RESUMEN
BACKGROUND: HIPEC is a new treatment modality for abdominal cancers that combines cytoreductive surgery with Hyperthermic, Intraoperative Peritoneal Chemotherapy, followed by systemic chemotherapy. A significant survival benefit has been shown for HIPEC compared with systemic therapy alone. However, it is not clear what is the contribution of i.p. drug delivery and what influence the mild hyperthermia has on the uptake of cisplatin in abdominal tumors. MATERIALS AND METHODS: We used a peritoneal perfusion system in rats to compare the pharmacokinetics and pharmacodynamics of cisplatin, after normothermic (37 degrees C/90 minutes) and hyperthermic (40 degrees C/90 minutes) intra-peritoneal perfusion, with an i.p. bolus injection. RESULTS: Hyperthermic perfusion with 15 micrograms/ml (in 200 ml) cisplatin gave equivalent plasma drug levels to a maximum tolerated dose (MTD) i.p. bolus injection of 4 mg/kg (36 micrograms/ml in 20 ml). The drug concentration in small (1-5 mm) intra-peritoneal tumors was also comparable for both these treatments, and for normothermic perfusion. CONCLUSION: Mild hyperthermic perfusion with cisplatin (40 degrees C/90 minutes) did not improve drug uptake in small intra-peritoneal tumors, relative to normothermic perfusion or i.p. bolus injection.
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Antineoplásicos/farmacología , Cisplatino/farmacología , Hipertermia Inducida , Neoplasias Peritoneales/terapia , Absorción , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Cisplatino/administración & dosificación , Cisplatino/sangre , Cisplatino/farmacocinética , Cisplatino/uso terapéutico , Neoplasias del Colon/patología , Terapia Combinada , Femenino , Infusiones Parenterales , Inyecciones Intraperitoneales , Periodo Intraoperatorio , Riñón/metabolismo , Hígado/metabolismo , Dosis Máxima Tolerada , Trasplante de Neoplasias , Perfusión , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/secundario , Peritoneo/metabolismo , Ratas , Distribución TisularRESUMEN
The in vivo pharmacokinetics of protoporphyrin IX (PpIX) after administration of 5-aminolevulinic acid (ALA) cannot be described accurately by mathematical models using first-order rate processes. We have replaced first-order reaction rates by dose-dependent (Michaelis-Menten [MM]) reaction rates in a mathematical compartment model. Different combinations of first-order and dose-dependent reaction rates were evaluated to see which one would improve the goodness-of-fit to experimentally determined in vivo PpIX fluorescence kinetics as a function of concentration. The mathematical models that were evaluated are all based on a three-compartment model for drug distribution, conversion to PpIX and subsequent conversion to heme. Implementation of dose-dependent reaction rates improved the goodness-of-fit and enabled interpolation to other drug doses. For most data sets the time constant for delivery to the target cells turned out to be dose dependent. For all data sets the use of MM rates for the conversion of ALA to PpIX yielded better fits. The clearance of PpIX turned out to be a first-order process for all doses and types of administration. Fluorescence curves measured on a specific tissue type but obtained in different studies with different measurement techniques could be described with a single set of parameters.
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Protoporfirinas/farmacocinética , Ácido Aminolevulínico/administración & dosificación , Ácido Aminolevulínico/farmacocinética , Animales , Relación Dosis-Respuesta a Droga , Fluorescencia , Cinética , Matemática , Ratones , Modelos Biológicos , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacocinética , Piel/efectos de los fármacos , Piel/metabolismoRESUMEN
Human papillomavirus (HPV) infections play an important role in the development of cervical neoplasia. To get to a better understanding of the role of cytokines in the development of these neoplasias, we analysed the presence of various cytokines in cervicovaginal washings of healthy volunteers (n=22), cervical intraepithelial neoplasia (CIN) patients (n=63) and cervical cancer patients (n=33). IL-12p40, IL-10, TGF-beta1, TNF-alpha and IL-1beta levels were significantly higher in patients with cervical cancer than in controls and CIN patients. The levels of IFN-gamma were not different. Our data demonstrate alterations in the local cervical immune environment in cervical cancer patients. This could have important consequences for the further development of immune modulating therapies and vaccination strategies.
