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Escherichia coli (E. coli) was among the first organisms to have its complete genome published (Genome Sequence of E. coli 1997 Science). It is used as a model system in microbiology research. E. coli can cause life-threatening illnesses, particularly in children and the elderly. Possible contamination by the bacteria also results in product recalls, which, alongside the potential danger posed to individuals, can have significant financial consequences. We report the detection of live Escherichia coli (E. coli) in liquid samples using a biosensor based on a field-effect transistor (FET) biosensor with B/N co-coped reduced graphene oxide (rGO) gel (BN-rGO) as the transducer material. The FET was functionalized with antibodies to detect E. coli K12 O-antigens in phosphate-buffered saline (PBS). The biosensor detected the presence of planktonic E. coli bacterial cells within a mere 2 min. The biosensor exhibited a limit of detection (LOD) of 10 cells per sample, which can be extrapolated to a limit of detection at the level of a single cell per sample and a detection range of at least 10-108 CFU/mL. The selectivity of the biosensor for E. coli was demonstrated using Bacillus thuringiensis (B. thuringiensis) as a sample contaminant. We also present a comparison of our functionalized BN-rGO FET biosensor with established detection methods of E. coli k12 bacteria, as well as with state-of-the-art detection mechanisms.
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Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma worldwide, accounting for up to 40% of new non-Hodgkin Lymphoma (NHL) globally. People living with HIV are up to 17 times more likely to develop NHL, and as such, DLBCL is the leading cause of cancer death in this high-risk population. While histologically indistinguishable, HIV-associated (HIV+) and HIV-negative (HIV-) DLBCL are molecularly distinct, and biological differences may have implications for the development of future therapeutic interventions. Further, the impact of immunologic differences in people with HIV, including preceding ART, remains largely unknown. Here, we investigate the impact of HIV infection and ART exposure on the clinical features of DLBCL and T-cell immune response by performing imaging mass cytometry on our unique patient cohort in Malawi. In this cohort, HIV infection is positively prognostic, and HIV+/ART-naïve patients have the best outcomes. No established biomarkers other than Ki67 are associated with HIV or ART status, and the only tumour-intrinsic biomarkers that remain prognostic are MYC and MYC/BCL2 protein co-expression. Finally, TCR clonality is associated with distinct tumour-T cell interactions by HIV/ART status, indicating differential anti-tumour immune responses. We demonstrate previously undescribed HIV and ART-related differences in the DLBCL tumour microenvironment.
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Infecciones por VIH , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Linfocitos T/inmunología , Antirretrovirales/uso terapéuticoRESUMEN
The most common subtype of lymphoma globally, diffuse large B cell lymphoma (DLBCL), is a leading cause of cancer death in people with HIV. The restructuring of the T cell compartment because of HIV infection and antiretroviral therapy (ART) may have implications for modern treatment selection, but current understanding of these dynamic interactions is limited. Here, we investigated the T cell response to DLBCL by sequencing the T cell receptor (TCR) repertoire in a cohort of HIV-negative (HIV-), HIV+/ART-experienced, and HIV+/ART-naive patients with DLBCL. HIV+/ART-naive tumor TCR repertoires were more clonal and more distinct from each other than HIV- and HIV+/ART-experienced ones. Further, increased overlap between tumor and blood TCR repertoires was associated with improved survival and HIV/ART status. Our study describes TCR repertoire characteristics for the first time to our knowledge in an African DLBCL cohort and demonstrates contributions of HIV infection and ART exposure to the DLBCL TCR repertoire.
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Infecciones por VIH , Linfoma de Células B Grandes Difuso , Receptores de Antígenos de Linfocitos T , Humanos , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/virología , Infecciones por VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Masculino , Receptores de Antígenos de Linfocitos T/metabolismo , Femenino , Persona de Mediana Edad , Adulto , Linfocitos T/inmunología , Antirretrovirales/uso terapéuticoRESUMEN
High-grade serous ovarian carcinoma (HGSOC), the deadliest form of ovarian cancer, is typically diagnosed after it has metastasized and often relapses after standard-of-care platinum-based chemotherapy, likely due to advanced tumor stage, heterogeneity, and immune evasion and tumor-promoting signaling from the tumor microenvironment. To understand how spatial heterogeneity contributes to HGSOC progression and early relapse, we profiled an HGSOC tissue microarray of patient-matched longitudinal samples from 42 patients. We found spatial patterns associated with early relapse, including changes in T cell localization, malformed tertiary lymphoid structure (TLS)-like aggregates, and increased podoplanin-positive cancer-associated fibroblasts (CAFs). Using spatial features to compartmentalize the tissue, we found that plasma cells distribute in two different compartments associated with TLS-like aggregates and CAFs, and these distinct microenvironments may account for the conflicting reports about the role of plasma cells in HGSOC prognosis.
