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1.
Lancet Oncol ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31427204

RESUMO

BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.

2.
Transplant Proc ; 51(6): 1732-1738, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31301858

RESUMO

Plasma cell-rich acute rejection (PCAR) and antibody-mediated rejection (ABMR), for which a standard treatment has not yet been established, are associated with poor graft survival after kidney transplantation. Here, we report a case series of 3 Japanese patients diagnosed with PCAR accompanied by ABMR. Steroid pulse therapy and rabbit antithymocyte globulin, plasma exchange, intravenous immunoglobulin, and rituximab therapies were sequentially performed in the first case. A graft biopsy after each treatment showed that plasma cell infiltration persisted. Five months after the initiation of rejection therapy, the patient was subjected to bortezomib therapy, which led to the partial elimination of plasma cells from the graft. However, the graft function gradually deteriorated, and hemodialysis treatment was warranted. In the other 2 cases, the patients received the same combination of therapy including bortezomib within a short period. Graft biopsies performed subsequently showed a marked decrease in the number of infiltrated plasma cells, and stabilization of renal graft function was achieved in both cases. Bortezomib, which targets plasma cells, is a potent drug that eliminates infiltrated plasma cells from the graft in PCAR. Thus, in addition to conventional therapy comprising plasma exchange, intravenous immunoglobulin, and rituximab against ABMR, bortezomib may be necessary to administer without any delay to control PCAR.

3.
Int. braz. j. urol ; 45(3): 503-513, May-June 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1012320

RESUMO

ABSTRACT Purpose: The purposes of the present study were to evaluate growth rate of nonfunctioning adrenal incidentalomas (AIs) and their development to hormonal hypersecretion on follow-up. Materials and methods: A retrospective study was conducted from the electronic medical records. A total of 314 patients were diagnosed with adrenal tumors between 2000 and 2016. After excluding patients who had overt adrenal endocrine disorders or whose adrenal tumors were clinically diagnosed as metastatic malignancies, we investigated 108 patients with nonfunctioning AIs including characteristics, the treatment, the way of follow-up and pathology. Results: Fifteen patients received immediate adrenalectomy because of the initial tumor size or patient's preference. Pathological examination revealed malignancy in 2 patients. In the remaining 93 patients, radiological examinations were performed periodically. Tumor enlargement of ≥ 1.0cm was observed in 8.6% of the patients who were followed up as nonfunctioning AIs with a median follow-up period of 61.5 months (range: 4-192). Eleven patients underwent adrenalectomy. On the pathological examinations, all of the tumors, which showed a size increase, were diagnosed as benign tumors. Regarding the followed up patients without adrenalectomy, only 2.4% of the patients had tumor enlargement during the prolonged follow-up. Furthermore, none of the patients developed hormonal hypersecretion or clinical signs such as obesity, glucose intolerance or poorly controlled hypertension. Conclusions: Tumor enlargement of AIs did not correlate with malignancy. The value of repeat radiological and hormonal examinations may be limited in the long-term follow-up of patients whose AIs are not enlarged.

4.
Int J Clin Oncol ; 24(9): 1089-1098, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31218529

RESUMO

BACKGROUND: Nivolumab has demonstrated antitumor activity and manageable safety in the single-arm, phase II CheckMate 275 study in patients with unresectable locally advanced or metastatic platinum-resistant urothelial carcinoma. We report updated results of the global population and a subanalysis of Japanese patients from this study. METHODS: Patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) confirmed by blinded independent review committee (BIRC) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS) by BIRC and overall survival (OS). Safety was also reported. The minimum follow-up was 21 months. RESULTS: Overall, 270 patients were treated with nivolumab globally; 23 patients were Japanese. In the global and Japanese populations, respectively, ORR per BIRC was 20.4% and 21.7%; median PFS was 1.9 (95% confidence interval [CI] 1.9-2.3) and 3.8 months (95% CI 1.9-7.2); and median OS was 8.6 (95% CI 6.1-11.3) and 21.0 months (95% CI 7.2-not reached). The most common any grade treatment-related adverse events were fatigue (18.1%) and diarrhea (12.2%) in the global population; the most common in the Japanese population were diarrhea (26.1%) and pyrexia (13.0%). Grade 3 or 4 treatment-related adverse events occurred in 61 (22.6%) and seven (30.4%) of the global and Japanese patients, respectively. CONCLUSIONS: Nivolumab continues to show antitumor activity and survival in the global population of CheckMate 275. Meaningful clinical benefit was also observed in Japanese patients. No new safety signals were identified.

