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JAMA Network Open Jun 2024Among patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate, a treatment sequence initiated with biosimilar disease-modifying... (Comparative Study)
Comparative Study
IMPORTANCE
Among patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate, a treatment sequence initiated with biosimilar disease-modifying antirheumatic drugs (DMARDs) provides better clinical efficacy compared with conventional synthetic DMARDs recommended by current treatment guidelines; but its cost-effectiveness evidence remains unclear.
OBJECTIVE
To evaluate the cost-effectiveness of the treatment sequence initiated with biosimilar DMARDs after failure with methotrexate vs leflunomide and inform formulary listing decisions.
DESIGN, SETTING, AND PARTICIPANTS
This economic evaluation's cost-effectiveness analysis was performed at a Hong Kong public institution using the Markov disease transition model to simulate the lifetime disease progression and cost for patients with RA, using monetary value in 2022. Scenario and sensitivity analyses were performed to test the internal validity of the modeling conclusion. Participants included patients diagnosed with RA from 2000 to 2021 who were retrieved retrospectively from local electronic medical records to generate model input parameters. Statistical analysis was performed from January 2023 to March 2024.
INTERVENTIONS
The model assesses 3 competing treatment sequences initiated with biosimilar infliximab (CT-P13), biosimilar adalimumab (ABP-501), and leflunomide; all used in combination with methotrexate.
MAIN OUTCOMES AND MEASURES
Lifetime health care cost and quality-adjusted life-years (QALYs) of the simulated cohort.
RESULTS
In total, 25 099 patients with RA were identified (mean [SD] age, 56 [17] years; 19 469 [72.7%] women). In the base-case analysis, the lifetime health care cost and QALYs for the treatment sequence initiated with leflunomide were US $154 632 and 14.82 QALYs, respectively; for biosimilar infliximab, they were US $152 326 and 15.35 QALYs, respectively; and for biosimilar adalimumab, they were US $145 419 and 15.55 QALYs, respectively. Both biosimilar sequences presented lower costs and greater QALYs than the leflunomide sequence. In the deterministic sensitivity analysis, the incremental cost-effectiveness ratio (US$/QALY) comparing biosimilar infliximab sequence vs leflunomide sequence and biosimilar adalimumab sequence vs leflunomide sequence ranged from -15 797 to -8615 and -9088 to 10 238, respectively, all below the predefined willingness-to-pay threshold (US $48 555/QALY gain). In the probabilistic sensitivity analysis, the probability of treatment sequence initiated with leflunomide, biosimilar infliximab, and biosmilar adalimumab being cost-effective out of 10 000 iterations was 0%, 9%, and 91%, respectively.
CONCLUSIONS AND RELEVANCE
In this economic evaluation study, the treatment sequences initiated with biosimilar DMARDs were cost-effective compared with the treatment sequence initiated with leflunomide in managing patients with RA who experienced failure with the initial methotrexate treatment. These results suggest the need to update clinical treatment guidelines for initiating biosimilars immediately after the failure of methotrexate for patients with RA.
Topics: Humans; Arthritis, Rheumatoid; Leflunomide; Biosimilar Pharmaceuticals; Cost-Benefit Analysis; Antirheumatic Agents; Female; Male; Middle Aged; Infliximab; Adult; Hong Kong; Retrospective Studies; Quality-Adjusted Life Years; Adalimumab; Aged
PubMed: 38922614
DOI: 10.1001/jamanetworkopen.2024.18800 -
Cancer Discovery Jun 2024Comprehensive m6A epitranscriptome profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 non-neoplastic lung (NL)...
Comprehensive m6A epitranscriptome profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 non-neoplastic lung (NL) tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptome, proteome and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with NL tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hyper-methylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics through interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small molecule inhibitor markedly diminished both EML4 m6A and protein abundance, and efficiently suppressed lung metastases in vivo.
PubMed: 38922581
DOI: 10.1158/2159-8290.CD-23-1212 -
Breast Cancer Research and Treatment Jun 2024This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone...