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Antineoplásicos , Fibroblastos Asociados al Cáncer , Neoplasias Ováricas , Femenino , Humanos , Fibroblastos Asociados al Cáncer/patología , Recurrencia Local de Neoplasia , Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Recurrencia , Microambiente TumoralRESUMEN
PURPOSE: About a third of patients with relapsed or refractory classic Hodgkin lymphoma (r/r CHL) succumb to their disease after high-dose chemotherapy followed by autologous stem-cell transplantation (HDC/ASCT). Here, we aimed to describe spatially resolved tumor microenvironment (TME) ecosystems to establish novel biomarkers associated with treatment failure in r/r CHL. PATIENTS AND METHODS: We performed imaging mass cytometry (IMC) on 71 paired primary diagnostic and relapse biopsies using a marker panel specific to CHL biology. For each cell type in the TME, we calculated a spatial score measuring the distance of nearest neighbor cells to the malignant Hodgkin Reed Sternberg cells within the close interaction range. Spatial scores were used as features in prognostic model development for post-ASCT outcomes. RESULTS: Highly multiplexed IMC data revealed shared TME patterns in paired diagnostic and early r/r CHL samples, whereas TME patterns were more divergent in pairs of diagnostic and late relapse samples. Integrated analysis of IMC and single-cell RNA sequencing data identified unique architecture defined by CXCR5+ Hodgkin and Reed Sternberg (HRS) cells and their strong spatial relationship with CXCL13+ macrophages in the TME. We developed a prognostic assay (RHL4S) using four spatially resolved parameters, CXCR5+ HRS cells, PD1+CD4+ T cells, CD68+ tumor-associated macrophages, and CXCR5+ B cells, which effectively separated patients into high-risk versus low-risk groups with significantly different post-ASCT outcomes. The RHL4S assay was validated in an independent r/r CHL cohort using a multicolor immunofluorescence assay. CONCLUSION: We identified the interaction of CXCR5+ HRS cells with ligand-expressing CXCL13+ macrophages as a prominent crosstalk axis in relapsed CHL. Harnessing this TME biology, we developed a novel prognostic model applicable to r/r CHL biopsies, RHL4S, opening new avenues for spatial biomarker development.
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Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Microambiente Tumoral , Ecosistema , Recurrencia Local de Neoplasia , Resultado del Tratamiento , RecurrenciaRESUMEN
Patients with cancer are at increased risk of death from COVID-19 and have reduced immune responses to SARS-CoV2 vaccines, necessitating regular boosters. We performed comprehensive chart reviews, surveys of patients attitudes, serology for SARS-CoV-2 antibodies and T-cell receptor (TCR) ß sequencing for cellular responses on a cohort of 982 cancer patients receiving active cancer therapy accrued between November-3-2020 and Mar-31-2023. We found that 92·3% of patients received the primer vaccine, 70·8% received one monovalent booster, but only 30·1% received a bivalent booster. Booster uptake was lower under age 50, and among African American or Hispanic patients. Nearly all patients seroconverted after 2+ booster vaccinations (>99%) and improved cellular responses, demonstrating that repeated boosters could overcome poor response to vaccination. Receipt of booster vaccinations was associated with a lower risk of all-cause mortality (HR=0·61, P=0·024). Booster uptake in high-risk cancer patients remains low and strategies to encourage booster uptake are needed. Highlights: COVID-19 booster vaccinations increase antibody levels and maintain T-cell responses against SARS-CoV-2 in patients receiving various anti-cancer therapiesBooster vaccinations reduced all-cause mortality in patientsA significant proportion of patients remain unboosted and strategies are needed to encourage patients to be up-to-date with vaccinations.
