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ABSTRACT: B-cell maturation antigen (BCMA)-targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 × BCMA bispecific antibody, 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy-naïve patients. Prior therapy-mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and 1 of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from 1 patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA-directed treatments, underscoring the importance of verifying the presence of a target antigen.
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Antígeno de Maduración de Linfocitos B , Resistencia a Antineoplásicos , Mieloma Múltiple , Humanos , Mieloma Múltiple/inmunología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Antígeno de Maduración de Linfocitos B/genética , Antígeno de Maduración de Linfocitos B/inmunología , Masculino , Femenino , Persona de Mediana Edad , Anticuerpos Biespecíficos/uso terapéutico , Anciano , Anticuerpos Monoclonales HumanizadosRESUMEN
Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.
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Secuenciación de Nucleótidos de Alto Rendimiento , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , AdultoAsunto(s)
Dermatitis , Linfoma Cutáneo de Células T , Neoplasias Cutáneas , Humanos , Inmunohistoquímica , Estudios Retrospectivos , Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Dermatitis/diagnóstico , Dermatitis/etiologíaRESUMEN
Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in post-treatment settings can be crucial for relapse risk stratification in patients with B-cell and plasma cell neoplasms. Prior studies have focused on validation of various technical aspects of the MRD assays, but more studies are warranted to establish the performance characteristics and enable standardization and broad utilization in routine clinical practice. Here, the authors describe an NGS-based IGH MRD quantification assay, incorporating a spike-in calibrator for monitoring B-cell and plasma cell neoplasms based on their unique IGH rearrangement status. Comparison of MRD status (positive or undetectable) by NGS and flow cytometry (FC) assays showed high concordance (91%, 471/519 cases) and overall good linear correlation in MRD quantitation, particularly for chronic lymphocytic leukemia and B-lymphoblastic leukemia/lymphoma (R = 0.85). Quantitative correlation was lower for plasma cell neoplasms, where underestimation by FC is a known limitation. No significant effects on sequencing efficiency by the spike-in calibrator were observed, with excellent inter- and intra-assay reproducibility within the authors' laboratory, and in comparison to an external laboratory, using the same assay and protocols. Assays performed both at internal and external laboratories showed highly concordant MRD detection (100%) and quantitation (R = 0.97). Overall, this NGS-based MRD assay showed highly reproducible results with quantitation that correlated well with FC MRD assessment, particularly for B-cell neoplasms.
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Leucemia Linfocítica Crónica de Células B , Mieloma Múltiple , Humanos , Reproducibilidad de los Resultados , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genéticaRESUMEN
ABSTRACT: Teclistamab, a B-cell maturation antigen (BCMA)- and CD3-targeting bispecific antibody, is an effective novel treatment for relapsed/refractory multiple myeloma (R/RMM), but efficacy in patients exposed to BCMA-directed therapies and mechanisms of resistance have yet to be fully delineated. We conducted a real-world retrospective study of commercial teclistamab, capturing both clinical outcomes and immune correlates of treatment response in a cohort of patients (n = 52) with advanced R/RMM. Teclistamab was highly effective with an overall response rate (ORR) of 64%, including an ORR of 50% for patients with prior anti-BCMA therapy. Pretreatment plasma cell BCMA expression levels had no bearing on response. However, comprehensive pretreatment immune profiling identified that effector CD8+ T-cell populations were associated with response to therapy and a regulatory T-cell population associated with nonresponse, indicating a contribution of immune status in outcomes with potential utility as a biomarker signature to guide patient management.
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Antineoplásicos , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Antígeno de Maduración de Linfocitos B/uso terapéutico , Estudios Retrospectivos , Antineoplásicos/uso terapéutico , Linfocitos T CD8-positivos/metabolismoRESUMEN
Plastics are widely used in human daily life, which bring great convenience. Nevertheless, the disposal of a large amount of plastic wastes also brings great pressure to the environment. Polyethylene terephthalate (PET) is a polymer thermoplastic material produced from petroleum. It has become one of the most commonly used plastics in the world due to its durability, high transparency, light weight and other characteristics. PET can exist in nature for a long time due to its complex structure and the difficulty in degradation, which causes serious pollution to the global ecological environment, and threatens human health. The degradation of PET wastes has since become one of the global challenges. Compared with physical and chemical methods, biodegradation is the greenest way for treating PET wastes. This review summarizes the recent advances on PET biodegradation including microbial and enzymatic degradation of PET, biodegradation pathway, biodegradation mechanisms, and molecular modification of PET-degrading enzymes. In addition, the prospect for achieveing efficient degradation of PET, searching and improving microorganisms or enzymes that can degrade PET of high crystallinity are presented, with the aimto facilitate the development, application and molecular modification of PET biodegradation microorganisms or enzymes.
