0.08-0.51) and three-dose vaccinated patients (OR 0.26, 95% CI 0.14-0.47; OR 0.21, 95% CI 0.08-0.58) had a lower risk of aggravation and the composite endpoint; similar results were observed in the non-comorbidity group. Two or more doses of inactivated vaccines could prevent deterioration and poor prognosis in Omicron-infected patients, regardless of the presence of an underlying disease. Our findings support maximizing coverage with inactivated vaccines in highly vaccinated populations, such as those in China.

Eribulin plus carboplatin combination for HER2-negative metastatic breast cancer: a multicenter, real-world cohort study

BackgroundPre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC.Patients and methodsThis multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated.ResultsFrom March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 − mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 − subtype. The median treatment was 6 cycles (range, 2 − 8 cycles). In the full cohort, TNBC, and HR + HER2 − subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed.ConclusionErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment.

Intravitreal faricimab for treatment naïve patients with neovascular age-related macular degeneration: a real-world prospective study

BackgroundIntravitreal faricimab, a bispecific antibody targeting both angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A), was recently introduced for the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular oedema and cystoid macular oedema secondary to retinal vein occlusion. The aim of our study was to assess the efficacy, safety and durability of intravitreal faricimab in a real-world cohort of treatment-naïve patients with nAMD.MethodsSingle-centre, prospective cohort study of 21 eyes from 19 treatment-naïve nAMD patients who were treated with intravitreal faricimab from October 2022 to April 2024. Patients underwent a loading dose (LD) of 4 monthly faricimab injections followed by a treat-and-extend regimen. Primary outcomes included best-corrected visual acuity (BCVA) and structural parameters from spectral-domain optical coherence tomography (SD-OCT). Secondary outcomes included the proportion of eyes achieving a dry macula, maximal fluid-free interval and intended interval at last follow-up.ResultsThe study included 21 eyes of 19 patients (mean age 83.1 years). After LD, 93.3% of eyes achieved a dry macular SD-OCT scan within a median time of 8 weeks. At the first extension, 53% of eyes remained dry, while 47% showed fluid recurrence. Long-term analysis (n = 14) revealed significant reductions in macular volume (MV), central subfield thickness (CST), and pigment epithelial detachment (PED) height over a median follow-up of 64.9 weeks, with sustained visual and anatomical improvements. Median BCVA, CST, and MV at the final follow-up were significantly improved from baseline (p < 0.01). The intended interval between injections was ≥ 12 weeks in 42.86% of eyes. No cases of intraocular inflammation were observed, although 10% experienced retinal pigment epithelial tears.ConclusionsIntravitreal faricimab demonstrated favourable efficacy, safety, and durability outcomes in a real-world cohort of treatment-naïve nAMD patients.

The Real-World Outcomes of Relapsed/Refractory Multiple Myeloma Treated with Elotuzumab, Pomalidomide, and Dexamethasone.

Introduction: A combination of elotuzumab, pomalidomide, and dexamethasone (EPd) was approved for the treatment of relapsed/refractory multiple myeloma (RRMM) following the ELOQUENT-3 phase II clinical trial. However, the clinical experience with this therapy is still limited. In this retrospective study, we analyzed the efficacy and safety of EPd in a real-world cohort of RRMM patients. Patients and Methods: The medical records of 22 patients who received EPd for RRMM at Yokohama Municipal Citizen's Hospital (Japan) between January 2020 and July 2021 were reviewed. Results: The median age of our cohort was 73.5 years. The overall response rate was 55%. With a median follow-up of 20.2 months, the median progression-free survival (PFS) was 9.1 months (95% confidence interval [CI], 2.5-23.0 months). The median PFS was shorter in patients with a poor performance status (PS) than in those with favorable PS (2.5 vs. 10.8 months; p < 0.01). Patients with prior daratumumab had significantly shorter PFS than those without prior daratumumab (2.1 vs. 23.0 months; p < 0.01). Additionally, patients with prior pomalidomide had significantly shorter PFS (1.7 vs. 10.3 months; p < 0.01). In the multivariate analysis, poor PS (hazard ratio [HR] = 4.1, 95% CI: 1.1-15.6; p = 0.04) and prior exposure to daratumumab (HR = 3.8, 95% CI: 1.1-13.8; p = 0.04) remained significantly associated with shorter PFS. Conclusions: The results of our study suggest that EPd is an active and well-tolerated regimen in RRMM, even in real-world patients. Furthermore, EPd may be useful, especially in daratumumab-naïve patients.

