RESUMEN
BACKGROUND AND OBJECTIVE: Cervical intraepithelial neoplasia (CIN) is associated with genital human papillomavirus (HPV) infection and represents the precursor of cervical cancer. Established ablative treatment methods may cause substantial complications in following pregnancies including premature delivery and the birth of low-weight babies. Photodynamic therapy (PDT) of CIN using esters of 5-aminolevulinic acid (5-ALA) represents a promising alternative. However, it has not been analyzed yet if the PDT itself leads to sustained damage of the cervical tissue. This study aims at evaluating the effect of hexylaminolevulinate (HAL) and methylaminolevulinate (MAL) PDT on cervical tissue. STUDY DESIGN/MATERIALS AND METHODS: Twenty-five patients underwent 1-2 PDT cycles for CIN 1-3 applying topical HAL and MAL. Before and 6 months after PDT, biopsies were obtained from the cervix. Macroscopic changes of the cervix were evaluated. We assessed H&E slides for signs of sustained tissue damage. Furthermore, expression profiles of p16(INK4a), Ki67, Bcl-2, Bax, and CD31 were evaluated. RESULTS: PDT was performed satisfactory in all patients. No macroscopic changes of the cervix were encountered and histological evaluation revealed no signs of apoptosis, necrosis, irritation, vascular changes and fibroses 6 months after PDT. Ki67 and p16(INK4a) were useful for the prediction of response to PDT. Bcl-2 and Bax showed no significant expression profile changes after PDT and the micro-vessel pattern was not altered. CONCLUSIONS: HAL and MAL PDT do not leave any sustained damage in normal cervical tissue. This is of paramount importance as cervical insufficiency or stenosis may have implications on pregnancy and cervical cancer screening.
Asunto(s)
Ácido Aminolevulínico/análogos & derivados , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/patología , Administración Tópica , Adulto , Ácido Aminolevulínico/administración & dosificación , Biomarcadores de Tumor/metabolismo , Estudios de Cohortes , Método Doble Ciego , Epitelio/efectos de los fármacos , Epitelio/metabolismo , Epitelio/patología , Femenino , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismo , Adulto Joven , Displasia del Cuello del Útero/tratamiento farmacológico , Displasia del Cuello del Útero/metabolismoRESUMEN
OBJECTIVE: Photodynamic therapy has the potential of a minimal invasive outpatient procedure for CIN patients at reproductive ages. The purpose of this study was to examine the pharmacokinetics and selectivity of porphyrin synthesis after topical application of hexaminolevulinate (HAL) in patients with cervical intraepithelial neoplasia (CIN). STUDY DESIGN: Twenty-four women with CIN 1-3 received 4 mmol/L or 10 mmol/L HAL dissolved in thermolabile pluronic F 127 gel topically 5-720 minutes before surgical conization. The microscopic fluorescence pattern was quantified by ex vivo fluorescence spectroscopy at a wavelength of 635 nm and semiquantitatively by digital image analysis from cryosections. RESULTS: With 4 and 10 mmol/L HAL, porphyrin fluorescence intensity increased over time, reaching a peak after 180-540 minutes application intervals in CIN and normal epithelium. However, the peak was much more pronounced in CIN than in normal tissues. The fluorescence intensity with 10 mmol/L was significantly higher than that with 4 mmol/L in CIN tissues (P < .05). Maximum intensity could generally be detected in the lower layer of the epithelium. CONCLUSION: HAL seems to be a promising molecule for fluorescence diagnosis. For further treatment studies, we recommend application of 10 mmol/L HAL 300-540 minutes before photodynamic therapy in CIN.
Asunto(s)
Ácido Aminolevulínico/análogos & derivados , Radioisótopos de Carbono/administración & dosificación , Radioisótopos de Carbono/farmacocinética , Fotoquimioterapia , Porfirinas/análisis , Displasia del Cuello del Útero/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Administración Tópica , Adulto , Ácido Aminolevulínico/administración & dosificación , Ácido Aminolevulínico/farmacocinética , Femenino , Fluorescencia , Humanos , Persona de Mediana Edad , Porfirinas/biosíntesisRESUMEN
OBJECTIVE: To study the pharmacokinetics and selectivity of 5-aminolevulinic acid (5-ALA) from 5-ALA thermolabile gel formulation in cervical intraepithelial neoplasia (CIN). The novel thermogel Pluronic F127 is liquid at cold temperatures and turns into a gel-like consistency at body temperature, thereby improving adhesion of 5-ALA to the cervix uteri. METHODS: 27 female patients with CIN 1-3 were included in this study. Thirty minutes to 12 h before conisation, 10 mL of thermo-gel containing either 4, 10, or 20% of 5-ALA were topically applied to the cervix. Biopsies were taken from the lesions as well as normal surrounding epithelial tissue for histological examination, fluorescence microscopy and spectrometry. RESULTS: The thermogel Pluronic F127 was easy to handle and proved reliable as vehicle carrier. 5-ALA induced porphyrin fluorescence was maximal after application of 10% 5-ALA thermogel. We observed the higher porphyrin fluorescence intensity within the CIN lesions (1,116 +/- 241 AU), as compared to normal adjacent epithelium (704 +/- 166 AU). This difference was statistically significant (p < 0.05). Four to six hours after application, porphyrin fluorescence in dysplastic epithelium reached maximal intensity, and tumor selectivity was the highest in CIN 3 achieving a tumor-to-normal ratio of 3.5. Compared to other studies employing 5-ALA, the thermogel preparation of 5-ALA leads to twofold increase in the porphyrin selectivity. CONCLUSIONS: The thermogel Pluronic F127 seems to improve the local cervical drug application. Based on these results, we recommend the application of a 10% 5-ALA thermogel formulation 4-6 h prior to photodynamic therapy in CIN.