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Cuello del Útero/metabolismo , Citocinas/biosíntesis , Neoplasias del Cuello Uterino/metabolismo , Vagina/metabolismo , Adulto , Estudios de Casos y Controles , Cuello del Útero/virología , Citocinas/metabolismo , Femenino , Humanos , Interferón gamma/biosíntesis , Interleucina-1/biosíntesis , Interleucina-10/biosíntesis , Interleucina-12/biosíntesis , Persona de Mediana Edad , Papillomaviridae/metabolismo , Factor de Crecimiento Transformador beta/biosíntesis , Factor de Crecimiento Transformador beta1 , Factor de Necrosis Tumoral alfa/biosíntesis , Neoplasias del Cuello Uterino/virología , Vagina/virologíaRESUMEN
Human papillomavirus (HPV) infections are known to play an important role in the pathogenesis of cervical neoplasia. Considering the morbidity and mortality of cervical cancer, infection with HPV can be regarded as a worldwide problem, especially in developing countries. Currently, many studies focus on the development of both prophylactic and therapeutic HPV vaccines. Crucial for these vaccination protocols to be successful is that they will result in a long-lasting ability to generate an immune response that will eliminate the virus. HPV transmission and subsequent infection is a local event in the lower female genital tract and therefore the efficacy of vaccines against this locally transmitted infection can be best assessed by parameters of local immunity. In this review we describe both the epidemiology of HPV-related cervical neoplasia and the general aspects of mucosal immunity in the female genital tract while focusing on the local humoral immunity in HPV-related cervical neoplasia.
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Países en Desarrollo , Papillomaviridae/patogenicidad , Infecciones por Papillomavirus/complicaciones , Infecciones Tumorales por Virus/complicaciones , Sistema Urogenital/inmunología , Sistema Urogenital/virología , Neoplasias del Cuello Uterino/virología , Transmisión de Enfermedad Infecciosa , Femenino , Humanos , Incidencia , Membrana Mucosa/inmunología , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/inmunología , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/inmunología , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/inmunología , Vacunas ViralesRESUMEN
Between March and September 1988, 74 patients with progressive ovarian cancer after prior platinum-based therapy were treated with the luteinizing hormone-releasing hormone (LHRH) agonist Triptorelin (Decapeptyl degrees). Treatment consisted of i.m. injection of 3.75 mg of microencapsulated Triptorelin on days 1, 8 and 28 followed by 4-weekly injections until tumor progression. No objective responses were observed. Eleven out of 68 evaluable patients (16%) had stable disease. The median progression-free survival was 5 months in patients with disease stabilization and 2 months for all evaluable patients. The median survival for patients with disease stabilization was 17 months, whereas for all patients it was 4 months. The treatment was well tolerated; the only reported adverse events were incidental hot flushes. This study showed that the LHRH agonist Triptorelin has only modest efficacy in patients pretreated with platinum-containing chemotherapy.
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Antineoplásicos Hormonales/uso terapéutico , Carcinoma/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Pamoato de Triptorelina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/mortalidad , Evaluación de Medicamentos , Resistencia a Medicamentos , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Compuestos de Platino/uso terapéutico , Terapia Recuperativa , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Serum antibodies against the E6 and E7 proteins of human papillomavirus (HPV) 16 and 18 are associated with cervical cancer. The aim of this study was to investigate the presence of local antibodies against HPV in cervicovaginal washings (CWs). In this study antibodies against the native HPV16 and HPV18 E6/E7 proteins were detectable in CWs (48%) and sera (29%) from patients with cervical cancer (n = 21) utilizing a sandwich protein enzyme-linked immunosorbent assay (ELISA). In paired CWs and sera from patients with cervical intraepithelial neoplasia (n = 38) and from healthy women (n = 22) no antibodies against these proteins were found. In 10 of 11 patients, the antibody response corresponded with the HPV type in the cervical smear and/or tumor tissue, which indicates the HPV type specificity of the assay. In 7 of 11 patients with antibody reactivity against HPV16 or HPV18 E6 and/or E7 proteins a higher level of antibody reactivity in the CWs than in the paired serum samples was found at similar inputs of total IgG. This suggests that the antibodies in the CWs against the investigated HPV proteins in these patients were locally produced.