Sacituzumab Govitecan for Second and Subsequent Line Palliative Treatment of Patients with Triple-Negative Breast Cancer: A Polish Real-World Multicenter Cohort Study.

Sacituzumab govitecan (SG) is approved for patients with previously treated metastatic or locally advanced triple-negative breast cancer (TNBC), as per the ASCENT trial results. Real-world studies (RWSs) cover more diverse patients than clinical trials, offering crucial data for healthcare policies. This study aimed to investigate the safety and efficacy of SG in real-world Polish patients with previously treated metastatic TNBC. In this ambispective multicenter cohort study, we collected demographic and clinical data. Premedication, adjustments in SG dosage, and treatment regimen adhered to the product's characteristics. We included 79 female patients. The median age at SG initiation was 53years; 32% of patients were initially diagnosed with a non-TNBC subtype. The median number of previous palliative lines was 2. Seven patients presented with brain metastases. The median overall survival was 10.3months, and the median progression-free survival (PFS) was 4.4months. The overall response rate was 35%, with a median time to response of 2months. SG was discontinued by 70% of patients, primarily due to disease progression (95%). Treatment delays due to adverse events (AEs) occurred in 67% and dose reductions in 25% of patients, with neutropenia being the most common. Grade ≥ 2 AEs included neutropenia (43%), anemia (10.1%), and diarrhea (4%). A longer interval between breast cancer diagnosis and SG initiation or between metastasis diagnosis and SG initiation correlated with improved PFS, likely reflecting the disease's biological aggressiveness rather than treatment efficacy. In this RWS, SG demonstrated effectiveness and safety in patients with previously treated metastatic TNBC, consistent with ASCENT trial outcomes. Further research is needed to explore the efficacy of SG in different patient populations and healthcare systems.

MR radiomics unveils neoadjuvant chemo-responsiveness with insights into selective treatment de-intensification in HPV-positive oropharyngeal carcinoma

BackgroundAccurate prediction of neoadjuvant chemotherapy (NAC) response allows for NAC-guided personalized treatment de-intensification in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). In this study, we aimed to apply baseline MR radiomic features to predict NAC response to help select NAC-guided de-intensification candidates, and to explore biological underpinnings of response-oriented radiomics. MethodsPre-treatment MR images and clinical data of 131 patients with HPV-positive OPSCC were retrieved from Fudan University Shanghai Cancer Center. Patients were divided into training cohort (n = 47), validation cohort 1 (n = 49) from NAC response-adapted de-intensification trial (IChoice-01, NCT04012502) and real-world validation cohort 2 (n = 35). NAC prediction model using linear support vector machine (SVM) was built and validated. Subsequent nomograms combined radiomics and clinical characteristics were established to predict survival outcomes. RNA-seq and proteomic data were compared to interpret the molecular features underlying radiomic signatures with differential NAC response. FindingsFor NAC response prediction, the fusion model with both oropharyngeal and nodal signatures achieved encouraging performance to predict good responders in the training cohort (AUC 0·89, 95% CI, 0·79-0·95) and validation cohort 1 (AUC 0·71, 95% CI, 0·59-0·83). For prognosis prediction, radiomics-based nomograms exhibited satisfactory discriminative ability between low-risk and high-risk patients (PFS, C-index 0·85, 0·76 and 0·83; OS, C-index 0·79, 0·76 and 0·87, respectively) in three cohorts. Expression analysis unveiled NAC poor responders had predominantly enhanced keratinization while good responders were featured by upregulated immune response and oxidative stress. InterpretationThe MR-based radiomic models and prognostic models efficiently discriminate among patients with different NAC response and survival risk, which help candidate selection in HPV-positive OPSCC with regard to personalized treatment de-intensification.

