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1.
Anticancer Res ; 39(11): 6265-6271, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704856

RESUMO

BACKGROUND/AIM: The present study aimed to examine the influence of antibiotics (AB) on the clinical outcomes of Japanese patients treated with immune check point inhibitors (ICIs) for metastatic renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: A total of 31 patients with metastatic RCC treated with ICIs from November 2016 to April 2019 were retrospectively reviewed and analyzed. RESULTS: Five patients were treated with AB prior to ICIs treatment. Median progression free survival (PFS) of patients treated with AB vs. patients not treated with AB was 2.8 months and 18.4 months, respectively. The difference between PFS was statistically significant (p=0.0004). In multivariate analyses, AB use (p=0.0377) and presence of immune related adverse events (p=0.0042) were independent prognostic factors for PFS in association with ICIs therapy. CONCLUSION: The use of AB before ICIs treatment was a predictor of poor ICIs response in metastatic RCC.


Assuntos
Antibacterianos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/secundário , Feminino , Humanos , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Japão , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento
2.
Rinsho Ketsueki ; 60(9): 1341-1350, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597862

RESUMO

It has been eight years since the first immune checkpoint-blocking antibody, ipilimumab, was approved for metastatic malignant melanoma treatment by FDA in 2011. During this period, several other immune checkpoint blockers have been newly developed and approved for certain cancers, including malignant melanoma. However, there have been several concerns with some of these. The overall response rate did not exceed 30% in many cancers; although combination therapy with ipilimumab and nivolumab increased efficacy, immune-related adverse events also increased. This observation facilitated the reverse translational research (rTR) approach, using clinical specimens from treated patients to gradually elucidate the mechanism of resistance and biomarkers to select patients who can potentially benefit from immunotherapy. This has also promoted the development of novel combination therapies. In this review, immunological findings that highlight the resistance mechanisms of cancers against immune checkpoint blockers and the novel attempts to achieve a break-through will be discussed.


Assuntos
Imunoterapia , Ipilimumab/uso terapêutico , Melanoma/terapia , Nivolumabe/uso terapêutico , Neoplasias Cutâneas/terapia , Resistencia a Medicamentos Antineoplásicos , Humanos , Pesquisa Médica Translacional
3.
Am Surg ; 85(10): 1118-1124, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31657306

RESUMO

Prospective randomized studies have demonstrated a survival benefit of immunotherapy in stage IV cutaneous melanoma. Some retrospective studies have hypothesized a synergistic effect of radiation and immunotherapy. Our objective was to identify whether there is a survival benefit for patients treated with radiation and immunotherapy in stage IV cutaneous melanoma of the head and neck (CMHN). The National Cancer Database was used to identify patients with stage IV CMHN between 2012 and 2014. These patients were stratified based on receipt of radiation and immunotherapy. Adjusted Cox regression was used to analyze overall survival. A total of 542 patients were identified with stage IV CMHN, of whom 153 (28%) patients received immunotherapy. Receipt of immunotherapy (hazard ratio [HR] 0.69, P = 0.02) and negative LNs (HR 0.50, P = 0.002) were independently associated with improved survival, whereas radiation conferred no survival benefit (HR 1.17, P = 0.26). Patients who received immunotherapy without radiation were associated with significantly improved survival compared with those who received immunotherapy with radiation (P < 0.0001). However, of patients who received radiation, the addition of immunotherapy did not seem to improve survival (P = 0.979). In stage IV CMHN, immunotherapy confers a 32 per cent survival benefit. The use of immunotherapy in patients who require radiation, however, is not associated with improved survival.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/mortalidade , Ipilimumab/uso terapêutico , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adulto , Idoso , Análise de Variância , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Imunoterapia/métodos , Linfonodos/patologia , Masculino , Melanoma/mortalidade , Melanoma/patologia , Melanoma/radioterapia , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Radioimunoterapia/métodos , Radioimunoterapia/mortalidade , Radioterapia/mortalidade , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/radioterapia , Análise de Sobrevida , Fatores de Tempo
4.
Medicine (Baltimore) ; 98(30): e16439, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348245