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Quantitative metrics for vaccine-induced T-cell responses are an important need for developing correlates of protection and their use in vaccine-based medical management and population health. Molecular TCR analysis is an appealing strategy but currently requires a targeted methodology involving complex integration of ex vivo data (antigen-specific functional T-cell cytokine responses and TCR molecular responses) that uncover only public antigen-specific metrics. Here, we describe an untargeted private TCR method that measures breadth and depth metrics of the T-cell response to vaccine challenge using a simple pre- and post-vaccine subject sampling, TCR immunoseq analysis, and a bioinformatic approach using self-organizing maps and GLIPH2. Among 515 subjects undergoing SARS-CoV-2 mRNA vaccination, we found that breadth and depth metrics were moderately correlated between the targeted public TCR response and untargeted private TCR response methods. The untargeted private TCR method was sufficiently sensitive to distinguish subgroups of potential clinical significance also observed using public TCR methods (the reduced T-cell vaccine response with age and the paradoxically elevated T-cell vaccine response of patients on anti-TNF immunotherapy). These observations suggest the promise of this untargeted private TCR method to produce T-cell vaccine-response metrics in an antigen-agnostic and individual-autonomous context.
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Vacunas contra la COVID-19 , COVID-19 , Humanos , SARS-CoV-2 , Sitios de Unión de Anticuerpos , Inhibidores del Factor de Necrosis Tumoral , Linfocitos T CD8-positivos , COVID-19/prevención & control , Vacunación , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
INTRODUCTION: Patients with prediabetes who contract SARS-CoV-2 infection (COVID-19) could be at higher risk of developing frank diabetes compared those who do not. This study aims to investigate the incidence of new-onset diabetes in patients with prediabetes after COVID-19 and if it differs from those not infected. RESEARCH DESIGN AND METHODS: Using electronic medical record data, 42 877 patients with COVID-19, 3102 were identified as having a history of prediabetes in the Montefiore Health System, Bronx, New York. During the same time period, 34 786 individuals without COVID-19 with history of prediabetes were identified and 9306 were propensity matched as controls. SARS-CoV-2 infection status was determined by a real-time PCR test between March 11, 2020 and August 17, 2022. The primary outcomes were new-onset in-hospital diabetes mellitus (I-DM) and new-onset persistent diabetes mellitus (P-DM) at 5 months after SARS-CoV-2 infection. RESULTS: Compared with hospitalized patients without COVID-19 with history of prediabetes, hospitalized patients with COVID-19 with history of prediabetes had a higher incidence of I-DM (21.9% vs 6.02%, p<0.001) and of P-DM 5 months postinfection (14.75% vs 7.51%, p<0.001). Non-hospitalized patients with and without COVID-19 with history of prediabetes had similar incidence of P-DM (4.15% and 4.1%, p>0.05). Critical illness (HR 4.6 (95% CI 3.5 to 6.1), p<0.005), in-hospital steroid treatment (HR 2.88 (95% CI 2.2 to 3.8), p<0.005), SARS-CoV-2 infection status (HR 1.8 (95% CI 1.4 to 2.3), p<0.005), and hemoglobin A1c (HbA1c) (HR 1.7 (95% CI 1.6 to 1.8), p<0.005) were significant predictors of I-DM. I-DM (HR 23.2 (95% CI 16.1 to 33.4), p<0.005), critical illness (HR 2.4 (95% CI 1.6 to 3.8), p<0.005), and HbA1c (HR 1.3 (95% CI 1.1 to 1.4), p<0.005) were significant predictors of P-DM at follow-up. CONCLUSIONS: SARS-CoV-2 infection confers a higher risk for developing persistent diabetes 5 months post-COVID-19 in patients with prediabetes who were hospitalized for COVID-19 compared with COVID-19-negative counterparts with prediabetes. In-hospital diabetes, critical illness, and elevated HbA1c are risk factors for developing persistent diabetes. Patients with prediabetes with severe COVID-19 disease may need more diligent monitoring for developing P-DM postacute SARS-CoV-2 infection.
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COVID-19 , Diabetes Mellitus , Estado Prediabético , Humanos , Estado Prediabético/complicaciones , Estado Prediabético/epidemiología , COVID-19/complicaciones , COVID-19/epidemiología , Hemoglobina Glucada , Estudios Retrospectivos , Enfermedad Crítica , SARS-CoV-2 , Diabetes Mellitus/epidemiologíaRESUMEN
Among the many recently developed photo-catalytic materials, graphitic carbon nitride (g-C3N4) shows great promise as a catalytic material for water splitting, hydrogen generation, and related catalytic applications. Herein, synthesized bulk g-C3N4is simply irradiated under a 35 fs pulse at mixed photon energies (800 nm and its second harmonic). g-C3N4was synthesized from melamine following a facile thermal polymerization procedure. The prepared material was introduced, in an aqueous environment, to the femtosecond laser for various lengths of time. The treated material demonstrates a significant increase in surface area, relative to the untreated samples, indicating that irradiation is a successful method for exfoliation. The subsequent characterization reveals that the mixed irradiation process drives significant defect generation and sheet growth, which is not seen under 800 nm irradiation. Extended mixed irradiation results in 4 nm thick nanosheets with lateral dimensions 4× that of the bulk material. The treated material shows improved dye absorption/removal. This novel method of defect generation and nanosheet growth shows great potential as a g-C3N4pre-treatment method for co-catalytic applications. Herein it is shown that femtosecond laser irradiation drives exfoliation beyond 100 nm particle sizes, and sheet-like morphologies under extended irradiation, which must be taken into account when using this method to improve material performance.