Prognostic value of TMTC1 in pan-cancer analysis

BackgroundTransmembrane and tetratricopeptide repeat containing 1 (TMTC1) is a recently discovered enzyme involved in the O-mannosylation of cadherins and protocadherins. It has been implicated in various types of cancer, but the overall prognostic significance of TMTC1 in pan-cancer and its potential as an immunotherapeutic target remain unclear. MethodsWe applied various bioinformatics methods to investigate the potential oncogenic roles of TMTC1 using public databases. This analysis involved examining the expression, prognosis, genetic alterations, immune infiltration, immunotherapy response, drug sensitivity, and regulatory mechanisms of the TMTC1 gene in diverse cancer types. ResultsIn this study, we observed that TMTC1 expression is reduced in 19 types of cancer (ACC, BLCA, BRCA, CESC, COAD, ESCA, GBM, KICH, KIRC, KIRP, LAML, LUAD, LUSC, PRAD, READ, STAD, THCA, UCEC, and UCS) compared to normal tissues. Conversely, TMTC1 expression is elevated in OV and PAAD relative to normal tissues. Moreover, our analysis revealed that high expression of TMTC1 was associated with worse overall survival (OS) outcomes in patients with ACC, BLCA, COAD, GBM, KIRP, OV, STAD, and UCEC, but better OS outcomes in patients with CESC, KIRC, LUSC, and PAAD. Notably, patients with TMTC1 mutations or deep deletions demonstrated longer OS, while those with TMTC1 amplification showed shorter OS. There was a significant correlation between the expression level of TMTC1 and the infiltration of cancer-associated fibroblasts (CAFs) and endothelial cells. Using data from six real-world immunotherapy cohorts of BLCA, SKCM and RCC, we discovered that high TMTC1 expression was associated with better OS or progression-free survival (PFS). Lastly, through TMTC1-related gene enrichment analysis, some biological processes and pathways were found to be significantly enriched, such as vascular endothelial growth factor receptor signaling pathway and ECM-receptor interaction. ConclusionsOur study demonstrates the prognostic significance of TMTC1 in pan-cancer and highlights its potential as an immunotherapeutic target.

Functional activation of the AKT-mTOR signalling axis in a real-world metastatic breast cancer cohort.

Mutations of the PIK3CA/AKT/mTOR axis are common events in metastatic breast cancers (MBCs). This study was designed to evaluate the extent to which genetic alterations of the PIK3CA/AKT/mTOR can predict protein activation of this signalling axis in MBCs. Molecular profiles were generated by CLIA-certified laboratories from a real-world evidence cohort of 171 MBC patients. Genetic alterations of the PIK3CA pathway were measured using next-generation sequencing. Activation levels of AKT and downstream signalling molecules were quantified using two orthogonal proteomic methods. Protein activity was correlated with underlying genomic profiles and response to CDK4/6 inhibition in combination with endocrine treatment (ET). Oncogenic alterations of the PIK3CA/AKT/PTEN pathway were identified in 49.7% of cases. Genomic profiles emerged as poor predictors of protein activity (AUC:0.69), and AKT phosphorylation levels mimicked those of mutant lesions in 76.9% of wild-type tumours. High phosphorylation levels of the PI3K/AKT/mTOR downstream target p70S6 Kinase (T389) were associated with shorter PFS in patients treated with CDK4/6 inhibitors in combination with ET (HR:4.18 95%CI:1.19-14.63); this association was not seen when patients were classified by mutational status. Phosphoprotein-based measurements of drug targets and downstream substrates should be captured along with genomic information to identify MBCs driven by the PI3K/AKT/mTOR signalling.

Association of Disease-Modifying Treatment With Outcome in Patients With Relapsing Multiple Sclerosis and Isolated MRI Activity.

Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome. Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon β, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses. A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%. In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred. This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.

Abstract A087: Clinical outcomes in Black patients with EGFR-mutated NSCLC treated with osimertinib

