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BACKGROUND: Androgen deprivation therapy (ADT) with a GnRH agonist or the GnRH antagonist degarelix is a central component in the treatment of prostate cancer (PCa). Little is currently known regarding the decision criteria. Knowledge of these could improve the success of treatment in the future. OBJECTIVES: To identify factors influencing the treatment decision in patients with hormone-sensitive prostate cancer receiving ADT and to determine the incidence of concomitant disease in both treatment groups. METHODS: The two-arm, prospective, non-interventional study "ProComD" was conducted from September 2014 to June 2019 at 80 study centers in Germany. After the therapy decision was made, patients with hormone-sensitive prostate cancer needing ADT were included in the study. Data were collected during routine visits. RESULTS: Data from 413 patients were evaluated (degarelix Nâ¯= 268; GnRH agonists Nâ¯= 145). Key factors influencing the therapy decision for both treatment options included comorbidities (42% of all patients), compliance (64%), and age (81%). The source of information consulted most frequently regarding existing comorbidities was the patient's medical history conducted by the treating urologist themselves (65% in both groups). For patients with pre-existing cardiovascular diseases, the doctor's letter (45.8% degarelix vs. 38.9% GnRH agonists) or the medical history questionnaire (38.9% degarelix vs. 20% GnRH agonists) was additionally taken into account. CONCLUSION: Comorbidities along with age and compliance are among the key factors influencing the treatment decisions made by urologists.
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Antagonistas de Androgênios , Neoplasias da Próstata , Antagonistas de Androgênios/efeitos adversos , Androgênios , Hormônio Liberador de Gonadotropina , Humanos , Masculino , Estudos Prospectivos , Neoplasias da Próstata/tratamento farmacológicoRESUMO
In this study, a nanocomposite of reduced graphene oxide (RGO) nanofiller-reinforcement poly(lactic acid) (PLA)/poly(ethylene glycol) (PEG) matrix was prepared via the melt blending method. The flexibility of PLA was improved by blending the polymer with a PEG plasticizer as a second polymer. To enhance the electromagnetic interference shielding properties of the nanocomposite, different RGO wt % were combined with the PLA/PEG blend. Using Fourier-transform infrared (FT-IR) spectroscopy, field emission scanning electron microscopy (FE-SEM) and X-ray diffraction, the structural, microstructure, and morphological properties of the polymer and the RGO/PLA/PEG nanocomposites were examined. These studies showed that the RGO addition did not considerably affect the crystallinity of the resulting nanomaterials. Thermal analysis (TGA) reveals that the addition of RGO highly improved the thermal stability of PLA/PEG nanocomposites. The dielectric properties and electromagnetic interference shielding effectiveness of the synthesized nanocomposites were calculated and showed a higher SE total value than the target value (20 dB). On the other hand, the results showed an increased power loss by increasing the frequency and conversely decreased with an increased percentage of filler.
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BACKGROUND: This study aimed to evaluate the rates of infective complication related to transrectal prostate biopsy (TRPB) as our centre changed its protocol from six doses over 3 days to a single pre-procedure prophylactic dose. METHODS: This prospective cohort study identified infective complication in patients who attended and subsequently underwent TRPB at the time of their one-stop prostate clinic at our public tertiary hospital between August 2011 and April 2017. Patients who underwent TRPB between August 2011 and November 2014 received six doses of 500 mg of ciprofloxacin, taken twice daily over 3 days. This protocol was changed to a single dose of 500 mg of ciprofloxacin prior to biopsy from February 2015 to April 2017. Patients who had travelled to South East Asia in the 6 months prior to TRPB received a single dose of 1 g intravenous ertapenem prior to biopsy, and this remained unchanged throughout the study period. The rates of infective complication were recorded and compared between the groups of patients who had undergone six doses versus a single dose of prophylactic ciprofloxacin. RESULTS: A total of 766 patients underwent TRPB from August 2011 to April 2017. Of these, 357 patients received the 3-day course of prophylaxis (Group 1) and 409 patients received the single dose prophylaxis (Group 2). Fifty-five patients were excluded from analysis. There was no significant difference in infective complications between the two groups (3.4% (11/326) Group 1 versus 4.9% (19/385) Group 2, P = 0.40). CONCLUSION: Our study supports the use of a single dose of ciprofloxacin as sufficient antibiotic prophylaxis prior to TRPB.