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Petróleo , Tereftalatos Polietilenos , Humanos , Tereftalatos Polietilenos/metabolismo , Polímeros , Biodegradación AmbientalRESUMEN
Morphology-based classification of cells in the bone marrow aspirate (BMA) is a key step in the diagnosis and management of hematologic malignancies. However, it is time-intensive and must be performed by expert hematopathologists and laboratory professionals. We curated a large, high-quality dataset of 41,595 hematopathologist consensus-annotated single-cell images extracted from BMA whole slide images (WSIs) containing 23 morphologic classes from the clinical archives of the University of California, San Francisco. We trained a convolutional neural network, DeepHeme, to classify images in this dataset, achieving a mean area under the curve (AUC) of 0.99. DeepHeme was then externally validated on WSIs from Memorial Sloan Kettering Cancer Center, with a similar AUC of 0.98, demonstrating robust generalization. When compared to individual hematopathologists from three different top academic medical centers, the algorithm outperformed all three. Finally, DeepHeme reliably identified cell states such as mitosis, paving the way for image-based quantification of mitotic index in a cell-specific manner, which may have important clinical applications.
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Somatic hypermutation status of the IGHV gene is essential for treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Unlike the conventional low-throughput method, assessment of somatic hypermutation by next-generation sequencing (NGS) has potential for uniformity and scalability. However, it lacks standardization or guidelines for routine clinical use. We critically assessed the performance of an amplicon-based NGS assay across 458 samples. Using a validation cohort (35 samples), the comparison of two platforms (Ion Torrent versus Illumina) and two primer sets [leader versus framework region 1 (FR1)] in their ability to identify clonotypic IGHV rearrangement(s) revealed 97% concordance. The mutation rates were identical by both platforms when using the same primer set (FR1), whereas a slight overestimation bias (+0.326%) was found when comparing FR1 with leader primers. However, for nearly all patients this did not affect the stratification into mutated or unmutated categories, suggesting that use of FR1 may provide comparable results if leader sequencing is not available and allowing for a simpler NGS laboratory workflow. In routine clinical practice (423 samples), the productive rearrangement was successfully detected by either primer set (leader, 97.7%; FR1, 94.7%), and a combination of both in problematic cases reduced the failure rate to 1.2%. Higher sensitivity of the NGS-based analysis also detected a higher frequency of double IGHV rearrangements (19.1%) compared with traditional approaches.
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Leucemia Linfocítica Crónica de Células B , Linfoma de Células B , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Reordenamiento Génico , Linfoma de Células B/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.
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Neoplasias Hematológicas , Neoplasias , Humanos , Neoplasias/genética , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento , ADNRESUMEN
Androgens are functionally required for the normal growth of the prostate gland and in prostate tumor development and progression. Epithelial-mesenchymal-transition (EMT) is an important process during normal development and in cancer cell metastasis induced by factors within the microenvironment, such as transforming growth factor-beta (TGF-beta). This study examined the ability of androgens to influence EMT of prostate cancer epithelial cells. The EMT pattern was evaluated on the basis of expression of the epithelial markers E-cadherin/beta-catenin, and the mesenchymal markers N-cadherin, as well as cytoskeleton reorganization in response to 5alpha-dihydrotestosterone (DHT; 1 nM) and/or TGF-beta (5 ng/ml). Overexpressing and silencing approaches to regulate androgen receptor (AR) expression were conducted to determine the involvement of AR in EMT in the presence or absence of an AR antagonist. Our results demonstrate that androgens induce the EMT pattern in prostate tumor epithelial cell with Snail activation and lead to significant changes in prostate cancer cell migration and invasion potential. Expression levels of AR inversely correlated with androgen-mediated EMT in prostate tumor epithelial cells, pointing to a low AR content required for the EMT phenotype. These findings indicate the ability of androgens to induce EMT by potentially bypassing the functional involvement of TGF-beta, thus contributing to metastatic behavior of prostate cancer cells.-Zhum, M.-L., Kyprianou, N. Role of androgens and the androgen receptor in epithelial-mesenchymal transition and invasion of prostate cancer cells.
