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BACKGROUND: The phase I/II FIGHT-101 study (NCT02393248) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of pemigatinib, a potent and selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor, as monotherapy or in combination therapy, for refractory advanced malignancies, with and without fibroblast growth factor (FGF) and receptor (FGFR) gene alterations. PATIENTS AND METHODS: Eligible, molecularly unselected patients with advanced malignancies were included in part 1 (dose escalation; 3 + 3 design) to determine the maximum tolerated dose. Part 2 (dose expansion) evaluated the recommended phase II dose in tumors with or where FGF/FGFR activity is relevant. RESULTS: Patients (N = 128) received pemigatinib 1-20 mg once daily intermittently (2 weeks on/1 week off; n = 70) or continuously (n = 58). No dose-limiting toxicities were reported. Doses ≥4 mg were pharmacologically active (maximum tolerated dose not reached; recommended phase II dose 13.5 mg once daily). The most common treatment-emergent adverse event (TEAE) was hyperphosphatemia (75.0%; grade ≥3, 2.3%); the most common grade ≥3 TEAE was fatigue (10.2%). Dose interruption, dose reduction, and TEAE-related treatment discontinuation occurred in 66 (51.6%), 14 (10.9%), and 13 (10.2%) patients, respectively. Overall, 12 partial responses were achieved, most commonly in cholangiocarcinoma (n = 5) as well as in a broad spectrum of tumors including head and neck, pancreatic, gallbladder, uterine, urothelial carcinoma, recurrent pilocytic astrocytoma, and non-small-cell lung cancer (each n = 1); median duration of response was 7.3 months [95% confidence interval (CI) 3.3-14.5 months]. Overall response rate was highest for patients with FGFR fusions/rearrangements [n = 5; 25.0% (95% CI 8.7% to 49.1%)], followed by those with FGFR mutations [n = 3; 23.1% (95% CI 5.0% to 53.8%)]. CONCLUSIONS: Pemigatinib was associated with a manageable safety profile and pharmacodynamic and clinical activity, with responses seen across tumors and driven by FGFR fusions/rearrangements and mutations. These results prompted a registrational study in cholangiocarcinoma and phase II/III trials in multiple tumor types demonstrating the benefit of precision therapy, even in early phase trials.
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Neoplasias dos Ductos Biliares , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células de Transição , Colangiocarcinoma , Neoplasias Pulmonares , Neoplasias , Neoplasias da Bexiga Urinária , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células de Transição/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Morfolinas , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Pirróis , Receptores de Fatores de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
Breast cancer is highly prevalent in South Africa, and up to 10% of breast cancer cases may be hereditary. The landscape of genetic testing options for hereditary breast cancer (HBC) has changed significantly over the past decade, and healthcare providers are faced with multiple options when referring breast cancer patients for genetic testing. We have performed a retrospective study of 3 years' worth of breast cancer genetic testing referrals to our laboratory. While Afrikaner and Ashkenazi Jewish founder screens may be appropriate as first-line tests in a limited subset of patients, we have shown that in the majority of cases it is more effective to adopt a multigene panel approach. While variants in the BRCA1 and BRCA2 genes still account for a significant proportion of cases, close to 40% of pathogenic variants were found in genes other than BRCA1 or BRCA2. There are many factors that healthcare providers should consider when requesting genetic testing for breast cancer patients and families, including family history, ancestral background, cost, medical aid scheme reimbursement and scope of testing. We summarise our findings and provide advantages and disadvantages of each approach, with the aim of assisting clinicians and genetic counsellors to make appropriate testing decisions.
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Neoplasias da Mama/diagnóstico , Testes Genéticos , Proteína BRCA2/genética , Neoplasias da Mama/genética , Efeito Fundador , Humanos , Herança Multifatorial , Estudos Retrospectivos , África do Sul , Ubiquitina-Proteína Ligases/genéticaRESUMO
[1]Relativistic electron intensities in Earth's outer radiation belt can vary by multiple orders of magnitude on the time scales ranging from minutes to days. One fundamental process contributing to dynamic variability of radiation belt intensities is the radial transport of relativistic electrons across their drift shells. In this paper we analyze the properties of three-dimensional radial transport in a global magnetic field model driven by variations in the solar wind dynamic pressure. We use a test particle approach which captures anomalous effects such as drift orbit bifurcations. We show that the bifurcations lead to an order of magnitude increase in radial transport rates and enhance the energization at large equatorial pitch angles. Even at quiet time fluctuations in dynamic pressure, radial transport at large pitch angles exhibits strong deviations from the diffusion approximation. The radial transport rates are much lower at small pitch angle values which results in a better agreement with the diffusion approximation.