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OBJECTIVES: To quantify and examine the causes of delays in the diagnosis and initial treatment of patients with bladder cancer in Western Australia. SUBJECTS AND METHODS: All attendances at a one-stop haematuria clinic at a public tertiary-level hospital in Western Australia between May 2008 and April 2014 were reviewed retrospectively. All patients diagnosed with a bladder tumour over this period were identified. These patients and their general practitioners were contacted retrospectively and invited to participate in telephone interviews, with additional data collected from clinical records as required. Waiting times to presentation, referral, assessment, and initial treatment were established for patients who presented with visible haematuria. RESULTS: Of 1 365 attendances, 151 patients were diagnosed with a bladder tumour and 100 of these were both suitable and agreed to participate in the study. For patients with visible haematuria the median (range) waiting time from initial bleeding to surgery was 69.5 (9-1 165) days. This was comprised of a median (range) pre-referral waiting time of 12 (0-1 137) days, assessment waiting time of 23.5 (0-207) days, and treatment waiting time of 20 (1-69) days. Reasons for prolonged waiting times included poor public awareness, patient fear and anxiety, delayed and non-referral from primary care, administrative delays, and resource limitations. CONCLUSION: Many patients experience significant delays in the diagnosis and treatment of their bladder cancer in Western Australia, and this probably reflects national trends. These concerning data warrant consideration of how delays can be reduced to improve outcomes for these patients.
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Diagnóstico Tardio/estatística & dados numéricos , Tempo para o Tratamento/estatística & dados numéricos , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Clínicos Gerais , Hematúria , Humanos , Masculino , Pessoa de Meia-Idade , Encaminhamento e Consulta , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/epidemiologia , Austrália Ocidental/epidemiologiaRESUMO
Hepatic portal venous gas (HPVG) is a rare ominous radiological sign usually indicative of mesenteric ischemia. Increased detection of HPVG has been associated with a growing number of non-ischemic causes. A 64-year-old gentleman following radical cystectomy and neobladder formation developed clinical signs suggestive of bowel obstruction. HPVG was demonstrated on abdominal imaging. Urgent laparotomy revealed no evidence of ischemia. We hypothesize an obstructed neobladder permitted gas to enter the mesenteric circulation. The patient made a complete recovery with supportive management.
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BACKGROUND: Few studies illustrate the contributions made by various specialties in pioneering commonly performed noninvasive and minimally invasive cosmetic and surgical procedures. OBJECTIVE: To evaluate the contributions made by various specialties in pioneering noninvasive and minimally invasive cosmetic and surgical procedures. MATERIALS AND METHODS: Key words using the Medical Search Headings Database were used to query in the Thomson Reuters Web of Science Database. The 25 most highly cited studies were sorted according to the citation number. The author specialty was identified and assigned scores based on the number of citations. RESULTS: Dermatology was identified as the specialty with the greatest contribution to botulinum toxin treatments for rhytides, injectable fillers, laser treatments, chemical peels, and noninvasive body contouring. Neurology was identified as the leading specialty in botulinum toxin treatments for hyperhidrosis, and vascular surgery was identified as leading specialty in sclerotherapy. Plastic surgery was identified as having made the greatest contribution to hair transplantation, and liposuction. CONCLUSION: Dermatology was identified as the leading specialty for the majority of noninvasive and minimally invasive cosmetic procedures. Other specialties have also contributed important literature to this area.