5.
Hepatol Res ; 2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31077507

RESUMO

Hepatitis E virus (HEV) infection has been recognized as an acute condition. However, recent reports have shown that immunocompromised patients, such as those receiving solid-organ transplantation, can develop chronic hepatitis with HEV infection. We report two cases of chronic hepatitis E after kidney transplantation (KT) who were successfully treated with ribavirin monotherapy. Several years after KT, both patients had sustained elevations in the levels of liver enzymes for a period of more than 6 months. Both patients had HEV infection, genotype 3a. Histological studies showed infiltration of inflammatory cells without fibrosis. Treatment included ribavirin monotherapy at a dosage of 600 mg daily for 3 months. One month after therapy initiation, HEV-RNA turned to negative, and remained negative at 24 weeks after ribavirin therapy without severe complications. Although the treatment of chronic hepatitis E is not fully established, ribavirin therapy can be a safe and effective treatment for chronic hepatitis E.

6.
Jpn J Clin Oncol ; 49(6): 506-514, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30941424

RESUMO

BACKGROUND: Nivolumab treatment resulted in superior efficacy and safety versus everolimus treatment in the 2-year follow-up of the CheckMate 025 Phase III study, with consistent results in the global population and the Japanese population. Here, we report the 3-year follow-up in both groups. METHODS: Patients were randomized 1:1 to nivolumab 3 mg/kg intravenously every 2 weeks or everolimus 10 mg orally once daily until progression/intolerable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included objective response rate, progression-free survival, safety and patient-reported quality of life. RESULTS: Of 410 and 411 patients randomized to nivolumab and everolimus, 37 and 26 were Japanese, respectively. The median OS for the global population was 25.8 months with nivolumab and 19.7 months with everolimus (hazard ratio 0.74; 95.5% confidence interval [CI]: 0.63-0.88; P = 0.0005); in the Japanese population, median OS was 45.9 months and not reached (hazard ratio 1.08; 95% CI: 0.50-2.34; P = 0.85), respectively. The investigator-assessed objective response rate was 26% versus 5% with nivolumab versus everolimus (odds ratio [OR] 6.19; 95% CI: 3.82-10.06) in the global population and 43% versus 8% in the Japanese population (OR 6.80; 95% CI: 1.60-28.91; P = 0.0035), respectively. The incidence of any-grade treatment-related adverse events was lower with nivolumab versus everolimus in both the global patient population (80% versus 89%) and the Japanese population (81% versus 100%). CONCLUSIONS: At the 3-year follow-up, the efficacy and safety results of CheckMate 025 are generally consistent in the global and the Japanese populations.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Carcinoma de Células Renais/etnologia , Carcinoma de Células Renais/mortalidade , Progressão da Doença , Feminino , Seguimentos , Humanos , Neoplasias Renais/etnologia , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade
7.
Urol Int ; 102(4): 462-467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30917379

RESUMO

BACKGROUND: The management of febrile urinary tract infection (fUTI) in patients with vesicoureteral reflux (VUR) is crucial to prevent renal scarring. Continuous antibiotic prophylaxis (CAP) is the most widely used initial treatment for VUR. However, the optimal duration of CAP is still unclear. We aimed to clarify an appropriate patient population and the optimal timing to discontinue CAP. METHODS: We reviewed the records of 247 patients with primary VUR between January 2000 and December 2015. Seventy-two patients who discontinued CAP despite persistent VUR were enrolled. Kaplan-Meier method and Cox proportional hazard model was used in statistical analysis. RESULTS: Following the discontinuation of CAP, fUTI developed in 25 patients after a median of 9 months (range 0-81). VUR resolved spontaneously in 9 out of 47 patients without recurrence during follow-up. Multivariate analysis showed bilateral VUR and duration of CAP of less than 1 year after the last fUTI were significant risk factors for recurrence. CONCLUSION: Among the risk factors examined, patients administered CAP for less than 1 year after the last fUTI and those with bilateral VUR had significantly more frequent recurrence. Our study suggests that the administration of CAP for more than 1 year after the last fUTI is beneficial in avoiding recurrent fUTI.

