First-line Therapy Research Articles

A comparison of isolated limb infusion/perfusion, immune checkpoint inhibitors, and intralesional therapy as first-line treatment for patients with melanoma in-transit metastases.

Isolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in-transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first-line ILI/ILP, ICI, and TVEC. Retrospective review from 12 international institutions included patients treated from 1990 to 2022 with first-line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM. A total of 551 patients were treated, with ILI/ILP (n=356), ICI (n=125), and TVEC (n=70) with median follow-up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p =.002). Breslow thickness was lowest with TVEC (p =.007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p =.01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p =.029) and a longer local progression-free survival (PFS) (hazard ratio [HR], 0.40; p =.003). ILI/ILP had shorter local PFS (HR, 1.72; p =.012), PFS (HR, 1.79; p <.001), distant metastasis-free survival (DMFS) (HR, 1.75; p =.014), overall survival (HR, 1.82; p =.009), and melanoma-specific survival (HR, 2.29; p =.004). Stage IIIB disease had longer DMFS (HR, 0.24; p <.001) compared to IIIC/D. TVEC as first-line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first-line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.

Decorin as a key marker of desmoplastic cancer-associated fibroblasts mediating first-line immune checkpoint blockade resistance in metastatic gastric cancer.

Gastric cancer (GC) remains a significant cause of cancer-related mortality worldwide. Despite the transformative impact of immune checkpoint blockade (ICB) therapies across various cancers, only a minority of patients with metastatic GC (mGC) benefit, emphasizing the urgent need for precise biomarkers to predict therapeutic responses and optimize patient selection. In this multi-omics study, we conducted whole exome and transcriptome sequencing on 12 tumors from mGC patients treated with nivolumab as first-line therapy. To validate our findings, we performed whole transcriptome sequencing on 17 additional tumors and analyzed 45 tumors from public dataset (PRJEB25780) of patients who received ICB therapy as second or third-line treatment. Comprehensive multi-omics analyses were conducted using single-cell RNA sequencing (n = 5, GSE167297) and spatial transcriptome sequencing (n = 2, independent internal dataset). ICB-sensitive tumors exhibited robust activation of the interferon response pathway, while ICB-resistant tumors displayed epithelial-mesenchymal transition signatures. Intriguingly, at the single-cell level, genes associated with ICB sensitivity were predominantly expressed in immune cells, whereas genes associated with resistance were primarily found in cancer-associated fibroblasts (CAFs), particularly the desmoplastic CAF (dCAF) subtype. We identified DCN as a hallmark dCAF marker, and high DCN expression was inversely correlated with PD-L1 levels, ICB resistance, and poor prognosis in mGC (log-rank p = 0.027). This study elucidates the critical influence of the tumor microenvironment, specifically dCAFs, in mediating ICB resistance in mGC. Our findings highlight DCN as a representative marker for dCAF and a promising negative predictive biomarker for ICB response. These findings highlight the complex stromal-immune interactions and open avenues for personalized treatment for mGC.

Management of portal vein thrombosis in liver transplant candidates.

Portal vein thrombosis (PVT) is a frequent event among patients with advanced liver disease, with a prevalence reaching up to 26% in those awaiting liver transplantation (LT). Extensive thrombosis affecting the mesenteric vein confluence correlates with increased morbidity and mortality post-LT, particularly when it impedes physiological anastomosis or contraindicates the LT. Current guidelines advocate for routine PVT screening in all potential liver transplant candidates and prompt treatment upon detection. The main objective in LT candidates is to facilitate physiological portal-to-portal anastomosis. Anticoagulation serves as the first-line therapy, achieving recanalization rates between 33 and 75%. Discontinuation of anticoagulation significantly heightens the risk of rethrombosis in a substantial proportion of patients and therefore, it is recommended to continue anticoagulation until LT for those awaiting LT or potential LT candidates. Nevertheless, 30-60% of patients fail to respond to anticoagulation, with PVT progression occurring in up to 14% despite anticoagulation. In such cases, TIPS placement emerges as a viable alternative to maintain portal vein patency. While the feasibility of TIPS placement diminished with the presence of portal cavernoma or chronic portal vein thrombosis, the introduction of novel interventional radiological techniques to recanalize the portal venous axis through transplenic, transmesenteric and/or transhepatic routes is revolutionizing this landscape. These advancements achieve TIPS placement and recanalization in 90-100% of patients, warranting consideration in cirrhotic patients with chronic PVT for whom LT would otherwise be contraindicated or when physiological anastomosis is not feasible.

