RESUMO
Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.
Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Progressão da Doença , Neoplasias Renais/genética , Neoplasias Renais/patologia , Mutação , Regiões 5' não Traduzidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 5 , Feminino , Dosagem de Genes , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Telomerase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.
Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Biomarcadores Tumorais , Cromossomos , Evolução Clonal , Progressão da Doença , Evolução Molecular , Feminino , Heterogeneidade Genética , Variação Genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Mutação , Metástase Neoplásica , Fenótipo , Filogenia , Prognóstico , Estudos Prospectivos , Análise de Sequência de DNARESUMO
Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.
Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Mutação , Metástase Neoplásica , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , Mapeamento Cromossômico , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 9 , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Trombose , Resultado do TratamentoRESUMO
INTRODUCTION: Drug treatment for cancer has changed dramatically over the past decade with many new drugs often with multiple applications. More recently, the detailed pathway for approval from the National Institute for Health and Care Excellence (NICE) in the UK has been simplified. To explore how these changes have impacted on systemic anti-cancer therapy tumour site-specific prescribing and workload activities, we have reviewed the prescribing records for 2014-2018 in a UK cancer network. METHODS: Information about the numbers of new systemic anti-cancer therapy drugs and NICE approvals were obtained from print editions of the British National Formulary (BNF) and the NICE website. Data on the numbers of new chemotherapy courses and individual treatment-related attendances were obtained from the cancer network Chemocare electronic prescribing system. RESULTS: During the five-year study period, there were 49 new systemic anti-cancer therapy drugs for all tumour types, and a total of 65 NICE technology approvals for solid tumour indications. Overall numbers of treatment courses increased by 40.7% and total treatment-related visits by 80.6%. There was a wide variation across tumour types with the highest number of increased visits seen for melanoma (349.3%) and prostate cancer (242.3%), but in contrast, no appreciable increases were seen for lower gastrointestinal cancers or small cell lung cancer. CONCLUSION: The study confirms the major impact of the arrival of new drug technology and positive NICE appraisals on increasing systemic anti-cancer therapy prescribing and chemotherapy unit activity. The data in this study may be of help in planning for future service delivery planning and workforce configurations.
Assuntos
Antineoplásicos/administração & dosagem , Institutos de Câncer/tendências , Redes Comunitárias/tendências , Sistemas de Liberação de Medicamentos/tendências , Drogas em Investigação/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Humanos , Melanoma/tratamento farmacológico , Melanoma/epidemiologia , Reino Unido/epidemiologiaRESUMO
PURPOSE OF REVIEW: Despite the availability of multiple targeted therapies, the 5-year survival rate of patients with metastatic clear cell renal cell carcinoma (ccRCC) rarely exceeds 10%. Recent insights into the mutational landscape and evolutionary dynamics of ccRCC have offered up a plausible explanation for these outcomes. The purpose of this review is to link the research findings to potential changes in clinical practice. RECENT FINDINGS: Intratumour heterogeneity (ITH) dominates the evolutionary landscape in ccRCC at the genetic, transcriptomic and proteomic level. Spatial and temporal separation of tumour subclones within the primary tumour as well as between primary and metastatic sites has been demonstrated at single nucleotide resolution. In the cases analysed to date, approximately two-thirds of somatic mutations are not shared between multiple biopsies from the same primary tumour. Very few of the key disease-driving events are shared across all primary tumour regions (with the exception of VHL and loss of chromosome 3p), whereas the majority are restricted to one or more tumour regions (TP53, SETD2, BAP1, PTEN, mTOR, PIK3CA and KDM5C). SUMMARY: ITH must be considered in the management of ccRCC with respect to diagnostic procedures, prognostic and predictive biomarkers and drug development.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Mutação , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Biópsia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/secundário , Análise Mutacional de DNA , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Fenótipo , Medicina de Precisão , Valor Preditivo dos Testes , Fatores de Risco , Transdução de Sinais/genéticaRESUMO
BACKGROUND AND AIM: The presence of spur-cell anemia (SCA) is due to lipid disturbances of the erythrocyte membrane and may develop in patients with advanced liver cirrhosis. The accurate predicting value of SC for survival has not been clarified. The aim of this study was to evaluate SCA as a prognostic indicator in patients with cirrhosis. METHODS: We prospectively evaluated clinical, laboratory parameters, and survival in patients with cirrhosis, with or without SCA, during the period 2008-2011. Patients who had at admission renal failure, other causes of hemolytic anemia, hepatocellular carcinoma, sepsis, and/or active bleeding, were excluded. One hundred sixteen patients with cirrhosis were included. The presence of SCA (SC rate higher or equal to 5% [≥ 5%]) was diagnosed in 36 (31%) patients. RESULTS: Patients with SCA compared to those without had more advanced liver disease (higher Model for End-Stage Liver Disease [MELD], P < 0.001), higher total bilirubin (P < 0.001), and International Normalized Ratio (P < 0.001). Patients with SCA had worse survival (log rank P < 0.001). Survival of patients with SCA at the first, second, and third month of follow-up was 77%, 45%, and 33%, respectively. In multivariate Cox's regression analysis, the presence of SCA was an independent predictor of mortality (hazard ratio = 3.17 [95% CI 1.55-6.48]). CONCLUSIONS: The presence of spur-cell anemia is not uncommon in cirrhosis and seems to be strongly associated with mortality. SCA can be used in combination with MELD as an additional predictor of early mortality.