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Bibliometria , Técnicas Cosméticas , Procedimentos Cirúrgicos Dermatológicos , Dermatologia/estatística & dados numéricos , Neurologia/estatística & dados numéricos , Cirurgia Plástica/estatística & dados numéricos , Pesquisa Biomédica/estatística & dados numéricos , Toxinas Botulínicas/uso terapêutico , Abrasão Química , Preenchedores Dérmicos/uso terapêutico , Cabelo/transplante , Remoção de Cabelo , Ablação por Ultrassom Focalizado de Alta Intensidade , Humanos , Hiperidrose/tratamento farmacológico , Hiperidrose/cirurgia , Terapia a Laser , Lipectomia , Mamoplastia , Procedimentos Cirúrgicos Minimamente Invasivos , Publicações Periódicas como Assunto/estatística & dados numéricos , Rejuvenescimento , Rinoplastia , Escleroterapia , Envelhecimento da PeleRESUMO
BACKGROUND: The public preference for provider type in performing cutaneous surgery and cosmetic procedures is unknown in the United States. METHODS: An internet-based survey was administered to the lay public. Respondents were asked to select the health care provider (dermatologist, plastic surgeon, primary care physician, general surgeon, and nurse practitioner/physician's assistant) they mostly prefer to perform different cutaneous cosmetic and surgical procedures. RESULTS: Three hundred fifty-four respondents undertook the survey. Dermatologists were identified as the most preferable health care provider to evaluate and biopsy worrisome lesions on the face (69.8%), perform skin cancer surgery on the back (73.4%), perform skin cancer surgery on the face (62.7%), and perform laser procedures (56.3%) by most of the respondents. For filler injections, the responders similarly identified plastic surgeons and dermatologists (47.3% vs 44.6%, respectively) as the most preferred health care provider. For botulinum toxin injections, there was a slight preference for plastic surgeons followed by dermatologists (50.6% vs 38.4%). Plastic surgeons were the preferred health care provider for procedures such as liposuction (74.4%) and face-lift surgery (96.1%) by most of the respondents. CONCLUSION: Dermatologists are recognized as the preferred health care providers over plastic surgeons, primary care physicians, general surgeons, and nurse practitioners/physician's assistants to perform a variety of cutaneous cosmetic and surgical procedures including skin cancer surgery, on the face and body, and laser procedures. The general public expressed similar preferences for dermatologists and plastic surgeons regarding filler injections.
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Competência Clínica , Técnicas Cosméticas/estatística & dados numéricos , Procedimentos Cirúrgicos Dermatológicos/estatística & dados numéricos , Pessoal de Saúde/estatística & dados numéricos , Preferência do Paciente/estatística & dados numéricos , Adolescente , Adulto , Idoso , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente/estatística & dados numéricos , Assistentes Médicos/estatística & dados numéricos , Médicos de Atenção Primária/estatística & dados numéricos , Neoplasias Cutâneas/cirurgia , Cirurgia Plástica/estatística & dados numéricos , Estados UnidosRESUMO
PURPOSE: Surgical resection of the primary tumour in patients with advanced colorectal cancer (crc) remains controversial. This review compares survival in patients with advanced crc who underwent surgical resection of the primary tumour with that in patients not undergoing resection, and determines rates of post-operative mortality and nonfatal complications, the primary tumour complication rate, the non-resection surgical procedures rate, and quality of life (qol). METHODS: Reports in the central, medline, and embase databases were searched for relevant studies, which were selected using pre-specified eligibility criteria. The search was also restricted to publication dates from 1980 onward, the English language, and studies involving human subjects. Screening, evaluation of relevant articles, and data abstraction were performed in duplicate, and agreement between the abstractors was assessed. Articles that met the inclusion criteria were assessed for quality using the Newcastle-Ottawa Scale. Data were collected and synthesized per protocol. RESULTS: From among the 3379 reports located, fifteen retrospective observational studies were selected. Of the 12,416 patients in the selected studies, 8620 (69%) underwent surgery. Median survival was 15.2 months (range: 10-30.7 months) in the resection group and 11.4 months (range: 3-22 months) in the non-resection group. Hazard ratio for survival was 0.69 [95% confidence interval (ci): 0.61 to 0.79] favouring surgical resection. Mean rates of postoperative mortality and nonfatal complications were 4.9% (95% ci: 0% to 9.7%) and 25.9% (95%ci: 20.1% to 31.6%) respectively. The mean primary tumour complication rate was 29.7% (95% ci: 18.5% to 41.0%), and the non-resection surgical procedures rate in the non-resection group was 27.6% (95 ci: 15.4% to 39.9%). No study provided qol data. CONCLUSIONS: Although this review supports primary tumour resection in advanced crc, the results have significant biases. Randomized trials are warranted to confirm the findings.