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The discovery and characterization of antigen-specific CD8+ T cell clonotypes typically involves the labor-intensive synthesis and construction of peptide-MHC tetramers. We adapt single-chain trimer (SCT) technologies into a high throughput platform for pMHC library generation, showing that hundreds can be rapidly prepared across multiple Class I HLA alleles. We use this platform to explore the impact of peptide and SCT template mutations on protein expression yield, thermal stability, and functionality. SCT libraries were an efficient tool for identifying T cells recognizing commonly reported viral epitopes. We then construct SCT libraries to capture SARS-CoV-2 specific CD8+ T cells from COVID-19 participants and healthy donors. The immunogenicity of these epitopes is validated by functional assays of T cells with cloned TCRs captured using SCT libraries. These technologies should enable the rapid analyses of peptide-based T cell responses across several contexts, including autoimmunity, cancer, or infectious disease.
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Linfocitos T CD8-positivos , COVID-19 , Humanos , SARS-CoV-2/genética , Antígenos , Epítopos , Péptidos/genéticaRESUMEN
Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment. Fatty liver upregulated Rab27a expression, which facilitated EV production from hepatocytes. In the liver, these EVs transferred YAP signaling-regulating microRNAs to cancer cells to augment YAP activity by suppressing LATS2. Increased YAP activity in CRC liver metastasis with fatty liver promoted cancer cell growth and an immunosuppressive microenvironment by M2 macrophage infiltration through CYR61 production. Patients with CRC liver metastasis and fatty liver had elevated nuclear YAP expression, CYR61 expression, and M2 macrophage infiltration. Our data indicate that fatty liver-induced EV-microRNAs, YAP signaling, and an immunosuppressive microenvironment promote the growth of CRC liver metastasis.
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Neoplasias Colorrectales , Vesículas Extracelulares , Hígado Graso , Neoplasias Hepáticas , MicroARNs , Humanos , Microambiente Tumoral , Hígado Graso/metabolismo , MicroARNs/metabolismo , Neoplasias Hepáticas/metabolismo , Vesículas Extracelulares/metabolismo , Neoplasias Colorrectales/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Antigen-specific T cell receptor (TCR) sequences can have prognostic, predictive, and therapeutic value, but decoding the specificity of TCR recognition remains challenging. Unlike DNA strands that base pair, TCRs bind to their targets with different orientations and different lengths, which complicates comparisons. We present scanning parametrized by normalized TCR length (SPAN-TCR) to analyze antigen-specific TCR CDR3 sequences and identify patterns driving TCR-pMHC specificity. Using entropic analysis, SPAN-TCR identifies 2-mer motifs that decrease the diversity (entropy) of CDR3s. These motifs are the most common patterns that can predict CDR3 composition, and we identify "essential" motifs that decrease entropy in the same CDR3 α or ß chain containing the 2-mer, and "super-essential" motifs that decrease entropy in both chains. Molecular dynamics analysis further suggests that these motifs may play important roles in binding. We then employ SPAN-TCR to resolve similarities in TCR repertoires against different antigens using public databases of TCR sequences.
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Receptores de Antígenos de Linfocitos T alfa-beta , Receptores de Antígenos de Linfocitos T , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Entropía , Secuencia de Aminoácidos , AntígenosRESUMEN
CD8 + cytotoxic T cell responses against viral infection represent a major element of the adaptive immune response. We describe the development of a peptide antigen - major histompatibility complex (pMHC) library representing the full SARS-CoV-2 viral proteome, and comprised of 634 pMHC multimers representing the A*02.01, A*24.02, and B*07.02 HLA alleles, as well as specific antigens associated with the cytomegalovirus (CMV). These libraries were used to capture non-expanded CD8 + T cells from blood samples collected from 64 infected individuals, and then analyzed using single cell RNA-seq. The discovery and characterization of antigen-specific CD8 + T cell clonotypes typically involves the labor-intensive synthesis and construction of peptide-MHC tetramers. We adapted single-chain trimer (SCT) technologies into a high throughput platform for pMHC library generation, showing that hundreds can be rapidly prepared across multiple Class I HLA alleles. We used this platform to explore the impact of peptide and SCT template mutations on protein expression yield, thermal stability, and functionality. SCT libraries were an efficient tool for identifying T cells recognizing commonly reported viral epitopes. We then constructed SCT libraries designed to capture SARS-CoV-2 specific CD8 + T cells from COVID-19 participants and healthy donors. The immunogenicity of these epitopes was validated by functional assays of T cells with cloned TCRs captured using SCT libraries. These technologies should enable the rapid analyses of peptide-based T cell responses across several contexts, including autoimmunity, cancer, or infectious disease.