Assuntos
Anemia Hemolítica/mortalidade , Cirrose Hepática/mortalidade , Idoso , Anemia Hemolítica/etiologia , Feminino , Seguimentos , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Índice de Gravidade de Doença , Taxa de Sobrevida , Fatores de TempoRESUMO
There are numerous studies in the literature of anesthesia administered during colonoscopy including various methods, drugs, and monitoring systems; however, none of them has studied whether a university-degreed nurse anesthesia provider (known as a certified registered nurse anesthetist in the United States) is skillful enough to provide safe anesthesia in patients undergoing endoscopic procedures. The aim of our study was to determine whether anesthesia provided by a university-degreed nurse anesthesia provider during an endoscopic procedure is comparable in terms of safety and efficacy with routine sedation practice. This randomized, double-blind study included 100 adult patients who underwent colonoscopy conducted in the Evgenidion University Hospital during a single year. Subjects were divided into 2 groups: the first group received the usual scheme of intravenous sedation with midazolam and fentanyl administered by a member of the endoscopic team that was blind to Bispectral Index (BIS) values recordings (Group 0). The second group received intravenous bolus injection of propofol bolus by a university-degreed anesthesia registered nurse based on the BIS values (Group 1). The average of the mean BIS values of Group 0 was 85.07 (SD = 8.01) and for Group 1 was 76.1 (SD = 10.88; p = .04). The parameters of "patient memory during procedure" and the satisfaction scores (as self-assessed by the patients as well as 2 gastroenterologists) were also significantly different between the patients of the 2 groups (p = .000). Comparison between the 2 groups showed that the sedation offered by a university-degreed nurse anesthesia provider was absolutely safe and effective, offering particular comfort to the patient during the intervention and contributing significantly to its successful results.
Assuntos
Anestesia Geral/enfermagem , Colonoscopia , Enfermeiros Anestesistas , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Enfermeiros Anestesistas/educação , Papel do Profissional de Enfermagem , Estudos ProspectivosRESUMO
Perioperative use of a cell saver device can serve as a cost-beneficial alternative to the transfusion method, especially in countries where the cost of a single unit of blood is high. The purpose of this study, conducted in a Greek hospital, was to calculate the cost benefit of using a cell saver device to salvage intraoperative blood during open surgical abdominal aortic aneurysm repair or open aortofemoral bypass for occlusive disease. This retrospective study measured the amounts of salvaged blood and reinfused blood encountered during the procedure and then calculated the cost benefit of cell saver use. With the cost of a unit of blood purchased in Greece about 450 ($585), the blood units salvaged and reinfused were calculated at a mean cost benefit of 754 ($980) per case.
Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Transfusão de Sangue , Análise Custo-Benefício , Grécia , Hospitais Públicos , HumanosRESUMO
GOALS: Comparison of nitric oxide (NO) levels in cirrhotic patients with and without hepatic encephalopathy (HE), evaluation of possible correlation between HE and other clinical or laboratory characteristics, and estimation of utilization of NO levels in clinical practice. BACKGROUND: HE is a neuropsychiatric complication of cirrhosis. The exact pathogenetic mechanisms underlying the presence of HE are not known. However, dysfunction of the NO pathway and ammonia detoxification are thought to play a major role. STUDY: Sixty-seven cirrhotic patients, 36 (53.7%) without HE, and 31 (46.3%) with HE were included in the study. Eighteen healthy individuals were used as control group. Clinical and laboratory data, including ammonia and stable end products of NO using Griess reaction, were collected. RESULTS: NOx levels were statistically significantly higher in cirrhotic patients (225.5 µmol/L) than in control group [(67.94 µmol/L) (P=0.000)]. NOx levels were, also, statistically significantly higher in patients with HE compared with patients without HE (324.67 µmol/L vs. 141.96 µmol/L, P=0.000). Significant correlation between the presence of HE and NOx, ammonia, C-reactive protein, albumin, Model for End-Stage Liver Disease score, and Child-Pugh classification revealed. NOx levels also correlated with severity of HE. NOx and ammonia are independent factors predicting HE according to regression analysis. Diagnostic accuracy for the diagnosis of HE using a combination of NOx and ammonia was superior compared with standalone NOx or ammonia utilization. CONCLUSIONS: NOx levels are correlated with the presence and severity of HE. NOx levels determination, in addition to ammonia levels, could contribute in diagnosis of HE.
Assuntos
Amônia/sangue , Proteína C-Reativa/análise , Encefalopatia Hepática/etiologia , Cirrose Hepática/complicações , Óxido Nítrico/sangue , Idoso , Biomarcadores/sangue , Feminino , Grécia , Encefalopatia Hepática/sangue , Encefalopatia Hepática/diagnóstico , Humanos , Cirrose Hepática/sangue , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Índice de Gravidade de DoençaRESUMO
The currently available genetic tests for identification of the RET proto-oncogene mutation offer the possibility of prospective successful therapy before the hyperplasia of C-cells evolve to Medullary Thyroid Carcinoma. We present our experience regarding the preventive thyroidectomy of family members with history of Medullary Thyroid Carcinoma, who were found to be heterozygote for mutant RET proto-oncogene. We have retrospectively reviewed 19 members of 6 families with history of Medullary Thyroid Carcinoma, who were heterozygote for mutant RET protooncogene and underwent prophylactic thyroidectomy. All patients included in this series were below twenty years of age. The Medullary Thyroid Carcinoma was asymptomatic and the mutation of RET protooncogene has been also documented pre-operatively in all of them. All patients had undergone total thyroidectomy, while 1 with pheochromocytoma had undergone also left epinephridectomy. Fourteen patients (73.68%) had undergone lymph-nodes resection (in 10 of them the resection was central, in 3 unilateral and in 1 bilateral). Although none of our patients suffered from hyperparathyroidism, 7 parathyroid glands have been also resected from 3 patients, while auto-transfusion has been performed in one. In all patients, preoperative measurement of the calcitonin blood levels before and after stimulation with pentagastrin has been performed.
Assuntos
Carcinoma Medular/genética , Carcinoma Medular/cirurgia , Proteínas Proto-Oncogênicas c-ret/genética , Tireoidectomia , Adolescente , Carcinoma Neuroendócrino , Criança , Saúde da Família , Heterozigoto , Humanos , Proto-Oncogene Mas , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgiaRESUMO
AIM: To evaluate survival rate and clinical outcome of cholangiocarcinoma. METHODS: The medical records of 34 patients with cholangiocarcinoma, seen at a single hospital between the years 1999-2006, were retrospectively reviewed. RESULTS: Thirty-four patients with a median age of 75 years were included. Seventeen (50%) had painless jaundice at presentation. Sixteen (47.1%) were perihilar, 15 (44.1%) extrahepatic and three (8.8%) intrahepatic. Endoscopic retrograde cholangiography (ERCP) and/or magnetic resonance cholangiography (MRCP) were used for the diagnosis. Pathologic confirmation was obtained in seven and positive cytological examination in three. Thirteen patients had co-morbidities (38.2%). Four cases were managed with complete surgical resection. All the rest of the cases (30) were characterized as non-resectable due to advanced stage of the disease. Palliative biliary drainage was performed in 26/30 (86.6%). The mean follow-up was 32 mo (95% CI, 20-43 mo). Overall median survival was 8.7 mo (95% CI, 2-16 mo). The probability of 1-year, 2-year and 3-year survival was 46%, 20% and 7%, respectively. The survival was slightly longer in patients who underwent resection compared to those who did not, but this difference failed to reach statistical significance. Patients who underwent biliary drainage had an advantage in survival compared to those who did not (probability of survival 53% vs 0% at 1 year, respectively, P = 0.038). CONCLUSION: Patients with cholangiocarcinoma were usually elderly with co-morbidities and/or advanced disease at presentation. Even though a slight amelioration in survival with palliative biliary drainage was observed, patients had dismal outcome without resection of the tumor.
Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos/cirurgia , Procedimentos Cirúrgicos do Sistema Biliar , Colangiocarcinoma/mortalidade , Colangiocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Procedimentos Cirúrgicos do Sistema Biliar/instrumentação , Colangiocarcinoma/patologia , Colangiopancreatografia Retrógrada Endoscópica , Colangiopancreatografia por Ressonância Magnética , Feminino , Grécia/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Paliativos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Stents , Fatores de Tempo , Resultado do TratamentoRESUMO
Classical interferon-alpha has been shown to be correlated with the development of a variety of autoimmune disorders. A 38 year-old female patient developed simultaneously diabetic ketoacidosis and hyperthyroidism 5 mo following initiation of treatment with pegylated interferon-alpha and ribavirin for chronic hepatitis C. High titers of glutamic acid decarboxylase, antinuclear and thyroid (thyroid peroxidase and thyroglobulin) antibodies were detected. Antiviral treatment was withdrawn and the patient was treated with insulin for insulin-dependent diabetes mellitus and propranolol for hyperthyroidism. Twelve months after cessation of pegylated interferon-alpha therapy the patient was euthyroid without any medication but remained insulin-dependent.
Assuntos
Antivirais/efeitos adversos , Cetoacidose Diabética/induzido quimicamente , Hepatite C Crônica/tratamento farmacológico , Hipertireoidismo/induzido quimicamente , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Adulto , Feminino , Humanos , Interferon alfa-2 , Proteínas RecombinantesRESUMO
Autoimmune thyroid diseases have been correlated with a variety of autoimmune diseases also affecting the skin. A 56-year-old patient with a history of vitiligo is presented who was admitted for hyperthyroidism (Graves disease) and a blistering eruption. Clinical and histological appearance of the skin disorder, rapid response to corticosteroids, recurrence and remission of the lesions with discontinuation and reintroduction of corticosteroids, respectively, were all suggestive of an autoimmune blistering disease accompanying autoimmune hyperthyroidism and vitiligo.
Assuntos
Doenças Autoimunes/complicações , Doença de Graves/complicações , Dermatopatias Vesiculobolhosas/complicações , Vitiligo/complicações , Corticosteroides/uso terapêutico , Doenças Autoimunes/patologia , Doenças Autoimunes/fisiopatologia , Doença de Graves/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Dermatopatias Vesiculobolhosas/tratamento farmacológico , Dermatopatias Vesiculobolhosas/patologia , Vitiligo/patologiaRESUMO
Although autopsy series report liver granulomas in up to 70% of patients, computed tomography detection of hepatic and splenic lesions is described in 5% and 15% of sarcoidosis cases, respectively. A rather rare case of liver sarcoidosis mimicking macronodular cirrhosis is presented by this current article. Imaging findings in our patient were in compliance with the diagnosis of liver cirrhosis, although liver biopsy findings eventually revealed sarcoid granulomas located in the portal and lobular areas without fibrotic lesions. Histological and imaging modalities in liver sarcoidosis are discussed.
