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1.
Biochemistry (Mosc) ; 86(11): 1469-1476, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34906050

RESUMO

Vaccination is the most effective mean of preventing influenza virus infections. However, vaccination-induced adverse reactions of the nervous system, the causes of which are unknown, lead to concerns on the safety of influenza A vaccine. In this study, we used flow cytometry, cell ELISA, and immunofluorescence to find that H1-84 monoclonal antibody (mAb) against the191/199 region of the H1N1 influenza virus hemagglutinin (HA) protein binds to neural cells and mediates cell damage. Using molecular simulation software, such as PyMOL and PDB viewer, we demonstrated that the HA191/199 region maintains the overall structure of the HA head. Since the HA191/199 region cannot be removed from the HA structure, it has to be altered via introducing point mutations by site-directed mutagenesis. This will provide an innovative theoretical support for the subsequent modification the influenza A vaccine for increasing its safety.


Assuntos
Anticorpos Monoclonais Murinos , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vírus da Influenza A Subtipo H1N1 , Simulação de Dinâmica Molecular , Neurônios/metabolismo , Anticorpos Monoclonais Murinos/química , Anticorpos Monoclonais Murinos/imunologia , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Linhagem Celular Tumoral , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/química , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Mutagênese Sítio-Dirigida , Neurônios/patologia , Domínios Proteicos
2.
Croat Med J ; 62(5): 455-463, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34730885

RESUMO

AIM: To compare the outcomes of Croatian patients with mantle cell lymphoma (MCL) who started treatment in 2007 and 2008 (historical cohort) and of those who started treatment between 2015 and 2017 (recent cohort). METHODS: The historical cohort consisted of 40 patients who started treatment with rituximab in 2007 and 2008. Data on the recent cohort, consisting of 89 patients, were collected retrospectively from the electronic databases of Croatian hospitals with hematology units. Demographic characteristics and data on induction regimens, autologous stem cell transplantation (ASCT), and rituximab maintenance in the first remission, event-free survival (EFS), and overall survival (OS) were available for both cohorts, and data on cell morphology, mantle cell international prognostic index (MIPI), and Ki67 expression only for the recent cohort. RESULTS: The recent cohort had significantly better two-year EFS and OS (EFS 58% vs 40%, P=0.014; OS 80% vs 56%, P=0.009), especially in patients below 65. In univariate analysis, induction regimen, ASCT, and maintenance were significant prognostic factors for EFS and the former two for OS. In the multivariate analysis, only ASCT remained significant. Bendamustine+rituximab (BR) induction improved the outcomes of non-transplantable patients over R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, steroid). Blastoid morphology and high MIPI were adverse prognostic factors for EFS and OS. CONCLUSION: In the last decade, the outcome of newly diagnosed MCL patients improved. ASCT in the first remission was the main contributor in transplantable patients and BR in non-transplantable. Regularly updated national guidelines may help in a timely adoption of new treatments, thus improving the results.


Assuntos
Doenças Hematológicas , Transplante de Células-Tronco Hematopoéticas , Linfoma de Célula do Manto , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Croácia , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Estudos Retrospectivos , Transplante Autólogo
3.
Biosci Rep ; 41(9)2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34519332

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic of the Coronavirus disease in late 2019 (COVID-19). Vaccine development efforts have predominantly been aimed at 'Extra-viral' Spike (S) protein as vaccine vehicles, but there are concerns regarding 'viral immune escape' since multiple mutations may enable the mutated virus strains to escape from immunity against S protein. The 'Intra-viral' Nucleocapsid (N-protein) is relatively conserved among mutant strains of coronaviruses during spread and evolution. Herein, we demonstrate novel vaccine candidates against SARS-CoV-2 by using the whole conserved N-protein or its fragment/peptides. Using ELISA assay, we showed that high titers of specific anti-N antibodies (IgG, IgG1, IgG2a, IgM) were maintained for a reasonably long duration (> 5 months), suggesting that N-protein is an excellent immunogen to stimulate host immune system and robust B-cell activation. We synthesized three peptides located at the conserved regions of N-protein among CoVs. One peptide showed as a good immunogen for vaccination as well. Cytokine arrays on post-vaccination mouse sera showed progressive up-regulation of various cytokines such as IFN-γ and CCL5, suggesting that TH1 associated responses are also stimulated. Furthermore, vaccinated mice exhibited an elevated memory T cells population. Here, we propose an unconventional vaccine strategy targeting the conserved N-protein as an alternative vaccine target for coronaviruses. Moreover, we generated a mouse monoclonal antibody specifically against an epitope shared between SARS-CoV and SARS-CoV-2, and we are currently developing the First-in-Class humanized anti-N-protein antibody to potentially treat patients infected by various CoVs in the future.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Animais , Anticorpos Monoclonais Murinos , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/genética , Proteínas do Nucleocapsídeo de Coronavírus/genética , Epitopos/imunologia , Humanos , Evasão da Resposta Imune , Imunogenicidade da Vacina , Camundongos , Modelos Animais , Pandemias/prevenção & controle , Vírus da SARS/genética , Vírus da SARS/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Homologia de Sequência de Aminoácidos , Glicoproteína da Espícula de Coronavírus/imunologia , Células Th1/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia
4.
MEDICC Rev ; 23(3-4): 21-28, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34516533