Modeling Drug Responses and Evolutionary Dynamics using Patient-Derived Xenografts Reveals Precision Medicine Strategies for Triple Negative Breast Cancer.

The inter- and intra-tumor heterogeneity of triple negative breast cancers (TNBC), which is reflected in diverse drug responses, interplays with tumor evolution. Here, we developed a preclinical experimental and analytical framework using treatment-naive TNBC patient-derived tumor xenografts (PDTX) to test their predictive value in personalized cancer treatment approaches. Patients and their matched PDTX exhibited concordant drug responses to neoadjuvant therapy using two trial designs and dosing schedules. This platform enabled analysis of non-genetic mechanisms involved in relapse dynamics. Treatment resulted in permanent phenotypic changes with functional and therapeutic consequences. High throughput drug screening methods in ex vivo patient derived tumor xenograft cells (PDTCs) revealed patient-specific drug response changes dependent on first-line therapy. This was validated in vivo, as exemplified by a change in olaparib sensitivity in tumors previously treated with clinically relevant cycles of standard-of-care chemotherapy. In summary, PDTXs provide a robust tool to test patient drug responses and therapeutic regimens and to model evolutionary trajectories. However, high inter-model variability and permanent non-genomic transcriptional changes constrain their use for personalized cancer therapy. This work highlights important considerations associated with preclinical drug response modeling and potential uses of the platform to identify efficacious and preferential sequential therapeutic regimens.

First-choice hormonal therapies for children with infantile epileptic spasms syndrome in South Asia: A network meta-analysis of randomized controlled trials.

Considering the peculiar challenges with infantile epileptic spasms syndrome (IESS) in South Asia and a wide variation in the usage of hormonal therapies, we compared the efficacy and safety of various hormonal therapies for children with IESS in South Asia. We searched PubMed, Embase, Scopus, and Web of Science databases from the inception until April 2024. We included only randomized clinical trials (RCTs) evaluating the efficacy and safety of hormonal therapies for IESS in the South Asian region. Complete cessation of epileptic spasms (ES), electro-clinical response, and time taken to be spasm-free at 2 or 6 weeks of therapy were efficacy outcomes, while the occurrence of adverse events was the safety outcome. Effect estimates were reported as odds ratio (OR) or mean difference (MD) with 95% confidence intervals (CI) and Cochrane risk of bias 2.0 (ROB 2.0) used for quality assessment of each study. The surface under the cumulative ranking curve (SUCRA) was used to rank the different therapies and reported as a p-score ranging from 0 to 1. Of 747 citations, nine RCTs comprising 566 children with IESS were included. After 2-week treatment, dexamethasone (OR: 6.72; 95% CI: 1.47, 30.72), adrenocorticotropic hormone therapy (ACTH) high dose (HD) (OR: 5.30; 95% CI: 1.05, 26.91), and prednisolone HD (OR: 2.41; 95% CI:1.07, 5.46) had shown significantly greater efficacy for cessation of EScompared with ACTH low dose (LD). Similarly, for electroclinical response, dexamethasone (OR: 9.63; 95% CI: 1.99, 46.70) and prednisolone HD (OR: 3.46; 95% CI: 1.38, 8.68) had greater efficacy compared with ACTH LD. Safety outcomes revealed that hypertension was significantly less common with ACTH LD and prednisolone HD as compared with ACTH HD. This study provides quality evidence on preferred first-choice hormonal therapy for managing IESS in South Asia. ACTH HD, dexamethasone, and prednisolone HD are the most effective hormonal therapy options with dose-dependent therapeutic efficacy. PLAIN LANGUAGE SUMMARY: This study provides insights into the selection of first-line hormonal therapies among the various treatments for managing infantile epileptic spasms syndrome (IESS) in South Asia. The study findings suggested that the effectiveness of these therapies is dose-dependent, with high doses of ACTH, dexamethasone, and prednisolone being the most effective for achieving cessation of epileptic spasms.