Abstract Introduction: Epidermal growth factor receptor (EGFR) gene mutations are present in about 15% of non–small cell lung cancer (NSCLC) cases in the U.S. The FLAURA study, in which the tyrosine kinase inhibitor (TKI) Osimertinib demonstrated a median PFS of 18.9 months, set the current standard in the U.S. for front-line treatment of advanced NSCLC with sensitizing EGFR mutations. However, Black patients were greatly underrepresented in the FLAURA study (&amp;lt;1% of trial population) and two retrospective single-institution studies suggest inferior survival in Black patients with EGFR-mutant NSCLC treated with TKIs versus (vs.) other races. Research is needed using large real-world cohorts to evaluate real-world progression-free survival (rwPFS) and overall survival (OS) in Black patients with EGFR-mutant NSCLC to determine whether they derive comparable benefit from Osimertinib as other races. Methods: The nationwide Flatiron Health Electronic Health Record (EHR)-derived de-identified database was used to analyze data from 1503 patients with advanced NSCLC bearing an EGFR exon 19 deletion or L858R mutation who received front-line Osimertinib. The de-identified data originated from 280 US cancer clinics (∼800 sites of care). Patients were stratified by race (Black vs. White) and characteristics were compared using chi-square, Fisher’s exact, and t-tests. Kaplan-Meier curves estimated rwPFS (based on clinician documentation of progression) and OS in months (m). Differences in survival were assessed between Black and White patients using multivariable Cox proportional hazards models that adjusted for age, gender, EGFR subtype, histology, diagnosis year, smoking history, performance status, insurance status, and socioeconomic index. Results: In our cohort, comprised of 179 Black and 1324 White patients with EGFR-mutant NSCLC, median age and percentage with a smoking history did not differ by race. However, Black patients were more likely to be female (74.3% vs. 66.4%, p=0.03), possess an exon 19 deletion tumor (74.3% vs. 58.3%, p&amp;lt;0.001) or be in a low socioeconomic index category (30.2% vs. 8.7%, p&amp;lt;0.001) than White patients. Median rwPFS did not significantly differ between Black and White patients treated with Osimertinib (15.1 m vs. 14.1 m, HR 0.91, p=0.39). Similarly, no significant difference in OS was observed among Black patients treated with Osimertinib as compared to Whites (29.2 m vs. 32.5 m, HR 1.07, p=0.57). Conclusion: This real-world analysis of one of the largest cohorts of Black patients with EGFR-mutant NSCLC to date, did not observe differences in rwPFS and OS as compared to White patients following front-line Osimertinib therapy. Efforts should be made to ensure all patients receive mutational testing upfront so they can receive optimal first line therapy. Citation Format: Neel Belani, Farsha Rizwan, Jill Hasler, Jessica Bauman, Khadijah Mitchell, Hossein Borghaei, Joseph N Bodor. Clinical outcomes in Black patients with EGFR-mutated NSCLC treated with osimertinib [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A087.

Abstract C083: Meta-analysis reveals differences in somatic alterations by genetic ancestry across common cancers

Abstract Genetic similarity of populations (or genetic ancestry) contributes to cancer driving alterations. We performed a meta-analysis leveraging two real-world cohorts of targeted gene panel sequencing, comprising 275,605 tumor samples, to investigate ancestry-associated somatic alterations across 14 common cancers. We focused on five continental ancestries – European (EUR), African (AFR), East Asian (EAS), South Asian (SAS), and admixed American (AMR). Genetic ancestry was inferred using single nucleotide polymorphism markers from captured regions of gene panel sequencing in each cohort. The combined cohort from Memorial Sloan Kettering – Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) and Foundation Medicine (FMI) contains a substantial number (45,131) of non-EUR samples. Within each cohort, we performed multivariate logistic regression to test association of each cancer gene alteration with proportion of genetic ancestry as a continuous variable, controlling for relevant covariates (age, sex, gene panel version, and histological subtypes) for every combination of ancestry and cancer type. Our analysis focused on oncogenic or likely oncogenic alterations spanning mutations, copy number alterations, and structural rearrangements for each gene. We then aggregated the logistic regression results from the two cohorts using a fixed effects model of meta-analysis weighted by cohort sample size. We found 444 significant associations involving 116 unique genes with consistent logistic regression coefficients between cohorts and False Discovery Rate (FDR)-adjusted p-value &amp;lt; 0.1. These genes were involved in cancer-specific and cross-cancer associations. TP53, KRAS, and TERT were the top three recurrent ancestry-associated genes respectively. TERT promoter mutations were depleted in patients of AFR or EAS ancestry, but enriched in EUR ancestry in bladder urothelial carcinoma, glioblastoma, cutaneous melanoma, and hepatocellular carcinoma. Additionally, TP53 mutations were enriched in AFR and EAS ancestry across multiple cancers, consistent with previous reports, but depleted in prostate cancer in both AFR and EAS ancestries. Among the novel cancer-specific associations with FDA-approved targeted therapies, we found that CDK12 mutations in prostate adenocarcinoma were enriched in EAS ancestry while ERBB2 mutations in lung adenocarcinoma were enriched in AMR ancestry. We also found novel potential drug targets/biomarkers associated with AFR ancestry, such as enrichment of BAP1 mutations in head and neck squamous cell carcinoma and depletion of FGFR2 mutations in uterine endometrioid carcinoma. Overall, our work identified ancestry-associated somatic alteration differences of cancer genes in a combined cohort with a large number of non-European samples. This work underscores the value of studying under-represented populations to replicate or reveal new potential targets for precision oncology. Citation Format: Setor Amuzu, Amy Xie, Xuechun Bai, Kelly R. Pekala, David Ma, Tomin Perea-Chamblee, Kanika Aurora, Garrett Frampton, Michael Berger, Nikolaus Schultz, Justin Y. Newberg, Jian Carrot-Zhang. Meta-analysis reveals differences in somatic alterations by genetic ancestry across common cancers [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C083.