Prognostic value of the 21-Gene Breast Recurrence Score® assay for hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer: subanalysis from Japan Breast Cancer Research Group-M07 (FUTURE trial).
PURPOSE
This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial).
METHODS
Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0-17, Intermediate: 18-30, High: 31-100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV).
RESULTS
In total, 102 patients [Low: n = 44 (43.1%), Intermediate: n = 38 (37.5%), High: n = 20 (19.6%)] in Group A, and 45 in Group B, who had progression in Group A were analyzed. The median follow-up time was 23.8 months for Group A and 8.9 months for Group B. Multivariate analysis in Group A showed that low-risk [hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.04-0.53, P = 0.003] and intermediate-risk (HR 0.22, 95% CI 0.06-0.78) with de novo stage IV breast cancer were significantly associated with better prognosis compared to high-risk. However, no significant difference was observed among patients with recurrence. No prognostic significance was observed in Group B.
CONCLUSION
We found a distinct prognostic value of the 21-Gene Breast Recurrence Score® assay by the types of ABCs and a poor prognostic value of the high RS for patients with de novo stage IV BC treated with fulvestrant monotherapy. Further validations of these findings are required.
PubMed: 38922548
DOI: 10.1007/s10549-024-07414-7 -
International Urology and Nephrology Jun 2024Mohs micrographic surgery (MMS) is a low-risk penile cancer management option. However, contemporary patients' short-term oncologic control and preoperative...
PURPOSE
Mohs micrographic surgery (MMS) is a low-risk penile cancer management option. However, contemporary patients' short-term oncologic control and preoperative characteristics predicting reconstruction needs are undefined. This study assesses MMS's oncologic efficacy for low-risk penile cancer and identifies baseline predictors of post-resection reconstruction referral.
METHODS
We retrospectively reviewed 73 adult males with 78 penile cutaneous malignancies treated with MMS from 2005 to 2019. Patients underwent MMS with or without surgical reconstruction. Demographic information, MMS operative details, lesion pathology, and short-term outcomes were recorded. Descriptive statistics for all variables were calculated, and logistic regression identified predictive factors for urologic referral for complex reconstruction.
RESULTS
Seventy-three men with 78 lesions, all staged ≤ cT1a prior to MMS, were identified. Twenty-one men were found to have invasive SCC. Median follow-up was 2.0 years (IQR 0.8-5.2 years). MMS was able to clear the disease in 90.4% of cases. One patient had disease related death following progression. Dermatology closed primarily in 68% of patients. Twenty percent of patients had a complication, most commonly poor wound healing. On univariate and multivariate linear regression analysis, lesion size > 3 cm and involvement of the glans independently predicted the need for referral to a reconstructive surgeon.
CONCLUSIONS
MMS for penile cancer appears to provide sound oncologic control in the properly selected patient. Involvement of a reconstructive surgeon may be needed for glandular and large lesions, necessitating early referral to a comprehensive multidisciplinary care team.
PubMed: 38922534
DOI: 10.1007/s11255-024-04121-6 -
Cell Biology and Toxicology Jun 2024The primary objective of this investigation is to delve into the involvement of the long noncoding RNA (lncRNA) SPACA6P-AS in breast cancer (BC) development, focusing on...
OBJECTIVE
The primary objective of this investigation is to delve into the involvement of the long noncoding RNA (lncRNA) SPACA6P-AS in breast cancer (BC) development, focusing on its expression pattern, association with clinical-pathological features, impact on prognosis, as well as its molecular and immunological implications.
METHODS
Bioinformatics analysis was conducted utilizing RNA sequencing data of 1083 BC patients from the TCGA database. Functional exploration of SPACA6P-AS was carried out through the construction of survival curves, GO and KEGG enrichment analysis, and single-sample gene set enrichment analysis (ssGSEA). Furthermore, its functionality was validated through in vitro cell experiments and in vivo nude mouse model experiments.