8.
Int Braz J Urol ; 45(3): 503-513, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785700

RESUMO

PURPOSE: The purposes of the present study were to evaluate growth rate of nonfunctioning adrenal incidentalomas (AIs) and their development to hormonal hypersecretion on follow-up. MATERIALS AND METHODS: A retrospective study was conducted from the electronic medical records. A total of 314 patients were diagnosed with adrenal tumors between 2000 and 2016. After excluding patients who had overt adrenal endocrine disorders or whose adrenal tumors were clinically diagnosed as metastatic malignancies, we investigated 108 patients with nonfunctioning AIs including characteristics, the treatment, the way of follow-up and pathology. RESULTS: Fifteen patients received immediate adrenalectomy because of the initial tumor size or patient's preference. Pathological examination revealed malignancy in 2 patients. In the remaining 93 patients, radiological examinations were performed periodically. Tumor enlargement of ≥ 1.0cm was observed in 8.6% of the patients who were followed up as nonfunctioning AIs with a median follow-up period of 61.5 months (range: 4-192). Eleven patients underwent adrenalectomy. On the pathological examinations, all of the tumors, which showed a size increase, were diagnosed as benign tumors. Regarding the followed up patients without adrenalectomy, only 2.4% of the patients had tumor enlargement during the prolonged follow-up. Furthermore, none of the patients developed hormonal hypersecretion or clinical signs such as obesity, glucose intolerance or poorly controlled hypertension. CONCLUSIONS: Tumor enlargement of AIs did not correlate with malignancy. The value of repeat radiological and hormonal examinations may be limited in the long-term follow-up of patients whose AIs are not enlarged.


Assuntos
Corticosteroides/sangue , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/sangue , Neoplasias das Glândulas Suprarrenais/patologia , Adrenalectomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de Tempo , Tomografia Computadorizada por Raios X , Carga Tumoral
9.
BMC Cancer ; 19(1): 17, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616534

RESUMO

BACKGROUND: A prospective, randomised phase II study demonstrated clinical benefit of axitinib dose titration in a subset of treatment-naïve patients treated with axitinib for metastatic renal cell carcinoma. This analysis evaluated patient baseline characteristics that may impact overall survival (OS) with axitinib dose titration. METHODS: Following a 4-week lead-in period during which all patients received axitinib 5 mg twice-daily (bid); patients meeting the predefined randomisation criteria were randomly assigned to receive axitinib 5 mg bid plus either axitinib or placebo titration. In exploratory analyses, patients were grouped into those who achieved OS ≥24 versus < 24 months, and compared their baseline characteristics with Fisher's exact test or Cochran-Armitage trend exact test, with a 5% significance level. Potential predictive baseline characteristics associated with effect of axitinib dose titration on OS were investigated using a Cox proportional hazard model. RESULTS: Overall, 112 patients were randomised. Three of 56 patients receiving axitinib titration were censored; of the remaining 53, 33 (62%) achieved OS ≥24 months versus 20 (38%) with OS < 24 months. Patients with OS ≥24 vs. < 24 months, respectively, had significantly fewer metastatic sites (≤2 metastases: 52% vs. 10%; ≥3 metastases: 48% vs. 90%), fewer lymph node (45% vs. 75%) or liver (15% vs. 45%) metastases, higher haemoglobin level (i.e., ≥ lower limit of normal: 67% vs. 25%) at baseline, lower neutrophil (≤ upper limit of normal, 97% vs. 75%) and platelet (≤ upper limit of normal, 82% vs. 50%) levels at baseline and ≥ 1 year between histopathological diagnosis and treatment (64% vs. 15%). The primary reason for treatment discontinuation in both OS groups was disease progression. The frequency of toxicity-related discontinuation was comparable between the 2 groups, indicating that it was not a factor for a shorter OS. The multivariate analysis showed that ≥1 year from histopathological diagnosis to treatment and baseline haemoglobin level equal or greater than lower limit of normal were significant covariates associated with favourable OS in patients receiving axitinib titration. CONCLUSIONS: The current analyses identified potentially predictive factors that could help selecting patients who may benefit from axitinib dose titration. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00835978. Registered prospectively, February 4, 2009.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Axitinibe/efeitos adversos , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/secundário , Idoso , Antineoplásicos/administração & dosagem , Axitinibe/administração & dosagem , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do Tratamento , Suspensão de Tratamento
10.
Int J Urol ; 2018 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-30345560