Updated diagnostic and therapeutic management for membranous nephropathy.

Pioneering contributions in membranous nephropathy over the last decade have greatly enhanced our comprehension of its pathogenesis, diagnosis, and treatments, igniting renewed interest in this entity. This review provides an updated perspective on the diagnosis and therapeutic management of membranous nephropathy. The identification of antiphospholipase A2 receptor (PLA2R) antibodies in 50-80% of membranous nephropathy patients was a key breakthrough. High or increasing PLA2R antibody levels are linked to persistent nephrotic syndrome and the need for targeted treatment. Given the high specificity of PLA2R antibodies, a kidney biopsy may not be required for pure nephrotic syndrome cases with no comorbidities. Over the years, various target antigens and associated conditions have been identified in membranous nephropathy patients, leading to a reclassification of membranous nephropathy. Treatment approaches vary based on baseline characteristics and changes in proteinuria and PLA2R titers. Rituximab has emerged as the first-line therapy for most patients without severe risk factors, with other emerging therapies under development. Advances in the diagnosis and treatment of membranous nephropathy have moved the management towards a more precision-based approach, though further studies and new therapies are needed for a comprehensive management strategy.

Assessment of the Additive Effect of Oral Streptomycin with Traditional Regimen Therapy to Eradicate H-Pylori

Recently, an increased incidence of gastrointestinal disorders due to the overgrowth of H. pylori bacteria has been noticed remarkably. One of the clinical manifestations of H. pylori overgrowth is the increased incidence of gastric ulcers. The first line of therapy that is used frequently is triple antibiotic therapy plus gastric reducing agents, notably proton pump inhibitors (P.P.Is). Streptomycin (SM) is an injectable aminoglycoside antibiotic that has enhanced activity on gran-negative microbes. To evaluate the additive effect of SM when used orally on eradicating H. pylori by standard triple therapy. 109 patients were enrolled in this study with a gastroenterologist diagnosed with gastric ulcer caused by H. pylori colonization; 60 patients received triple therapy with oral SM, and the rest received only standard triple therapy. After 14 days of treatment, a urea breath test was done again (after baseline reading), and statistical analysis was performed to evaluate the effect of SM. The Results showed that there was a significant difference in the degree of response to triple therapy plus SM as compared to using triple therapy alone.

Survival Outcomes of Patients with Primary Plasma Cell Leukemia in the Era of Proteasome Inhibitors and Immunomodulatory Agents: A Real-Life Multicenter Analysis.

In this study, we aimed to obtain real-life data on the use of antimyeloma agents, which significantly increase overall survival (OS) in multiple myeloma (MM) patients, in primary plasma cell leukemia (pPCL) patients with a poor prognosis. Data from 53 patients who were diagnosed with pPCL between 2011-2020 and who used at least one proteasome inhibitor (PI) and/or immunomodulatory (IMID) agent were analyzed retrospectively. Depending on the year of pPCL diagnosis, 20% leukocytes or ≥2×109/L plasma cells in the peripheral blood were used. The median age of the patients was 58 years, and 23 (43.4%) patients were over 65 years of age. For first-line treatment, PI or IMID alone was used in 31 (58.5%) patients, and PI and IMID were used simultaneously in 15 (28.3%) patients. Additionally, 21 (39.6%) patients received transplantation, and 13 (24.5%) patients received maintenance treatment. The median progression-free survival was 4 (1-42) months. When patients whose primary disease was refractory to first-line therapy were excluded, the duration of treatment was 6.5 months. The median OS was 15 months, with a median follow-up of 15 months. Only 7 (13.2%) of the patients were alive at the last follow-up visit. Those with higher beta-2 microglobulin levels and ISS stage 3 and nontransplant patients receiving first-line treatment had shorter OS (p=0.005, p=0.02 and p=0.008, respectively). Otherwise, the concomitant use of PIs and IMIDs, the addition of chemotherapy to induction therapy, and the response to induction therapy or maintenance therapy did not affect OS. In our study, as in previous similar studies, we could not see the increased survival trend in pPCL which is observed in MM. New studies are needed for pPCL patients, which is likely to increase with the new diagnostic criteria, based on current agents and information in MM.