RESUMO

BACKGROUND: We performed the meta-analysis to evaluate the overall safety of programmed cell death-1 (PD-1) or ligand 1 (PD-L1) inhibitor treatment for lung cancer patients. METHOD: Randomized controlled trials were collected according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Risk ratio (RR) of PD-1/PD-L1 inhibitor treatment-related death, treatment-related adverse events, any serious events, and any events leading to discontinuation were all taken into account for the final evaluation. RESULTS: Fourteen studies were collected for the meta-analysis. The RR of treatment-related death for PD-1/PD-L1 was significantly lower than that of the control group (RR = 0.37, 95% confidence interval, CI: [0.21, 0.66]). Similar analysis results could also be seen for the RR of treatment-related adverse events and adverse events leading to discontinuation. When PD-1/PD-L1 was combined with chemotherapy, it increased the RR of adverse events leading to discontinuation (RR = 1.68, 95% CI: [1.22, 3.32]). The RR of overall treatment-related adverse events was lower in nivolumab (PD-1) than that of the control group (nivolumab + ipilimumab) (RR = 0.77, 95% CI: [0.65, 0.90]). Similar analysis results could also be seen in the RR of treatment-related adverse events for grade 3 to 5 and adverse events leading to discontinuation. CONCLUSION: Compared with chemotherapy, RR of the treatment-related deaths associated with PD-1/PD-L1 inhibitor was significantly lower than that of the chemotherapy group, while it did not increase the RR when they were combined with chemotherapy or other drugs. When PD-1/PD-L1 was combined with chemotherapy, it increased the RR of adverse events leading to discontinuation.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Ipilimumab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Neoplasias Pulmonares/mortalidade , Gradação de Tumores , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida
5.
Cancer Immunol Immunother ; 68(8): 1359-1368, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31332464

RESUMO

Immune checkpoint inhibitors targeting coinhibitory pathways in T cells possess efficacy in combating cancer. In addition to PD-1/PD-L1 and CTLA-4 antibodies which are already established in tumor immunotherapy, immune checkpoints such as LAG-3 or BTLA are emerging, which may have the potential to enhance T-cell responses alone or in combination with PD-1 blockers. CD4+ T cells play a central role in the immune system and contribute to productive immune responses in multiple ways. The effects of immune checkpoint inhibitors on this cell subset may thus critically influence therapeutic outcomes. Here, we have used in vitro responses to tetanus toxoid (TT) as a model system to study the effects of immune checkpoint inhibitors on CD4+ T-cell responses. CFSE-labeled PBMCs of 65 donors were stimulated with TT in the presence of blocking antibodies to PD-L1, CTLA-4, LAG-3, or BTLA for 7 days. We found that the PD-L1 antibody greatly enhanced cytokine production and antigen-specific CD4+ T-cell proliferation, whereas blocking antibodies to BTLA or LAG-3 did not augment responses to TT. Surprisingly, the presence of the therapeutic CTLA-4 antibody ipilimumab resulted in a significant reduction of CD4+ T-cell proliferation and cytokine production. Stimulation experiments with an IgG4 variant of ipilimumab indicated that the inhibitory effect of ipilimumab was dependent on its IgG1 isotype. Our results indicate that the therapeutic CTLA-4 antibody ipilimumab can impair CD4+ effector T-cell responses and that this activity is mediated by its Fc part and CD16-expressing cells.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Ipilimumab/farmacologia , Neoplasias/terapia , Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/metabolismo , Ipilimumab/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Neoplasias/imunologia , Receptores Imunológicos/imunologia , Toxoide Tetânico/imunologia
6.
Cancer Immunol Immunother ; 68(8): 1331-1340, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317218