RESUMO

OBJECTIVES: To clarify treatment patterns and outcomes for patients with unresectable or metastatic renal cell carcinoma in the molecular target therapy era in Japan. METHODS: A multicenter, retrospective medical chart review study was carried out. Patients diagnosed with unresectable or metastatic renal cell carcinoma between January 2012 and August 2015 were enrolled. Data extracted from medical records included treatment duration, grade ≥3 adverse events, reason for discontinuation for each targeted therapy and survival data until August 2016. RESULTS: Of 277 eligible patients, 266, 170 and 77 received first-, second- and third-line systemic treatment, respectively. Tyrosine kinase inhibitors were the most common first-line therapy (72.2%), followed by mammalian target of rapamycin inhibitors (14.3%) and cytokines (13.5%). Among 170 patients who received second-line treatment, tyrosine kinase inhibitor-tyrosine kinase inhibitor was the most common sequence (58.8%), followed by tyrosine kinase inhibitor-mammalian target of rapamycin inhibitor (14.1%) and cytokine-tyrosine kinase inhibitor (14.1%). With a median follow-up period of 19.8 months, median overall survival was not reached at 48 months. Patients who discontinued first-line tyrosine kinase inhibitors in <6 months showed poorer overall survival compared with patients who received first-line tyrosine kinase inhibitors for ≥6 months. CONCLUSIONS: The present analysis illustrates the contemporary treatment patterns and prognosis for patients with unresectable or metastatic renal cancer in a real-world setting in Japan. Tyrosine kinase inhibitor-tyrosine kinase inhibitor represents the most commonly used sequence. Shorter treatment duration of first-line tyrosine kinase inhibitors is associated with poorer prognosis, suggesting the need for better treatment options.

11.
Clin Genitourin Cancer ; 16(6): e1201-e1214, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30224330

RESUMO

BACKGROUND: Standard treatments have not been established in metastatic papillary renal-cell carcinoma (PRCC). We aimed to investigate treatment outcomes in patients with mPRCC. PATIENTS AND METHODS: This study included 51 patients who were diagnosed with PRCC at 14 institutions. Pathologic slides were reviewed by pathologists. The associations between clinical factors and overall survival (OS) were analyzed. RESULTS: Final pathologic diagnoses could be determined in 50 patients. Thirty-five tumors were diagnosed as PRCC (type 2 PRCC, 91.4%), and 15 were diagnosed as other histologic types. Targeted therapies (TTs) were provided to 25 mPRCC patients. Patients treated with TT survived significantly longer than those treated before the era of TT (median OS, 22.5 vs. 6.3 months; P = .0035). Median OS of patients who experienced stable disease for ≥ 9 months using single TT was 43.1 months. Patients treated with a tyrosine kinase inhibitor (TKI) as first-line TT survived longer after TT initiation than those treated with an mTOR inhibitor (median, 22.4 vs. 11.7 months; P = .2684). Patients treated with TKIs in both first- and second-line settings had significantly better survival after TT initiation than those treated with a TKI in one therapy line and an mTOR inhibitor in the other (31.4 vs. 12.9 months, P = .0172). Patients treated with a TKI as second-line TT survived significantly longer after second-line TT initiation than did those treated with an mTOR inhibitor (16.2 vs. 7.4 months, P = .0016). CONCLUSION: Prognoses of patients with mPRCC were improved by TT, and TKIs appeared to be the treatment of choice in both the first- and second-line settings.

