Cervical cancer associated with genital prolapse--a brief review of the literature and long-term results of successful treatment with radiochemotherapy and surgery in a very frail patient.

BACKGROUND: A case of cervical cancer associated with irreducible procidentia successfully treated with external beam radiation and extracorporeal HDR-AL with concomitant chemotherapy followed by obliterative vaginal surgery is reported for the first time. CASE: A 73-year-old woman presented in frail condition suffering from a huge, irreducible uterovaginal procidentia combined with a squamous cell carcinoma of the cervix in FIGO Stage IIa. Successful treatment consisted of sequential application of combined radiotherapy with concurrent cisplatin chemotherapy followed by total vaginal hysterectomy and partial colpectomy with colpocleisis according to the Labhardt method. The five-year follow-up documents the excellent long-term results with regard to cervical cancer and pelvic floor stability. CONCLUSION: Especially in patients ineligible for extended surgery, radiochemotherapy followed by an obliterative surgical approach is feasible without aberrant wound healing and constitutes a suitable and efficient option for treating carcinomas of the cervix associated with irreducible genital prolapse.

Topical corticosteroid therapy for acute radiation dermatitis: a prospective, randomized, double-blind study.

BACKGROUND: Radiation dermatitis is a common side-effect of radiation therapy, but there is no current consensus about its appropriate therapy. OBJECTIVES: To compare treatment with topical 0.1% methylprednisolone vs. 0.5% dexpanthenol in a cohort of patients undergoing fractionated radiation therapy for breast cancer. METHODS: In a randomized, double-blind design, treatment was initiated at the beginning of radiation therapy and continued for 2 weeks after termination of radiation. Outcomes were compared by three different measures: clinical (symptom score), functional (transepidermal water loss, TEWL) and subjective (quality of life, QOL). RESULTS: In a preliminary cohort of untreated patients undergoing radiation therapy, clinical signs and TEWL levels increased progressively during radiation therapy, reaching highest values at 5 and 4 weeks, respectively. Although neither topical treatment reduced the incidence of radiation dermatitis, both delayed the emergence of greatest clinical and TEWL scores until approximately 6 and 5 weeks, respectively. With topical corticosteroids, clinical symptoms and TEWL were less pronounced than with dexpanthenol. Whereas general QOL improved after completion of radiation therapy, skin-related QOL declined. However, the skin-related QOL decline could be at least in part reversed by use of topical corticosteroid vs. dexpanthenol-containing emollient. CONCLUSIONS: We provide evidence that prophylactic and ongoing use of topical therapy with either topical corticosteroid or a dexpanthenol-containing emollient ameliorates, but does not prevent radiation dermatitis. Our data suggest, but do not prove, a benefit of a topical corticosteroid vs. a dexpanthenol-containing emollient. Further controlled studies with larger cohorts will be needed to determine optimal forms of topical therapy for radiation dermatitis.

Permeability barrier function of skin exposed to ionizing radiation.

OBJECTIVE: To characterize the epidermal permeability barrier function of skin during exposure to ionizing radiation. DESIGN: A prospective cohort study. SETTING: University hospital medical center. PATIENTS: Fifteen women receiving local radiation therapy (5000-6000 rad [50-60 Gy]) following breast-conserving surgery for breast cancer. MAIN OUTCOME MEASURES: Clinical symptoms and transepidermal water loss (TEWL). RESULTS: Epidermal permeability barrier function is impaired in patients who exhibit clinical signs of radiation dermatitis. The functional damage to the stratum corneum induced by ionizing radiation occurs with a delayed course, starting within a mean period of 11 days and reaching maximal values after a mean period of 27 days (range, 13-75 days). The onset of TEWL increase precedes the onset of radiation dermatitis and the maximal TEWL measurements precede the peak of skin changes. Patients with an early onset of TEWL increase show a longer duration of skin symptoms. CONCLUSIONS: Skin changes caused by radiation dermatitis are associated with an increase in TEWL. The barrier impairment is comparable to the changes observed with UV radiation exposure but exhibits an even more delayed course. Our results suggest that preservation of the epidermal permeability barrier function by topical treatment may ameliorate radiation dermatitis.

Decreased thyroid peroxidase expression in cultured thyrocytes after external gamma irradiation.

Impairment of thyroid function has been described in up to 50% of the patients after external irradiation of the neck region as well as after mantle irradiation. In order to assess radiation-induced alterations in cultured thyroid cells, the occurrence of apoptosis and necrosis as well as the expression of thyroid peroxidase (TPO) and of two members of the 70 kD heat shock family, HSP-73 and HSP-72, were analysed following gamma irradiation. Human thyroid epithelial cells (TEC) were purified from surgical tissue specimens, were cultured and irradiated with a single dose of 5 Gy or 50 Gy using Co60 as radioactive source. Analysis was performed 1, 3 and 5 day(s) after irradiation. Apoptosis and necrosis were assessed by DNA staining with propidium iodide and FACS analysis. TPO and HSP expression by SDS-PAGE and Western blotting. The cell viability of TEC was not affected by irradiation and there was no induction of HSP-72, a sensitive indicator of acute cellular stress. Interestingly, the expression of TPO, a key enzyme of thyroid hormone synthesis, decreased significantly in irradiated TEC, while HSP-73 expression remained unchanged. Decreased expression of TPO with a resulting suppression of thyroid hormone synthesis could contribute to an early development of thyroid dysfunction following irradiation. Thus, analysis of thyroid function, even early after external radiation therapy of the neck or after total body irradiation, seems to be indicated.