RESUMO

Expression of inhibitors of apoptosis protein (IAP) family members is associated with poor prognosis in cancer patients. Immunity to ML-IAP (livin) and survivin has been well studied in patients with a variety of tumors. XIAP, the most potent inhibitor of apoptosis, is widely expressed in melanoma. To better define its potential role as an immunogenic target, cellular and humoral responses to XIAP were investigated in patients with advanced melanoma. An overlapping peptide library covering the full length of the XIAP protein was used to screen T cell responses of peripheral blood mononuclear cells (PBMC) from stage-IV melanoma patients treated with or without anti-CTLA4 (ipilimumab). The screen identified an array of peptides that predominantly induced CD4+ T cell responses. XIAP epitope-specific CD4+ T cells revealed proliferative responses to melanoma cells that express XIAP. Humoral responses to XIAP were also explored. Cellular and humoral responses to XIAP were associated with beneficial clinical outcomes after ipilimumab-based treatment, supporting XIAP as a potential therapeutic target.


Assuntos
Antineoplásicos/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Imunoterapia/métodos , Ipilimumab/uso terapêutico , Melanoma/imunologia , Fragmentos de Peptídeos/imunologia , Neoplasias Cutâneas/imunologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/imunologia , Proliferação de Células , Células Cultivadas , ELISPOT , Humanos , Imunidade Humoral , Ativação Linfocitária , Melanoma/tratamento farmacológico , Estadiamento de Neoplasias , Neoplasias Cutâneas/tratamento farmacológico , Resultado do Tratamento
7.
Gan To Kagaku Ryoho ; 46(6): 1011-1015, 2019 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-31273167

RESUMO

Ipilimumab is the%ldquo;first in class"immune checkpoint inhibitors, which blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)to potentiate an anti-tumor effect of effector Tcells. Recently, the combination therapy with ipilimumab and anti- PD-1 antibody showed clinical benefit in some malignant tumors, advanced melanoma and renal cell cancer and so on. In this paper, we described clinical development of ipilimumab as the combination therapy including effectiveness and safety.


Assuntos
Ipilimumab/uso terapêutico , Melanoma , Antígeno CTLA-4 , Terapia Combinada , Humanos , Imunoterapia
8.
Gan To Kagaku Ryoho ; 46(6): 1017-1026, 2019 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-31273168

RESUMO

The treatment of cancer has been greatly improved in recent years by immune checkpoint inhibitors. Anti-CTLA-4 and anti- PD-1 antibodies, two types of immune checkpoint inhibitors, have great potential to prolong survival, while they have different characteristics of efficacy and safety profiles. Combination therapy with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibody nivolumab has better efficacy than monotherapy. On the other hand, immune checkpoint inhibitors can result in a wide variety of immune-related adverse events(irAEs), which should be carefully managed. Such irAE includes that of the gastrointestinal tract, liver, and endocrine system, and is increased in incidence and severity when combined with ipilimumab and nivolumab. It is known that clinical characteristics of irAEs are different from those of typical autoimmune diseases. Therefore, irAEs should be managed in line with the algorithms and the appropriate use guides specifically for these drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ipilimumab/uso terapêutico , Nivolumabe/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Terapia Combinada , Ipilimumab/efeitos adversos , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1
9.
Cancer Immunol Immunother ; 68(7): 1171-1178, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31172258

RESUMO

BACKGROUND: Immune checkpoint inhibitors are now standard-of-care treatments for metastatic cutaneous melanoma. However, for rare sub-groups, such as mucosal melanomas, few published data are available, and with no established therapeutic guidelines. Our objective was to assess the response to anti-CTLA4 and anti-PD1 immunotherapy in patients with mucosal melanomas. METHODS: We performed a single-center, prospective cohort analysis of patients with non-surgical locally advanced and/or metastatic mucosal melanoma receiving anti-CTLA4 and/or anti-PD1 immunotherapy from 2010 to 2016. RESULTS: Forty-four patients were enrolled, including 18 (40.9%) with head and neck, 12 (27.3%) with vulvo-vaginal and 14 (31.8%) with ano-rectal primary tumours. Eleven (25%) patients had stage 3 disease, and 11 (25%) had distant metastases. The first-line immunotherapy was ipilimumab in 24 patients and pembrolizumab in 20. The objective response rate (ORR) was 8.2% (one complete response) for ipilimumab and 35% (four complete responses) for pembrolizumab. No significant difference was observed for primary tumour location. The median follow-up was 24 months (range 4-73). The median progression-free survival (PFS) in the first-line ipilimumab and pembrolizumab groups was 3 months [95% confidence interval (CI) 2.5-4.6] and 5 months (95% CI 2.6-33.1), respectively (p = 0.0147). CONCLUSION: In the patients with unresectable and/or metastatic mucosal melanoma, we found ORR and PFS rates comparable to those in patients with cutaneous melanoma, with no significant differences in the types of mucosal surfaces involved. Anti-PD1 therapy has a more favorable benefit-risk ratio than ipilimumab and should be used preferentially.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia/métodos , Melanoma/tratamento farmacológico , Membrana Mucosa/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Feminino , Humanos , Ipilimumab/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Estudos Prospectivos , Estudos Retrospectivos
10.
Cancer Immunol Immunother ; 68(7): 1187-1194, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31187176

