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1.
Lancet Oncol ; 22(10): 1468-1482, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34592180

RESUMO

BACKGROUND: Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin-gemcitabine in patients with locally advanced or metastatic biliary tract cancer. METHODS: We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing. FINDINGS: Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1-14·1). Median progression-free survival was 6·5 months (80% CI 5·7-7·1) in the ramucirumab group, 7·0 months (6·2-7·1) in the merestinib group, and 6·6 months (5·6-6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90-1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73-1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1]). INTERPRETATION: Adding ramucirumab or merestinib to first-line cisplatin-gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection. FUNDING: Eli Lilly and Company.


Assuntos
Adenocarcinoma/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Biliar/tratamento farmacológico , Indazóis/administração & dosagem , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/administração & dosagem , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Indazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Fatores de Tempo
2.
World J Gastroenterol ; 27(32): 5424-5437, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34539142

RESUMO

BACKGROUND: Sorafenib is an oral drug that prolongs overall survival (OS) in patients with hepatocellular carcinoma. Adverse events, including hand-foot skin reaction (HFSR), lead to permanent sorafenib discontinuation. AIM: To clarify the association between interventions for adverse events and patient prognosis. METHODS: We performed a retrospective, multicenter study of patients treated with sorafenib monotherapy between May 2009 and March 2018. We developed a mutual cooperation system that was initiated at the start of sorafenib treatment to effectively manage adverse events. The mutual cooperation system entailed patients receiving consultations during which pharmacists provided accurate information about sorafenib to alleviate the fear and anxiety related to adverse events. We stratified the patients into three groups: Group A, patients without HFSR but with pharmacist intervention; Group B, patients with HFSR and pharmacist interventions unreported to oncologists (nonmutual cooperation system); and Group C, patients with HFSR and pharmacist interventions known to oncologists (mutual cooperation system). OS and time to treatment failure (TTF) were evaluated using the Kaplan-Meier method. RESULTS: We enrolled 134 patients (Group A, n = 41; Group B, n = 30; Group C, n = 63). The median OS was significantly different between Groups A and C (6.2 vs 13.9 mo, p < 0.01) but not between Groups A and B (6.2 vs 7.7 mo, P = 0.62). Group A vs Group C was an independent OS predictor (HR, 0.41; 95%CI: 0.25-0.66; P < 0.01). In Group B alone, TTF was significantly lower and the nonadherence rate was higher (P < 0.01). In addition, the Spearman's rank correlation coefficients between OS and TTF in each group were 0.41 (Group A; P < 0.01), 0.13 (Group B; P = 0.51), and 0.58 (Group C; P < 0.01). There was a highly significant correlation between OS and TTF in Group C. However, there was no correlation between OS and TTF in Group B. CONCLUSION: The mutual cooperation system increased treatment duration and improved prognosis in patients with HFSR. Future prospective studies (e.g., randomized controlled trials) and improved adherence could help prevent OS underestimation.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Estudos Prospectivos , Estudos Retrospectivos , Sorafenibe/uso terapêutico , Resultado do Tratamento
3.
J Med Case Rep ; 15(1): 481, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34544494

RESUMO

BACKGROUND: Sorafenib is an oral multikinase inhibitor that targets Raf serine/threonine receptor tyrosine kinases and inhibits tumor cell growth and angiogenesis. Cutaneous toxicities of sorafenib are common, including cutaneous eruptions (such as truncal erythema and seborrheic-dermatitis-like changes) and hand-foot syndrome. Keratoacanthomas and squamous cell carcinomas have been reported previously; however, we report a case of multiple eruptive keratoacanthomas in the form of Grzybowski syndrome after initiation of sorafenib. CASE PRESENTATION: We report a 63-year-old Caucasian male who developed multiple cutaneous eruptive keratoacanthomas after starting sorafenib 400 mg twice daily. He had a known history of hepatitis-C-related cirrhosis and hepatocellular carcinoma, and previously had actinic keratosis and skin squamous cell carcinoma excision. Approximately two and a half months after starting sorafenib, the patient initially developed two lesions, one on each forearm, and after excision, these lesions demonstrated histological features of squamous cell carcinoma. One month later, the patient presented with approximately 48 new skin lesions of varying size on the back, bilateral upper limbs, and face requiring excisional biopsy of a large number of these lesions. Histopathology showed eruptive invasive keratoacanthomas (Grzybowski syndrome). Sorafenib was temporarily stopped and subsequently restarted at a lower dose. Acitretin 25 mg daily was commenced after few weeks, and no further keratoacanthomas developed during his treatment. CONCLUSIONS: We report a unique case of sorafenib-associated Grzybowski syndrome. Temporary interruption and dose reduction of sorafenib and use of acitretin appeared to prevent further development of keratoacanthomas.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Exantema , Ceratoacantoma , Dermatopatias , Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Ceratoacantoma/induzido quimicamente , Ceratoacantoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Sorafenibe/efeitos adversos
4.
Elife ; 102021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34343089