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With the advent of genetic and epigenetic research, molecular techniques could someday be used to discriminate nevus from melanoma so that ambiguous melanocytic lesions could be more accurately classified or that prognostication could be improved in melanoma patients. That promised day might be closer than realized. The last 20 years of research in cytogenetic and genetic alterations in melanoma have culminated in defined chromosomal lesions discriminating benign from malignant melanocytic tumors. Exploiting these differences, fluorescence in situ hybridization (FISH) can reproducibly discriminate unequivocal melanomas from melanocytic nevi with high sensitivity and specificity. The discriminating power of FISH in melanocytic tumors with ambiguous histopathology is questionable, however, because there is no standard definition of "malignancy." Additional FISH studies on ambiguous cases are needed through international collaborations where large collections of such cases are shared and the "proof of malignancy" is established by adequate clinical follow-up. This contribution reviews the diagnostic utility of DNA-based FISH technology as it compares the diagnostic accuracy in melanocytic tumors with unambiguous vs ambiguous histopathology. The melanoma epigenome is further characterized through research into various activities of small interfering RNAs, such as microRNAs, providing the pathway for the application of microRNA-based strategies that could be the basis for future diagnostic biomarkers and molecular therapies in melanoma.
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Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Aberrações Cromossômicas , DNA de Neoplasias/genética , Epigenômica , Humanos , Hibridização in Situ Fluorescente/métodos , Melanoma/genética , Prognóstico , Sensibilidade e Especificidade , Neoplasias Cutâneas/genéticaRESUMO
The management of non-melanoma skin cancers (NMSCs) in solid organ transplant recipients (OTRs) presents a variety of clinical challenges for physicians. OTRs are at a 65-fold increased risk for developing cutaneous squamous cell carcinomas (SCC), the most common NMSC that develops after transplantation. Risk factors contributing to the development of NMSCs in OTRs include a past medical history of any previous skin cancer, a personal history of significant sun exposure and a fair skin complexion or phototype. Further, greater immunosuppressive medication levels lead to an increased risk of NMSCs. Among immunosuppressants, specific older agents such as azathioprine and cyclosporine may increase the risk of developing NMSCs in contrast to newer agents such as sirolimus. Early skin biopsy and treatment of premalignant and malignant lesions are essential for treating these patients successfully. In this regard, the concept of field cancerization has been instructive in broadening treatments to include entire affected areas rather than individual lesions given that the areas with significant ultraviolet irradiation will continue to develop numerous individual precancerous and cancerous lesions. Field therapy with photodynamic therapy or topical 5-fluorouracil, imiquimod or diclofenac is often used in OTRs according to individual patient tolerability. Prompt excision or Mohs micrographic surgery is the standard of care of primary, uncomplicated squamous cell and basal cell carcinomas. For patients with in-transit or metastatic squamous cell carcinomas, adjuvant radiation, chemotherapy, and staging by sentinel lymph node dissection may be employed. For patients who develop numerous SCC per year, chemoprophylaxis can be effective in limiting the burden of disease. In consultation with the multidisciplinary transplant team, the immunosuppressive regimen can be revised to lower overall immunosuppression or altered to include newer drugs that have decreased oncogenic potential in OTRs. The greatest impact may be made by the prevention of NMSCs through simple, but rigorous, patient education on the benefits of UV protection, periodic self-skin examinations, and regular follow-ups. Accordingly, vitamin D and calcium supplementation should also be incorporated in transplant recipients. Management of OTRs requires patient education, frequent motivation for vigilance, regular follow-up, and interdisciplinary collaboration between transplant surgeons, nephrologists, hepatologists, cardiologists, transplant nurses, dermatologists, oncologists, pharmacists, and other relevant physicians ideally orchestrated by the essential transplant coordinators.
