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1.
Ther Umsch ; 76(4): 195-198, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31498041

RESUMO

Immunotherapy - immune-related adverse events and their management Abstract. Checkpoint-Inhibition has become an important part of modern oncological treatment strategies for many patients with cancer. The development of this new class of anti-cancer drugs has begun for ten years and showed meanwhile a specific new side effect profile. Since the mode of action of checkpoint inhibitors is immune modulation the side effects are particularly different to so far established anti-cancer drugs. Because of the immunological nature of side effects, the spectrum is wide, and the symptoms are amble. Additionally, the side effects can appear at very different time points after the administration of the checkpoint inhibitor. Therefore, the recognition and the management are a new challenge for the care teams. Only if the whole care team is able to understand, diagnose and efficiently manage the side effects the therapeutic potential of this new class of anti-cancer drugs can be made useful for the patients. The article aims to provide information for the care teams to recognize and manage side effects of checkpoint-inhibitors.


Assuntos
Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias/terapia , Humanos , Fatores Imunológicos , Oncologia , Síndromes Neurotóxicas/etiologia
2.
J Immunother ; 42(7): 274-277, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31219972

RESUMO

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare, aggressive tumor arising from different localizations along the gastrointestinal tract with generally poor prognosis. We present the case of a 51-year-old female patient with histopathologically confirmed diagnosis of a MANEC of the descending colon. At presentation, the tumor had already spread to the liver causing extensive hepatic metastases. Immunohistochemical examination showed 5%-10% of tumor cells to express the programmed cell death receptor ligand 1 and FoundationOne testing revealed a high mutational tumor burden with 149 Muts/Mb. The patient responded very well clinically and radiologically to anti-programmed death 1 receptor monoclonal antibody pembrolizumab therapy after having undergone 3 previous systemic treatment regimens as well as selective internal radiation therapy of her hepatic metastases. Clinical improvement was evident after the first infusion already and is ongoing for 10 months so far with very little side effects including initial and short lived skin irritation as well as muscle pain. To our knowledge, this is the first published case where a MANEC was successfully treated with immunotherapy targeting the programmed death 1 receptor.

3.
J Thorac Oncol ; 13(11): 1784-1791, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30142389

RESUMO

INTRODUCTION: There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1). METHODS: Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative (<5%), intermediate (5%-49%), and high (≥50%). RESULTS: A total of 93 patients (48 from Switzerland and 45 from Australia) were treated; 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. CONCLUSION: These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti-PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM.

4.
Clin Cancer Res ; 24(16): 3981-3993, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29748183

RESUMO

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM.Results: All the three CARs demonstrated FAP-specific functionality in vitro Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality.Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981-93. ©2018 AACR.

5.
Oncoimmunology ; 7(2): e1378844, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29416939

RESUMO

Tertiary lymphoid structures (TLS) are associated with favorable outcome in non-metastatic colorectal carcinoma (nmCRC), but the dynamics of TLS maturation and its association with effective anti-tumor immune surveillance in nmCRC are unclear. Here, we hypothesized that not only the number of TLS but also their composition harbors information on recurrence risk in nmCRC. In a comprehensive molecular, tissue, laboratory, and clinical analysis of 109 patients with stage II/III nmCRC, we assessed TLS numbers and degree of maturation in surgical specimens by multi-parameter immunofluorescence of follicular dendritic cell (FDC) and germinal center (GC) markers. TLS formed in most tumors and were significantly more prevalent in highly-microsatellite-instable (MSI-H) and/or BRAF-mutant nmCRC. We could distinguish three sequential TLS maturation stages which were characterized by increasing prevalence of FDCs and mature B-cells: [1] Early TLS, composed of dense lymphocytic aggregates without FDCs, [2] Primary follicle-like TLS, having FDCs but no GC reaction, and [3] Secondary follicle-like TLS, having an active GC reaction. A simple integrated TLS immunoscore reflecting these parameters identified a large subgroup of nmCRC patients with a very low risk of recurrence independently of clinical co-variables such as ECOG performance status, age, stage, and adjuvant chemotherapy. We conclude that (1) mismatch repair and BRAF mutation status are associated with the formation of TLS in nmCRC, (2) TLS formation in nmCRC follows sequential maturation steps, culminating in germinal center formation, and (3) this maturation process harbors important prognostic information on the risk of disease recurrence.