Use of Anti-PD1 Blockade After Hedgehog Inhibitors or as First-Line Therapy for Gorlin Syndrome

This case series examines treatment with anti–programmed cell death 1 (PD1) immunotherapy for patients with basal cell nevus syndrome.

Management of Adult Patients with Newly Diagnosed or Relapsed Primary Immune Thrombocytopenia in Eastern Austria.

Treatment sequence in primary immune thrombocytopenia (ITP) is based on national and international recommendations, treatment availability, and physician expertise. This article aimed to provide real-world data on treatment sequence and responses to first- and second-line treatments in newly diagnosed and relapsed adult ITP patients. We analyzed a cohort of 46 adult ITP patients from the Vienna ITP Biobank, who started first-line therapy within 1 week before their first study visit between February 2016 and March 2023. We investigated clinical patient characteristics and patient management in our specialized center and examined the impact of the international ASH guidelines on ITP treatment. Forty-six primary ITP patients, 27 (58.7%) with newly diagnosed ITP and 19 (41.3%) with relapsed ITP, were investigated. Most patients were female (65.2%) with a median platelet count of 9 × 109/L, and 31 patients (67.4%) had bleeding symptoms. All patients received first-line treatment with oral prednisolone; 15 patients received oral prednisolone combined with intravenous immunoglobulins (IVIGs), which were more commonly administered in newly diagnosed than in relapsed ITP patients. First-line therapy resulted an overall response in 82.6% of patients after a median (interquartile range [IQR]) time of 10 (5-25) days. There was no difference in treatment responses between newly diagnosed and relapsed ITP patients, but newly diagnosed patients had a shorter time to response (median [IQR]: 8 [5-14] and 14 [8-27], p = 0.02). Twenty-three (50%) of the patients (11/27 newly diagnosed [40.7%], 12/19 relapsed [63.2%]) required second-line ITP therapy. Thrombopoietin-receptor agonists (TPO-RAs) were the most commonly used second-line therapy with a response rate of 73.7%, and a median (IQR) time to treatment response of 15 (12-20) days. Overall response rates to TPO-RA treatment did not differ between newly diagnosed and relapsed ITP. Following the publication of novel guidelines in 2019, the median (IQR) duration of corticosteroid treatment shortened (100-52 days, p = 0.01), as did the time to second-line treatment (160-47 days, p = 0.01), and the median number of first-line therapies decreased from 2 (1-3) to 1 (1-2). Initial treatment with corticosteroids was effective in the majority of newly diagnosed and relapsed ITP. Response rates to initial corticosteroid treatment in ITP patients are consistent with previous data, but only 50% achieve sustained remission. TPO-RAs, which are well tolerated and effective, are the most commonly used second-line therapy in our study population. International guidelines have led to faster treatment transitions and reduced splenectomy rates. Integration of real-life experience, expert consensus, and guidelines optimizes ITP patient management.

Real-world comparative Analysis of Liposomal Doxorubicin versus Paclitaxel as First-Line Therapy for Kaposi Sarcoma.

Real-world comparative Analysis of Liposomal Doxorubicin versus Paclitaxel as First-Line Therapy for Kaposi Sarcoma.

Total baseline tumor size predicts survival among patients with advanced small-cell lung cancer receiving chemotherapy plus programmed death-ligand 1 inhibitor as first-line therapy: a multicenter retrospective observational study