RESUMO

INTRODUCTION: Racotumomab is a therapeutic vaccine based on a monoclonal anti-idiotypic antibody developed by the Molecular Immunology Center in Havana, Cuba, that is registered in Cuba and Argentina for treatment of non-small cell lung cancer. It induces a specific humoral and cellular immune response against the N-glycolyl GM3 (NeuGcGM3) ganglioside present in tumor cells, thereby provoking the death of these cells. OBJECTIVE: Evaluate racotumomab vaccine use as switch maintenance and second-line therapy for patients with inoperable non-small cell lung cancer in routine clinical practice, outside the framework of clinical studies, and assess the overall survival, stage-specific survival and safety in these patients. METHODS: A descriptive, retrospective study was carried out in patients diagnosed with non-small cell lung cancer not suitable for surgical treatment, who received racotumomab as a part of switch maintenance or second-line treatments. Overall survival was defined from diagnosis and from the first immunization, until death. RESULTS: We included 71 patients treated with racotumomab, 57.7% (41/71) of whom were in stages IIIB and IV of non-small cell lung cancer. Of the patients, 84.5% (60/71) had no adverse events, and 15.5% (11/71) had mild adverse reactions. The median overall survival was 24.5 months, calculated from the first immunization, 17.2 months for those who received racotumomab as switch maintenance and 6.8 months for patients who had progressed after the first line of treatment. CONCLUSIONS: Racotumomab in routine clinical practice prolonged overall survival in patients with non-small cell lung cancer treated in switch maintenance, and in stage IV patients who received the treatment as second-line therapy. The vaccine was well tolerated.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais Murinos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cuba , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos
5.
Blood Adv ; 5(17): 3354-3361, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477816

RESUMO

Rituximab biosimilars are a cornerstone of treatment of advanced-stage follicular lymphoma (FL). This double-blind, parallel-group, phase 3 trial randomized (1:1) adults (≥18 years) with stage III to IV indolent B-cell lymphoma, including grades 1 to 3a FL, to receive CT-P10 or rituximab (375 mg/m2 IV), with cyclophosphamide, vincristine, and prednisone, every 3 weeks for 8 cycles (induction period). Patients achieving complete response (CR), unconfirmed CR, or partial response (PR) received CT-P10 or rituximab maintenance for 2 years (375 mg/m2, every 8 weeks). Primary end points were previously reported, proving noninferiority of efficacy and pharmacokinetic equivalence of CT-P10 to rituximab. Secondary end points included overall response rate (PR+CR) during the induction period per 2007 International Working Group (IWG) criteria, survival analyses, and overall safety. Between 28 July 2014 and 29 December 2015, 140 patients were randomized (70 per group). Median follow-up was 39.9 months (interquartile range, 36.7-43.5). Per 1999 IWG criteria, 4-year Kaplan-Meier estimates (95% confidence interval [CI]) for CT-P10 and rituximab were 61% (47% to 73%) and 55% (36% to 70%) for progression-free survival (hazard ratio, 1.33 [95% CI, 0.67-2.63]; P=.409), respectively, and 88% (77% to 94%) and 93% (83% to 97%) for overall survival (5.29 [0.84-33.53]; P=.077). Overall, 90% (CT-P10) and 86% (rituximab) of patients experienced treatment-emergent adverse events. Long-term safety profiles were similar between groups. Findings confirm favorable outcomes for CT-P10-treated patients with advanced-stage FL and demonstrate comparable long-term efficacy and overall safety between CT-P10 and rituximab. This trial was registered at www.clinicaltrials.gov as #NCT02162771.