RESUMO

Poly(ADP-ribose) polymerase (PARP) enzymes initiate (mt)DNA repair mechanisms and use nicotinamide adenine dinucleotide (NAD+) as energy source. Prolonged PARP activity can drain cellular NAD+ reserves, leading to de-regulation of important molecular processes. Here, we provide evidence of a pathophysiological mechanism that connects mtDNA damage to cardiac dysfunction via reduced NAD+ levels and loss of mitochondrial function and communication. Using a transgenic model, we demonstrate that high levels of mice cardiomyocyte mtDNA damage cause a reduction in NAD+ levels due to extreme DNA repair activity, causing impaired activation of NAD+-dependent SIRT3. In addition, we show that myocardial mtDNA damage in combination with high dosages of nicotinamideriboside (NR) causes an inhibition of sirtuin activity due to accumulation of nicotinamide (NAM), in addition to irregular cardiac mitochondrial morphology. Consequently, high doses of NR should be used with caution, especially when cardiomyopathic symptoms are caused by mitochondrial dysfunction and instability of mtDNA.


Assuntos
Reparo do DNA , DNA Mitocondrial/metabolismo , Cardiopatias/fisiopatologia , Coração/fisiopatologia , Miocárdio/metabolismo , NAD/metabolismo , Animais , Dano ao DNA , Células HeLa , Humanos , Camundongos , Mitocôndrias/metabolismo , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Compostos de Piridínio/efeitos adversos , Sirtuínas/antagonistas & inibidores
5.
In Vivo ; 35(5): 2969-2974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410996

RESUMO

BACKGROUND: We report two cases in which severe skin disorders developed during sorafenib treatment in patients with renal cell carcinoma (RCC) who had previously received nivolumab. CASE REPORT: Case 1: A 50-year-old man with RCC received nivolumab as the fifth-line therapy followed by sorafenib as the sixth-line therapy. On day 15 of sorafenib administration, the patient was hospitalized with systemic erythema multiforme, acne-like skin rash, and hand-foot syndrome. Case 2: A 40-year-old man with RCC received nivolumab as the second-line therapy followed by sorafenib as the fifth-line treatment. On day 12 of sorafenib administration, the patient was hospitalized with an acne-like skin rash and hand-foot syndrome. The skin disorders in the two cases improved within 2-3 weeks after sorafenib discontinuation and the start of treatment with topical and oral steroids. CONCLUSION: When using sorafenib in patients previously treated with nivolumab, close attention should be paid to the onset of serious skin disorders.


Assuntos
Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Adulto , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Nivolumabe/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Sorafenibe/efeitos adversos , Resultado do Tratamento
6.
Expert Opin Investig Drugs ; 30(8): 803-811, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34130563

RESUMO

Introduction: Tyrosine kinase inhibitors (TKIs) have drastically changed the outcome of chronic myeloid leukemia (CML) patients. However, a subset of patients experienced resistance and/or intolerance and need to switch to other agents. Resistance to second-generation TKIs used in first-line treatment is less of an issue when compared to imatinib in first line. New drugs that are able to improve efficacy, without long-term off-target effects are needed. Allosteric inhibitors such as asciminib (ABL001) were created to overcome resistance and off-target toxicity.Areas covered: In this review, we report the mechanism of action, pharmacokinetic data, and the clinical trial results of asciminib tested in chronic phase CML patients.Expert Opinion: Asciminib, the first example of allosteric inhibition, could be a promising approach as third-line therapy and in the subset of patients with T315I mutation that, for coexistent comorbidities, cannot receive other drugs. Future results will probably help to move the drug to earlier lines of treatment.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Niacinamida/análogos & derivados , Pirazóis/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos
7.
World J Surg Oncol ; 19(1): 168, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112190