Asunto(s)
Ácido Aminolevulínico/administración & dosificación , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Poloxámero , Espectrometría de Fluorescencia , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/tratamiento farmacológico , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Biopsia , Cuello del Útero/patología , Conización , Interpretación Estadística de Datos , Femenino , Geles , Humanos , Persona de Mediana Edad , Porfirinas , Factores de Tiempo , Neoplasias del Cuello Uterino/patología , Displasia del Cuello del Útero/patologíaRESUMEN
PURPOSE: Reconstructive surgical treatment with osteopromotive membranes has become an integral part of implant dentistry. Nevertheless, there are still instances in which this technique alone is of limited or no benefit. The aim of the present study was to determine whether a combination of titanium membranes coated with transforming growth factor beta1 (TGF-beta1) and insulin-like growth factor I (IGF-I) is of value in the regeneration of so-called critical-size defects in the rat model. An analysis was made of whether or not locally administered antibiotics are deleterious to bone regeneration. MATERIALS AND METHODS: A total of 24 rats were included in the study and were divided into 4 groups, each with 6 animals. Critical-size defects were created bilaterally and covered by titanium membranes coated with (1) polylactide, (2) polylactide and clindamycin, (3) polylactide and growth factors, or (4) polylactide, clindamycin, and growth factors. All 24 contralateral defects were covered by titanium membranes without any substrate (controls). Four weeks after treatment the animals were sacrificed. RESULTS: In groups 3 and 4, most defects showed thin but almost complete bridging of the defects with new bone formation. In particular, clindamycin had no inhibitory effect on the regeneration of bone. Nevertheless, after 28 days, there was no significant difference between the individual groups (including controls) with respect to the total amount of newly formed bone. DISCUSSION AND CONCLUSION: These results support the hypothesis that coating titanium membranes with TGF-beta1/IGF-I leads to almost complete bony bridging of critical-size defects without voluminous carrier materials. Moreover, simultaneous administration of clindamycin seems possible.
Asunto(s)
Antibacterianos/uso terapéutico , Materiales Biocompatibles/uso terapéutico , Regeneración Ósea/efectos de los fármacos , Enfermedades Mandibulares/cirugía , Membranas Artificiales , Osteogénesis/efectos de los fármacos , Animales , Antibacterianos/administración & dosificación , Clindamicina/administración & dosificación , Clindamicina/uso terapéutico , Materiales Biocompatibles Revestidos/uso terapéutico , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos , Femenino , Procesamiento de Imagen Asistido por Computador , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Enfermedades Mandibulares/patología , Poliésteres/uso terapéutico , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Titanio/química , Factor de Crecimiento Transformador beta/administración & dosificación , Factor de Crecimiento Transformador beta/uso terapéutico , Factor de Crecimiento Transformador beta1 , Cicatrización de Heridas/efectos de los fármacosRESUMEN
The current definition of gastrointestinal tumors (GIST) as CD117-positive mesenchymal tumors of uncertain malignant potential fails to include a number of cases with similar histology. In an attempt to improve the classification of these neoplasms, we conducted an immunohistochemical analysis of 244 mesenchymal tumors with histological features of GIST. According to their immunophenotype, the tumors were classified as GISTs, which are characterized by CD117 (c-kit) expression; gastrointestinal CD117-negative CD34 positive stromal tumors (GINST); alpha-smooth muscle actin and/or desmin positive gastrointestinal leiomyogenic tumors (GILT); S-100 and glial fibrillary acidic protein positive gastrointestinal glial/schwannian tumors (GIGT); gastrointestinal neuronal/glial tumors (GINT), which are positive for S-100/glial fibrillary acidic protein plus neuronal/glial markers; and gastrointestinal fibrous tumors (GIFT), which are only vimentin positive. The most common type of tumors were GIST, followed in order of frequency by GINST, GILT, GIGT, GIFT, and GINT. GISTs did not show any preferential location, whereas GINSTs occurred almost exclusively in the stomach and duodenum, and GILTs preferentially in the large intestine. Over a median follow-up period of 71 months, malignant behavior, i.e., metastatic spread, was observed in all tumor types except GINTs. Malignancy was associated with distal gut location, high mitotic activity, large tumor size, and nuclear pleomorphism, though none of these criteria alone discriminated between benign and malignant. Kaplan-Meier analysis of disease-specific survival showed significant differences in the long-term outcome of the newly defined subgroups. We conclude that, despite strong morphological similarities, gastrointestinal mesenchymal tumors are heterogeneous in their immunophenotype and biology.