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BACKGROUND: Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC). METHODS: Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m(-2) intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (≥50% PSA reduction confirmed ≥28 days apart). According to the Simon two-stage design, ≥3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available. RESULTS: In all, 53 patients received ≥2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m(-2) during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity. CONCLUSION: This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzotiazóis/administração & dosagem , Benzotiazóis/efeitos adversos , Epotilonas/administração & dosagem , Epotilonas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Orquiectomia , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prognóstico , Estudos Prospectivos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgiaRESUMO
OBJECTIVE: To determine the frequency and distribution of polyglutamine spinocerebellar ataxias (SCAs) from referrals over a 24-year period to the National Health Laboratory Service (NHLS) in South Africa (SA). METHODS: Paper-based clinical reports in the University of Cape Town laboratory and the NHLS electronic patient record database spanning a 24-year period were mined for information regarding the molecular diagnosis, ethnicity and CAG repeat length for individuals referred for molecular genetic testing for the polyglutamine SCAs. RESULTS: SCA1 and 7 are the most frequent types of polyglutamine SCA in the SA patient population, followed by SCA2, 3 and 6. SCA1 is the most common type in the coloured, white and Indian populations, whereas the majority of indigenous black African patients are affected with SCA7 and 2. Of individuals tested, 22% were found to be positive for one of the polyglutamine SCAs. CONCLUSION: Although trends in the frequency and distribution of the polyglutamine SCAs in SA have not changed significantly since our previous study in 2003, they differ remarkably from those reported elsewhere, and reflect the unique genetic and demographic background of SA. The provision of accurate and complete patient information and family history is crucial to the diagnostic process, to enable comprehensive epidemiological studies and assist in developing therapeutic and patient management strategies.
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Peptídeos/genética , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética , Feminino , Humanos , Incidência , Masculino , Técnicas de Diagnóstico Molecular , África do Sul/epidemiologia , Ataxias Espinocerebelares/etnologia , Repetições de Trinucleotídeos/genéticaRESUMO
UNLABELLED: The auditory evoked potential termed the middle latency response (MLR) has been suggested as an indicator of adequacy of anaesthesia during surgery. However, the response is small and must be extracted from high levels of background noise. A key consideration in using the MLR for clinical monitoring is whether data quality is sufficient to detect small changes. The aim of this study was to investigate the quality of the MLR recorded during anaesthesia, as a rigorous analysis of data quality is lacking in many studies. MLR recordings from patients sedated in intensive care after cardiac surgery were compared to recordings from a reference group of young volunteers with normal hearing. Data quality was measured with the F(sp) parameter. A bootstrap analysis was used to measure statistical response presence and to detect within-subject changes during clinical anaesthesia. Noise levels were high in the normative group probably due to myogenic and EEG activity. With 5 Hz click stimulation, MLR presence in the normative group was below 30%. Response presence improved using stimulation paradigms with chirps or maximum length sequences and reached 100% with a combination of maximum length sequences and chirps. F(sp) values generally improved during anaesthesia as noise levels reduced and MLR presence was 100% for MLS click stimulation. Changes in the MLR amplitude with propofol infusion rate were small. Some within-subject changes in MLR amplitude were detected using the bootstrap analysis, but 100% detection was not possible. CONCLUSION: Obtaining good quality MLR data in awake subjects is challenging. Data quality improves during clinical anaesthesia and with advanced stimulation methods, but reliable detection of changes in the MLR for clinical monitoring remains a challenge.