RESUMO

BACKGROUND: Sorafenib was reported as a useful adjuvant treatment in patients with hepatocellular carcinoma who underwent surgical resection. However, its therapeutic value remains controversial. This meta-analysis examined the available data regarding the efficacy and safety of sorafenib in patients with hepatocellular carcinoma after radical surgery. METHODS: The meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered in advance with PROSPERO (CRD42021233868). We searched PubMed, Embase, Cochrane Library, and Web of Science to identify eligible studies. Overall survival, recurrence-free survival, and recurrence rates were analyzed, and adverse events were reviewed. Hazard ratios or pooled risk ratios with 95% CIs were collected and analyzed using STATA version 12.0 in a fixed-effects or random-effects meta-analysis model. RESULTS: In total, 2655 patients from 13 studies were ultimately included in this meta-analysis. The combined results illustrated that sorafenib was associated with better overall survival than the control (hazard ratio = 0.71, 95% CI = 0.59-0.86; P < 0.001). Similarly, the drug also improved recurrence-free survival (hazard ratio = 0.68, 95% CI = 0.54-0.86, P = 0.001). Combined data revealed that patients treated with sorafenib after resection had a lower recurrence rate (pooled risk ratio = 0.78, 95% CI = 0.68-0.90, P < 0.001). The primary adverse events were hand-foot skin reaction, fatigue, and diarrhea of mild-to-moderate severity, whereas grade 4 adverse events were rare (< 1%). CONCLUSIONS: This meta-analysis demonstrated that adjuvant sorafenib therapy after resection in patients with hepatocellular carcinoma could prolong overall survival and recurrence-free survival and reduce recurrence rates without intolerable side effects. However, more evidence is needed before reaching a definitive conclusion.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/tratamento farmacológico , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Prognóstico , Sorafenibe/uso terapêutico , Resultado do Tratamento
8.
Liver Int ; 41(9): 2200-2211, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33966333

RESUMO

BACKGROUND AND AIMS: The effectiveness of systemic treatment in advanced hepatocellular carcinoma (HCC) depends on the selection of patients, management of cirrhosis complications and expertise to treat adverse events. The aims of the study are to assess the frequency and management of cardiovascular events in HCC patients treated with sorafenib (SOR) and to create a scale to predict the onset of major adverse cardiovascular events (MACE). METHOD: Observational retrospective study with consecutive HCC patients treated with SOR between 2007 and 2019 in a western centre. In order to classify cardiovascular risk pre-SOR, we designed the CARDIOSOR scale with age, hypertension, diabetes, dyslipidaemia and peripheral vascular disease. Other adverse events, dosing and outcome data were collected during a homogeneous protocolled follow-up. RESULTS: Two hundred ninety-nine patients were included (219 BCLC-C). The median overall survival was 11.1 months (IQR 5.6-20.5), and duration of treatment was 7.4 months (IQR 3.3-14.7). Seventeen patients (6%) stopped SOR due to cardiovascular event. Thirty-three patients suffered MACE (7 heart failure, 11 acute coronary syndrome, 12 cerebrovascular accident and 8 peripheral vascular ischemia); 99 had a minor cardiovascular event, mainly hypertension (n = 81). Age was the only independent factor associated to MACE (HR 1.07; 95% CI 1.03-1.12; P = .002). The CARDIOSOR scale allows to identify the group of patients with higher risk of MACE (sHR 3.4; 95% CI 1.4-6.7; P = .04). CONCLUSION: The incidence of cardiovascular events in HCC patients treated with SOR is higher than expected. Multidisciplinary approach and clinical tools like CARDIOSOR scale could be helpful to manage these patients.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Doenças Cardiovasculares , Neoplasias Hepáticas , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Estudos Retrospectivos , Sorafenibe/uso terapêutico , Resultado do Tratamento
9.
Dermatol Ther ; 34(3): e14892, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33595161