IntroductionTotal baseline tumor size (BTS) is a prognostic factor for programmed death 1 and programmed death-ligand 1 (PD-L1) inhibitor treatments. However, the prognostic value of total BTS for patients with small-cell lung cancer (SCLC) who receive chemotherapy plus PD-L1 inhibitor remains unknown. Thus, in this study, we aimed to determine whether total BTS is associated with prognosis in patients with SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.MethodsThis study included patients with extensive-stage SCLC or post-chemoradiotherapy recurrence of limited-stage SCLC who received chemotherapy plus PD-L1 inhibitor as first-line therapy from August 2019 to December 2022. The two lesions with the largest diameter among the measurable lesions in each organ were selected from up to five organs (maximum of 10 lesions), and the sum of all diameters was defined as total BTS. The patients were divided into two groups, large or small, with total BTS using X-tile software. Median survival was analyzed using the Kaplan–Meier method, and the groups were compared using the log-rank test. Univariate and multivariate analyses examined the association between total BTS and prognosis.ResultsFifty patients were included; 14% had large total BTS (&amp;gt;183.2 mm) and 86% had small total BTS (≤183.2 mm). The median observation period was 10.5 months. The large total BTS group showed significantly worse overall survival than the small total BTS group (median: 26.8 months vs. 5.7 months, P = 0.0003). The multivariate analysis indicated that large total BTS was an independent negative predictor of overall survival (hazard ratio: 7.14, 95% confidence interval: 1.89–26.96).DiscussionTotal BTS is a potentially useful prognostic factor for patients with advanced SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.

Apheresis therapies in MOGAD: a retrospective study of 117 therapeutic interventions in 571 attacks

BackgroundIncomplete attack remission is the main cause of disability in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Apheresis therapies such as plasma exchange and immunoadsorption are widely used in neuroimmunology. Data...

Contemporary use of fibrinolytics in the management of pediatric empyema.

This study seeks to investigate the contemporary use and effectiveness of fibrinolysis as a first-line option in pediatric empyema. The Pediatric Health Information System (PHIS) was queried to identify patients with empyema without fistula (2018-2023). First-line treatments were chest drainage (CD), chest drainage with fibrinolysis (CDF), and video-assisted thoracoscopic surgery/open decortication (VATS/OD). Outcomes between groups were compared using Kruskal-Wallis and Chi-Square tests. Multivariate generalized linear model was used to account for covariates. 581 individuals/cases met inclusion criteria. CD accounted for 11.9% of cases, CDF for 67.6%, and VATS/OD for 20.7%. After adjusting for covariates differences in LOS were not significant (p = 0.393). Subsequent VATS/ODs were required in 6.9% of CDF cases, 8.9% of CD, and 3.3% of primary VATS/OD. Additionally, 32.5% of primary VATS/OD received adjuvant fibrinolysis. Complications were more often observed in the VATS/OD group compared to CD and CDF (11.7% vs 5.8% and 4.1% respectively; p = .008). There were no differences in 30-day readmission rate (VATS/OD:1.2%, CTD:1.5%, and CTDF:1%; p = 0.83). Fibrinolysis is now utilized as first-line treatment for most patients and as adjunct in other approaches. The findings justify further implementation as it is the less invasive first-line primary therapy in patients with empyema.

IgA Vasculitis (Henoch-Schönlein Purpura): An Update on Treatment.

Objective: IgA vasculitis (IgAV), previously named as Henoch-Schönlein purpura, is the most frequent systemic vasculitis in children. In adults, IgAV is less common although it is associated with more severe disease. In fact, the frequency of glomerulonephritis (referred to as IgAV nephritis) in adults is higher than in children and tends to present more severely, with around 10-30% of those affected eventually progressing to end-stage renal disease. In this review, we describe the pathophysiology, main clinical features, diagnosis of the disease, and latest clinical data regarding IgAV therapy. Methods: A narrative literature review, primarily based on articles published in PubMed, was conducted. In addition to discussing the main aspects of glucocorticoids and conventional disease-modifying drugs used in the management of IgAV, this review focuses on the latest information reported regarding biologics and potential future therapies. Results: Glucocorticoids are the first-line therapy for IgAV, especially in adults with severe manifestations. Colchicine, dapsone, and methotrexate can be useful for controlling minor manifestations. Several immunomodulatory agents, such as cyclosporine A, tacrolimus, and mycophenolate mofetil, have shown favorable results as glucocorticoid-sparing agents. Leflunomide has shown promising results but requires further study. The use of rituximab has demonstrated efficacy in reducing relapse frequency, lowering the cumulative glucocorticoid burden, and achieving long-term remission of the disease in children and adults with IgAV. Immunoglobulins and plasma exchange therapy can also be useful in difficult and life-threatening situations. Other potential therapies with encouraging results include TRF-budesonide, B-cell-directed therapy, B-cell-depleting agents, sodium-glucose cotransporter-2 inhibitors, endothelin receptor antagonists, and complement pathway inhibitors. Conclusions: Glucocorticoids are the first-line therapy for IgAV, especially in adults with severe manifestations. The role of various immunomodulatory therapies, such as calcineurin inhibitors and mycophenolate mofetil, remains promising, while rituximab reduces the long-term side effects of glucocorticoids and can help achieve disease remission. Other potential therapies with encouraging results require further research.