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Anticuerpos Antivirales/análisis , Proteínas de Unión al ADN , Proteínas Oncogénicas Virales/inmunología , Proteínas Represoras , Displasia del Cuello del Útero/inmunología , Neoplasias del Cuello Uterino/inmunología , Anticuerpos Antivirales/sangre , Moco del Cuello Uterino/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Proteínas E7 de Papillomavirus , Neoplasias del Cuello Uterino/sangre , Excreción Vaginal/inmunología , Displasia del Cuello del Útero/sangreRESUMEN
AIMS: The feasibility, morbidity and toxicity of an intensified surgical treatment strategy consisting of aggressive cytoreductive surgery, intra-operative intraperitoneal perfusion of cisplatin and hyperthermia were evaluated in women with recurrent ovarian cancer. METHODS: Five heavily pre-treated patients with extensive abdominal tumour bulk entered this pilot study. In all cases aggressive cytoreduction leaving tumour remnants <5 mm in diameter could be performed. This was followed intra-operatively by perfusion of the abdominal cavity with hyperthermic cisplatin 50-70 mg/m(2)for 90 min. During perfusion the intra-abdominal temperature was maintained at 40 degrees C. The median duration of surgery was 10 hours (range 9-11 hours). RESULTS: No major intra- or post-operative complications emerged. Median post-operative ileus (resuming of soft diet) was 11 days (9-13 days). The mean period of hospitalization was 25 days (range 17-42). Toxicity due to i.p. cisplatin was mainly metabolic and of grade 1-2, while no nephrotoxicity was observed. The pharmacokinetics of cisplatin indicated that the maximum concentration of cisplatin measured in the perfusate was 15 times higher than in plasma. CONCLUSIONS: We conclude that aggressive cytoreduction combined with hyperthermic intra-operative intraperitoneal cisplatin was feasible in a small group of heavily pre-treated ovarian cancer patients with extensive tumour bulk with acceptable morbidity and toxicity. Further studies are required in larger groups of patients to further establish the feasibility of this intensified treatment strategy. We stress that OVHIPEC is not a treatment modality on its own for advanced ovarian cancer. The effectiveness of OVHIPEC is likely to be dependent on the effectiveness of post-operative adjuvant chemotherapeutic regimens.
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Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Hipertermia Inducida , Recurrencia Local de Neoplasia/terapia , Neoplasias Ováricas/terapia , Abdomen , Adulto , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Hipertermia Inducida/efectos adversos , Hipertermia Inducida/métodos , Infusiones Parenterales , Cuidados Intraoperatorios , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Perfusión , Proyectos PilotoRESUMEN
In 75% of cases, ovarian carcinoma has already metastasized in the abdominal cavity at the time of diagnosis. For determination of the necessity for a supplementary therapy, in addition to surgical resection, it is important to localize and stage microscopical intraperitoneal metastases of the tumor. Intraperitoneal photodetection of tumor metastases is based on preferential tumor distribution of a fluorescent tumor marker. The time-dependent differences in drug concentration between tumor and normal (T/N) tissues can be used to visualize small tumors. We performed fluorescence measurements on abdominal organs and tumor in the peritoneal cavity of rats. 5-Aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) was used as the fluorescent marker. Three different drug doses (100, 25 and 5 mg/kg) were used and PpIX fluorescence profiles were followed up to 24 h after intravenous administration. Maximum T/N ratios were found 2-3 h after administration of ALA with all drug doses. A significant T/N tissue contrast was obtained for all abdominal organs tested after administration of 5 mg/kg.