RESUMO

The incidence of skin cancer has gradually increased in the last years and exposition to ultraviolet radiation remains the main risk factor. We performed a comprehensive review on the role of nicotinamide (NAM) in the chemoprevention of skin cancers. NAM, a water-soluble form of vitamin B3, interferes with skin carcinogenesis as it regulates immunosuppressor genes such as p53 and sirtuins and restores intracellular level of NAD+, a co-enzyme essential for energy production. Efficacy and safety of NAM was evaluated in a Phase III double-blinded control-placebo study (ONTRAC), thus demonstrating that the incidence of actinic keratoses and non-melanoma skin cancers was lower in the nicotinamide group than in placebo group. Further studies showed the efficacy of NAM also in transplanted patients and among inhabitants living in arsenic contamination areas. Despite the quick response to NAM supplementation, its intake need to be carried on chronically as the efficacy seems to vanish rapidly.


Assuntos
Niacinamida , Neoplasias Cutâneas , Quimioprevenção , Humanos , Niacinamida/efeitos adversos , Pele , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/prevenção & controle , Raios Ultravioleta
11.
Clinics (Sao Paulo) ; 76: e2498, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33503195

RESUMO

OBJECTIVES: To evaluate the efficacy and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma (HCC). METHODS: We analyzed data from a cohort of patients with advanced HCC treated using systemic treatment according to the local institutional protocol. Patients were divided into two groups, Group A, individuals <70 years of age, and Group B, individuals 70 years of age or older at the time of treatment initiation. Efficacy, measured based on overall survival (OS) and time to treatment failure (TTF), and toxicity were compared between groups. RESULTS: A total of 238 patients with advanced HCC who received sorafenib between 2007 and 2018 were evaluated. The median age for Group A was 59.1 years and that for Group B 73.6 years. The major prognostic characteristics were balanced between the groups. There were no significant differences in OS between Group A (8.0 months, 95%CI 6.34-9.3) and Group B (9.0 months, 95%CI 5.38-12.62), p=0.433, or in TTF between Group A (3.0 months, 95%CI 2.39-3.60) and Group B (3.0 months, 95%CI 1.68-4.32), p=0.936. There were no significant differences between Groups A and B with respect to the incidence of adverse events or treatment discontinuation because of toxicity. CONCLUSION: Efficacy and safety of sorafenib did not differ significantly between younger and older patients with HCC. Our data suggest that age alone should not restrict clinical decision-making for patients with advanced HCC.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Prognóstico , Sorafenibe/efeitos adversos
12.
Pediatr Dermatol ; 38(2): 518-519, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33481286

RESUMO

Sorafenib is a multikinase inhibitor increasingly used for the treatment of several solid tumors. Different types of keratotic lesions, such as squamous cell carcinoma, actinic keratosis, or infundibular cyst, have been reported in association with this therapy. We present a 15-year-old male diagnosed with desmoid fibromatosis who developed multiple penile and scrotal infundibular cysts while receiving treatment with sorafenib.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Cutâneas , Adolescente , Humanos , Masculino , Niacinamida/efeitos adversos , Compostos de Fenilureia , Sorafenibe
14.
J Clin Gastroenterol ; 55(2): 169-173, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32520885

RESUMO

BACKGROUND: Recent studies have revealed that coadministration of gastric acid suppressants reduces the efficacy of the tyrosine kinase inhibitors erlotinib and sunitinib in patients with non-small cell lung cancer and renal cell carcinoma, respectively. The authors have therefore assessed if the concurrent use of gastric acid suppressants and sorafenib impairs outcomes in patients with advanced hepatocellular carcinoma (HCC). METHODS: A retrospective analysis was conducted on all patients treated with sorafenib for advanced HCC at a single tertiary referral unit in the United Kingdom, between January 2008 and January 2014. A multivariate Cox proportional hazard model was used to assess the effect of the concomitant use of gastric acid suppression and sorafenib on progression-free survival (PFS) and overall survival (OS). RESULTS: Data were collected from 197 patients, of which 182 could be assessed for this study; 77 (42%) were on concurrent gastric acid suppression therapy. After adjusting for imbalances between the groups, a Cox regression analysis gave an adjusted hazard ratio for the concurrent acid suppression group compared with the no acid suppression group of 5.4 (95% confidence interval, 3.6-7.9) for PFS and 1.85 (95% confidence interval, 1.3-2.6) for OS. CONCLUSIONS: This single-center experience shows that patients with advanced HCC taking sorafenib and concomitant gastric acid suppression therapy have significantly inferior PFS and OS. This is the first time that this negative interaction has been reported and further prospective validation is warranted.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Hepáticas , Neoplasias Pulmonares , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Intervalo Livre de Doença , Ácido Gástrico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Niacinamida/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Estudos Retrospectivos , Sorafenibe , Resultado do Tratamento , Reino Unido
15.
J Clin Gastroenterol ; 55(3): 263-270, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32530871