Assuntos
Medicamentos Biossimilares , Linfoma Folicular , Anticorpos Monoclonais Murinos , Humanos , Linfoma Folicular/diagnóstico por imagem , Linfoma Folicular/tratamento farmacológico , Rituximab/efeitos adversos
6.
J Int Med Res ; 49(9): 3000605211006644, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34590922

RESUMO

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of non-Hodgkin's lymphoma, and is divided into Western and Asian variants. The latter is rarely found to have neurological system involvement. In China, there have only been a few diagnosed cases of IVLBCL. Here, we present a Chinese case of Asian-variant IVLBCL with neurological symptoms. A 32-year-old Chinese man presented with bilateral lower limb numbness and persistent fever. He also complained of difficulties in urination and defecation. In addition, splenomegaly and pancytopenia were observed. We identified 3% dysplastic lymphocytes in his peripheral blood film, and his bone marrow biopsy led to a diagnosis of Asian-variant IVLBCL. Lumbar spine magnetic resonance imaging, which revealed an edematous spinal cord, further confirmed neurological involvement. The patient refused treatment from the time of diagnosis, and died 2 months after being discharged. IVLBCL is a highly aggressive but nonspecific clinical manifestation that is difficult to diagnose; therefore, a greater understanding of the disease is needed. The current first-line therapy involves R-CHOP combination therapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab); however, the overall prognosis of IVLBCL remains poor.


Assuntos
Linfo-Histiocitose Hemofagocítica , Linfoma Difuso de Grandes Células B , Adulto , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Vincristina/uso terapêutico
7.
BMJ Case Rep ; 14(8)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34353823

RESUMO

Central nervous system lymphoproliferative disorder (CNS-PTLD) after organ transplant is a unique clinicopathological entity and is associated with poor survival rates. When the CNS is involved, intravenous rituximab might not be the treatment of choice, due to its poor CNS penetration. However, intrathecal (IT) administration of rituximab has shown to be safe and efficient in small studies and in case series. We report here the case of a patient with late development of CNS-PTLD after kidney-pancreas transplantation who achieved complete remission after surgical resection and four cycles of IT rituximab and we provide a review of the literature for this treatment option.


Assuntos
Transtornos Linfoproliferativos , Anticorpos Monoclonais Murinos , Sistema Nervoso Central , Humanos , Rim , Transtornos Linfoproliferativos/tratamento farmacológico , Pâncreas , Rituximab , Células-Tronco
8.
Blood Adv ; 5(19): 3862-3872, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34461634

RESUMO

Primary mediastinal B-cell lymphoma (PMBL) is a rare type of aggressive lymphoma typically affecting young female patients. The first-line standard of care remains debated. We performed a large multicenter retrospective study in 25 centers in France and Belgium to describe PMBL patient outcomes after first-line treatment in real-life settings. A total of 313 patients were enrolled and received rituximab (R) plus ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) (n = 180) or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) delivered every 14 days (R-CHOP14, n = 76) or 21 days (R-CHOP21, n = 57) and consolidation strategies in modalities that varied according to time and institution, mainly guided by positron emission tomography. Consolidation autologous stem cell transplantation was performed for 46 (25.6%), 24 (31.6%), and 1 (1.8%) patient in the R-ACVBP, R-CHOP14, and R-CHOP21 groups, respectively (P < .001); only 17 (5.4%) patients received mediastinal radiotherapy. The end-of-treatment complete metabolic response rates were 86.3%, 86.8%, and 76.6% (P = .23) in the R-ACVBP, R-CHOP14, and R-CHOP21 groups. The median follow-up was 44 months, and the R-ACVBP, R-CHOP14, and R-CHOP21 three-year progression-free survival probabilities were 89.4% (95% confidence interval [CI], 84.8-94.2), 89.4% (95% CI, 82.7-96.6), and 74.7% (95% CI, 64-87.1) (P = .018). A baseline total metabolic tumor volume (TMTV) ≥360 cm3 was associated with a lower progression-free survival (hazard ratio, 2.18; 95% CI, 1.05-4.53). Excess febrile neutropenia (24.4% vs 5.3% vs 5.3%; P < .001) and mucositis (22.8% vs 3.9% vs 1.8%; P < .001) were observed with R-ACVBP compared with the R-CHOP regimens. Patients with PMBL treated with dose-dense immunochemotherapy without radiotherapy have excellent outcomes. R-ACVBP acute toxicity was higher than that of R-CHOP14. Our data confirmed the prognostic importance of baseline TMTV.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Estudos Retrospectivos , Transplante Autólogo , Resultado do Tratamento
9.
Signal Transduct Target Ther ; 6(1): 315, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433803