Efficacy, safety and differential outcomes of immune‐chemotherapy with gemcitabine, cisplatin and durvalumab in patients with biliary tract cancers: A multicenter real world cohort

Efficacy, safety and differential outcomes of immune‐chemotherapy with gemcitabine, cisplatin and durvalumab in patients with biliary tract cancers: A multicenter real world cohort

Risk of New-Onset Diabetes Before and During the COVID-19 Pandemic: A Real-World Cohort Study

Risk of New-Onset Diabetes Before and During the COVID-19 Pandemic: A Real-World Cohort Study

Sequential vs. concurrent systemic therapies in combination with FOLFOX-HAIC for locally advanced hepatocellular carcinoma: a single-center, real-world cohort study

BackgroundTri-combination therapy based on hepatic arterial infusion chemotherapy (HAIC) of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the locally advanced hepatocellular carcinoma (HCC) patients have been proven effective. However, whether it was best for these HCC patients to start with the most potent therapeutic pattern was still under debate. This retrospective study evaluated the efficacy and safety of FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules.MethodsThis real-world study included 117 unresectable HCC patients who initially received either FOLFOX-HAIC monotherapy (HAIC group, n = 44) or concurrent ICIs and TKIs (ConHAIC group, n = 73) from March 2020 and June 2022, during the period of FOLFOX-HAIC monotherapy in HAIC group, patients in the HAIC group (n = 30) experienced progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs sequentially (SeqHAIC group). The progression-free survival (PFS) and overall survival (OS), as primary outcomes, were compared between patients in the SeqHAIC and ConHAIC groups.ResultsThe median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74–37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85–18.89 months) and no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848–2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574–2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups. As for the tumor responses, there was no significant difference between the two groups regarding tumor responses, overall response rates (p = 0.658) and disease control rates (p = 0.641) were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively.ConclusionOur study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

Clinical value of plasma pTau181 to predict Alzheimer's disease pathology in a large real-world cohort of a memory clinic

BackgroundThe identification of patients with an elevated risk of developing Alzheimer’s disease (AD) dementia and eligible for the disease modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic. MethodsThree independent cohorts (modelling [n=991, 59.7% female], testing [n=642, 56.2% female] and validation [n=441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181. FindingsCSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker’s performance. The general Aβ(+) vs Aβ(-) ROC curve showed an AUC = 0.77 [0.74 to 0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85 to 0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72 to 96.52], specificity of 72.38 % [62.51 to 79.01], VPP of 77.85% [70.61 to 83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort.The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05 to 3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value. InterpretationPlasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable.Funding: this study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A.

Phosphoproteomics predict response to midostaurin plus chemotherapy in independent cohorts of FLT3-mutated acute myeloid leukaemia