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Anestesia/métodos , Potenciais Evocados Auditivos/efeitos dos fármacos , Potenciais Evocados Auditivos/fisiologia , Projetos de Pesquisa , Adulto , Idoso , Procedimentos Cirúrgicos Cardíacos , Eletroencefalografia , Feminino , Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Propofol/administração & dosagem , Propofol/farmacologia , Adulto JovemRESUMO
The usefulness of mannitol in the priming fluid for cardiopulmonary bypass is uncertain in patients with normal renal function, and has not been studied in patients with established renal dysfunction. We studied 50 patients with serum creatinine between 130 and 250 micromol.l(-1) having cardiac surgery. Patients were randomised to receive mannitol 0.5 g.kg(-1), or an equivalent volume of Hartmann's solution, in the bypass prime. There were no differences between the groups in plasma creatinine or change in creatinine from baseline, urine output, or fluid balance over the first three postoperative days. We conclude that mannitol has no effect on routine measures of renal function during cardiac surgery in patients with established renal dysfunction.
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Ponte Cardiopulmonar/métodos , Diuréticos Osmóticos/uso terapêutico , Rim/efeitos dos fármacos , Manitol/uso terapêutico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Ponte Cardiopulmonar/efeitos adversos , Creatinina/sangue , Feminino , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Mannitol is often added to the cardiopulmonary bypass pump prime to reduce the incidence of renal dysfunction, but studies so far have been inconclusive. Urinary excretion of microalbumin and retinol binding protein are more sensitive than routine biochemical tests of renal function after cardiac surgery. We performed a double-blind, randomised, controlled trial in cardiac surgical patients with pre-operative plasma creatinine < 130 micromol x l(-1). Twenty patients received 0.5 g x kg(-1) of mannitol in the pump prime, whereas 20 control patients received an equivalent volume of Hartmann's solution. Blood and urine samples were taken on the day before surgery and daily for 5 days postoperatively for measurement of plasma urea and creatinine, urinary creatinine, retinol binding protein and microalbumin. We found no differences between the mannitol and control patients for any measured variable, and conclude that mannitol has little impact on renal function in patients with normal pre-operative plasma creatinine concentrations.
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Injúria Renal Aguda/prevenção & controle , Ponte Cardiopulmonar , Rim/efeitos dos fármacos , Manitol/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Idoso , Albuminúria/prevenção & controle , Creatinina/sangue , Creatinina/urina , Método Duplo-Cego , Feminino , Humanos , Rim/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
The therapeutic benefit of lymph node dissection (LND) in women with endometrial cancer remains controversial. The purpose of this study is to analyze the impact of LND on survival. Data were obtained from the Surveillance, Epidemiology, and End Results program of the US National Cancer Institute for the years 1988-2003. Women with adenocarcinoma of the endometrium who underwent surgery as primary management of their disease were eligible. Multivariate analyses of pertinent variables were performed for the end points of overall survival and cause-specific survival. Women included in the analysis were 42,184. The average frequency of LND was 31%, 40%, 47%, and 53%, for the years 1988-1991, 1992-1995, 1996-1999, and 2000-2003, respectively (P < 0.0001). On multivariate analysis, presence of LND was associated with overall and uterine-specific survival benefits with hazard ratios (HR) of 0.81 (P < 0.0001) and 0.78 (P < 0.0001) and removal of greater than 11 lymph nodes (LN) associated with a HR of 0.74 (P < 0.0001) and 0.69 (P < 0.0001), respectively. Further multivariate analyses demonstrated greater than 11 LN to associate with all other cause-specific and cardiac-specific survival benefits, with HR of 0.77 (P < 0.0001) and 0.82 (P = 0.0062), respectively. We conclude that the presence of LND and increased number of nodes dissected predicted for improved overall and uterine-specific survival in women with adenocarcinoma of the endometrium. Improved cause-specific survival was most pronounced for greater than 11 nodes removed and stage II or higher disease. The improvement in noncancer-related mortality with LND predicted by this data suggests the presence of inherit biases, and the need for caution in analyzing retrospective data.