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SARS-CoV-2 vaccines have unquestionably blunted the overall impact of the COVID-19 pandemic, but host factors such as age, sex, obesity, and other co-morbidities can affect vaccine efficacy. We identified individuals in a relatively healthy population of healthcare workers (CORALE study cohort) who had unexpectedly low peak anti-spike receptor binding domain (S-RBD) antibody levels after receiving the BNT162b2 vaccine. Compared to matched controls, "low responders" had fewer spike-specific antibody-producing B cells after the second and third/booster doses. Moreover, their spike-specific T cell receptor (TCR) repertoire had less depth and their CD4+ and CD8+T cell responses to spike peptide stimulation were less robust. Single cell transcriptomic evaluation of peripheral blood mononuclear cells revealed activation of aging pathways in low responder B and CD4+T cells that could underlie their attenuated anti-S-RBD antibody production. Premature lymphocyte aging may therefore contribute to a less effective humoral response and could reduce vaccination efficacy.
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Multiplexed immune cell profiling of the tumor microenvironment (TME) in cancer has improved our understanding of cancer immunology, but complex spatial analyses of tumor-immune interactions in lymphoma are lacking. Here, we used imaging mass cytometry (IMC) on 33 cases of diffuse large B-cell lymphoma (DLBCL) to characterize tumor and immune cell architecture and correlate it to clinicopathological features such as cell of origin, gene mutations, and responsiveness to chemotherapy. To understand the poor response of DLBCL to immune checkpoint inhibitors (ICI), we compared our results to IMC data from Hodgkin lymphoma, a cancer highly responsive to ICI, and observed differences in the expression of PD-L1, PD-1, and TIM-3. We created a spatial classification of tumor cells and identified tumor-centric subregions of immune activation, immune suppression, and immune exclusion within the topology of DLBCL. Finally, the spatial analysis allowed us to identify markers such as CXCR3, which are associated with penetration of immune cells into immune desert regions, with important implications for engineered cellular therapies. This is the first study to integrate tumor mutational profiling, cell of origin classification, and multiplexed immuno-phenotyping of the TME into a spatial analysis of DLBCL at the single-cell level. We demonstrate that, far from being histopathologically monotonous, DLBCL has a complex tumor architecture, and that changes in tumor topology can be correlated with clinically relevant features. This analysis identifies candidate biomarkers and therapeutic targets such as TIM-3, CCR4, and CXCR3 that are relevant for combination treatment strategies in immuno-oncology and cellular therapies.
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Enfermedad de Hodgkin , Linfoma de Células B Grandes Difuso , Receptor 2 Celular del Virus de la Hepatitis A , Humanos , Linfoma de Células B Grandes Difuso/patología , Análisis Espacial , Microambiente Tumoral/genéticaRESUMEN
T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vß gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.
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COVID-19 , Enfermedades Inflamatorias del Intestino , Vacuna nCoV-2019 mRNA-1273 , Ad26COVS1 , Vacuna BNT162 , Vacunas contra la COVID-19 , Humanos , Inmunidad Humoral , Receptores de Antígenos de Linfocitos T/genética , SARS-CoV-2 , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 vaccination in inflammatory bowel disease patients are poorly correlated. T-cell responses are preserved by most biologic therapies, but augmented by anti-tumor necrosis factor (anti-TNF) treatment. While anti-TNF therapy blunts the antibody response, cellular immunity after vaccination is robust.