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Colorantes Fluorescentes/farmacocinética , Mesalamina/farmacocinética , Neoplasias Peritoneales/metabolismo , Protoporfirinas/farmacocinética , Animales , Relación Dosis-Respuesta a Droga , Femenino , Trasplante de Neoplasias , Neoplasias Peritoneales/diagnóstico , Neoplasias Peritoneales/secundario , Ratas , Ratas Wistar , Espectrometría de Fluorescencia , Distribución TisularRESUMEN
Little information is available about the cervicovaginal mucosal antibodies against human papillomavirus (HPV) proteins. In this study specific IgG antibodies against HPV 16 E7 protein were determined in paired samples of cervicovaginal washing fluid and serum from patients with cervical cancer (n = 22), cervical intraepithelial neoplasia (CIN) (n = 38), healthy individuals (n = 22), and serum from children (n = 41) by a radioactive immunoprecipitation assay (RIPA). HPV 16 E7 specific IgG antibodies were found in cervicovaginal washings (n = 8) and in sera (n = 8) of the patients with cervical cancer. About 60% of the patients with HPV 16 positive cervical cancer had HPV 16 E7 specific IgG antibodies. Titration studies showed that the IgG antibody reactivity in cervicovaginal washings was higher than in the paired serum samples of six patients with cervical cancer (P < 0.001). In the CIN group we found no IgG reactivity in the serum, but in five patients we found a low IgG reactivity in the cervicovaginal washings. No IgG reactivity was found in cervicovaginal washings and sera from healthy individuals and sera from children. HPV 16 E7 specific IgG antibodies seem to be locally produced in a number of patients with HPV 16 positive (pre)malignant cervical lesions. For more definitive evidence for the local production of these antibodies immunostaining should be performed to demonstrate the presence of specific anti-HPV 16 E7 IgG producing plasma cells in the cervical epithelium.
RESUMEN
OBJECTIVE: To apply (HIPEC) using mitomycin in patients with peritoneal carcinomatosis. DESIGN: Descriptive. METHOD: The HIPEC treatment includes cytoreductive surgery and subsequent peritoneal lavage with exposure of the superficial tumour residues to a high concentration of a cytostatic drug at an intra-abdominal temperature of 40-42 degrees C. The HIPEC treatment was given to 24 patients with pseudomyxoma peritonei and to 29 patients with peritoneal carcinomatosis of colorectal origin. The adequate dose of mitomycin was determined in the Netherlands Cancer Institute in 26 patients: doses of 15 mg/m2 (n = 8), 25 mg/m2 (n = 3), 35 mg/m2 (n = 7) and 40 mg/m2 (n = 8) were administered. RESULTS: The maximal tolerable dose of mitomycin appeared to be 35 mg/m2, while unacceptable toxicity was recorded at a dose of 40 mg/m2. Therefore 35 mg/m2 was used in subsequent cases. Among the patients with pseudomyxoma peritonei 8 developed severe complications, two of which were fatal. After a median follow-up of 12 months, 21 patients were alive of whom 18 were free of disease. Among the patients with peritoneal carcinomatosis of colorectal origin one patient died from a treatment-related complication. After a median follow-up of 18 months, 18 patients were alive of whom 11 were free of disease. The actuarial 2 year survival was 59%. CONCLUSION: In the Netherlands Cancer Institute HIPEC treatment is considered the treatment of choice for pseudomyxoma peritonei. The results in cases of peritoneal carcinomatosis of colorectal origin are promising, but the results of a randomized trial are awaited.
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Antibióticos Antineoplásicos/administración & dosificación , Carcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Hipertermia Inducida , Mitomicina/administración & dosificación , Neoplasias Peritoneales/tratamiento farmacológico , Seudomixoma Peritoneal/tratamiento farmacológico , Antibióticos Antineoplásicos/uso terapéutico , Carcinoma/secundario , Carcinoma/cirugía , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Mitomicina/uso terapéutico , Países Bajos , Lavado Peritoneal , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/cirugía , Seudomixoma Peritoneal/cirugía , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The aim of this study was to assess the expression of cytokine transcripts, reflecting the type of ongoing immune responses at the site of human papillomavirus (HPV) infection, in relation to the development of cervical neoplasia. To this end reverse transcription-polymerase chain reaction (RT-PCR) was performed for interferon (IFN) gamma, interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12 (p35 and p40), and transforming growth factor (TGF beta 1) in snap-frozen cervical biopsies, which were tested for the presence of high risk HPV DNA and histologically classified from normal to invasive carcinoma (n = 40). IFN gamma, IL-10 and IL-12 (p35 and p40) transcripts were found to be expressed at significantly lower frequencies in invasive carcinoma as compared with premalignant biopsies (P = 0.006, P = 0.007 and P = 0.002, respectively). IFN gamma IL-10 mRNA were associated with the presence of the IL-12 p35 and p40 transcripts (P = 0.008 and P < 0.00001, respectively). These results are consistent with a locally reduced cellular (type 1) immunity correlating with HPV-induced invasive cervical carcinoma.