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Desdiferenciación Celular/efectos de los fármacos , Dihidrotestosterona/farmacología , Células Epiteliales/patología , Mesodermo/patología , Metástasis de la Neoplasia/patología , Neoplasias de la Próstata/patología , Receptores Androgénicos/fisiología , Antagonistas de Receptores Androgénicos , Western Blotting , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) requires prompt initiation of therapeutic plasma exchange (TPE) to avoid significant morbidity and mortality. ADAMTS13 activity testing defines TTP, however, at most institutions this is a send-out test and therapy is often initiated prior to measurement availability. We describe our experience looking at absolute immature platelet counts (A-IPC) in patients suspected with TTP at presentation and in response to therapy. MATERIALS AND METHODS: Forty-eight patients treated for suspected TTP with A-IPC measure on admission and during hospitalization met inclusion criteria. Of these patients, sixteen had new-onset TTP (ADAMTS13 < 10%), ten were relapsing patients (first diagnosis prior to study period), and 22 were classified as non-TTP (ADAMTS13 ≥ 10%). RESULTS: Patients with ADAMTS13 deficiency (TTP) had A-IPC different from those without deficiency. A-IPC of 1-2 × 109/L at presentation had high sensitivity and specificity with a negative predictive value of 95.5 to 100%. Two-to-three-fold increases in A-IPC from count prior to TPE initiation was limited to ADAMTS13 deficient patients who was the group responding to therapy. Increases were higher in patients with new disease onset compared to relapsing patients (p = 0.018). Likewise, relapsing patients' A-IPC appeared dependent upon platelet count at time of relapse. A-IPC predicted and correlated with ADAMTS13 deficiency in new-onset TTP (p = 0.0002). CONCLUSIONS: Only patients with A-IPC-fold increases responded to TPE with platelet count normalization. Our results represent a proof of concept that A-IPC measurements can supplement ADAMTS13 testing and determine response to TPE. Future studies are needed to establish ways to apply these findings in the setting of suspected TTP.
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Púrpura Trombocitopénica Trombótica , Proteína ADAMTS13 , Plaquetas , Humanos , Intercambio Plasmático , Recuento de Plaquetas , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/terapia , RecurrenciaRESUMEN
BACKGROUND: Congenital biliary atresia is a type of obstruction of the bile ducts inside and outside the liver, which can lead to cholestatic liver cirrhosis and eventually liver failure. The preduodenal portal vein (PD-PV) is a rare developmental malformation of the PV. The PV courses in front of the duodenum. However, very few cases of neonatal biliary atresia combined with PD-PV have been reported in the scientific literature. CASE SUMMARY: A 1-mo-and-4-d-old child was admitted to the hospital in January because of yellowish skin. After surgical consultation, surgical intervention was recommended. The child underwent Hilar-jejunal anastomosis, duodenal rhomboid anastomosis, and abdominal drainage under general anesthesia. During the operation, the PV was located at the anterior edge of the duodenum. CONCLUSION: Diagnoses: (1) Congenital biliary atresia; (2) PD-PV; and (3) Congenital cardiovascular malformations. Outcomes: Recommendation for liver transplantation. Lessons: The choice of treatment options for neonatal biliary atresia combined with PD-PV.
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The 2016 International Myeloma Working Group consensus recommendations emphasize high-sensitivity methods for minimal residual disease (MRD) detection, treatment response assessment, and prognostication. Next-generation sequencing (NGS) of IGH gene rearrangements is highly specific and sensitive, but its description in routine clinical practice and performance comparison with high-sensitivity flow cytometry (hsFC) remain limited. In this large, single-institution study including 438 samples from 251 patients, the use of NGS targeting the IGH and IGK genes for clonal characterization and monitoring, with comparison to hsFC, is described. The index clone characterization success rate was 93.6% (235/251), which depended on plasma cell (PC) cellularity, reaching 98% when PC ≥10% and below 80% when PC <5%. A total of 85% of cases were successfully characterized using leader and FR1 primer sets, and most clones showed high somatic hypermutation rates (median, 8.1%). Among monitoring samples from 124 patients, 78.6% (147/187) had detectable disease by NGS. Concordance with hsFC was 92.9% (170/183). Discordant cases encompassed 8 of 124 hsFC MRD+/NGS MRD- patients (6.5%) and 4 of 124 hsFC MRD-/NGS MRD+ patients (3.2%), all with low-level disease near detection limits for both assays. Among concordant hsFC MRD-/NGS MRD- cases, only 5 of 24 patients (20.8%) showed subsequent overt relapse at 3-year follow-up. HsFC and NGS showed similar operational sensitivity, and the choice of test may depend on practical, rather than test performance, considerations.