RESUMO

BACKGROUND: PD-1 inhibition (PD-1i) is the standard of care in melanoma and other malignancies. In patients with bone metastases of solid tumors, the monoclonal antibody denosumab directed against RANKL is approved for the prevention of skeletal-related events. However, RANKL is not only relevant in osteoclastogenesis, but also has immunological effects. Hence, we aimed at investigating, whether the combination of PD-1i and denosumab produces synergistic effects in metastatic melanoma treatment. METHODS: We retrospectively collected and analyzed clinical data of metastatic melanoma patients with bone metastases, who received PD-1i and denosumab therapy. RESULTS: 29 patients were identified with a median age of 60.7 years: 20 were male and 9 were female. 20 patients (69%) were in stage IV M1c and 9 (31%) in stage IV M1d; 52% had an increased serum LDH. 24 patients (83%) received PD-1i as first-line therapy and five patients (17%) as second- or third-line therapy. 13 patients received the triple combination nivolumab, ipilimumab and denosumab (N + I+D), 16 patients received PD-1i and denosumab (PD-1i + D). Within a median follow-up time of 19.8 months, 17 patients progressed with a median time to progression of 6 months. The objective response rate was 54% in the N + I + D group and 50% in the PD-1i + D group. Recalcification of bone metastases was radiologically observed in 18 (62%) patients. No unexpected treatment-related adverse events emerged. CONCLUSIONS: The combination therapy of metastatic melanoma with PD-1i and denosumab was feasible without unexpected safety issues and showed a promising efficacy signal. Further investigation in prospective studies is needed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Denosumab/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Denosumab/farmacologia , Feminino , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Ligante RANK/antagonistas & inibidores , Ligante RANK/imunologia , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia
11.
Melanoma Res ; 29(3): 311-312, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31026247

RESUMO

We report a case of major regression of multiple atypical melanocytic nevi with a vitiligoid reaction in a patient with metastatic melanoma who achieved long-lasting complete remission after ipilimumab therapy. In 2008, a 54-year-old man presented with a dysplastic nevus syndrome. The patient was diagnosed with a scalp ulcerated melanoma (Breslow index 5.1 mm and Clark level IV), which was removed surgically. Four years later in April 2012, the patient was diagnosed with a right parietal skin metastasis, brain, lymph nodes, and bilateral lung metastases. The patient was first treated with vemurafenib, which had to be stopped because of renal toxicity. Disease stabilization was achieved after the second line of treatment with immunotherapy (ipilimumab, four infusions). However, 6 months later, the lung metastases had progressed. The patient was treated with pulmonary stereotactic radiotherapy associated with a second cycle of ipilimumab. After 6 months, he achieved complete remission. Simultaneously, the patient presented a generalized regression of his nevi with a vitiligoid reaction, or halo nevus, associated with a vitiligo located on the hands and inguinal areas. Vitiligo is a frequent immune-related adverse event of immunotherapy. Immunotherapy-induced halo nevus reaction is much less frequent than vitiligo. It was associated in the two case reports from the literature and in our patient with a quick and long-lasting complete remission of nodes and visceral metastases. Therefore, it might correspond to a stronger antimelanocyte immune reaction, associated with a favorable prognosis. The generalized halo nevi reaction in our patient could be more important because of the two cycles of ipilimumab compared with a single one. In conclusion, this case report suggests that a major regression of multiple nevi on ipilimumab might be associated with immunotherapy response.