Assuntos
Hepatite/diagnóstico por imagem , Cirrose Hepática/diagnóstico por imagem , Sarcoidose/diagnóstico por imagem , Meios de Contraste , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
AIM: To validate the statistic utility of both the Maddrey Discriminant Function score and the Model for End-Stage Liver Disease as predictors of short term (30 d and 90 d) mortality in patients with alcoholic hepatitis and to assess prognostic factors among clinical characteristics and laboratory variables of patients with alcoholic hepatitis. METHODS: Thirty-four patients with the diagnosis of alcoholic hepatitis admitted to Hippokration University Hospital of Athens from 2000 to 2005 were assessed in the current retrospective study and a statistical analysis was conducted. RESULTS: 30- and 90-d mortality rates were reported at 5.9% (2/34) and 14.7% (5/34), respectively. Significant correlation was demonstrated for the Model for End-Stage Liver Disease (P30 = 0.094, P90 = 0.046) and the Maddrey Discriminant Function score (P30 = 0.033, P90 = 0.038) with 30- and 90-d mortality whereas a significant association was also established for alanine aminotransferase (P = 0.057), fibrin degradation products (P = 0.048) and C-reactive protein (P = 0.067) with 90-d mortality. For 30-d mortality the Area Under the Curve was 0.969 (95%CI: 0.902-1.036, P = 0.028) for the Model for End-Stage Liver Disease score and 0.984 (95%CI: 0.942-1.027, P = 0.023) for the Maddrey Discriminant Function score with the optimal cut off point of 30.5 (sensitivity 1, specificity 0.937) and 108.68 (sensitivity 1, specificity 0.969), respectively. Accordingly, for 90-d mortality the Area Under the Curve was 0.762 (95%CI: 0.559-0.965, P = 0.065) for the Model for End-Stage Liver Disease score and 0.752 (95%CI: 0.465-1.038, P = 0.076) for the Maddrey Discriminant Function score with the optimal cut off point of 19 (sensitivity 0.6, specificity 0.6) and 92 (sensitivity 0.6, specificity 0.946), respectively. The observed Kaplan Meier survival rates for different score-categories were compared with log-rank tests and higher score values were correlated with a lower survival. CONCLUSION: Equivalency of the Model for End-Stage Liver Disease and the Maddrey Discriminant Function score is implied by the current study, verified by the plotted Receiver Operative Curves and the estimated survival rates. A statistically significant utility of C-reactive protein, fibrin degradation products and alanine aminotransferase as independent predictors of 90-d mortality has also been verified.
Assuntos
Hepatite Alcoólica/diagnóstico , Adulto , Alanina Transaminase/sangue , Proteína C-Reativa/metabolismo , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hepatite Alcoólica/sangue , Hepatite Alcoólica/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos RetrospectivosRESUMO
Cyproterone acetate (CPA) is a steroidal synthetic progestagen and anti-androgenic compound widely administered in prostate cancer which has been evidentially correlated with a severe hepatotoxic potency. Three male patients aged 78-83 years are presented, in whom severe hepatotoxic reactions emerged after CPA administration. Patients were treated with CPA at the doses of 200-300 mg/d for malignant prostate disease for 3-12 mo prior to the acute manifestation of the hepatic disease. Clinical features compatible with mixed hepatocellular and cholestatic liver disease including jaundice, white stools and dark urine, manifested in all three cases whereas encephalopathy and ascites were present in two of the patients. Other primary causes of hepatotoxicity (alcohol consumption and viral hepatitis) were also verified in two cases, and in those patients biopsy findings revealed the presence of cirrhotic lesions in liver parenchyma. Discontinuation of the therapeutic agent led to the amelioration of the clinical profile in all the patients whereas a patient died 40 d after hospital admission due to sepsis, despite acute liver disease improvement. The current article highlights the hepatotoxic potency of a widely administered therapeutic agent and illustrates the importance of clinical surveillance especially in patients with previous hepatic diseases. Three relevant cases are reported and a review of the published literature is made.