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Citocinas/metabolismo , Proteínas de Neoplasias/metabolismo , Lesiones Precancerosas/metabolismo , ARN Mensajero/metabolismo , Displasia del Cuello del Útero/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Adulto , Citocinas/genética , Femenino , Humanos , Inmunohistoquímica , Proteínas de Neoplasias/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
OBJECTIVE: Conflicting data exist on IL-6 production by human papillomavirus (HPV) immortalized cell lines and several cervical carcinoma cell lines. However, no information has been reported on the levels of cytokines in cervicovaginal washings in relation to cervical neoplasia. The aim of this study was to investigate whether local production of IL-6 could be found and whether the level of this cytokine was related to the severity of cervical neoplasia. IL-8 was measured to obtain additional information on an inflammatory cytokine with possible epithelial origin. METHODS: Cervicovaginal washings and sera were obtained from 35 patients with invasive cervical cancer, 62 patients with cervical intraepithelial neoplasia (CIN), and 25 control subjects. IL-6 and IL-8 levels were determined by ELISA. HPV DNA in cervical smears was detected by a HPV-16-specific PCR method and additionally by CPI/IIG PCR. Histological analysis of the inflammatory infiltrate was performed on hematoxylin-eosin-stained tissue sections. RESULTS: In the patients with cervical cancer, those with CIN, and the controls, the median IL-6 concentration in cervicovaginal washings was 171 pg/ml (interquartile range: 54-780), 22 pg/ml (<2-73), and < 2 pg/ml (<2-<2), respectively. For IL-8, the levels were 2756 pg/ml (1651-7107), 489 pg/ml (248-1158), and 631 pg/ml (346-897), respectively. In most subjects the local levels were much higher than in serum. Local IL-6 and IL-8 levels were significantly higher in patients with cervical carcinoma compared with CIN patients and controls. Likewise, local IL-6 levels were increased in patients with CIN compared with controls. No relation was found between cytokine levels and CIN grade or between cytokine levels and the inflammatory infiltrate scored by histological analysis. CONCLUSIONS: There is local production of IL-6 and IL-8 in cervicovaginal secretions, and the production of IL-6 was related to the severity of cervical neoplasia.
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Carcinoma/metabolismo , Moco del Cuello Uterino/química , Interleucina-6/análisis , Interleucina-8/análisis , Neoplasias del Cuello Uterino/metabolismo , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Vagina/metabolismoRESUMEN
PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recuento de Células Sanguíneas , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Fatiga/inducido químicamente , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Náusea/inducido químicamente , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Trombocitopenia/inducido químicamente , Topotecan/administración & dosificación , Topotecan/farmacocinéticaRESUMEN
The purpose of this study was to investigate the influence of hyperthermia on cisplatin pharmacokinetics and DNA adduct formation. The latter was investigated both in tumour cell lines in vitro and in tumour cells and buccal cells from cancer patients. The patients had advanced ovarian carcinoma and were entered into a phase I study for cytoreductive surgery followed by hyperthermia in combination with intraperitoneal cisplatin administration. The cisplatin-DNA modifications in vivo and in vitro were studied by an immunocytochemical method with the polyclonal antiserum NKI-A59. The patient samples for pharmacokinetic determinations were analysed by flameless atomic absorption spectrometry. In vitro, the combination of hyperthermia and cisplatin enhanced cell killing compared with either treatment alone, such that the cisplatin-resistant ovarian cell line A2780/DDP became almost as sensitive as the parent A2780 cell line (resistance factor reduced from 30 to 2 at the IC50). In addition, increased cisplatin-DNA adducts were observed in the resistant cell line after the combined treatment compared with cisplatin alone. A good correlation was found between nuclear staining density and surviving fraction for all groups, indicating that the DNA adducts generated are an important determinant of toxicity and that the mechanism by which hyperthermia enhances kill is by increasing adduct levels. In the patients, the ratio of drug concentration in the peritoneal perfusate compared with that in plasma was found to be approximately 15, indicating a favourable pharmacokinetic ratio. Cisplatin-DNA adduct formation in tumour cells from patients was higher than in buccal cells, reflecting this higher drug exposure, i.e. local plus systemic versus systemic only. In addition, the tumour cells but not buccal cells were exposed to hyperthermia. The higher number of tumour adducts also suggests that a favourable therapeutic ratio could be achieved. Platinum-DNA adduct formation was found to decrease with distance from the surface of the tumour nodules. However, at a distance of 3-5 mm, the nuclear staining density levels were still measurable and higher than in buccal cells. In conclusion, the combined pharmacokinetic and adduct data in patients support the advantages of the intraperitoneal route for drug administration, and the addition of heat.