Analisis Minimalisasi Biaya Terapi Antibiotik Ceftriaxone dan Cefotaxime Pada Pasien Pneumonia di Instalasi Rawat Inap RSUD Kabupaten Kediri

Pneumonia is an infection caused by pathogenic microorganisms such as microbes, bacteria, fungi and viruses that cause inflammation of the lung tissue. The prevalence of pneumonia has increased every year. The first-line therapy used at the Kediri District Hospital is the use of ceftriaxone and cefotaxime antibiotics. Decision making on antibiotic use has an influence on the amount of medical costs incurred by patients. This study aims to determine which antibiotics are more cost-minimal and whether there is a significant difference between the use of ceftriaxone and cefotaxime antibiotic therapy at Kediri District Hospital. The design of this study was cross sectional, data collection was done retrospectively. The analysis method used independent t-test statistical test. The perspective in this study was seen through the provider, namely the hospital, a total of 215 pneumonia patients and the sample for this study was 63 patients. With 32 patients receiving ceftriaxone antibiotic therapy and 31 patients receiving cefotaxime antibiotic therapy. Total direct medical costs were categorized into four types of costs, namely treatment costs, antibiotic costs, other drug costs, laboratory and radiology costs. The average total direct medical costs of patients who received ceftriaxone antibiotic therapy were more cost minimal than patients who received cefotaxime antibiotics, namely Rp.2,296,449 and Rp.2,464,470. The results of the difference test using independent t-test statistics show a p-value of 0.219 so that it can be interpreted that there is no significant difference.

PSA Kinetics Affect Prognosis in Patients With Castration-resistant Prostate Cancer Treated With Enzalutamide.

There is little evidence regarding the predictive value of prostate-specific antigen (PSA) kinetics in patients with castration-resistant prostate cancer treated with an androgen receptor signaling inhibitor. This study investigated the correlation between PSA kinetics and prognosis in patients with castration-resistant prostate cancer treated with enzalutamide. We analyzed data from 103 patients who received enzalutamide as primary treatment for castration-resistant prostate cancer at our hospital, focusing on the associations between overall survival and PSA kinetics variables, such as maximal PSA response, PSA nadir, and time to PSA nadir. The median PSA level at the initiation of enzalutamide was 18.1 ng/ml (interquartile range=7.9-61.2 ng/ml). The median maximal PSA response rate was 88% (interquartile range 55-98), and the median PSA nadir was 1.84 (interquartile range (IQR)=0.38-14.7) ng/ml. The median time to PSA nadir was 19 (IQR=6-28.5) weeks. Maximal PSA response rate <90% [hazard ratio (HR)=2.28, 95% confidence interval (CI)=1.03-5.03, p=0.0413], PSA nadir >2 ng/ml (HR=2.30, 95%CI=1.05-5.07, p=0.0379), time to nadir <19 weeks (HR=2.48, 95%CI=1.15-5.35, p=0.0204) were all independently predictive of shortened overall survival even after adjusting for pre-treatment factors. Maximal PSA response, PSA nadir, and time to PSA nadir correlated with survival in patients with castration-resistant prostate cancer receiving enzalutamide as a first-line therapy.