Assuntos
Síndrome do Nevo Displásico/tratamento farmacológico , Ipilimumab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Síndrome do Nevo Displásico/patologia , Humanos , Neoplasias Pulmonares/secundário , Masculino , Melanoma/patologia , Melanoma/secundário , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Neoplasias Cutâneas/patologia
12.
Int J Mol Sci ; 20(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003463

RESUMO

Immunotherapy using immune checkpoints inhibitors has become the standard treatment for first and second line therapy in patients with non-small cell lung cancer (NSCLC). However, proper predictive factors allowing precise qualification of NSCLC patients for immunotherapy have not been developed so far. Expression of PD-L1 on tumor cells and tumor mutation burden are used in qualification of patients to first line therapy with pembrolizumab and atezolizumab in combination with ipilimumab in prospective clinical trials. Nevertheless, not all patients with these predictive factors benefit from immunotherapy. Major methodological difficulties in testing of these factors and in the interpretation of test results still exist. Therefore, other predictive factors are sought. Intensive research on the recognition of tumor immunophenotype and gut microbiome in NSCLC patients are underway. The first correlations between the effectiveness of immunotherapy and the intensity of inflammatory response in the tumor, microbiome diversity, and the occurrence of certain bacterial species in gut have been described. The purpose of our manuscript is to draw attention to factors affecting the efficacy of immunotherapy with anti-PD-L1 antibodies in NSCLC patients. Additional markers, for example TMB (tumor mutations burden) or microbiome profile, are needed to more accurately determine which patients will benefit from immunotherapy treatment.


Assuntos
Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia , Receptor de Morte Celular Programada 1/genética , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Imunofenotipagem/métodos , Ipilimumab/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
14.
Emerg Med J ; 36(5): 306-309, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30910911

RESUMO

OBJECTIVES: We sought to estimate the prevalence of patients with cancer presenting to the emergency department (ED) who are undergoing treatment with immune checkpoint blockade (ICB) therapy; report their chief complaints; describe and estimate the prevalence of immune-related adverse events (IRAEs). METHODS: Four abstractors reviewed the medical records of patients with cancer treated with ICB who presented to an ED in Paris, France between January 2012 and June 2017. Chief complaints, underlying malignancy and ICB characteristics, and the final diagnoses according to the emergency physician were recorded. Abstractors noted if an emergency physician identified that a patient was receiving an ICB and if the emergency physician considered the possibility of an IRAE. The gold standard as to whether an IRAE was the cause was the patients' referring oncologist's opinion that the ED symptoms were attributed to ICB and IRAE according to post-ED medical records. Descriptive statistics were reported. RESULTS: Among the 409 patients treated with ICB at our institution, 139 presented to the ED. Chief complaints were fatigue (25.2%), fever (23%), vomiting (13.7%), diarrhoea (13.7%), dyspnoea (12.2%), abdominal pain (11.5%), confusion (8.6%) and headache (7.9%). Symptoms were due to IRAEs in 20 (14.4%) cases. The most frequent IRAEs were colitis (40%), endocrine toxicity (30%), hepatitis (25%) and pulmonary toxicity (5%). Patients with IRAEs compared with those without them more frequently had melanoma; had received more distinct courses of ICB treatment, an increased number of ICB medications and ICB cycles; and had a shorter time course since the last infusion of ICB. Emergency physicians considered the possibility of an IRAE in 24 (17.3%) of cases and diagnosed IRAE in 10 (50%) of those with later confirmed IRAE. IRAE was more likely to be missed when the referring oncologist was not contacted or when the patient had respiratory symptoms, fatigue or fever. CONCLUSIONS: ICB exposes patients to potentially severe IRAEs. Emergency physicians must identify patients treated with ICB and consider their toxicity when patients present to the ED with symptoms compatible with IRAEs.