13.
Lancet Oncol ; 19(4): 451-460, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29530667

RESUMO

BACKGROUND: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. METHODS: The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. FINDINGS: Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54-100) of six patients in the dose-finding phase and 26 (53%, 38-68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44-71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. INTERPRETATION: The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy. FUNDING: Pfizer and Merck.

14.
N Engl J Med ; 378(14): 1277-1290, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29562145

RESUMO

BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS: A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/administração & dosagem , Ipilimumab/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Pirróis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/mortalidade , Intervalo Livre de Doença , Humanos , Indóis/efeitos adversos , Ipilimumab/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nivolumabe , Pirróis/efeitos adversos , Qualidade de Vida , Risco , Sunitinibe , Análise de Sobrevida , Taxa de Sobrevida
16.
Prostate ; 78(3): 222-232, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29194690

RESUMO

BACKGROUND: Clarifying the mechanisms underlying prostate cancer (PC) progression and resistance to androgen deprivation therapy (ADT) is an urgent clinical issue. ADT influences steroidal metabolism in patients with PC and promotes the accumulation of carbon 21 steroids (C21s), such as progestin. Because the enzymes responsible for C21s metabolism are similar to those for androgen metabolism, PC cells may be able to metabolize C21s intracellularly. Therefore, there is a possibility that intracrine C21s are implicated in PC progression and resistance to ADT, and the influence of C21s on PC cells is yet to be elucidated. In the present study, we focused on 20ß-hydroxy-5α-dihydroprogesterone (20ß-OHDHP), a C21s metabolized from progestin, and showed that 20ß-OHDHP is synthesized in PC cells and is able to directly stimulate the androgen receptor (AR). METHODS: LNCaP, VCaP, and DU145 cells, which express a mutant AR (mAR), wild-type AR (wAR), and glucocorticoid receptor (GR), respectively, were incubated in the presence of several agents. After incubation, cell growth was determined by the MTS assay. PSA levels were determined by an enzyme immunoassay, and C21s and androgen levels were measured using liquid chromatography-mass spectrometry. Gene expression was analyzed by quantitative real-time polymerase chain reaction, and steroidal-receptor-related signaling was determined by a reporter assay. RESULTS: We affirmed that 20ß-OHDHP was synthesized from pregnenolone intracellularly in LNCaP and VCaP cells, and 20ß-OHDHP significantly promoted the growth of both cell lines without androgen conversion. 20ß-OHDHP directly stimulated both mAR and wAR. The presence of 20ß-OHDHP was sufficient for the proliferation and survival of LNCaP or VCaP cells, and 20ß-OHDHP promoted cell growth even in the presence of abiraterone. Using DU145 cells, we affirmed that 20ß-OHDHP did not stimulate GR, which has a potential to bypass AR signaling in PC cells promote PC cell growth. CONCLUSIONS: Under ADT, 20ß-OHDHP synthesized intracellularly from accumulated progestin in PC cells may accelerate cell growth via stimulation of both wAR and mAR. This pathway may represent an interesting candidate for targeted therapy.


Assuntos
20-alfa-Di-Hidroprogesterona/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino
18.
Nihon Hinyokika Gakkai Zasshi ; 109(1): 14-19, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30662046