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Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Cisplatino/metabolismo , Aductos de ADN/metabolismo , Hipertermia Inducida/métodos , Neoplasias Ováricas/terapia , Adulto , Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Terapia Combinada , ADN de Neoplasias/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Parenterales , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Células Tumorales CultivadasRESUMEN
Human papillomavirus (HPV) DNA in vulvar intraepithelial neoplasia (VIN) is associated with multifocality of VIN III and with multicentricity of other neoplastic squamous lesions in the cervix and vagina. The aim of this study was to establish the prevalence and type of HPV DNA in the lesions of vaginal intraepithelial neoplasia (VaIN) and cervical intraepithelial neoplasia (CIN) in patients with VIN III using the polymerase chain reaction (PCR). HPV DNA detection and histologic analysis were performed on alternating sections of paraffin-embedded biopsies of concomitant CIN and VaIN in 27 patients with VIN III. PCR was performed with consensus primers and HPV typing was performed by direct sequencing of the PCR amplimers. HPV DNA was detected in all VIN III lesions (93% contained HPV-16 DNA); in 96% of the CIN lesions (73% contained HPV-16 DNA); and in all VaIN lesions (75% contained HPV-16 DNA). The HPV type was not the same in 22% of the different lesions of VIN, CIN, and VaIN, even if the biopsies were taken at the same time.
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Papillomaviridae/genética , Neoplasias de la Vulva/virología , Adulto , ADN Viral/análisis , Femenino , Humanos , Neoplasias del Cuello Uterino/complicaciones , Neoplasias del Cuello Uterino/virología , Neoplasias Vaginales/complicaciones , Neoplasias Vaginales/virología , Neoplasias de la Vulva/complicacionesRESUMEN
van Beurden M, van der Vange N, ten Kate FJW, de Craen AJM, Schilthuis MS, Lammes FB. Restricted surgical management of vulvar intraepithelial neoplasia 3: Focus on exclusion of invasion and on relief of symptoms. Int J Gynecol Cancer 1998; 8: 73-77. A study was undertaken to determine the effectiveness of extensive and restricted surgery for vulvar intraepithelial neoplasia (VIN) 3. All consecutive patients with VIN 3 admitted to a tertiary referral hospital were included. The main outcome measures were relief and recurrence of symptoms and progression to invasive disease in patients with VIN 3 after extensive or restricted surgery. Of every vulvoscopic visible lesion a biopsy was taken to establish extent and grade of VIN and to rule out invasive carcinoma. Patients with unifocal VIN 3 underwent extensive surgery. Patients with multifocal VIN 3 underwent extensive or restricted surgery or an expectant management was adopted, depending on the existence of symptoms and the presence of invasive vulvar carcinoma. Forty-seven patients were evaluated. Eighty-three percent of patients had a long history of symptoms. Eight patients (17%) had unifocal VIN 3. In 9% of the patients a superficially invasive vulvar carcinoma was found, ie with a depth of invasion of 1 mm or less. Only 20% of the extensively operated patients had free surgical margins. There was recurrence of symptoms in all of the extensively operated patients, in contrast to a 26% persistence or recurrence rate of symptoms in the restrictedly operated patients. In patients with multifocal VIN 3 who underwent restricted surgery, young age of the patient (P = 0.02) and large extension of VIN 3 (P = 0.02) were significant factors in predicting persistence or recurrence of symptoms. Only once was a superficially invasive vulvar carcinoma diagnosed during follow-up, and this was in an extensively operated patient. Vulvoscopically directed biopsies in VIN 3 are a safe method to exclude invasive disease. Restricted surgery is effective in relieving symptoms in multifocal VIN 3.