RESUMO

The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 "knock-in" mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and "alanine walk" studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and "broad-spectrum" management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.


Assuntos
Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Anticorpos Monoclonais Murinos/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Anticorpos Monoclonais Murinos/imunologia , Antivirais/imunologia , Chlorocebus aethiops , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Células Vero
10.
ACS Chem Biol ; 16(8): 1344-1349, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34255482

RESUMO

Glycerol phosphate (GroP)-based teichoic acids (TAs) are antigenic cell-wall components found in both enterococcus and staphylococcus species. Their immunogenicity has been explored using both native and synthetic structures, but no details have yet been reported on the structural basis of their interaction with antibodies. This work represents the first case study in which a monoclonal antibody, generated against a synthetic TA, was developed and employed for molecular-level binding analysis using TA microarrays, ELISA, SPR-analyses, and STD-NMR spectroscopy. Our findings show that the number and the chirality of the GroP residues are crucial for interaction and that the sugar appendage contributes to the presentation of the backbone to the binding site of the antibody.


Assuntos
Anticorpos Monoclonais Murinos/metabolismo , Epitopos/metabolismo , Glicerofosfatos/metabolismo , Ácidos Teicoicos/metabolismo , Animais , Anticorpos Monoclonais Murinos/imunologia , Ensaio de Imunoadsorção Enzimática , Epitopos/química , Epitopos/imunologia , Glicerofosfatos/química , Glicerofosfatos/imunologia , Camundongos , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Ácidos Teicoicos/química , Ácidos Teicoicos/imunologia
11.
ESMO Open ; 6(4): 100210, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34271313

RESUMO

BACKGROUND: R-CHOP-21 has been the standard treatment for diffuse large B-cell lymphoma (DLBCL), but there is a paucity of evidence focusing on the number of cycles of regimens. PATIENTS AND METHODS: We conducted a retrospective study to compare the effectiveness of six cycles of standard regimens versus eight cycles for overall survival (OS) in DLBCL patients using propensity score matching, in consideration of relative dose intensity (RDI). RESULTS: A total of 685 patients with newly diagnosed DLBCL were identified in three institutions from 2007 to 2017. Patients treated using six cycles of standard regimens were matched by propensity scores with those treated using eight cycles. A 1 : 1 propensity score matching yielded 138 patient pairs. Eight cycles did not significantly improve OS in the conventional Cox proportional hazards model (hazard ratio 0.849, 95% confidence interval 0.453-1.588, P = 0.608). Restricted cubic spline Cox models for OS confirmed that the effect of the number of cycles was not modified by total average RDI, the International Prognostic Index, and age. Occurrence of adverse events did not differ between six and eight cycles. CONCLUSION: Even considering the impact of RDI, six cycles of the initial standard regimen for DLBCL is not inferior to eight cycles.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida , Doxorrubicina , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Rituximab , Vincristina
12.
Crit Rev Oncol Hematol ; 163: 103377, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34087342

RESUMO

Doxorubicin represents the mainstay in the upfront treatment of diffuse large B-cell lymphoma (DLBCL) patients. However, its administration is sometimes hampered by the coexistence of former comorbidities/cardiac issues, especially in the elderly population. Liposome encapsulated drug delivery systems have been adopted to reduce the exposure of normal tissues to the drug, both in solid cancers and lymphomas. Despite claims for lower toxicity, the efficacy of non-pegylated liposome doxorubicin (NPLD) in DLBCL, as compared to standard doxorubicin, has never been established. We systematically reviewed relevant literature of NPLD in lymphoma treatment. Adjusting for age/comorbidities, our metanalysis revealed that the use of combinations including NPLD (R-COMP) were non-inferior in terms of response, overall and progression-free survival to the standard of care (R-CHOP) in overlapping series of DLBCL patients. R-COMP may represent a safe and active option for elderly patients with DLBCL, or for those with some extent of cardiac impairment at baseline.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Idoso , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/efeitos adversos
13.
J Int Med Res ; 49(6): 3000605211017037, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34082600