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Hospedeiro Imunocomprometido/imunologia , Transplante de Órgãos/efeitos adversos , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/terapia , Antineoplásicos/uso terapêutico , Terapia Combinada , Humanos , Estilo de Vida , Neoplasias Cutâneas/patologia , Fator de Proteção SolarAssuntos
Germinoma/terapia , Púrpura Trombocitopênica Idiopática/etiologia , Transplante de Células-Tronco/efeitos adversos , Transplante Autólogo/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Germinoma/tratamento farmacológico , Germinoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Esplenectomia , Resultado do TratamentoRESUMO
AIM: A randomised, controlled clinical trial was initiated in 1984 to test whether 1 cycle of anthracycline-containing adjuvant chemotherapy improves the outcome of breast cancer patients presenting with stage II disease and negative oestrogen and progesterone receptors (ER, PgR), as compared with 6 cycles of dose-reduced CMF. PATIENTS AND METHODS: Within 7 years 263 women with stage II breast cancer were randomised either to receive 1 cycle of doxorubicin, vinblastine, cyclophosphamide, methotrexate and 5- fluorouracil (AV-CMF) or to receive 6 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Patients were stratified for tumour stage, nodal stage, menopausal status, type of surgery and participating centre. RESULTS: After a median follow-up of 100 months, neither disease-free (DFS) nor overall survival (OS) differed significantly between the two groups. CONCLUSIONS: Compared to 6 cycles of a non-standard low-dose CMF regimen 1 cycle of anthracycline- containing adjuvant chemotherapy failed to improve the outcome in women with stage II receptor-negative breast cancer in terms of DFS and OS.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/mortalidade , Carcinoma Lobular/patologia , Quimioterapia Adjuvante , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Terapia Combinada , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Esquema de Medicação , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Metástase Linfática , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Taxa de Sobrevida , Vincristina/efeitos adversos , Vincristina/uso terapêuticoRESUMO
There is no established second-line treatment for advanced pancreatic cancer after gemcitabine failure. In view of the urgent need for such therapy, and since preclinical and phase I clinical data suggest an encouraging, potentially synergistic activity between raltitrexed and irinotecan, the present randomised phase II study was initiated. A total of 38 patients with metastatic pancreatic adenocarcinoma, who progressed while receiving or within 6 months after discontinuation of palliative first-line chemotherapy with gemcitabine, were enrolled in this study. They were randomised to 3-weekly courses of raltitrexed 3 mg x m(-2) on day 1 (arm A) or irinotecan 200 mg x m(-2) on day 1 plus raltitrexed 3 mg x m(-2) on day 2 (arm B). The primary study end point was objective response, secondary end points included progression-free survival (PFS) and overall survival (OS), as well as clinical benefit response in symptomatic patients (n=28). In the combination arm, the IRC-confirmed objective response rate was 16% (three out of 19 patients had a partial remission; 95% CI, 3-40%), which was clearly superior to that in the comparator/control arm with raltitrexed alone, in which no response was obtained. Therefore, the trial was already stopped at the first stage of accrual. Also, the secondary study end points, median PFS (2.5 vs 4.0 months), OS (4.3 vs 6.5 months), and clinical benefit response (8 vs 29%) were superior in the combination arm. The objective and subjective benefits of raltitrexed+irinotecan were not negated by severe, clinically relevant treatment-related toxicities: gastrointestinal symptoms (42 vs 68%), partial alopecia (0 vs 42%), and cholinergic syndrome (0 vs 21%) were more commonly noted in arm B; however, grade 3 adverse events occurred in only three patients in both treatment groups. Our data indicate that combined raltitrexed+irinotecan seems to be an effective salvage regimen in patients with gemcitabine-pretreated pancreatic cancer. The superior response activity, PFS and OS (when compared to raltitrexed), as well as its tolerability and ease of administration suggest that future trials with this combination are warranted.