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Neoplasias do Endométrio/mortalidade , Excisão de Linfonodo/mortalidade , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Programa de SEER , Análise de Sobrevida , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Leucocyte-depleting arterial line filters have not dramatically improved lung function after cardiopulmonary bypass (CPB), but patients with pre-existing lung dysfunction may benefit from their use. METHODS: We randomized 32 patients with mild lung dysfunction having elective first-time coronary revascularization to either a leucocyte depleting or a standard 40-mm arterial line filter during CPB. The alveolar arterial oxygenation index was calculated before and 5 min after CPB, then at 1, 2, 4, 8, and 18 h after surgery. Time to extubation on the ITU was recorded. Preoperative, immediate postoperative, and 24 h postoperative chest x-rays were scored for extravascular lung water. RESULTS: Postoperative alveolar-arterial oxygenation indices were better in the patients who received leucocyte depletion during CPB (1.65+/-0.96 in the study group vs 2.90+/-1.72 in the control group, P<0.05). The duration of postoperative mechanical ventilation was less in the leucocyte-depleted group (4.8+/-2.1 vs 8.3+/-4.7 h in the control group, P<0.05). The extravascular lung water scores immediately postoperatively were 13.0+/-8.6 in the study group vs 19.6+/-10.8 in the control group (P=0.04), and at 24 h postoperatively, 9.7+/-7.7 vs 15.2+/-9.9 for controls. CONCLUSIONS: For patients with mild lung dysfunction, a leucocyte-depleting arterial line filter improves postoperative oxygenation, reduces extravascular lung water accumulation, and reduces time on artificial ventilator after CPB. There may be an economic argument for the routine use of leucocyte-depleting filters for every patient during CPB.
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Ponte Cardiopulmonar/métodos , Cuidados Intraoperatórios/métodos , Leucaférese , Pulmão/fisiopatologia , Oxigênio/sangue , Adolescente , Adulto , Idoso , Água Extravascular Pulmonar/metabolismo , Humanos , Pessoa de Meia-Idade , Consumo de Oxigênio , Período Pós-OperatórioRESUMO
The majority of novel anticancer drugs developed to date are intended for parenteral administration. Paradoxically, most of these drugs are water-insoluble, delaying their clinical development. A common approach to confering water solubility to drugs is to use amphiphilic, solubilizing agents, such as polyethoxylated castor oil (e.g., Cremophor EL, CrmEL). However, these vehicles are themselves associated with a number of pharmacokinetic and pharmaceutical concerns. The present work is aimed at evaluating a novel polymeric solubilizer for anticancer drugs, i.e., poly(N-vinylpyrrolidone)-block-poly(D,L-lactide) (PVP-b-PDLLA). This copolymer self-assembles in water to yield polymeric micelles (PM) that efficiently solubilize anticancer drugs, such as paclitaxel (PTX), docetaxel (DCTX), teniposide (TEN) and etoposide (ETO). A PM-PTX formulation was evaluated, both, in vitro on three different cancer cell lines and in vivo for its safety, pharmacokinetics, biodistribution and antitumor activity. In vitro, cytotoxicity studies revealed that the drug-loaded PM formulation was equipotent to the commercial PTX formulation (Taxol). In the absence of drug, PVP-b-PDLLA with 37% DLLA content was less cytotoxic than CrmEL. In vivo, acute toxicity was assessed in mice after a single injection of escalating dose levels of formulated PTX. PM-PTX was well tolerated and the maximum tolerated dose (MTD) was not reached even at 100 mg/kg, whereas the MTD of Taxol was established at 20 mg/kg. At 60 mg/kg, PM-PTX demonstrated greater in vivo antitumor activity than Taxol injected at its MTD. Finally, it was shown in mice and rabbits that the areas under the plasma concentration-time curves were inversely related to PM drug loading.
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Antineoplásicos/química , Ácido Láctico/química , Ácido Poliglicólico/química , Polímeros/química , Povidona/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Química Farmacêutica , Feminino , Meia-Vida , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Solubilidade , Distribuição TecidualRESUMO
An instrument is described that measures irradiance and the angular distribution of the intensity of ultraviolet radiation sources inside phototherapy cabinets. Failed lamps and lamps with higher or lower outputs are readily identified. The measurements are controlled from outside the cabinet, thus reducing the risk to staff from exposure to ultraviolet radiation.