RESUMO

Primary colonic lymphoma is a very rare malignant tumor with no standard treatment. We report two cases of primary colonic lymphoma successfully treated with surgery and chemotherapy, and chemotherapy alone, respectively. The first case was a 61-year-old woman who presented with abdominal pain of more than 1 month. The patient was diagnosed with a colonic tumor, and immunohistochemical examinations confirmed the initial diagnosis of colonic lymphoma. The patient underwent laparoscopic-assisted right hemicolectomy followed by postoperative adjuvant chemotherapy with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen, combined with targeted therapy with rituximab (R-CHOP). The second case was a 78-year-old man who presented with a complaint of abdominal distention for more than 1 year. Diffuse large B-cell lymphoma was definitively diagnosed by immunohistochemical examinations, and the patient underwent systemic chemotherapy with the R-CHOP regimen. Primary colonic lymphoma is a rare type of non-Hodgkin's lymphoma (NHL), and the clinical treatment is not standardized, unlike for many other types of lymphoma. Therefore, treatment is mainly based on the patient's symptoms to determine whether surgery or systemic chemotherapy is appropriate. Rituximab is effective in some patients and may play an important role in the treatment of unresectable or asymptomatic colonic lymphoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Colo , Idoso , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
15.
Blood Adv ; 5(9): 2426-2437, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33961018

RESUMO

The dilemma of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone+rituximab) is often faced by clinicians. We conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. We searched MEDLINE, EMBASE, and Cochrane CENTRAL for studies with ≥100 patients treated with R-CHOP/R-CHOP-like therapies published from January 2002 through November 2020. Studies were included if they reported the impact of R-CHOP DI on survival outcomes. We screened records, extracted data, and reviewed all the studies for quality and statistical appraisal. Of 380 screened records, 13 studies including 5188 patients were reviewed. DI was often calculated as the ratio of the cumulative delivered dose of prespecified drug(s) to the cumulative planned dose multiplied by a time-correction factor. Lower DI (intended or relative) was associated with inferior survival in 7 of 9 studies reporting crude survival analyses. Multivariable analysis using DI as a covariate was performed in 10 studies. Six showed an association (P < .05) with adjustment for other covariates, and 4 did not. Most studies and those larger studies of higher quality showed poorer outcomes associated with reduced DI. In subgroups aged ≥80 years, survival was not consistently affected by reduced DI. DI-specific randomized trials are warranted, but these data support full-dose R-CHOP in elderly and fit patients aged <80 years with DLBCL, but not in those aged ≥80 years, where dose-reduced R-CHOP does not appear to compromise survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Idoso , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
16.
Anal Chem ; 93(17): 6865-6872, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33881841

RESUMO

Antibodies not only play a major role in clinical diagnostics and biopharmaceutical analysis but also are a class of drugs that are regularly used to treat numerous diseases. The identification of antibody-epitope binding sites is then of great interest to many emerging medical and bioanalytical applications, particularly to design monoclonal antibodies (mAb) mimics taking advantage of amino acid residues involved in the binding. Among relevant antibodies, the monoclonal antibody rituximab has received significant attention as it is exploited to treat several cancers including non-Hodgkin's lymphoma and chronic lymphocytic leukemia, as well as some autoimmune disorders such as rheumatoid arthritis. The binding of rituximab to the targeted cells occurs via the recognition of the CD20 epitope. A crystallographic study has shown that the binding area, named paratope, is located at the surface of rituximab. Combining the SPOT method and the complementary surface plasmon resonance technique allowed us to detect an extended recognition domain buried in the pocket of the rituximab Fab formed by four ß-sheets. More generally, the present study offers a comprehensive approach to identify antibody-epitope binding sites.