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Adenocarcinoma/tratamento farmacológico , Antineoplásicos/toxicidade , Camptotecina/análogos & derivados , Camptotecina/toxicidade , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Quinazolinas/toxicidade , Tiofenos/toxicidade , Adenocarcinoma/mortalidade , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/toxicidade , Antineoplásicos/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêutico , Análise de Sobrevida , Tiofenos/administração & dosagem , Tiofenos/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Gemcitabine is an active antitumor agent in the treatment of advanced pancreatic cancer, and has shown potential synergistic activity with the oral fluoropyrimidine capecitabine in previous phase I/II trials. Based on this background and in order to define the therapeutic potential and tolerance of this combination more precisely, the present randomized multicenter phase II trial was initiated. PATIENTS AND METHODS: We prospectively randomized 83 patients to treatment with biweekly gemcitabine 2,200 mg/m(2) given as a 30 min intravenous infusion on day 1, or the same treatment plus oral capecitabine 2,500 mg/m(2) given from days 1 to 7. In both arms, chemotherapy was administered for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of the two treatment arms was evaluated according to standard criteria, i.e. objective response, progression-free survival (PFS) and overall survival (OS), as well as by analysis of clinical benefit response. RESULTS: The overall objective response rate among the 42 patients treated with gemcitabine alone was 14% compared with 7/41 (17%) among those treated with the combination arm. Similar to response rates, there was no apparent difference between the two groups in terms of median PFS (4.0 versus 5.1 months) and median OS (8.2 versus 9.5 months) in the gemcitabine and combination arm, respectively. Of 61 patients with tumor-related symptoms, who were considered evaluable for clinical benefit response, 10/30 (33%) and 15/31 (48.4%) experienced significant palliation in the gemcitabine and combination arm, respectively. Chemotherapy was well tolerated in both arms with only four versus six patients experiencing WHO grade 3 symptoms. Apart from the occurrence of hand-foot syndrome in 10 patients, no major increase in incidence and/or degree of adverse reactions was noted in the combination arm. CONCLUSIONS: Results of this trial suggest a fairly good therapeutic index for the combination of biweekly high-dose gemcitabine and capecitabine for the treatment of advanced pancreatic cancer. Despite a somewhat superior clinical benefit response rate, no advantage over single-agent gemcitabine, however, was noted in terms of objective efficacy parameters.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/secundário , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/secundário , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/análogos & derivados , Doença de Mão, Pé e Boca/etiologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Taxa de Sobrevida , Síndrome , Resultado do Tratamento , GencitabinaRESUMO
OBJECTIVE: Various strategies have been attempted to design efficient protocols for ovarian cancer gene therapy but there has been little progress in their clinical application. In this study, we formulated and evaluated a new cationic liposome prepared with dioleoyltrimethylaminopropane (DOTAP), 1,2-dioleoyl-3-phosphophatidylethanolamine (DOPE), and cholesterol (Chol) (DDC) for plasmid DNA transfer into ovarian cancer cells. METHOD: The DDC liposome was prepared by mixing the DOTAP:DOPE:Cholin a 1:0.7:0.3 molar ratio using the extrusion method. Plasmid DNA (pEGFP-C1) and DDC were complexed at various weight ratios to find the optimum condition and the percentage of transfected cells was determined by selecting a green fluorescence protein (GFP) expressing cells in flow cytometry. The transfection efficiency of the DDC liposome was compared with 3[N-(N,N-dimethylaminoethylene) carbamoyl] cholesterol (DC-Chol)/DOPE liposome and commercially available lifopectin. RESULTS: The optimal transfection of plasmid DNA was achieved at a 1:4 (w/w) ratio of DDC to DNA. The DDC/DNA complex exhibited higher transfection efficiency in human ovarian cancer cells (OVCAR-3 and SK-OV-3 cells) compared to that in other types of cell lines (NCI-NIH:522 and HepG2 cells). Flow cytometric analysis revealed that the DDC/DNA complex exhibited an over fourfold increase in GFP expression levels compared with DC-Chol/DOPE or lipofectin in OVCAR-3 cells. This result was further confirmed by confocal microscopy and RT-PCR analysis. CONCLUSION: These results suggest that our newly formulated cationic liposome (DDC) appears to be a promising nonviral vector for treating ovarian adenocarcinoma because of its selective high gene transfer ability in ovarian cancer cells.