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OBJECTIVE: To determine the normal vulvar findings by naked eye examination and by vulvoscopy in healthy women without vulvar complaints. DESIGN: Observational study. POPULATION: Forty healthy volunteers without vulvar complaints recruited via a newspaper advertisement. METHODS: Vulvar examination, human papillomavirus (HPV) polymerase chain reaction of vulvar and cervical swabs, saline and KOH smears and vulvoscopy before and after the application of 5% acetic acid. MAIN OUTCOME MEASURES: Prevalence of vestibular erythema, vestibular papillomatosis, HPV infection on the vulva and in the cervix and vulvoscopic findings. RESULTS: The mean age of the women was 37.8 years (median 38.0, range 21-56). Nine women were current smokers and 21 had previously smoked. Naked eye vulvar examination showed vestibular papillomatosis in 13 women (33%) and vestibular erythema in 17 women (43%). The touch test was positive in 9 of the 17 women (53%) with vestibular erythema. Vulvoscopy after the application of acetic acid 5% showed an acetowhite vestibule in all women. Twelve women (30%) had acetowhite lesions outside the vestibule. Six women (15%) were positive for HPV DNA. The presence of HPV DNA did not correlate with vestibular erythema or vestibular papillomatosis. There was a weak association between HPV DNA and acetowhite lesions outside the vestibule (P = 0.055, Fisher's exact test). In this group the younger women significantly more often had vestibular papillomatosis (t-statistic = 3.07; P = 0.003) and women who smoke more often had a genital HPV infection (P = 0.016, Fisher's exact test). CONCLUSIONS: Vestibular erythema, vestibular papillomatosis, and acetowhite lesions are common in this group of healthy women without vulvar complaints.
Asunto(s)
Vulva/anatomía & histología , Adulto , Colposcopía , ADN Viral/análisis , Femenino , Herpes Genital/patología , Herpes Genital/virología , Humanos , Persona de Mediana Edad , Examen Físico , Glándulas Sebáceas/anatomía & histología , Simplexvirus/aislamiento & purificación , Enfermedades de la Vulva/patología , Enfermedades de la Vulva/virologíaRESUMEN
BACKGROUND: The incidence of vulvar intraepithelial neoplasia Grade III (VIN III) is increasing and is diagnosed at a younger age than previously. VIN III is often multifocal and frequently coexists with multicentric dysplastic lesions in the cervix and vagina. Warty-type VIN III more often has been found to contain human papillomavirus (HPV) DNA than basaloid-type VIN III: The authors performed HPV DNA polymerase chain reaction (PCR) analysis in 48 VIN III biopsies and reverse transcriptase (RT)-PCR in 8 HPV-16 DNA-positive multifocal VIN III biopsies to detect E6/E7 transcripts. METHODS: Human papillomavirus DNA detection and histologic analysis were performed on alternating slides of paraffin embedded biopsies. Polymerase chain reaction was performed with consensus primers, and HPV typing was performed by direct sequencing. Total RNA was isolated from frozen biopsies by centrifuging a guanidinium thiocyanate (GTC) lysate through a cesium chloride (CsCl) cushion. The RT reaction was performed using a 3' primer, located just downstream of the E7 stop codon, and the PCR reaction was performed using the same 3' primer and a 5' primer located just downstream of the E6 start codon. RESULTS: The mean age of the 48 patients was 37.7 years. Eighty-one percent had multifocal VIN III: Sixty-six percent had multicentric neoplasia. Forty-six percent of the biopsies were warty-type, 17% basaloid-type, 35% mixed-type and 2% differentiated-type. Ninety-two percent were HPV-positive and 83% contained HPV-16 DNA. Human papillomavirus DNA was more often present in multifocal VIN III lesions than in unifocal VIN III lesions and also more often in VIN III lesions coexisting with other dysplastic multicentric lesions than in unicentric VIN III lesions. Warty-type VIN III more often contained koilocytes than basaloid-type VIN III: A correlation between different morphologic forms of VIN III and the presence of HPV DNA was not found. Both types of VIN III often coexist in one lesion. In all the RT-PCRs, a 593-base-pair fragment was detected, corresponding to the expected length of the major E6*-E7 mRNA. CONCLUSIONS: The observed high prevalence of transcriptionally active HPV DNA associated with multifocal and multicentric dysplasia suggests a role of HPV in the pathogenesis of these lesions. A positive correlation between different morphologic forms of VIN III and the presence of HPV DNA was not found.