Assuntos
Antígenos CD20 , Ressonância de Plasmônio de Superfície , Anticorpos Monoclonais Murinos , Sítios de Ligação , Epitopos , Rituximab
17.
Chin Med Sci J ; 36(1): 72-77, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33853712

RESUMO

A 90-year-old man was diagnosed with primary gastric diffuse large B-cell lymphoma (PGDLBL) by PET/CT examination, gastroscopy, biopsy and histopathological analysis at a regular physical check in April, 2016. The patient received R-CO chemotherapy (rituximab, cyclophosphamide, and vincristine) and radiotherapy subsequently, with enteral nutritional treatment through 3-cavity nasogastric tube due to development of pyloric obstruction. To satisfy patient's strong desire of eating by himself, we performed surgery of exploratory laparotomy and Roux-en-Y gastric bypass (RGB) to relieve pylorus obstruction. Postoperatively, the patient resumed oral feeding, supplemented by nasogastric tube feeding at 1350 - 1550 Kcal daily. He is now 94 years old with fairly well nutrition and normal communication. The outcome of 4 year follow-up suggests that nutritional treatment and palliative medicine are important for improving prognosis and life-quality of very elderly patients with end-stage tumors apart from the effective chemotherapy, radiotherapy, and surgery.


Assuntos
Linfoma Difuso de Grandes Células B , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma não Hodgkin , Masculino , Cuidados Paliativos , Prednisona/uso terapêutico , Neoplasias Gástricas , Resultado do Tratamento
18.
Sci Transl Med ; 13(589)2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33853929

RESUMO

Rituximab (RTX), an antibody targeting CD20, is widely used as a first-line therapeutic strategy in B cell-mediated autoimmune diseases. However, a large proportion of patients either do not respond to the treatment or relapse during B cell reconstitution. Here, we characterize the cellular basis responsible for disease relapse in secondary lymphoid organs in humans, taking advantage of the opportunity offered by therapeutic splenectomy in patients with relapsing immune thrombocytopenia. By analyzing the B and plasma cell immunoglobulin gene repertoire at bulk and antigen-specific single-cell level, we demonstrate that relapses are associated with two responses coexisting in germinal centers and involving preexisting mutated memory B cells that survived RTX treatment and naive B cells generated upon reconstitution of the B cell compartment. To identify distinctive characteristics of the memory B cells that escaped RTX-mediated depletion, we analyzed RTX refractory patients who did not respond to treatment at the time of B cell depletion. We identified, by single-cell RNA sequencing (scRNA-seq) analysis, a population of quiescent splenic memory B cells that present a unique, yet reversible, RTX-shaped phenotype characterized by down-modulation of B cell-specific factors and expression of prosurvival genes. Our results clearly demonstrate that these RTX-resistant autoreactive memory B cells reactivate as RTX is cleared and give rise to plasma cells and further germinal center reactions. Their continued surface expression of CD19 makes them efficient targets for current anti-CD19 therapies. This study thus identifies a pathogenic contributor to autoimmune diseases that can be targeted by available therapeutic agents.


Assuntos
Púrpura Trombocitopênica Idiopática , Anticorpos Monoclonais Murinos , Linfócitos B , Humanos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Recidiva , Rituximab/farmacologia , Rituximab/uso terapêutico
20.
J Surg Oncol ; 123(8): 1736-1741, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33772776

RESUMO

BACKGROUND AND OBJECTIVES: The diagnosis of lymphovascular invasion (LVI) is often inaccurate with routine histology. This study aimed to evaluate the use of immunohistochemistry (IHC) in detecting LVI and reevaluate the clinical implications of LVI in gastric cancer. METHODS: This prospective unrandomized cohort study analyzed the rates of LVI positivity and its relevance with other clinicopathologic features. RESULTS: Between November 2017 and April 2018, 558 patients undergoing curative gastrectomy were enrolled and assigned to the IHC group (n = 285) and hematoxylin-eosin group (n = 273). The use of IHC increased the rates of LVI positivity (60.8% vs. 43.3%, p < .001) and decreased the rates of undetermined LVI subtype (7.7% vs. 27.1%, p < .001). The LVI-negative patients identified by IHC had fewer lymph node metastases (16.8% vs. 34.6%, p = .002) and earlier pathological stage (p = .004) than those identified by routine histology. The LVI-positive patients identified by IHC had a higher percentage of perineural invasion (p = .019). CONCLUSIONS: The use of endothelial markers significantly enhanced the detection of LVI. The LVI detected by IHC could be a better predictor of lymph node metastasis and biological aggressiveness in gastric cancer.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Anticorpos Monoclonais Murinos/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Idoso , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Valor Preditivo dos Testes
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