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Análise de Falha de Equipamento/instrumentação , Radiometria/instrumentação , Software , Terapia Ultravioleta/instrumentação , Calibragem , Desenho de Equipamento , Análise de Falha de Equipamento/métodos , Análise de Falha de Equipamento/normas , Humanos , Manutenção/métodos , Radiometria/métodos , Sensibilidade e Especificidade , Terapia Ultravioleta/normasRESUMO
A novel tandem quadrupole mass spectrometer is described that enables gaseous collision-induced dissociation (CID) and surface-induced dissociation (SID) experiments. The instrument consists of a commercially available triple quadrupole mass spectrometer connected to an SID region and an additional, orthogonal quadrupole mass analyser. The performance of the instrument was evaluated using leucine-enkephalin, allowing a comparison between CID and SID, and with previous reports of other SID instruments. The reproducibility of SID data was assessed by replicate determinations of the collision energy required for 50% dissociation of leucine-enkephalin; excellent precision was observed (standard deviation of 0.6 eV) though, unexpectedly, the reproducibility of the equivalent figure for CID was superior. Several peptides were analysed using SID in conjunction with liquid secondary-ion mass spectrometry or electrospray; a comparison of the fragmentation of singly protonated peptide ions and the further dissociation of y-type fragments was consistent with the equivalence of the latter fragments to protonated peptides. Few product ions attributable to high-energy cleavages of amino acid side-chains were observed. The SID properties were investigated of a series of peptides differing only in the derivatization of a cysteine residue; similar decomposition efficiencies were observed for all except the cysteic acid analogue, which demonstrated significantly more facile fragmentation.
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Espectrometria de Massas/instrumentação , Sequência de Aminoácidos , Angiotensinogênio/química , Bradicinina/análogos & derivados , Bradicinina/química , Cisteína/química , Dinorfinas/química , Encefalina Leucina/química , Fibrinopeptídeo A/química , Espectrometria de Massas/métodos , Dados de Sequência Molecular , Estrutura Molecular , Fragmentos de Peptídeos/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , TermodinâmicaRESUMO
PURPOSE: The primary objective of this phase I trial was to determine the maximum-tolerated dose of radiation that could be delivered to the primary tumor concurrent with full-dose gemcitabine in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Thirty seven patients with unresectable (n = 34) or incompletely resected pancreatic cancer (n = 3) were treated. Gemcitabine was administered as a 30-minute intravenous infusion at a dose of 1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Radiation therapy was initiated on day 1 and directed at the primary tumor alone, without prophylactic nodal coverage. The starting radiation dose was 24 Gy in 1.6-Gy fractions. Escalation was achieved by increasing the fraction size in increments of 0.2 Gy, keeping the duration of radiation constant at 3 weeks. A second cycle of gemcitabine alone was intended after a 1-week rest. RESULTS: Two of six assessable patients experienced dose-limiting toxicity at the final planned dose level of the trial (42 Gy in 2.8-Gy fractions), one with grade 4 vomiting and one with gastric/duodenal ulceration. Two additional patients at this dose level experienced late gastrointestinal toxicity that required surgical management. CONCLUSION: The final dose investigated (42 Gy) is not recommended for further study considering the occurrence of both acute and late toxicity. However, a phase II trial of this novel gemcitabine-based chemoradiotherapy approach, at a radiation dose of 36 Gy in 2.4-Gy fractions, is recommended on the basis of tolerance, patterns of failure, and survival data.
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Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Radiossensibilizantes/uso terapêutico , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Seguimentos , Humanos , Infusões Intravenosas , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Doses de Radiação , Tomografia Computadorizada por Raios X , Resultado do Tratamento , GencitabinaRESUMO
We investigated the relationship between the latency of the Nb wave of the auditory evoked response (AER) and periods of awareness during propofol anaesthesia. In the anaesthetic room before cardiac surgery the AER was recorded continuously in 14 patients. Awareness was measured by the ability of the patient to respond to command using the isolated forearm technique (IFT). The Nb latencies were shorter when the patients were able to respond than at loss of response (P<0.001). In six patients who repeated this transition from response to loss of response, there was a high and significant correlation between Nb latencies. None of the patients had any recollection of events after the initial induction of anaesthesia as measured by explicit and implicit memory tests. These results suggest that the Nb latency of the AER may represent an indication of awareness in individual patients, but wide inter-patient variability limits its practical usefulness. In addition, because no evidence of memory was demonstrated, even when patients were known to be awake, the relationship between AER and memory processing remains unclear.