6.
Biol Blood Marrow Transplant ; 24(4): 694-699, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29246820

RESUMO

Vinorelbine combined with filgrastim at a dose of 10 µg/kg of body weight (BW) per day is a reliable and well-tolerated regimen for mobilization of hematopoietic progenitor cells (HPCs) in patients with multiple myeloma. This prospective, randomized, phase II study was initiated to assess the feasibility of a reduced filgrastim dosage. Vinorelbine was combined with either standard-dose filgrastim (10 µg/kg BW per day) or reduced-dose filgrastim (5 µg/kg BW per day). Leukapheresis sessions were planned to start at day 8 and were continued until the predefined target amount of 4 × 106 HPCs/kg BW was collected. The study demonstrated the feasibility of vinorelbine combined with reduced daily filgrastim with a mean of 1.29 leukapheresis sessions necessary per patient (95% confidence interval, .95 to 1.7). All patients could start leukapheresis as planned at day 8, and the collection success rate was 100% for the whole patient collective after a maximum of 2 leukapheresis sessions. No statistically significant differences with regard to the amount of HPCs collected between the 2 groups were observed (P = .99). Accordingly, no differences were seen with regard to length of hospitalization for autotransplant (P = .34) and duration of neutrophil (P = .93) and platelet engraftment (P = .42). Patients receiving reduced-dose filgrastim reported significantly lower peak pain values in a numeric analogue scale (P = .01), and the costs were significantly lower than in patients undergoing standard-dose chemomobilization (P = .001). Vinorelbine 35 mg/m2 plus filgrastim 5 µg/kg BW once per day until completion of HPC collection is feasible and appears to be advantageous with respect to the severity of pain intensity and treatment costs.

7.
Expert Rev Gastroenterol Hepatol ; 11(9): 865-869, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28697656

RESUMO

BACKGROUND: Population-based data on the development of second malignant neoplasms (SMNs) following the diagnosis of hepatocellular carcinoma (HCC) are uncommon. We evaluated this clinical vignette in HCC patients within the Surveillance, Epidemiology and End Results (SEER) database. METHODS: The SEER database (1973-2012) was queried using the SEER*Stat program to determine the clinico-pathological features of HCC patients with more than one year survival who developed SMNs. Standardized incidence ratios (SIRs) were calculated to determine the risk of each type of subsequent cancers. Relative risk was assessed to determine the impact of liver transplantation on the development of second malignant neoplasms. RESULTS: On SIR analysis, the following sites have an enhanced risk of developing an SMN following the diagnosis of HCC: tongue, anal canal, liver, lung, kidney, thyroid, non-Hodgkin lymphoma (both nodal and extra-nodal disease) and acute monocytic leukemia (P < 0.05 for all sites). A significantly higher RR was found for the development of lung cancer (RR = 2.096), thyroid cancer (RR = 3.045) and non-Hodgkin lymphoma (RR = 3.822) among patients who underwent liver transplantation compared to those who did not (P < 0.05). CONCLUSION: There is an excess risk for developing a number of SMNs among patients diagnosed with HCC.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Idoso , Feminino , Humanos , Masculino , Segunda Neoplasia Primária/etiologia , Estudos Retrospectivos , Fatores de Risco , Programa de SEER , Estados Unidos
8.
Expert Rev Neurother ; 17(7): 725-736, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28548892

RESUMO

INTRODUCTION: Immune-related neurologic toxicities are uncommon but serious adverse events that may be associated with the use of immune checkpoint inhibitors. The objective of this review is to assess the incidence and risk of neurologic toxicities which are potentially immune-related and occur with immune checkpoint treatment of solid tumors. Areas covered: PubMed database has been searched till January 2017. Clinical trials, case series and case reports reporting the occurrence of immune-related neurologic toxicities in solid tumor patients treated with immune checkpoint inhibitors were included. Eighteen trials with 4469 participants were included. The most common neurologic toxicities reported with these agents included sensory and motor peripheral neuropathies. Moreover, 17 case reports describing immune-related neurological events occurring with 22 patients were included. Expert commentary: Immune-related neurological toxicities occur uncommonly in cancer patients treated immune checkpoint inhibitors. Further studies are needed to better describe the course of these events (i.e. time to onset, time to resolution and responsiveness to different immunosuppressives).