RESUMO

GOALS: To describe the occurrence of malabsorption (MA) in hepatocellular carcinoma (HCC) patients under sorafenib, the potential relationship with pancreatic insufficiency (PI), and the role of pancreatic enzymes supplementation. BACKGROUND: With the increasing options of second-line systemic therapies for HCC, the recognition of drug intolerance using practical tools is crucial. It has been proposed that a MA syndrome could be due to sorafenib-induced pancreatic dysfunction. STUDY: All sorafenib-treated patients with suspicion of MA (defined as decreased stool consistency lasting >4 wk or presenting ≥10% body weight loss without HCC progression) were prospectively evaluated by serum markers, endoscopy, and imaging techniques. RESULTS: We evaluated 81 sorafenib-treated patients and 21 developed MA suspicion (85.7% male, 81.5% Child-Pugh A, 52.4% BCLC-B, and 47.6% BCLC-C) within a median 5.9 months after starting sorafenib. The median treatment duration, follow-up, and overall survival after MA suspicion were 5.9, 20.3, and 20.3 months, respectively. Nine of them (42.9%) presented hyperparathyroidism secondary to vitamin D deficiency and 8 with PI. A gradual decrease in pancreatic volume of up to 19% was observed among patients with PI. Six of the 8 patients with PI received pancreatic enzymes, with complete recovery from MA symptoms and stabilization of pancreatic volume. CONCLUSIONS: We validated the association between MA and PI in 10% of sorafenib-treated patients. Pancreatic enzymes supplementation successfully led to symptomatic recovery. Awareness of this adverse event can help in the management of sorafenib irrespective of cancer type and likely, of other tyrosine kinase inhibitors for HCC patients.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Insuficiência Pancreática Exócrina , Neoplasias Hepáticas , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Sorafenibe/efeitos adversos , Resultado do Tratamento
17.
J Am Acad Dermatol ; 84(4): 1042-1050, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32360756

RESUMO

Dietary supplements are commonly recommended by dermatologists in the treatment of skin, hair, and nail disorders. This review of oral over-the-counter supplement use in dermatology summarizes current evidence for the use of zinc, biotin, vitamin D, nicotinamide, and Polypodium in the management of common dermatologic disorders. Evidence for the safety and efficacy of these supplements is limited. Very few large-scale randomized controlled trials exist for these over-the-counter supplements, particularly biotin and Polypodium. The lack of standardized dosing and standardized outcome measures makes comparison across existing studies challenging, and the lack of adverse events reporting in the majority of studies limits analysis of supplement safety. The most promising evidence exists for the use of nicotinamide in preventing nonmelanoma skin cancers. There is some evidence for the role of vitamin D in decreasing melanoma risk and progression in some individuals and for the photoprotective role of Polypodium, although additional high-quality studies are needed to determine appropriate dosing. Current evidence is insufficient to recommend the use of biotin or zinc supplements in dermatology. Large-scale randomized controlled trials investigating safety and efficacy are needed before widespread incorporation of these oral supplements into the general practice of dermatology.