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Anestésicos Intravenosos/farmacologia , Potenciais Evocados Auditivos/efeitos dos fármacos , Monitorização Intraoperatória/métodos , Propofol/farmacologia , Idoso , Anestesia Intravenosa , Conscientização/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Humanos , Memória/efeitos dos fármacos , Pessoa de Meia-Idade , Tempo de Reação/efeitos dos fármacosRESUMO
BACKGROUND: A Phase II study was initiated to evaluate the effectiveness of an oral regimen of etoposide and estramustine in patients with early recurrent prostate carcinoma. METHODS: Patients with early recurrent prostate carcinoma as indicated by an increasing prostate specific antigen (PSA) level and without any evidence of metastatic disease were treated with oral etoposide 50 mg/m2/day and estramustine 15 mg/kg/day in divided doses for 21 days, followed by a 7-day rest period. Patients received a maximum of four cycles. RESULTS: Eighteen patients were entered in this study. The median serum PSA was 3.1 (range, 0.3-30.3) at the time of entry into the trial. Sixteen patients were assessable for response. Serum PSA declined to undetectable levels in 13 patients with 2 additional patients meeting the criteria for partial response; the median duration of response was 8.5 months (range, 1-18 months). Most patients developed gastrointestinal, cardiac, or hematologic complications. Grade 3 toxicities included neutropenia (one patient), deep venous thrombosis (three patients), and chest pain (one patient). One patient developed acute myelogenous leukemia (French-American-British, acute myelogenous leukemia M5) 23 months after initiating the chemotherapy. CONCLUSIONS: The combination of oral etoposide and oral estramustine resulted in a high rate but only a short duration of response in patients with early recurrent prostate carcinoma. The regimen was poorly tolerated, and the toxicity was significant. This regimen should not be considered standard therapy for the treatment of early recurrent prostate carcinoma, but further exploration of treatment in this setting is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/patologia , Progressão da Doença , Intervalo Livre de Doença , Estramustina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/patologia , Resultado do TratamentoRESUMO
PURPOSE: To determine the efficacy and toxicity of the drug combination of carboplatin, paclitaxel, and gemcitabine in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: Patients eligible included those with advanced urothelial malignancy of any histology, no previous chemotherapy for metastatic disease, Southwest Oncology Group performance status of 2 or less, serum creatinine levels of 2 mg/dL or less, and adequate bone marrow and hepatic function. Treatment consisted of paclitaxel 200 mg/m2, carboplatin (target area under the curve = 5) on day 1, and gemcitabine 800 mg/m2 on days 1 and 8, repeated every 21 days. RESULTS: Forty-nine patients (44 men and five women) were enrolled; the patients' median age was 63 years, and their median creatinine clearance was 78 mL/min (range, 26 to 165 mL/min). Forty-three patients had transitional cell carcinoma, and six had squamous cell carcinoma or mixed histology. Ten patients had metastases to lymph nodes only, six had locally advanced disease, four had locally recurrent disease, 24 patients had visceral metastases, and five had soft tissue metastases. Twenty-one patients had disease in one site, 16 in two sites, and 12 in three sites. A total of 272 cycles were administered (median, six cycles; range, 1 to 15 cycles). Major toxicities were grade 3 and 4 neutropenia in 17 and 19 patients, respectively; grade 3 and 4 thrombocytopenia in 15 and six patients, respectively; grade 3 and 4 anemia in 10 and two patients, respectively; grade 3 neuropathy in four patients; and diarrhea in two patients. The incidence of febrile neutropenia was 1.4%; no patients died of drug toxicity. Forty-seven of the 49 patients were assessable for response. Fifteen (32%) patients experienced a complete response, and 17 (36%) patients experienced a partial response (32 of 47 patients, 68%; 95% confidence interval, 56.27 to 82.86). Responses were seen in all sites, including 15 (68%) of 22 patients with visceral metastases. The median survival was 14.7 months, with a 1-year survival of 59%. CONCLUSION: Combination paclitaxel, carboplatin, and gemcitabine is active; an encouraging number of patients with advanced urothelial carcinoma treated with this regimen experienced complete remission.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/mortalidade , GencitabinaRESUMO
Pelvic recurrence following cystectomy is a devastating problem for both physician and patient. Patients who recur locally usually do so within the first 2 years following surgery. Stage, grade, and possibly p53 status of the tumor are prognostic indicators for local failure. Patients with extensive disease at the time of diagnosis may benefit from adjuvant or neoadjuvant treatment to attempt to decrease the rate of recurrence. Treatment of patients with local failure should use a multimodality approach that includes systemic chemotherapy with or without local radiation therapy or surgery. Although rare, long-term survival can be achieved in selected patients.