Assuntos
Antagonistas de Androgênios/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Acetato de Ciproterona/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/administração & dosagem , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Acetato de Ciproterona/administração & dosagem , Humanos , Hepatopatias/patologia , Hepatopatias/fisiopatologia , Masculino , Neoplasias da Próstata/tratamento farmacológicoRESUMO
Patients with brain metastases from malignant melanoma historically have a very poor outcome. Surgery and radiotherapy can be used, but for the majority of patients the disease will progress quickly. In the recent past, patients with brain metastases derived only minimal benefit from cytotoxic chemotherapy. Novel therapies that have been shown to be superior to chemotherapy in metastatic melanoma have made their way in clinic and data regarding their use in patients with treated or untreated brain metastases are encouraging. In this paper we describe the use of vemurafenib, dabrafenib, and ipilimumab in patients with melanoma disseminated to the brain in addition to other treatments currently in development.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Terapia Combinada , Humanos , Imidazóis/administração & dosagem , Indóis/administração & dosagem , Ipilimumab , Melanoma/genética , Melanoma/patologia , Mutação , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , VemurafenibRESUMO
Despite the available prevention and early detection strategies, advanced squamous-cell carcinoma of the uterine cervix remains a major concern for public health. Systemic treatment with cisplatin, either in combination with external beam irradiation for locally advanced disease, or as monotherapy for recurrent/metastatic disease has been the cornerstone of treatment for more than two decades. Cisplatin has been also combined with a number of agents including paclitaxel, topotecan, gemcitabine, vinorelbine and ifosfamide, leading to encouraging response rates and increases in progression-free survival in a series of randomized phase III trials. Platinum-based triplets have been also tested, albeit at the cost of substantial toxicity. More recently, combinations with molecular agents targeting critical pathways in cervical malignant transformation are being assessed in clinical trials. In the current review, we discuss all recent advances in the systemic treatment of metastatic cervical cancer with emphasis on the results of large randomized phase III trials. Concerns regarding treatment-related toxicity in the context of co-morbidities and the need for potent predictive biomarkers for individualized treatment are also addressed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Metástase Neoplásica , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias do Colo do Útero/patologiaRESUMO
Despite the available prevention and early detection strategies, squamous-cell carcinoma of the uterine cervix is still diagnosed as locally advanced disease in a considerable proportion of patients. As a potent sensitizer of cancer cells, cisplatin has been the "traditional partner" of external beam irradiation in this setting for more than two decades. Induction chemotherapy strategies followed by concurrent chemoradiation or surgery and preoperative concurrent chemoradiation have been recently implemented in clinical trials in an effort to optimize local control and to minimize the risk of distant metastases. In this context, cisplatin has been combined with a number of other potential radiosensitizers, including 5-fluorouracil, capecitabine, and gemcitabine. In patients resistant or intolerant to platinum compounds, numerous non-platinum-containing regimens have been developed, implementing various antimetabolites, taxanes, antineoplastic antibiotics, and topoisomerase II inhibitors. More recently, molecular agents targeting critical pathways in cervical malignant transformation are being assessed in early clinical trials in combination with external-beam irradiation. In the current work, we review the evolving role of cisplatin and other platinum compounds, either alone or in combination regimens, in the context of other potent radiosensitizers. The emerging role of molecular targeted agents, as candidate partners of external beam irradiation, is also discussed.
RESUMO
BACKGROUND: Testicular cancer is a rare tumor type accounting for 1% of malignancies in men. It is, however, the most common cancer in young men in Western populations. The incidence of testicular cancer is increasing globally, although a decline in mortality rates has been reported in Western countries. It is important to identify whether the variations in trends observed between populations are linked to genetic or environmental factors. METHODS: Age-standardized incidence rates and age-standardized mortality rates for testicular cancer were obtained for men of all ages in ten countries from the Americas, Asia, Europe, and Oceania using the Cancer Incidence in Five Continents (CI5plus) and World Health Organization (WHO) mortality databases. The annual percent change was calculated using Joinpoint regression to assess temporal changes between geographical regions. RESULTS: Testicular cancer age-standardized incidence rates are highest in New Zealand (7.8), UK (6.3), Australia (6.1), Sweden (5.6), USA (5.2), Poland (4.9), and Spain (3.8) per 100,000 men. India, China, and Colombia had the lowest incidence (0.5, 1.3, and 2.2, respectively) per 100,000 men. The annual percent changes for overall testicular cancer incidence significantly increased in the European countries Sweden 2.4%, (2.2; 2.6); UK 2.9%, (2.2; 3.6); and Spain 5.0%, (1.7; 8.4), Australia 3.0%, (2.2; 3.7), and China 3.5%, (1.9; 5.1). India had the lowest overall testicular cancer incidence -1.7%, (-2.5; -0.8). Annual percent changes for overall testicular cancer mortality rates were decreasing in all study populations, with the greatest decline observed in Sweden -4.2%, (-4.8; -3.6) and China -4.9%, (-6.5; -3.3). CONCLUSION: Testicular cancer is increasing in incidence in many countries; however, mortality rates remain low and most men are cured. An understanding of the risks and long-term side effects of treatment are important in managing men with this disease.