9.
J Geriatr Oncol ; 8(4): 277-283, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28389117

RESUMO

BACKGROUND: Scarce evidence exists regarding the management of elderly patients (≥70years) with hepatocellular carcinoma (HCC). This study assessed the presentation and outcomes of elderly patients with early stage HCC. METHODS: Patient with early stage HCC (T1/T2N0M0), ≥70years, diagnosed between 2004 and 2013 were identified from the SEER (Surveillance, Epidemiology, and End Results) database. Propensity score matching (for receipt of localized treatment) was performed considering baseline characteristics (age, gender, race, tumor (T) stage, tumor size, fibrosis score, alpha fetoprotein level and histological subtype). RESULTS: A total of 6693 patients were identified. The median age group was 75-80years, and 2457 patients received local treatment (either surgical or non-surgical treatment). Both before and after propensity score matching, cancer-specific and overall survival (P<0.0001 for all) were better in the local treatment group. When stratifying the overall survival according to age group (70-80years vs. >80years) in the post matching cohort, patients treated with local treatment have better overall survival than those not treated regardless of the age group (P<0.0001 for both groups). In multivariate analysis of the matched population: local treatment, normal AFP and age (70-80years) were associated with better overall survival (P<0.0001, P<0.0001, P=0.047; respectively). CONCLUSION: Within the known limitations of the current SEER analysis, it may be cautiously suggested that elderly patients with early HCC should be properly selected for potentially curative local therapies. Prospective confirmation of these results should be conducted.


Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/mortalidade , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Estadiamento de Neoplasias , Pontuação de Propensão , Programa de SEER , Resultado do Tratamento , Estados Unidos/epidemiologia
10.
World J Gastroenterol ; 23(10): 1872-1880, 2017 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-28348494

RESUMO

AIM: To evaluate the prognostic value of site-specific metastases among patients with metastatic pancreatic carcinoma registered within the Surveillance, Epidemiology and End Results (SEER) database. METHODS: SEER database (2010-2013) has been queried through SEER*Stat program to determine the presentation, treatment outcomes and prognostic outcomes of metastatic pancreatic adenocarcinoma according to the site of metastasis. In this study, metastatic pancreatic adenocarcinoma patients were classified according to the site of metastases (liver, lung, bone, brain and distant lymph nodes). We utilized chi-square test to compare the clinicopathological characteristics among different sites of metastases. We used Kaplan-Meier analysis and log-rank testing for survival comparisons. We employed Cox proportional model to perform multivariate analyses of the patient population; and accordingly hazard ratios with corresponding 95%CI were generated. Statistical significance was considered if a two-tailed P value < 0.05 was achieved. RESULTS: A total of 13233 patients with stage IV pancreatic cancer and known sites of distant metastases were identified in the period from 2010-2013 and they were included into the current analysis. Patients with isolated distant nodal involvement or lung metastases have better overall and pancreatic cancer-specific survival compared to patients with isolated liver metastases (for overall survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001) (for pancreatic cancer-specific survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001). Multivariate analysis revealed that age < 65 years, white race, being married, female gender; surgery to the primary tumor and surgery to the metastatic disease were associated with better overall survival and pancreatic cancer-specific survival. CONCLUSION: Pancreatic adenocarcinoma patients with isolated liver metastases have worse outcomes compared to patients with isolated lung or distant nodal metastases. Further research is needed to identify the highly selected subset of patients who may benefit from local treatment of the primary tumor and/or metastatic disease.


Assuntos
Adenocarcinoma/mortalidade , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/mortalidade , Neoplasias Pancreáticas/mortalidade , Programa de SEER/estatística & dados numéricos , Adenocarcinoma/patologia , Fatores Etários , Idoso , Distribuição de Qui-Quadrado , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores Sexuais , Estados Unidos/epidemiologia
11.
Expert Rev Gastroenterol Hepatol ; 11(7): 695-701, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28276812

RESUMO

BACKGROUND: We the prognostic value of site-specific extra-hepatic disease in hepatocellular carcinoma (HCC) patients registered within the surveillance, epidemiology and end results (SEER) database. METHODS: SEER database (2010-2013) has been queried through SEER*Stat program to determine the prognosis of advanced HCC patients according to the site of extra-hepatic disease. Survival analysis has been conducted through Kaplan Meier analysis. RESULTS: A total of 4396 patients with stage IV HCC were identified in the period from 2010-2013 and they were included into this analysis. Patients with isolated regional lymph node involvement have better outcomes compared to patients with any other site of extra-hepatic disease (P < 0.0001 for both endpoints). Among patients with distant metastases, patients with bone metastases have better outcomes compared to patients with lung metastases (P < 0.0001 for both endpoints). Multivariate analysis revealed that younger age, normal alpha fetoprotein, single site of extra-hepatic disease, local treatment to the primary tumor and surgery to the metastatic disease were associated with better overall survival and liver cancer-specific survival. CONCLUSION: Within the limits of the current SEER analysis, HCC patients with isolated lung metastases seem to have worse outcomes compared to patients with isolated bone or regional nodal metastases.​.