Assuntos
Neoplasias Abdominais , Cistectomia , Segunda Neoplasia Primária , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias Abdominais/diagnóstico , Neoplasias Abdominais/prevenção & controle , Neoplasias Abdominais/terapia , Humanos , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/prevenção & controle , Segunda Neoplasia Primária/terapiaRESUMO
While surgery and radiation therapy remain the only definitive treatments for prostate cancer, single modality therapy has been associated with high failure rates in patients with aggressive disease. Although hormonal therapy has been effective in cases of metastatic disease, the timing of treatment with respect to definitive therapy remains controversial. This review will explore the efficacy of hormonal and chemotherapy in both the adjuvant and neoadjuvant settings. A MEDLINE search was performed to identify pertinent articles regarding both adjuvant and neoadjuvant therapy in prostate cancer. Articles of historical relevance in addition to those using large patient numbers with a randomized design were reviewed preferentially. Since hormonal therapy has been considered standard treatment at the time of cancer progression after definitive therapy, many of the randomized trials essentially compared adjuvant therapy to delayed therapy. Historical trials using adjuvant hormonal therapy have been limited due to difficulties in clinical staging, as well as toxicities attributed to the formulations used. More recently, hormonal therapy has been found to delay disease progression, increase disease-free survival, and decrease mortality when given immediately after prostatectomy or radiation therapy in selected patients. Neoadjuvant hormonal therapy can improve disease-free survival and local control when given before radiation therapy; it has only decreased positive surgical margins when given prior to radical prostatectomy. Although hormonal therapy given immediately after either radical prostatectomy or radiation therapy is highly effective, the side effects of persistent long-term use must be weighed for each patient. While the use of chemotherapy has been limited by the lack of active agents, newer combinations have shown effectiveness in patients with hormone refractory disease, raising the possibility of their use in the adjuvant setting.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Quimioterapia Adjuvante , Humanos , Masculino , Seleção de Pacientes , Neoplasias da Próstata/mortalidade , Fatores de Risco , Taxa de SobrevidaRESUMO
PURPOSE: Patients with locally advanced bladder cancer or who are not medically fit for surgery are a therapeutic dilemma. Radiotherapy with or without single agent cisplatin has been the major therapeutic modality. A phase II Southwest Oncology Group trial investigated the efficacy and feasibility of 5-fluorouracil, cisplatin and radiation in this patient subset. MATERIALS AND METHODS: Eligible patients had muscle invasive bladder cancer (clinical stages T2-T4) with nodal involvement at or below the level of bifurcation of the iliac vessels, were medically or surgically inoperable, or refused cystectomy. Patients underwent pretreatment cystoscopy and detailed tumor mapping, and were treated with 75 mg. /m.2 cisplatin on day 1 and 1 gm./m.2 daily, 5-fluorouracil on days 1 to 4 and definitive radiotherapy. Chemotherapy was repeated every 28 days, twice during and twice after radiation. RESULTS: From October 1993 to April 1998, 60 patients were enrolled in study. Of the 56 eligible patients 34% had unresectable tumors, 21% were not medically fit for surgery and 45% refused cystectomy. Overall, 68% of the patients had clinical T3 tumors or greater and 22% had nodal metastasis. Treatment was completed as planned in 32 of 56 (57%) patients. The most frequent grade 3 or 4 toxicities were neutropenia, stomatitis or mucositis, diarrhea, neuropathy and nausea. There were 53 patients who were evaluable for response, although response was not determined for 18. The overall response rate was 51% (95% confidence interval [CI] 37 to 65) based on intent to treat with a complete response rate of 49% (95% CI 35 to 63). Estimated median survival of the 56 patients was 27 months (95% CI 21 to 40 months) with an overall 5-year survival of 32%. The 5-year survival of the 25 patients who refused surgery was 45%. CONCLUSIONS: Concurrent 5-fluorouracil, cisplatin and radiation therapy is feasible. Despite a promising complete response rate, the overall 5-year survival suggests the need for more effective systemic therapy. The 5-year survival of patients who refused cystectomy suggests that this combined modality may provide another alternative to cystectomy for these patients.