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Células Clonales/patología , Citometría de Flujo , Secuenciación de Nucleótidos de Alto Rendimiento , Mieloma Múltiple/diagnóstico , Neoplasia Residual/diagnóstico , Secuencia de Bases , Estudios de Factibilidad , Humanos , Células Plasmáticas/patología , Recurrencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: Therapeutic plasma exchange (TPE) is mainstay therapy for thrombotic thrombocytopenic purpura (TTP). However, it remains controversial if ABO type influences diagnosis or time to remission. MATERIALS AND METHODS: We investigated if ABO type influences length of TPE regimen in TTP patients with ADAMTS13 deficiency at our institution. Seventy out of 71 patients with suspected TTP who had ADAMTS13 activity measured were included. ADAMTS13 activity <10% defined those with idiopathic/acquired TTP (41/70). RESULTS: We found that among patients with ADAMTS13 deficiency, non-O patients required a significantly greater number of TPE (NoP) compared to O patients (p = 0.039). Additionally, patients with ADAMTS13 deficiency regardless of ABO type needed more TPE to achieve platelet recovery compared to those patients without deficiency (p = 0.00002). In regard to other variables that may affect response to therapy in TTP patients, we found no association between obesity and NoP; however, obesity rate was higher among ADAMTS13 deficient patients compared to overall obesity rate of our regional general population. Likewise, were found that blood group O did not occur with greater frequency in our cohort. CONCLUSIONS: Our data indicates that ABO may affect the NoP patients required for disease remission. We found that non-O patients needed more procedures to overcome their disease. Further work with greater number of patients will be needed to determine if specific non-O blood types require more procedures to recover their platelet count.
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Antígenos de Grupos Sanguíneos , Púrpura Trombocitopénica Trombótica , Proteínas ADAM , Proteína ADAMTS13 , Plaquetas , Humanos , Intercambio Plasmático , Púrpura Trombocitopénica Trombótica/terapiaRESUMEN
Owing to the capacity of efficiently harvesting and converting incident energy, localized surface-plasmon resonance of noble metals was introduced into a metal-semiconductor design for promoting hydrogen evolution. In this study, a plasmonic nanodumbbell structure was employed to strategically modulate the energy transfer in the water reduction reaction. A maximum H2 evolution rate of 80 µmol g-1 h-1 was obtained in the Au-TiO2 nanodumbbells, and further improvement was achieved through surface modification with Pt nanoparticles functioning as active sites, leading to â¼4.3 times enhanced photocatalytic activity. Compared with similar nanostructures reported previously, the present superior photoactivity response is ascribed to the injection process of the energetic hot electrons generated from the excitation and decay of the longitudinal surface-plasmon resonance (LSPR) and transverse surface-plasmon resonance (TSPR) in the Au nanorods, which corresponds to the electric field distribution of the finite-difference-time-domain simulation. These intriguing results, originating from the positive synergistic effect of the plasmon and co-catalyst, demonstrated the mechanism of the plasmon-assisted photochemistry and provided a promising strategy for the rational design of novel plasmonic photocatalysts.
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Androgens promote the growth and differentiation of prostate cells through ligand activation of the androgen receptor (AR). Sensitization of the androgenic response by multifunctional growth factor signaling pathways is one of the mechanisms via which AR contributes to the emergence of androgen-independent prostate tumors. The ability of AR to cross-talk with key growth factor signaling events toward the regulation of cell cycle, apoptosis, and differentiation outcomes in prostate cancer cells is established. In this paper, we review the functional interaction between AR and an array of growth factor signal transduction events (including epidermal growth factor; fibroblast growth factor; IGF1; vascular endothelial growth factor; transforming growth factor-beta) in prostate tumors. The significance of this derailed cross-talk between androgens and key signaling networks in prostate cancer progression and its value as a therapeutic forum targeting androgen-independent metastatic prostate cancer is discussed.