Acute myeloid leukaemia (AML) is a bone marrow malignancy with poor prognosis. One of several treatments for AML is midostaurin combined with intensive chemotherapy (MIC), currently approved for FLT3 mutation-positive (FLT3-MP) AML. However, many patients carrying FLT3 mutations are refractory or experience an early relapse following MIC treatment, and might benefit more from receiving a different treatment. Development of a stratification method that outperforms FLT3 mutational status in predicting MIC response would thus benefit a large number of patients. We employed mass spectrometry phosphoproteomics to analyse 71 diagnosis samples of 47 patients with FLT3-MP AML who subsequently received MIC. We then used machine learning to identify biomarkers of response to MIC, and validated the resulting predictive model in two independent validation cohorts (n=20). We identified three distinct phosphoproteomic AML subtypes amongst long-term survivors. The subtypes showed similar duration of MIC response, but different modulation of AML-implicated pathways, and exhibited distinct, highly-predictive biomarkers of MIC response. Using these biomarkers, we built a phosphoproteomics-based predictive model of MIC response, which we called MPhos. When applied to two retrospective real-world patient test cohorts (n=20), MPhos predicted MIC response with 83% sensitivity and 100% specificity (log-rank p<7∗10-5, HR=0.005 [95% CI: 0-0.31]). In validation, MPhos outperformed the currently-used FLT3-based stratification method. Our findings have the potential to transform clinical decision-making, and highlight the important role that phosphoproteomics is destined to play in precision oncology. This work was funded by Innovate UK grants (application numbers: 22217 and 10054602) and by Kinomica Ltd.

Real-world data on long-acting intramuscular maintenance therapy with cabotegravir and rilpivirine mirror Phase 3 results.

Cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, an NNRTI, constitute the first long-acting (LA), injectable, two-drug ART regimen approved for the maintenance of virological suppression in persons living with HIV-1 (PLHIV). The aim of this study was to assess clinical effectiveness and tolerability of LA cabotegravir/rilpivirine in a real-world setting. We conducted a retrospective, single centre study, including all PLHIV receiving LA cabotegravir/rilpivirine as standard-of-care in our tertiary centre even if initiated in clinical trials. Between 2014 and 2022, 126 PLHIV initiated LA cabotegravir/rilpivirine. All were ART-experienced, and 98.4% had a viral load (VL) of <50 copies/mL before LA cabotegravir/rilpivirine initiation. Median BMI at cabotegravir/rilpivirine initiation was 24 IQR (23-28). During a median follow-up of 9 months IQR (7-24), 27 patients discontinued cabotegravir/rilpivirine because of virological failure, 6 for adverse events, 11 for personal reasons unrelated to treatment tolerance and 5 for other reasons. Virological failure was not associated with a higher BMI, nor with weight gain during LA intramuscular (IM) cabotegravir/rilpivirine treatment, inadequate cabotegravir and rilpivirine concentrations, VL blips or the use of oral lead-in (OLI) or not. No drug resistance-associated mutation emerged. Adverse events leading to treatment interruption were injection-site pain (n = 3) and neuropsychological side effects (n = 3). A correlation between BMI and both cabotegravir and rilpivirine concentrations at 1 month post-initiation of LA-IM cabotegravir/rilpivirine was observed, with no impact of OLI. Data from this real-world cohort of PLHIV who received cabotegravir/rilpivirine LA injections suggest that this regimen is effective and well tolerated. Virological failures were not associated with the acquisition of resistance mutations.

Outcomes with single-agent gilteritinib for relapsed or refractory FLT3-mutant AML after contemporary induction therapy

AbstractGilteritinib is the current standard of care for relapsed or refractory fms related receptor tyrosine kinase 3 (FLT3)–mutated acute myeloid leukemia in many countries, however outcomes for patients relapsing after contemporary first-line therapies (intensive chemotherapy with midostaurin, or nonintensive chemotherapy with venetoclax) are uncertain. Moreover, reported data on toxicity and health care resource use is limited. Here, we describe a large real-world cohort of 152 patients receiving single-agent gilteritinib in 38 UK hospitals. Median age was 61 years, and 36% had received ≥2 prior lines of therapy, including a FLT3 inhibitor in 41% and venetoclax in 24%. A median of 4 cycles of gilteritinib were administered, with 56% of patients requiring hospitalization in the first cycle (median, 10 days). Over half of patients required transfusion in each of the first 4 cycles. Complete remission (CR) was achieved in 21%, and CR with incomplete recovery (CRi) in a further 9%. Remission rates were lower for patients with FLT3–tyrosine kinase domain or adverse karyotype. Day-30 and day-60 mortality were 1% and 10.6%, respectively, and median overall survival was 9.5 months. On multivariable analysis, increasing age, KMT2A rearrangement, and complex karyotype were associated with worse survival whereas RUNX1 mutations were associated with improved survival. Twenty patients received gilteritinib as first salvage having progressed after first-line therapy with venetoclax, with CR/CRi achieved in 25% and median survival 4.5 months. Real-world results with gilteritinib mirror those seen in the clinical trials, but outcomes remain suboptimal, with more effective strategies needed.