Assuntos
Biotina/uso terapêutico , Suplementos Nutricionais , Niacinamida/uso terapêutico , Fitoterapia , Polypodium , Dermatopatias/tratamento farmacológico , Vitamina D/uso terapêutico , Zinco/uso terapêutico , Biotina/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Humanos , Niacinamida/efeitos adversos , Fitoterapia/efeitos adversos , Polypodium/efeitos adversos , Dermatopatias/prevenção & controle , Neoplasias Cutâneas/prevenção & controle , Vitamina D/efeitos adversos , Zinco/efeitos adversos
18.
Mod Rheumatol ; 31(3): 543-555, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33050760

RESUMO

OBJECTIVE: To evaluate the safety of peficitinib for the treatment of rheumatoid arthritis (RA) in Asian patients. METHODS: Safety data from one Phase 2b, two Phase 3, and one open-label long-term extension study [data cut-off 31 May 2018] were pooled into Phase 3 studies (peficitinib 100 and 150 mg/day, and placebo) and Phase 2/3 studies (all peficitinib-treated patients). Incidence rates per 100 patient-years (PY) of adverse events (AEs) of special interest were calculated. RESULTS: Overall, 1052 patients received peficitinib for 2336.3 PY of exposure (median 2.1 years); four deaths occurred, including one death after the studies. AE incidence was similar across peficitinib 100 and 150 mg/day groups (Phase 3 studies). Respective peficitinib and placebo incidence rates (95% confidence interval) per 100 PY were 2.9 (1.9, 4.6) and 0.0 for serious infections, 5.7 (4.2, 7.9) and 2.3 (0.6, 9.4) for herpes zoster-related disease, and 0.6 (0.2, 1.6) and 1.2 (0.2, 8.3) for malignancies (excluding non-melanoma skin cancer) (Phase 3 studies), and 0.1 (0.0, 0.3) for venous thromboembolism in all peficitinib-treated patients (Phase 2/3 studies). CONCLUSION: Peficitinib was well tolerated in Asian patients with RA over a median of 2 years, with no observed dose or temporal dependency for AEs with prolonged administration.


Assuntos
Adamantano/análogos & derivados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Niacinamida/análogos & derivados , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Adulto , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/etnologia , Grupo com Ancestrais do Continente Asiático , Tolerância a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Resultado do Tratamento
19.
Clinics ; 76: e2498, 2021. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1153964

RESUMO

OBJECTIVES: To evaluate the efficacy and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma (HCC). METHODS: We analyzed data from a cohort of patients with advanced HCC treated using systemic treatment according to the local institutional protocol. Patients were divided into two groups, Group A, individuals <70 years of age, and Group B, individuals 70 years of age or older at the time of treatment initiation. Efficacy, measured based on overall survival (OS) and time to treatment failure (TTF), and toxicity were compared between groups. RESULTS: A total of 238 patients with advanced HCC who received sorafenib between 2007 and 2018 were evaluated. The median age for Group A was 59.1 years and that for Group B 73.6 years. The major prognostic characteristics were balanced between the groups. There were no significant differences in OS between Group A (8.0 months, 95%CI 6.34-9.3) and Group B (9.0 months, 95%CI 5.38-12.62), p=0.433, or in TTF between Group A (3.0 months, 95%CI 2.39-3.60) and Group B (3.0 months, 95%CI 1.68-4.32), p=0.936. There were no significant differences between Groups A and B with respect to the incidence of adverse events or treatment discontinuation because of toxicity. CONCLUSION: Efficacy and safety of sorafenib did not differ significantly between younger and older patients with HCC. Our data suggest that age alone should not restrict clinical decision-making for patients with advanced HCC.


Assuntos
Humanos , Pessoa de Meia-Idade , Idoso , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Antineoplásicos/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Prognóstico , Niacinamida/efeitos adversos , Sorafenibe/efeitos adversos
20.
Skin Therapy Lett ; 25(5): 7-11, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33196157

RESUMO

Nicotinamide (or niacinamide), a form of vitamin B3 that is often confused with its precursor nicotinic acid (or niacin), is a low-cost, evidence-based oral treatment option for actinic keratosis, squamous cell carcinomas, basal cell carcinomas, and bullous pemphigoid. Despite its favorable safety profile and affordability, the integration of nicotinamide into clinical practice is an ongoing process, and like many over-the-counter supplements it has faced some barriers. The purpose of this article is to address some of those barriers by reviewing its efficacy, safety profile, and emphasizing the difference between nicotinamide and niacin. Lastly, we offer practical guidance around recommendations and the availability of nicotinamide, which can be hard to find for patients and providers alike.


Assuntos
Niacinamida/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Complexo Vitamínico B/uso terapêutico , Administração Oral , Suplementos Nutricionais , Humanos , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/efeitos adversos
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