Assuntos
Neoplasias Ósseas/mortalidade , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/mortalidade , Adulto , Fatores Etários , Idoso , Neoplasias Ósseas/secundário , Neoplasias Ósseas/cirurgia , Carcinoma Hepatocelular/secundário , Carcinoma Hepatocelular/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Programa de SEER , Taxa de Sobrevida , Estados Unidos/epidemiologia , alfa-Fetoproteínas/metabolismo
12.
Expert Rev Anticancer Ther ; 17(4): 387-394, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28277102

RESUMO

INTRODUCTION: Immune-related ocular toxicities are uncommon but serious adverse events that may be associated with the use of immune checkpoint inhibitors. The objective of this review is to assess the incidence and risk of ocular toxicities which are potentially immune-related and occur with immune checkpoint treatment of solid tumors. Areas covered: PubMed database has been searched till June 2016. Prospective clinical trials reporting the occurrence of immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors were included. Eleven trials with 4965 participants were included. These studies included one study for ipilimumab and tremelimumab, three studies for nivolumab, five studies for pembrolizumab and one study comparing pembrolizumab to ipilimumab. No atezolizumab studies were included. The most common ocular toxicities reported with these agents included uveitis and dry eyes. Pooled analysis for odds ratio of all-grade immune-related ocular toxicities is 3.40 [95% CI: 1.32-8.71; P = 0.01]. Expert commentary: Despite being uncommon, immune-related ocular toxicities (particularly uveitis and dry eyes) occur with a higher frequency in cancer patients treated immune checkpoint inhibitors compared to those treated with control regimens.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Oftalmopatias/induzido quimicamente , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Antineoplásicos/administração & dosagem , Síndromes do Olho Seco/induzido quimicamente , Síndromes do Olho Seco/epidemiologia , Síndromes do Olho Seco/imunologia , Oftalmopatias/epidemiologia , Oftalmopatias/imunologia , Humanos , Incidência , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Risco , Uveíte/induzido quimicamente , Uveíte/epidemiologia , Uveíte/imunologia
13.
Expert Rev Gastroenterol Hepatol ; 11(3): 249-258, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28099818

RESUMO

INTRODUCTION: We aimed to assess the efficacy and safety of delivering intraperitoneal chemotherapy and cytoreductive surgery for peritoneal metastases coupled with curative treatment of colorectal liver metastases. Areas covered: A comprehensive literature search using PubMed was conducted to screen for eligible records. Studies evaluating colorectal surgery and intraperitoneal chemotherapy combined with curative treatment of liver metastases were included. We excluded duplicate publications. Sixty-seven full-text papers were assessed and six papers were finally included. The overall survival in the included studies ranged from 6-49 months. Five-year survival ranged from 18%-28%, three-year survival ranged from 22%-42% and two-year survival ranged from 34%-78%. Survival was lower in patients with liver metastases and peritoneal carcinomatosis (PC) than those with PC alone in the majority of studies. Expert commentary: This review poses questions rather than presenting answers. The heterogeneity of survival data suggests the possible benefit of this aggressive treatment approach in selected patients. Standardization of the technique used for intraperitoneal chemotherapy instillation, agent used as well as the systemic chemotherapy and targeted therapy type and duration through prospective controlled trials is required to provide an evidence of a higher strength to support or prohibit this treatment strategy.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/patologia , Procedimentos Cirúrgicos de Citorredução , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Antineoplásicos/efeitos adversos , Quimioterapia Adjuvante , Neoplasias Colorretais/mortalidade , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Procedimentos Cirúrgicos de Citorredução/mortalidade , Progressão da Doença , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Terapia Neoadjuvante , Neoplasias Peritoneais/mortalidade , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
14.
J Clin Apher ; 32(1): 21-26, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27001243