Bevacizumab First in DRCR Protocol AC vs Real-World Physician Treatment Choice for Diabetic Macular Edema: Two-Year Cost Analysis.

Purpose: To compare the modeled costs of the Protocol AC bevacizumab-first treatment protocol (with a switch to aflibercept for sub-responders) with real-world costs for treatment-naïve patients with diabetic macular edema (DME) over a 2-year period. Methods: Published data from the Diabetic Retinopathy Clinical Research Network (DRCR) Protocol AC bevacizumab-first arm (154 eyes) were used to model 2-year treatment costs. Real-world costs were modeled using data from the Vestrum Health electronic medical records database from a 2016 to 2018 cohort of treatment-naïve eyes with DME (n = 1062) treated with antivascular endothelial growth factor monotherapy. The visual acuity (VA) before treatment in the real-world cohort was matched to Protocol AC. A secondary cost analysis further matched VA gains after treatment in the real-world cohort (n = 346) to Protocol AC. Results: In Protocol AC, the modeled 2-year DME treatment cost in the bevacizumab-first arm was $18,952, with a mean of 16.1 injections over 22.5 visits and 70% of eyes being switched to aflibercept by year 2. (Within 2 years, 57% of injections were bevacizumab and 43% were aflibercept.) Over the same period, the modeled 2-year real-world cost ($11,459) was 40% lower, with a mean of 8.6 injections over 13.8 visits (42% bevacizumab, 45% aflibercept, 13% ranibizumab). Even when matched for baseline VA and a 14-letter VA gain over 2 years, the real-world cost ($15,394) was still 19% lower than the modeled cost in the Protocol AC bevacizumab-first arm. Conclusions: The real-world cost of treating DME over 2 years was significantly lower than the Protocol AC bevacizumab-first cost. Application of Protocol AC findings into real-world utilization, as with step therapy mandates, should only be considered if the same intensive protocol could be followed. These data suggest that existing real-world costs that reflect physician choice are already significantly lower than protocol-mandated step therapy, even when controlling for similar VA outcomes.

Body mass index changes and their association with SARS-CoV-2 infection: a real-world analysis.

To study body mass index (BMI) changes among individuals aged 18-99 years with and without SARS-CoV-2 infection. Using real-world data from the OneFlorida+ Clinical Research Network of the National Patient-Centered Clinical Research Network, we compared changes over time in BMI in an Exposed cohort (positive SARS-CoV-2 test between March 2020-January 2022), to a contemporary Unexposed cohort (negative SARS-CoV-2 tests), and an age/sex-matched Historical control cohort (March 2018-January 2020). BMI (kg/m2) was retrieved from objective measures of height and weight in electronic health records. We used target trial approaches to estimate BMI at start of follow-up and change per 100 days of follow-up for Unexposed and Historical cohorts relative to the Exposed cohort by categories of sex, race & ethnicity, age, and hospitalization status. The study sample consisted of 249,743 participants (19.2% Exposed, 61.5% Unexposed, 19.3% Historical cohort) of whom 62% were women, 21.5% Non-Hispanic Black, 21.4% Hispanic and 5.6% Non-Hispanic other and had an average age of 51.9 years (SD: 18.9). At start of follow-up, relative to the Unexposed cohort (mean BMI: 29.3 kg/m2 [95% CI: 29.1, 29.4]), the Exposed (0.07 kg/m2 [95% CI; 0.01, 0.12]) had higher mean BMI and Historical controls (-0.20 kg/m2 [95% CI; -0.25, -0.15]) had lower mean BMI. Over 100 days, BMI did not change (0 kg/m2 [95% CI: -0.03, 0.03]) for the Exposed cohort, decreased (-0.04 kg/m2 [95% CI; -0.05, -0.02]) for the Unexposed cohort and increased (0.03 kg/m2 [95% CI; 0.01, 0.04]) for the Historical cohort. Observed differences in BMI at start of follow-up and over 100 days were consistent between Unexposed and Exposed cohorts for most subgroups, except at start of follow-up period among Males and those 65 years or older who had lower BMI among Exposed. In a diverse real-world cohort of adults, mean BMI of those with and without SARS-CoV2 infection varied in their trajectories. The mechanisms and implications of weight retention following SARS-CoV-2 infection remain unclear.