Fibroblast-like synoviocyte targeting antibodies are associated with failure to reach early and sustained remission or low disease activity after first-line therapy in rheumatoid arthritis

ObjectiveTo discover antibody biomarkers that can predict a lack of response to first-line therapy in rheumatoid arthritis (RA) patients.MethodsTwo RA cDNA phage display libraries were screened for novel antibodies in baseline RA sera from the Care in early RA (CareRA) trial, differentiating between patients who did or did not reach remission after first-line therapy (n=20 each). Antibody reactivity to identified University Hasselt (UH)-RA antigens was validated in baseline samples from 136 additional CareRA participants. The novel antibodies’ potential to predict failure to reach remission or low disease activity (LDA), according to the Disease Activity Score 28-joint C-reactive protein/erythrocyte sedimentation rate (DAS28CRP/ESR) and Clinical/Simplified Disease Activity Index (CDAI/SDAI), was studied by multivariate analyses. The presence of the antibody targets in RA synovial tissue and the fibroblast-like synoviocyte (FLS) cell line SW982 was determined by immunofluorescence.ResultsWe identified antibodies to 41 novel antigens. Antibodies against any of three antigens, UH-RA.305/318/329, discriminated between RA patients not reaching week (w)8 DAS28CRP remission and those that did (36% vs 13%,p=0.0031). In all patients, anti-UH-RA.305/318/329 antibody reactivity was associated with failure to reach week 8 DAS28CRP and DAS28ESR remission (OR 3.63,p=0.0031; OR 2.92,p=0.016; respectively), SDAI/CDAI sustained remission (OR 5.59,p=0.039 for both) and DAS28CRP and DAS28ESR sustained LDA (OR 3.7,p=0.009; OR 2.76,p=0.042; respectively). In rheumatoid factor/anti-citrullinated protein antibody (RF/ACPA) seronegative patients, these antibodies were strongly associated with failure to achieve week 8 DAS28CRP remission (OR 17.3,p=0.0029). Anti-UH-RA.305/329 antibodies were shown to target FLS in RA synovial tissue and SW982 cells.ConclusionWe identified three antibody biomarkers that are associated with failure to achieve remission/LDA after first-line RA therapy.

Characteristics and treatment patterns of long-surviving patients with multiple myeloma: over 13 years of follow-up in the Connect® MM Registry

BackgroundOver the last 15 years, improvements in patient management and treatments have been associated with longer survival in patients with multiple myeloma (MM). The Connect MM Registry is a long-running, US, multicenter, prospective observational cohort study of patients with newly diagnosed MM (NDMM). We assessed the demographics, clinical characteristics, and treatment patterns of long-term survivors (LTS) enrolled in this registry. MethodsAdults with NDMM (N=3,011) were enrolled from 250 community, academic, and government sites across the US from 2009-2016. Baseline characteristics, treatment patterns, quality of life (QoL), and overall survival (OS) were examined among LTS, defined as patients with follow-up of ≥8 years after enrollment. ResultsAs of February 7, 2023, 518 patients were LTS and 2,493 were non-LTS. LTS were generally younger and had better performance status at enrollment compared with non-LTS. Most (65%) LTS received stem cell transplants and few (2%) experienced disease progression within 6 months of starting first line of therapy. At data cutoff, 63% of LTS were still on treatment at their most recent visit. QoL scores and QoL questionnaire completion rates were consistently higher among LTS than non-LTS. The estimated 8-year OS rate of all patients enrolled in the registry was 40%, comparable to an observed 8-year survival of 39% from the Surveillance, Epidemiology, and End Results (SEER) database. ConclusionThis analysis provides insights on long-surviving patients with MM using real-world data and therefore presents generalizability beyond data obtained in long-term follow-up of clinical trials, underscoring the need for longitudinal follow-up through registries. DisclosuresHoward R. Terebelo, James Omel, Lynne I. Wagner, James W. Hardin Brian G. Durie, Mohit Narang, Kathleen Toomey, and Rafat Abonour report serving on a scientific steering committee for Bristol Myers Squibb. Robert M. Rifkin reports serving on a scientific steering committee for Bristol Myers Squibb; employment, stock, and other ownership interests with McKesson; participation on data safety monitoring board for CARsgen; and advisory role with Amgen, Bristol Myers Squibb; Coherus BioSciences, Genmab, Fresenius Kabi, and Janssen. Sikander Ailawadhi reports serving on a scientific steering committee for Bristol Myers Squibb; consulting fees from BeiGene, Bristol Myers Squibb, Cellectar, GSK, Janssen, Pfizer, Regeneron, Sanofi, and Takeda; and research funding from AbbVie, Amgen, Ascentage, Bristol Myers Squibb, Cellectar, GSK, Janssen, Pharmacyclics, and Sanofi. Cristina J. Gasparetto reports serving on a scientific steering committee for Bristol Myers Squibb; support for travel from Bristol Myers Squibb, Karyopharm, and Sanofi; advisory role for Bristol Myers Squibb, Janssen, and Pfizer; and for Bristol Myers Squibb, Karyopharm, and Sanofi. Prashant Joshi, E. Dawn Flick, Edward Yu, and Ying-Ming Jou report employment and stock and other ownership interests with Bristol Myers Squibb. Hans C. Lee reports serving on a scientific steering committee for Bristol Myers Squibb; consulting fees from Allogene, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Monte Rosa Therapeutics, Pfizer, Regeneron, Sanofi, and Takeda; and grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Regeneron, and Takeda. Sundar Jagannath reports serving on a scientific steering committee for Bristol Myers Squibb; consulting fees from Bristol Myers Squibb, Janssen, Karyopharm Therapeutics, Legend Biotech, Regeneron Sanofi, and Takeda; support for travel from ASCO, ASH, and IMS; participation on data safety monitoring boards for Bristol Myers Squibb, Janssen, and Sanofi; and leadership or fiduciary role for ASH, IMS, and SOHO. MicroAbstractPatient characteristics, treatment patterns, quality of life, and survival were analyzed among long-surviving patients of multiple myeloma from the Connect® MM Registry. Long survivors were generally younger and healthier at diagnosis when compared with non-long survivors. The results provided insights beyond the long-term follow-up of clinical trials, indicating the importance of real-world longitudinal follow-up.