Assuntos
Antineoplásicos Imunológicos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Neoplasias/tratamento farmacológico , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/toxicidade , Antineoplásicos Imunológicos/uso terapêutico , Serviço Hospitalar de Emergência/organização & administração , Serviço Hospitalar de Emergência/estatística & dados numéricos , Fadiga/etiologia , Feminino , Febre/etiologia , Humanos , Ipilimumab/uso terapêutico , Ipilimumab/toxicidade , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Nivolumabe/uso terapêutico , Nivolumabe/toxicidade , Paris/epidemiologia , Prevalência , Estudos Retrospectivos , Vômito/etiologia
15.
J Dermatol ; 46(5): 449-452, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30908705

RESUMO

Anti-programmed death 1 antibody monotherapy is a first-line and widely used immunotherapy for the treatment of advanced melanoma. However, its efficacy rate is lower in the Japanese population compared with the Caucasian population. Ipilimumab is another immune checkpoint inhibitor (ICI) that activates and increases T cells, which suppress the function of regulatory T cells. Previous reports have suggested that ipilimumab is useful for treating advanced melanoma, particularly in combination with radiation therapy. In this report, we described three cases of nivolumab-resistant melanoma successfully controlled by ipilimumab with intensity-modulated radiotherapy, which may enhance the therapeutic effects of the sequential administration of ICI.


Assuntos
Quimiorradioterapia/métodos , Ipilimumab/uso terapêutico , Melanoma/terapia , Radioterapia de Intensidade Modulada , Neoplasias Cutâneas/terapia , Adulto , Idoso , Feminino , Humanos , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Masculino , Melanoma/diagnóstico , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nivolumabe/uso terapêutico , Pele/diagnóstico por imagem , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
16.
Value Health ; 22(3): 276-283, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30832965

RESUMO

BACKGROUND: Immune-checkpoint inhibitors may provide long-term survival benefits via a cured proportion, yet data are usually insufficient to prove this upon submission to health technology assessment bodies. OBJECTIVE: We revisited the National Institute for Health and Care Excellence assessment of ipilimumab in melanoma (TA319). We used updated data from the pivotal trial to assess the accuracy of the extrapolation methods used and compared these to previously unused techniques to establish whether an alternative extrapolation may have provided more accurate survival projections. METHODS: We compared projections from the piecewise survival model used in TA319 and those produced by alternative models (fit to trial data with minimum follow-up of 3 years) to a longer-term data cut (5-year follow-up). We also compared projections to external data to help assess validity. Alternative approaches considered were parametric, spline-based, mixture, and mixture-cure models. RESULTS: Only the survival model used in TA319 and a mixture-cure model provided 5-year survival predictions close to those observed in the 5-year follow-up data set. Standard parametric, spline, and non-curative-mixture models substantially underestimated 5-year survival. Survival estimates from the TA319 model and the mixture-cure model diverge considerably after 5 years and remain unvalidated. CONCLUSIONS: In our case study, only models that incorporated an element of external information (through a cure fraction combined with background mortality rates or using registry data) provided accurate estimates of 5-year survival. Flexible models that were able to capture the complex hazard functions observed during the trial, but which did not incorporate external information, extrapolated poorly.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia/mortalidade , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Antineoplásicos Alquilantes/uso terapêutico , Estudos de Casos e Controles , Ensaios Clínicos Fase III como Assunto/métodos , Dacarbazina/uso terapêutico , Método Duplo-Cego , Humanos , Imunoterapia/tendências , Melanoma/imunologia , Estudos Multicêntricos como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Taxa de Sobrevida/tendências
17.
Dermatol Clin ; 37(2): 159-168, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850038