RESUMO

(Background) Long-term care is necessary for normal growth and development of pediatric recipients of kidney transplants. We report on our experience with pediatric kidney transplantation (KTx) during the past 19 years. (Methods) We retrospectively analyzed the data from 26 recipients who received KTx between 1996 and 2014 at Niigata University Hospital (one patient underwent two consecutive KTx during the designated period). All recipients were 16 years old or younger at the time of KTx. (Results) The graft survival rates at 1, 5, and 10 years after transplantation were 96%, 96%, and 88%, respectively. Three recipients lost the renal graft function due to graft thrombosis, antibody mediated rejection and steroid resistant rejection. Drug non-adherence was associated with rejection episodes, which led to the increasing of estimated glomerular filtration rate (eGFR) level. In addition, renal graft function was related to the growth after KTx. Eighteen recipients graduated from high school during follow-up periods and 17 recipients obtained employment. (Conclusion) Interventions promoting adherence should be implemented among pediatric recipients and parents to optimize graft survival and growth after KTx. Successful KTx contributed the high rate of social participation and employment after pediatric KTx.


Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Rim , Insuficiência Renal/cirurgia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Feminino , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/terapia , Sobrevivência de Enxerto , Humanos , Japão , Transplante de Rim/mortalidade , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Cooperação e Adesão ao Tratamento , Resultado do Tratamento , Cálculos Ureterais/epidemiologia , Cálculos Ureterais/terapia
19.
Nihon Hinyokika Gakkai Zasshi ; 109(2): 68-73, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-31006744

RESUMO

(Backgrounds) The efficacy of bortezomib for chronic antibody mediated rejection (CAMR) after kidney transplantation is still obscure. (Materials and methods) CAMR were persisted in 5 recipients who were treated with plasma exchange, low dose of IVIG, steroid pulse therapy, and rituximab. 1.3 mg/m2 of bortezomib was administered on days 1, 4, 8, 11. Serum creatinine (sCr) levels, anti-HLA antibodies, and histology were analyzed. (Results) Stable sCr levels were obtained in 3 out of 5 recipients. No one lost renal graft function during follow-up periods. Anti-HLA class I antibodies were significantly decreased after bortezomib treatment, however anti-HLA class II antibodies were not changed. Histology showed no improvement at 6 months after bortezomib administration. Two recipients whose sCr levels increased during follow-up had already had interstitial fibrosis and tubular atrophy (IF/TA) in histology before bortezomib treatment. (Conclusions) The use of bortezomib after IF/TA could be detected in histology may not contribute to stabilize renal graft function in CAMR.


Assuntos
Anticorpos , Bortezomib/administração & dosagem , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/terapia , Antígenos HLA/imunologia , Transplante de Rim , Adolescente , Adulto , Bortezomib/uso terapêutico , Criança , Doença Crônica , Feminino , Rejeição de Enxerto/tratamento farmacológico , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Adulto Jovem
20.
Urol Int ; 99(3): 283-289, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28723695

RESUMO

INTRODUCTION: We evaluated whether nephron sparing surgery (NSS) combined with meticulous suturing of the cut stump under clamping with cooling is beneficial for oncological outcomes and also assessed the relationship between cold ischemia time and deterioration of renal function. METHODS: One hundred and six patients with renal cell carcinoma (RCC) were subjected to this procedure. Oncological outcomes and renal function according to the estimated glomerular filtration rate (eGFR) and the tubular excretion rate on renoscintigraphy before and at 12 months after surgery were evaluated. RESULTS: Cancer recurrences were observed in 2 patients with past history of RCC; however, no patient died of cancer. Renal function was evaluated depending on 4 different ischemia times. All groups did not show a remarkable decrease of renal function in terms of eGFR. Renoscintigraphy revealed the deterioration of the affected kidney in patients with >60 min ischemia. CONCLUSION: The renoprotective procedure of NSS provided maximum preservation of renal function until 60 min of cold ischemia time.


Assuntos
Carcinoma de Células Renais/cirurgia , Isquemia Fria , Taxa de Filtração Glomerular , Neoplasias Renais/cirurgia , Rim/cirurgia , Nefrectomia/métodos , Néfrons/fisiopatologia , Adulto , Idoso , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/fisiopatologia , Isquemia Fria/efeitos adversos , Feminino , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Rim/fisiopatologia , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Nefrectomia/efeitos adversos , Néfrons/patologia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Risco , Técnicas de Sutura , Fatores de Tempo , Resultado do Tratamento
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