Putative mechanisms of primary resistance to EGFR-targeted therapies: A retrospective study

BackgroundsAdvanced lung adenocarcinoma (LUAD) patient with EGFR mutations often experience resistance to first-line epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) therapy. Nonetheless, the mechanism and biomarkers of primary resistance remain unclear. Further exploration of independent prognostic factors will help clinicians identify patients who may not respond to EGFR-TKIs and select appropriate treatment strategies. MethodsA retrospective study involving 124 patients with stage IV LUAD harboring a common sensitizing EGFR mutation (exon 19 deletion or L858R mutation) who received EGFR-TKIs as first-line therapy was performed. All participants were tested by DNA-targeted sequencing in baseline samples, and there were 19 patients with progression-free survival (PFS) ≤ 3 months (cohort 1, C1, primary resistance), 22 patients with 3 < PFS < 8 months (cohort 2, C2, poor response) without known mutations associated with resistance, and 83 patients with PFS ≥ 8 months (cohort 3, C3, normal). ResultsThe most commonly mutated genes at baseline in patients prior to treatment within the entire study population. were TP53 (65 %), MYC (19 %), CDKN2A (12 %), MUC16 (12 %) and RBM10 (12 %). The baseline characteristics, except for the proportions of patients with EGFR L858R mutation and exon 19 deletion in C1 plus C2 compared to C3 (p = 0.036), were not significantly different among the cohorts. The frequencies of PIK3C2G, STK11, EPAS1, RARA and BTG2 variation were significantly higher in C1, the primary resistance group. Multivariate Cox analysis revealed that PIK3C2G (HR 15.70 95 % CI 3.24–76.05, p < 0.001), STK11 (HR 17.04, 95 % CI 3.68–78.92, p < 0.001), EPAS1 (HR 11.99, 95 % CI 2.57–56.03, p = 0.002), and BTG2 amplification (HR 9.53, 95 % CI 1.67–54.28, p = 0.011) were significantly associated with shorter PFS. ConclusionsThe genomic landscape varies significantly among patients with LUAD, which should be considered when making personalized treatment decisions. This information could provide insights into molecular changes and their effects on clinical treatment in diverse patients with LUAD harboring sensitizing EGFR mutations.