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Adenocarcinoma/genética , DNA/administração & dosagem , Terapia Genética/métodos , Vetores Genéticos/farmacocinética , Lipídeos/farmacocinética , Neoplasias Ovarianas/genética , Fosfatidiletanolaminas , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Cátions , Colesterol/química , Colesterol/farmacocinética , DNA/genética , Ácidos Graxos Monoinsaturados/química , Ácidos Graxos Monoinsaturados/farmacocinética , Feminino , Vetores Genéticos/química , Glicerofosfolipídeos/química , Glicerofosfolipídeos/farmacocinética , Proteínas de Fluorescência Verde , Humanos , Lipídeos/química , Lipossomos , Proteínas Luminescentes/biossíntese , Proteínas Luminescentes/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacocinética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Células Tumorais CultivadasRESUMO
A 53-year-old African-American man with relapsed non-Hodgkin's lymphoma developed seizures and respiratory arrest 2 hours after an infusion of high-dose etoposide in preparation for an autologous bone marrow transplant. Laboratory tests revealed both rapid hemolysis and severe metabolic acidosis. The patient died the following day. Based on toxicities observed, we suspect that our patient possessed an ethnic polymorphism of the enzyme alcohol dehydrogenase. Further research is required to determine the relationship between the benzyl alcohol metabolic rate and toxicity and genetic polymorphisms of alcohol dehydrogenase in African-Americans.
Assuntos
Acidose/induzido quimicamente , Álcool Benzílico/efeitos adversos , Etoposídeo/efeitos adversos , Hemólise , Linfoma não Hodgkin/tratamento farmacológico , Insuficiência Respiratória/induzido quimicamente , Convulsões/induzido quimicamente , África/etnologia , Álcool Desidrogenase/genética , Álcool Benzílico/administração & dosagem , Combinação de Medicamentos , Evolução Fatal , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genéticaRESUMO
BACKGROUND: Oxaliplatin and raltitrexed both are active anticancer agents in the treatment of patients with advanced colorectal carcinoma: They have different mechanisms of action and toxicity profiles and have shown at least additive effects in experimental and preliminary clinical studies. The aim of this disease oriented Phase I-II study was to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLT), and the objective response rate of this combination in patients with advanced colorectal carcinoma. METHODS: Between April 1998 and March 1999, 69 patients with measurable metastatic colorectal carcinoma who previously were unexposed to palliative chemotherapy were enrolled. In the Phase I part of the study, 27 patients were treated with 3-weekly courses of a fixed dose of raltitrexed (3 mg/m(2) given as a 15-minute intravenous infusion) followed by a 2-hour infusion of oxaliplatin, which was escalated in consecutive cohorts of three to six patients from 85 mg/m(2) to 100 mg/m(2), 120 mg/m(2), 130 mg/m(2), and 140 mg/m(2). After having defined the toxic dose, 42 additional patients were entered at one dose level below to define the therapeutic index of this combination more precisely. RESULTS: In the Phase I part of the study, during the first three dose levels, only one patient each experienced DLT (Grade 3 increase in transaminases, diarrhea, and stomatitis); at level 4, two of the first six patients entered had Grade 3 neutropenic infection or peripheral neurotoxicity, whereas dose level 5 (oxaliplatin 140 mg/m(2)) constituted the toxic dose with three of three patients experiencing DLT (Grade 3 asthenia, transient amaurosis, and diarrhea with Grade 4 neutropenia). Externally reviewed objective responses were noted in 9 of these 27 patients (33%), and stable disease occurred in 12 patients (44.4%). Among the 42 patients who were treated subsequently at the MTD level (Phase II portion), 20 patients (47.6%) responded (95% confidence interval, 32-62.6%), and 21 patients (50%) had stable disease. Their median progression free survival was 9.0 months, and the median overall survival, with 42 patients (67%) currently alive, is > 14.5 months. Treatment tolerance at the MTD was acceptable, with only 9 of 42 patients (21%) experiencing Grade 3-4 neutropenia; Grade 3 nonhematologic adverse reactions included increase in serum transaminases in 6 patients, peripheral neuropathy in 3 patients, diarrhea in 3 patients, and both stomatitis and emesis in only 1 patient each. CONCLUSIONS: The described objective response and toxicity data, which are in agreement with preliminary results of other Phase I-II studies, support the promising therapeutic potential of this combination in the treatment of patients with advanced colorectal carcinoma. Due to its substantial antitumor activity, tolerance (at the recommended MTD level), and convenient 3-weekly outpatient administration schedule, further evaluation of this regimen seems warranted.