RESUMO

Biosimilars are increasingly being licensed as equipotent drugs, although efficacy and safety data are not available for all clinical indications. Accordingly, the efficacy of the biosimilar filgrastim Zarzio® combined with vinorelbine for chemo-mobilization of CD34+ hematopoietic progenitor cells (HPC) in patients with multiple myeloma has not been evaluated yet. We compared the efficacy of vinorelbine combined with this biosimilar filgrastim for HPC mobilization to vinorelbine plus original filgrastim (Neupogen®). Overall, 105 multiple myeloma patients received vinorelbine 35 mg/m2 intravenously on day 1 and either original filgrastim (n = 61;58%) or biosimilar filgrastim (n = 44;42%) at a dose of 5 µg per kg body weight (BW) twice daily subcutaneously starting day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and performed for a maximum of three consecutive days until at least 4 × 106 HPC/kg BW were collected. All patients proceeded to leukapheresis. In 102 (97%) patients the leukapheresis sessions were started as planned at day 8. The median number of collected HPC was 7.3 × 106 /kg BW (0.2-18.3) with original filgrastim compared to 9 × 106 /kg BW (4.2-23.8) with the biosimilar filgrastim (P = 0.16). HPC collection was successful in 57 (93%) of 61 patients of the original group and in all 44 (100%) patients of the biosimilar group (P = 0.14). No differences were observed regarding side effects. Duration of neutrophil engraftment after autologous HPC transplantation was similar between the two groups (P = 0.17). Biosimilar and original filgrastim achieve comparable results in combination with vinorelbine regarding HPC mobilization and transplantation outcome in multiple myeloma patients. J. Clin. Apheresis 32:21-26, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Medicamentos Biossimilares/farmacologia , Filgrastim/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Vimblastina/análogos & derivados , Medicamentos Biossimilares/administração & dosagem , Contagem de Células , Protocolos Clínicos , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Filgrastim/administração & dosagem , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Estudos Retrospectivos , Vimblastina/administração & dosagem , Vimblastina/farmacologia , Vinorelbina
15.
J Am Soc Mass Spectrom ; 27(6): 1105-12, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27067900

RESUMO

HLA-B27 homodimer formation is believed to be a hallmark of HLA-B27 associated spondyloarthritides. Recently, we have generated a homodimer-specific monoclonal antibody (HD6) and have demonstrated that HLA-B27 homodimer complexes are present on monocytes of healthy HLA-B27 gene carriers at low levels, with significantly increased levels at active disease. The capability of the HD6 antibody to discriminate between correctly formed HLA-B27 heterotrimers and pathology-associated homodimers is striking and cannot be explained by the primary structure of HLA-B27. We hypothesized that HD6 accesses a unique epitope and used affinity-mass spectrometry for its identification. The HD6 antibody was immobilized on an activated sepharose affinity column, and HLA-B27 homodimer characterized for affinity. The epitope was identified by proteolytic epitope excision and MALDI mass spectrometry, and shown to comprise a discontinuous Cys-203- 257-Cys mixed-disulfide peptide structure that is not accessible in HLA-B27 heterotrimers due to protection by noncovalently linked ß2-microglobulin. The epitope peptides were synthesized by solid phase peptide synthesis, and the two monomeric peptide components, HLA-B27(203-219) and HLA-B27(257-273), as well as the homo- and hetero-dimeric disulfide linked combinations prepared. The affinity binding constants KD towards the antibodies were determined using a surface acoustic wave (SAW) biosensor, and showed the highest affinity with a KD of approximately 40 nM to the HD6 antibody for the (203-219)-SS-(257-273) mixed disulfide epitope. Graphical Abstract ᅟ.

16.
J Dermatolog Treat ; 27(5): 436-8, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26864191

RESUMO

Schnitzler syndrome is a rare autoinflammatory disease, which is defined by the presence of two major criteria: chronic urticaria and monoclonal immunoglobulin M (IgM) or immunoglobulin G gammopathy, in combination with at least two additional minor criteria: recurrent fever, leukocytosis and/or elevated C-reactive protein (CRP), objective signs of abnormal bone remodelling and a neutrophilic infiltrate in skin biopsy. We report on a 68-year-old female patient with a 10-year medical history of chronic urticaria, recurrent fever, severe arthralgia and increased CRP. Over the years, multiple diagnostic investigations were performed without conclusive findings, and therapeutic attempts with anti-histamines and several immunosuppressive agents had failed. The decision to initiate monotherapy with interleukin-1 (IL-1) receptor antagonist was based on immunohistochemical detection of the abundance of IL-1ß positive cells in the patient's skin biopsy. After starting treatment with anakinra, disappearance of symptoms could be observed within 24 h. Discontinuation of the treatment resulted in a rapid relapse of the symptoms. Finally, already after the initiation of therapy with anakinra, the suspected diagnosis of Schnitzler syndrome could be confirmed by detection of IgM-gammopathy that was initially absent.