RESULTS
SPACA6P-AS showed a remarkable increase in expression levels in BC tissues (p < 0.001) and demonstrated a close relationship to poor prognosis (overall survival HR = 1.616, progression-free interval HR = 1.40, disease-specific survival HR = 1.54). Enrichment analysis revealed that SPACA6P-AS could impact biological functions such as protease regulation, endopeptidase inhibitor activity, taste receptor activity, taste transduction, and maturity-onset diabetes of the young pathway. ssGSEA analysis indicated a negative correlation between SPACA6P-AS expression and immune cell infiltration like dendritic cells and neutrophils, while a positive correlation was observed with central memory T cells and T helper 2 cells. Results from in vitro and in vivo experiments illustrated that silencing SPACA6P-AS significantly inhibited the proliferation, migration, and invasion capabilities of BC cells. In vitro experiments also highlighted that dendritic cells with silenced SPACA6P-AS exhibited enhanced capabilities in promoting the proliferation of autologous CD3 + T cells and cytokine secretion. These discoveries elucidate the potential multifaceted roles of SPACA6P-AS in BC, including its potential involvement in modulating immune cell infiltration in the tumor microenvironment.
CONCLUSION
The high expression of lncRNA SPACA6P-AS in BC is closely linked to poor prognosis and may facilitate tumor progression by influencing specific biological processes, signaling pathways, and the immune microenvironment. The regulatory role of SPACA6P-AS positions it as a prospective biomarker and target for therapeutic approaches for BC diagnosis and intervention.
Topics: Humans; Breast Neoplasms; Animals; RNA, Long Noncoding; Female; Gene Expression Regulation, Neoplastic; Mice, Nude; Mice; Cell Line, Tumor; Prognosis; Cell Proliferation; Mice, Inbred BALB C; Middle Aged; Cell Movement; Computational Biology
PubMed: 38922500
DOI: 10.1007/s10565-024-09870-9 -
Journal of Patient-reported Outcomes Jun 2024The Good Life with osteoArthritis: Denmark (GLA:D™), an evidence-based education and exercise program designed for conservative management of knee and hip...
BACKGROUND
The Good Life with osteoArthritis: Denmark (GLA:D™), an evidence-based education and exercise program designed for conservative management of knee and hip osteoarthritis (OA), has been shown to benefit participants by reducing pain, improving function, and quality of life. Standardized reporting in the GLA:D databases enabled the measurement of self-reported and performance-based outcomes. There is a paucity of qualitative research on the participants' perceptions of this program, and it is important to understand whether participants' perceptions of the benefits of the program align with reported quantitative findings.
METHODS
We conducted semi-structured telephone interviews with individuals who participated in the GLA:D program from January 2017 to December 2018 in Alberta, Canada. Data were analyzed using an interpretive description approach and thematic analysis to identify emergent themes and sub-themes associated with participants perceived benefits of the GLA:D program. We analyzed the data using NVivo Pro software. Member checking and bracketing were used to ensure the rigour of the analysis.
RESULTS
30 participants were interviewed (70% female, 57% rural, 73% knee OA). Most participants felt the program positively benefited them. Two themes emerged from the analysis: wellness and self-efficacy. Participants felt the program benefited their wellness, particularly with regard to pain relief, and improvements in mobility, strength, and overall well-being. Participants felt the program benefited them by promoting a sense of self-efficacy through improving the confidence to perform exercise and routine activities, as well as awareness, and motivation to manage their OA symptoms. Twenty percent of participants felt no benefits from the program due to experiencing increased pain and feeling their OA was too severe to participate.
DISCUSSION
The GLA:D program was viewed as beneficial to most participants, this study also identified factors (e.g., severe OA, extreme pain) as to why some participants did not experience meaningful improvements. Early intervention with the GLA:D program prior to individuals experiencing severe OA could help increase the number of participants who experience benefits from their participation.
CONCLUSION
As the GLA:D program expands across jurisdictions, providers of the program may consider recruitment earlier in disease progression and targeting those with mild and moderate OA.