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COVID-19 , Enfermedades Inflamatorias del Intestino , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , SARS-CoV-2 , Linfocitos T , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , VacunaciónRESUMEN
Importance: Although several cancer drugs receive US Food and Drug Administration (FDA) approval each month, it is unclear how many of these cancer drugs transform the treatment landscape significantly by tumor group. Specifically, it remains unclear how many of these newly approved cancer drugs displace the existing standard-of-care therapies for their indication vs being added to existing therapies. Objective: To examine how many cancer drugs displace the standard-of-care therapies vs being added to existing therapy or filling breaks in systemic treatments in the metastatic setting, adjuvant setting, or maintenance setting. Design, Setting, and Participants: Retrospective cross-sectional study using landmark trials leading to FDA approval of cancer drugs between May 1, 2016, and May 31, 2021. The study evaluated all FDA approvals for cancer drugs between May 1, 2016, and May 31, 2021, using the FDA Oncology (Cancer)/Hematologic Malignancies Approval Notifications website. All clinical trials leading to FDA approval of cancer drugs during this period were examined. Main Outcomes and Measures: A drug was determined to have displaced the prior standard-of-care therapy by evaluating the comparator arm (or lack thereof) in the clinical trial leading to the drug's approval and also by reviewing National Comprehensive Cancer Network Guidelines. Cancer drug approvals were categorized as first-line displacing if a drug was approved for use in the first-line setting and displaced the prior standard-of-care drug for an indication, first-line drug alternatives/new if a drug was approved for use in the first-line setting but did not displace the standard of care at the time of approval or was a new drug that was first of its class for an approved indication, add on if a drug was approved in combination with a previously approved therapy for a disease or if a drug was approved for use in the adjuvant or maintenance settings, and later line if a drug was approved for use in the second-, third-, or later-line settings. Results: Between May 1, 2016, and May 31, 2021, there were 207 FDA cancer drug approvals in oncology and malignant hematology. Of these 207 approvals, 28 drugs (14%) were first-line displacing therapies. A total of 32 drugs (15%) were first-line drug alternatives/new drugs. A total of 61 drugs (29%) were add-on therapies. Finally, 86 drugs (42%) were approved as later-line therapies. Conclusions and Relevance: In this study, most cancer drug approvals between 2016 and 2021 were in the later-line settings as opposed to displacing the current standard-of-care therapy for the approved indication. These later-line drugs may benefit patients with few alternatives but add to the cost of care because competition in the drug markets is a key factor in leading to lower drug prices.
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Aprobación de Drogas , Neoplasias , Estudios Transversales , Humanos , Neoplasias/tratamiento farmacológico , Estudios Retrospectivos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
PURPOSE: There are no universal guidelines for blood product transfusions in patients with hematologic malignancies (HMs). Excess utilization of platelet and RBC transfusion in patients with HM increases the cost of care and likelihood of adverse events. We aim to decrease the total number of transfused units and multiunit orders of platelets and RBCs in the HM clinic by 25% from March 2020 to December 2020. METHODS: A multidisciplinary, interprofessional team was formed. Baseline rates of blood product utilization were determined using Qlik Analytic software. Strategies to improve utilization were developed, and three interventions were initiated. Data were collected on monthly intervals. Data for total number of platelet and RBC units ordered, total multiunit orders, average number of units ordered per encounter, and pretransfusion hemoglobin thresholds were collected from May 2019 to December 2020. RESULTS: Through our Plan-Do-Study-Act cycles from March 2020 to December 2020, the total number of platelet transfusion orders per month decreased from 164 to 98, multiunit platelet orders decreased from 63 to 2, and the average number of platelet transfusions per encounter decreased from 1.62 to 1.03. The total number of RBC transfusion orders decreased from 172 to 141, multiunit RBC orders decreased from 25 to 16, and the average number of RBC transfusions per encounter decreased from 1.21 to 1.18. CONCLUSION: Implementation of our multidisciplinary interventions led to more appropriate use of blood products in the outpatient setting. Ongoing efforts are underway to continue to improve utilization in the inpatient and outpatient setting.
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Transfusión de Eritrocitos , Neoplasias Hematológicas , Transfusión Sanguínea , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/terapia , Hemoglobinas , Humanos , Programas InformáticosRESUMEN
Background: Numerous authors have used the 'parachute' analogy to comment on the importance of and need for randomized, controlled trials (RCTs) in the hierarchy of medical evidence. Methods: The authors completed a retrospective literature analysis examining publications citing the 2003 parachute paper by Smith and Pell and a 2018 RCT of a parachute by Yeh et al. For all of the articles that directly analogized a medical intervention to a parachute, the authors identified the desired outcome of the practice and searched PubMed for relevant RCTs. Results: Authors citing the parachute analogy are often critical of RCTs and often draw comparisons to interventions that are not parachutes.