Assuntos
Antirreumáticos/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Síndrome de Schnitzler/tratamento farmacológico , Idoso , Feminino , Humanos , Inflamação/tratamento farmacológico , Receptores de Interleucina-1/antagonistas & inibidores
17.
Prog Tumor Res ; 42: 110-35, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26383243

RESUMO

T cells are a new and promising antigen-specific therapeutic option for the treatment of malignant diseases. To achieve antigen specificity against tumor antigens, T cells can be manipulated by gene transfer to express chimeric antigen receptors (CARs). CAR-expressing T cells are called redirected T cells. CARs are composed of an extracellular antibody-derived antigen recognition domain, a transmembrane domain and a cytoplasmatic signal domain. Therefore, redirected T cells combine the exchangeable specificity of an antibody with the cytotoxic machinery of a T cell. Early clinical trials with redirected T cells targeting cluster of differentiation (CD) 19 have shown impressive results in CD19-positive hematological cancers. However, for solid cancers only limited clinical experience exists and new and innovative concepts have to be developed to overcome tumor-mediated immune suppression. Herein, we describe the general design of a CAR, the function of the different domains and the different strategies to produce redirected T cells. Furthermore, we summarize and discuss the preclinical and clinical data indicating the tremendous potential of redirected T cells to become a mainstay of cancer immunotherapy.


Assuntos
Antígenos de Neoplasias/imunologia , Engenharia Celular , Imunoterapia , Neoplasias/terapia , Linfócitos T/imunologia , Animais , Humanos , Imunomodulação , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/citologia , Linfócitos T/transplante
18.
PLoS One ; 10(6): e0130811, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26125554

RESUMO

OBJECTIVES: HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272-specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders. METHODS: The monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry. RESULTS: HD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules. CONCLUSION: HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders.


Assuntos
Anticorpos Monoclonais/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígeno HLA-B27/imunologia , Inflamação/imunologia , Animais , Comunicação Celular/imunologia , Linhagem Celular , Humanos , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos , Espondilartrite/imunologia
20.
Biol Blood Marrow Transplant ; 21(1): 74-80, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25278456

RESUMO

We aimed to assess the efficacy of vinorelbine plus granulocyte colony-stimulating factor (G-CSF) for chemo-mobilization of CD34(+) hematopoietic progenitor cells (HPC) in patients with multiple myeloma and to identify adverse risk factors for successful mobilization. Vinorelbine 35 mg/m(2) was administered intravenously on day 1 in an outpatient setting. Filgrastim 5 µg/kg body weight (BW) was given twice daily subcutaneously from day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and be performed for a maximum of 3 consecutive days until at least 4 × 10(6) CD34(+) cells per kg BW were collected. Overall, 223 patients were mobilized and 221 (99%) patients proceeded to leukapheresis. Three (1.5%) patients required an unscheduled hospitalization after chemo-mobilization because of neutropenic fever and renal failure (n = 1), severe bone pain (n = 1), and abdominal pain with constipation (n = 1). In 211 (95%) patients, the leukaphereses were started as planned at day 8, whereas in 8 (3%) patients the procedure was postponed to day 9 and in 2 (1%) patients to day 10. In the great majority of patients (77%), the predefined amount of HPC could be collected with 1 leukapheresis. Forty-four (20%) patients needed a second leukapheresis, whereas only 6 (3%) patients required a third leukapheresis procedure. The median number of CD34(+) cells collected was 6.56 × 10(6) (range, .18 to 25.9 × 10(6)) per kg BW at the first day of leukapheresis and 7.65 × 10(6) (range, .18 to 25.9 × 10(6)) per kg BW in total. HPC collection was successful in 212 (95%) patients after a maximum of 3 leukaphereses. Patient age (P = .02) and prior exposition to lenalidomide (P < .001) were independent risk factors for a lower HPC amount collected in multiple regression analysis. Vinorelbine plus G-CSF enables a very reliable prediction of the timing of leukapheresis and results in successful HPC collection in 95% of the patients.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/imunologia , Mieloma Múltiplo/terapia , Vimblastina/análogos & derivados , Adulto , Fatores Etários , Idoso , Antígenos CD34/genética , Antígenos CD34/imunologia , Contagem de Células , Quimioterapia Combinada , Feminino , Filgrastim , Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Lenalidomida , Leucaférese , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Transplante Autólogo , Resultado do Tratamento , Vimblastina/uso terapêutico , Vinorelbina
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