Topics: Humans; Female; Osteoarthritis, Knee; Male; Qualitative Research; Osteoarthritis, Hip; Middle Aged; Aged; Quality of Life; Exercise Therapy; Alberta; Interviews as Topic; Self Efficacy; Patient Education as Topic
PubMed: 38922491
DOI: 10.1186/s41687-024-00740-w -
Diabetologia Jun 2024Use of genetic risk scores (GRS) may help to distinguish between type 1 diabetes and type 2 diabetes, but less is known about whether GRS are associated with disease...
AIMS/HYPOTHESIS
Use of genetic risk scores (GRS) may help to distinguish between type 1 diabetes and type 2 diabetes, but less is known about whether GRS are associated with disease severity or progression after diagnosis. Therefore, we tested whether GRS are associated with residual beta cell function and glycaemic control in individuals with type 1 diabetes.
METHODS
Immunochip arrays and TOPMed were used to genotype a cross-sectional cohort (n=479, age 41.7 ± 14.9 years, duration of diabetes 16.0 years [IQR 6.0-29.0], HbA 55.6 ± 12.2 mmol/mol). Several GRS, which were originally developed to assess genetic risk of type 1 diabetes (GRS-1, GRS-2) and type 2 diabetes (GRS-T2D), were calculated. GRS-C1 and GRS-C2 were based on SNPs that have previously been shown to be associated with residual beta cell function. Regression models were used to investigate the association between GRS and residual beta cell function, assessed using the urinary C-peptide/creatinine ratio, and the association between GRS and continuous glucose monitor metrics.
RESULTS
Higher GRS-1 and higher GRS-2 both showed a significant association with undetectable UCPCR (OR 0.78; 95% CI 0.69, 0.89 and OR 0.84: 95% CI 0.75, 0.93, respectively), which were attenuated after correction for sex and age of onset (GRS-2) and disease duration (GRS-1). Higher GRS-C2 was associated with detectable urinary C-peptide/creatinine ratio (≥0.01 nmol/mmol) after correction for sex and age of onset (OR 6.95; 95% CI 1.19, 40.75). A higher GRS-T2D was associated with less time below range (TBR) (OR for TBR<4% 1.41; 95% CI 1.01 to 1.96) and lower glucose coefficient of variance (β -1.53; 95% CI -2.76, -0.29).
CONCLUSIONS/INTERPRETATION
Diabetes-related GRS are associated with residual beta cell function in individuals with type 1 diabetes. These findings suggest some genetic contribution to preservation of beta cell function.
PubMed: 38922416
DOI: 10.1007/s00125-024-06204-6 -
Journal of Cancer Research and Clinical... Jun 2024In this study, we aimed to evaluate the potential of routine blood markers, serum tumour markers and their combination in predicting RECIST-defined progression in...
PURPOSE
In this study, we aimed to evaluate the potential of routine blood markers, serum tumour markers and their combination in predicting RECIST-defined progression in patients with stage IV non-small cell lung cancer (NSCLC) undergoing treatment with immune checkpoint inhibitors.
METHODS
We employed time-varying statistical models and machine learning classifiers in a Monte Carlo cross-validation approach to investigate the association between RECIST-defined progression and blood markers, serum tumour markers and their combination, in a retrospective cohort of 164 patients with NSCLC.
RESULTS
The performance of the routine blood markers in the prediction of progression free survival was moderate. Serum tumour markers and their combination with routine blood markers generally improved performance compared to routine blood markers alone. Elevated levels of C-reactive protein (CRP) and alkaline phosphatase (ALP) ranked as the top predictive routine blood markers, and CYFRA 21.1 was consistently among the most predictive serum tumour markers. Using these classifiers to predict overall survival yielded moderate to high performance, even when cases of death-defined progression were excluded. Performance varied across the treatment journey.