RESUMO

Melanoma is rapidly evolving because of advances in noninvasive diagnosis, targeted therapies, and improved prognostic methods. This article discusses what is new in melanoma risk factors, prevention, clinical management, and targeted treatment. The incidence continues to increase worldwide, whereas mortality is steadily improving. This trend reinforces the importance of dermatologists comprehensively understanding all aspects of melanoma. Further research is needed to continue making a material impact on outcomes for patients.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Procedimentos Cirúrgicos Dermatológicos , Melanoma/terapia , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biópsia , Café , Espectroscopia Dielétrica , Detecção Precoce de Câncer , Predisposição Genética para Doença , Genômica , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Ipilimumab/uso terapêutico , Melanoma/diagnóstico , Melanoma/epidemiologia , Melanoma/genética , Microscopia Confocal , Nivolumabe/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Prevenção Primária , Prognóstico , Fatores de Proteção , Fatores de Risco , Prevenção Secundária , Biópsia de Linfonodo Sentinela , Fator de Proteção Solar , Protetores Solares/uso terapêutico , Ultrassonografia , Vemurafenib/uso terapêutico
18.
BMC Cancer ; 19(1): 231, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30871493

RESUMO

BACKGROUND: Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients. The impact of 2nd line chemotherapy is poorly defined. Recent data demonstrated effectiveness of checkpoint inhibitors in different squamous cell carcinomas. Therefore, we assess combined nivolumab/ipilimumab as 2nd line therapy in elderly ESCC patients. METHODS: RAMONA is a multicenter open-label phase II trial. The primary objective is to demonstrate a significant survival benefit of nivolumab/ipilimumab in advanced ESCC compared to historical data of standard chemotherapy. Primary endpoint is therefore overall survival (OS). Major secondary objective is the evaluation of tolerability. Time to QoL deterioration will thus be determined as key secondary endpoint. Further secondary endpoints are tumor response, PFS and safety. We aim to recruit a total of n = 75 subjects that have to be > 65 years old. Eligibility is determined by the geriatric status (G8 screening and Deficit Accumulation Frailty Index (DAFI)). A safety assessment will be performed after a 3 cycle run-in phase of nivolumab (240 mg Q2W) to justify escalation for eligible patients to combined nivolumab (240 mg Q2W) and ipilimumab (1 mg/kg Q6W), while the other patients will remain on nivolumab only. RAMONA also includes translational research sub-studies to identify predictive biomarkers, including PD-1 and PD-L1 evaluation at different time points, establishment of organoid cultures and microbiome analyses for response prediction. DISCUSSION: The RAMONA trial aims to implement checkpoint inhibitors for elderly patients with advanced ESCC as second line therapy. Novel biomarkers for checkpoint-inhibitor response are analyzed in extensive translational sub-studies. TRIAL REGISTRATION: EudraCT Number: 2017-002056-86 ; NCT03416244 , registered: 31.1.2018.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Ipilimumab/administração & dosagem , Nivolumabe/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Humanos , Ipilimumab/uso terapêutico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Análise de Sobrevida , Resultado do Tratamento
19.
J Clin Pharm Ther ; 44(3): 420-429, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30693536

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Clinical trials have demonstrated that the use of ipilimumab has led to considerable improvements in the clinical outcome in patients with advanced melanoma. We conducted a meta-analysis to systematically review the efficacy and safety of ipilimumab for advanced melanoma. STUDY DESIGN: The relevant randomized controlled trials in melanoma patients treated with ipilimumab were retrieved, and the systematic evaluation was conducted. EMBASE, MEDLINE and PubMed were searched for articles published till May 2018. RESULTS: A total of 16 reports from 12 trials were available for the meta-analysis. The meta-analysis provided evidence that the combination of programmed cell death protein 1 (PD-1) inhibitors and ipilimumab was more effective in improving progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) than either agent alone. However, ipilimumab was inferior to PD-1 inhibitors in improving PFS, OS and ORR. The combination of ipilimumab and anticancer therapy was superior to ipilimumab alone in improving ORR and was superior to anticancer therapy alone in improving OS, PFS and ORR. The adverse events associated with ipilimumab therapy were generally manageable. WHAT IS NEW AND CONCLUSION: This is the largest and most up-to-date meta-analysis evaluating the efficacy and safety of ipilimumab in treating advanced melanoma. The ipilimumab-containing therapy was efficacious in treating advanced melanoma with a manageable safety profile.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Intervalo Livre de Doença , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
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