Asunto(s)
Carcinoma in Situ/virología , Papillomaviridae/aislamiento & purificación , Neoplasias del Cuello Uterino/virología , Neoplasias Vaginales/virología , Neoplasias de la Vulva/virología , Adulto , Anciano , Carcinoma in Situ/patología , ADN Viral/análisis , Femenino , Humanos , Persona de Mediana Edad , Papillomaviridae/genética , Activación Transcripcional , Neoplasias de la Vulva/patologíaRESUMEN
OBJECTIVE: To assess the effect of pregnancy on the prognosis of cervical cancer and the morbidity of standard treatment. METHODS: We analyzed 44 women with cervical carcinoma associated with pregnancy, who were matched with 44 controls. Matching criteria were age, stage of disease (according to the International Federation of Gynecology and Obstetrics classification), tumor type, treatment modality, and period of treatment. RESULTS: In 23 cases, cervical cancer was diagnosed during pregnancy and in the other 21 cases, within 6 months after delivery. Thirty-nine women had early-stage disease (eight IA, 25 IB, and six IIA), and five had advanced stages (four IIB and one IIIB). The overall 5-year survival rate was 80% among subjects and 82% among controls, whereas the relative risk (RR) of dying within 5 years was 1.12 (95% confidence interval [CI] 0.48-2.65). With regard to the 5-year survival rate (85% for both subjects and controls, the RR of dying was 1.00 [95% CI 0.35-2.83]); no differences were found between subjects and controls for early-stage cervical carcinoma. The size of the group with advanced-stage cervical carcinoma was too small to allow any statistical analysis. No statistically significant differences in survival were observed between cases diagnosed during pregnancy and cases diagnosed after delivery. In addition, the mode of delivery had no effect on survival. Early complications within 6 weeks after treatment were seen 33 times in 25 subjects and 29 times in 23 controls. No differences were observed in the prevalence and type of early complications in subjects versus controls. Late complications after 6 weeks of treatment were seen nine times in nine subjects and 11 times in ten controls. No significant differences were observed in the prevalence and type of late complications in subjects versus controls. CONCLUSION: The prognosis of early-stage cervical cancer is similar in pregnant and nonpregnant patients when standard treatment is given. Because of the limited number of patients, no conclusions can be drawn about advanced-stage cervical cancer. The goal should be standard oncologic treatment, which does not lead to increased morbidity in pregnant patients.
Asunto(s)
Complicaciones Neoplásicas del Embarazo , Neoplasias del Cuello Uterino , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Terapia Combinada , Intervalos de Confianza , Femenino , Humanos , Embarazo , Complicaciones Neoplásicas del Embarazo/mortalidad , Complicaciones Neoplásicas del Embarazo/terapia , Resultado del Embarazo , Pronóstico , Riesgo , Tasa de Supervivencia , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/terapiaRESUMEN
The experience from using different hormonal trials in 33 ovarian cancer patients, who were beyond the stage of standard therapies and experimental cytotoxic therapies in a single institution, are reported. Agents used were progestins, an antiestrogen (tamoxifen), an antiandrogen (flutamide) and a GnRH-agonist (decapeptyl). Twenty-one patients completed at least 8 weeks of treatment. Two patients obtained an objective response (10%): one partial response on tamoxifen for 6 months and one complete response on decapeptyl for 38 + months. Two further patients achieved disease stabilizations on tamoxifen and flutamide for 6 and 8 months respectively. Although the objective response rate with hormonal therapies is limited in these circumstances the absence of important toxicities favor their use. It is suggested to further study this in patients who do not reach a complete response after standard induction chemotherapy, particularly in those with well-differentiated tumors.