CONCLUSION
Routine blood tests, especially when combined with serum tumour markers, show moderate predictive value of RECIST-defined progression in NSCLC patients receiving immune checkpoint inhibitors. The relationship between overall survival and RECIST-defined progression may be influenced by confounding factors.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Biomarkers, Tumor; Male; Retrospective Studies; Female; Middle Aged; Aged; Immune Checkpoint Inhibitors; Disease Progression; Immunotherapy; Response Evaluation Criteria in Solid Tumors; Adult; Aged, 80 and over; Prognosis
PubMed: 38922374
DOI: 10.1007/s00432-024-05814-2 -
Current Osteoporosis Reports Jun 2024Along with a strong impact on skeletal integrity, bone marrow adipose tissue (BMAT) is an important modulator of the adult hematopoietic system. This review will... (Review)
Review
PURPOSE OF REVIEW
Along with a strong impact on skeletal integrity, bone marrow adipose tissue (BMAT) is an important modulator of the adult hematopoietic system. This review will summarize the current knowledge on the causal relationship between bone marrow (BM) adipogenesis and the development and progression of hematologic malignancies.
RECENT FINDINGS
BM adipocytes (BMAds) support a number of processes promoting oncogenesis, including the evolution of clonal hematopoiesis, malignant cell survival, proliferation, angiogenesis, and chemoresistance. In addition, leukemic cells manipulate surrounding BMAds by promoting lipolysis and release of free fatty acids, which are then utilized by leukemic cells via β-oxidation. Therefore, limiting BM adipogenesis, blocking BMAd-derived adipokines, or lipid metabolism obstruction have been considered as potential treatment options for hematological malignancies. Leukemic stem cells rely heavily on BMAds within the structural BM microenvironment for necessary signals which foster disease progression. Further development of 3D constructs resembling BMAT at different skeletal regions are critical to better understand these relationships in geometric space and may provide essential insight into the development of hematologic malignancies within the BM niche. In turn, these mechanisms provide promising potential as novel approaches to targeting the microenvironment with new therapeutic strategies.
PubMed: 38922359
DOI: 10.1007/s11914-024-00879-x -
Annals of Hematology Jun 2024Approximately 40% of limited-stage (stage I and II) diffuse large B-cell lymphoma (LS-DLBCL) presents with extranodal disease. Extranodal LS-DLBCL may have significant...
Approximately 40% of limited-stage (stage I and II) diffuse large B-cell lymphoma (LS-DLBCL) presents with extranodal disease. Extranodal LS-DLBCL may have significant biological differences and associated with worse outcomes than nodal disease. Although rituximab based chemoimmunotherapy is standard of first-line treatment, the role of consolidative radiotherapy (RT) in this particular subgroup is controversial. In this multicenter retrospective study, we evaluated the survival benefit of consolidative RT in patients diagnosed with extranodal LS-DLBCL and received rituximab-based chemoimmunotherapy with or without consolidative RT. A total of 328 patients were included, 129 patients (39.3%) received chemoimmunotherapy and consolidative RT, and 199 patients (60.7%) received chemoimmunotherapy alone. With a median follow-up of 5.1 years (range, 0.3-14.8 years), 5-year progression-free survival (PFS) and overall survival (OS) for all patients were 75.4% and 83.9%, respectively. In multivariate analyses, the addition of consolidative RT was associated with superior OS (P = 0.004) and PFS (P = 0.005). High stage-modified International Prognosis Index (SM-IPI) risk predicted worse OS (P = 0.001) and PFS (P = 0.005). Also, propensity score-matched analyses showed RT improved both OS (hazard ratio [HR] 0.228, 95% confidence index [CI] 0.111-0.467, P < 0.001) and PFS (HR 0.308, 95% CI 0.167-0.566, P < 0.001). Among patients who achieved CR, 49 patients (16.6%) developed disease relapse, of which 30.6% relapsed at local sites. Consolidative RT significantly reduced relapse risk (P = 0.002). Our results demonstrated that consolidative RT significantly improved outcomes in patients with extranodal LS-DLBCL in the rituximab era.
PubMed: 38922341
DOI: 10.1007/s00277-024-05855-0