Head and neck tumors: fractionated frameless stereotactic interstitial brachytherapy-initial experience.

The authors used a frameless stereotactic navigation system, the Vogele-Bale-Hohner head holder, and a targeting device to reproducibly position brachytherapy needles for fractionated interstitial brachytherapy in 12 patients with inoperable cancers of the head and neck. In all cases, deviations of the needle relative to the planned position were within 1-15 mm depending on the location of the tumor.

[First experiences with computer-assisted frameless stereotactic interstitial brachytherapy (CASIB)]. / Erste Erfahrungen mit computerunterstützter stereotaktischer interstitieller Brachytherapie.

PURPOSE: To reach an optimal treatment result and to avoid damage to critical structures a homogeneous dose distribution in the tumor volume with a rapid decreasing dose to the surrounding structures is necessary. Fractionated interstitial brachytherapy of tumors in the ENT region employing needles depends on exact localization of the target volume during all fractions. Therefore reproducibility of positioning of the needle(s) plays an important role. MATERIAL AND METHODS: We used the ISG Viewing Wand system in combination with the Vogele-Bale-Hohner (VBH) head holder and a new targeting device. Point of entrance, pathway, and target point of the needle were planned and insertion of the needle simulated in advance. To date we have treated 7 patients with inoperable tumors in the ENT region. The actual position of the needle in the control CT was compared to the planned position. RESULTS: The accuracy of positioning of the needle depended on the location of the tumor. In a patient with a recurrent retroorbital adenocarcinoma the mean accuracy was 1 mm. Due to soft tissue displacement in the neck region and the resulting necessity to readjust the targeting device the needle was placed with a mean deviation of 15 mm between the planned and the actual position. CONCLUSIONS: Computer-assisted frameless stereotactic interstitial brachytherapy allows for precise, reproducible and preplanned insertion of hollow needles into target structures closely adherent to the surrounding tissue, thus avoiding damage of neighbouring structures. This technique is of great advantage in treating deeply seated tumors which are fixed to bony structures, especially at the skull base. Inaccuracy in the neck region caused by soft tissue shift requires improvement of the immobilization in this region.

Heat shock protein 60 mRNA is not increased in Graves' disease thyroid tissue.

Heat shock proteins (hsps) are highly conserved proteins which carry vital functions by assisting intracellular protein transport and degregation. Hsps of the 60-kD family have been shown to be strongly immunogenic and to be overexpressed in many autoimmune diseases. Hsp60 reactive T cells from thyroids from patients with Graves disease have been isolated, but hsp60 expression in Graves disease has not been investigated. We therefore investigated the expression of hsp60 mRNA in thyroids from patients with Graves disease and from non autoimmune controls. Expression of hsp60 mRNA could be detected in all Graves disease thyroids. This expression was not influenced by preoperative treatment with antithyroid drugs. Hsp60 mRNA was expressed in non autoimmune controls, too. There was no quantitative difference between autoimmune thyroids and controls, revealed by computer scanning of Northern blots. Our results demonstrate, that in contrast to some other autoimmune diseases hsp60 mRNA is not overexpressed in thyroids from patients with Graves disease.

The production of an amyloidogenic metabolite of the Alzheimer amyloid beta precursor protein (APP) in thyroid cells is stimulated by interleukin 1 beta, but inhibited by interferon gamma.

Thyroid epithelial cells have been shown to have a high APP expression and to produce large amounts of its metabolic derivatives, namely secreted APPs and a potentially amyloidogenic 41-kDa C-terminal fragment. It was the aim of the present study to analyze how APP production and metabolism were regulated in human thyroid cells. The effects of three cytokines, interferon gamma (IFN gamma), interleukin 1beta (IL-1 beta) and transforming growth factor (TGF) beta, were investigated. Cell extracts and supernatants were studied by immunoblotting using specific N- and C-terminal APP antibodies. Quantification was performed by densitometric scanning. We demonstrate that IFN gamma has a strong suppressive effect on the production and metabolism of APP. From a concentration of 30 U/ml upwards it reduces the cellular APP content, decreases the amounts of secreted APPs and inhibits the generation of the 41-kDa amyloidogenic APP fragment. In contrast, IL-1 beta has a stimulatory influence on the generation of the amyloidogenic 41-kDa APP metabolite, but does not affect the cellular holoprotein or APPs. TGFbeta has no significant effect on APP. Our results demonstrate that cytokines can regulate APP production and metabolism in thyroid cells. IFN gamma is the first naturally occurring agent described to inhibit the generation of amyloidogenic APP fragments. It may be of relevance in preventing amyloid deposition during inflammatory processes in the thyroid gland, but may exert a similar protective effect in other non-neuronal and neuronal tissues.

Hyperthermia inhibits proliferation and stimulates the expression of differentiation markers in cultured thyroid carcinoma cells.

In the last two decades hyperthermia has increasingly been used as adjuvant therapy for the treatment of malignant tumours. The effects of heat were therefore analysed on cultured thyroid epithelial cells from patients with thyroid cancer and from non-malignant control thyroids. Purified thyroid cells were subjected to heat treatment (42.5 degrees C; 90 min). After 24 h [3H]thymidine incorporation was assessed and the expression of heat shock protein 72 (hsp72), thyroglobulin, CD54 (ICAM-I) and MHC class-Il were analysed by immunofluorescence staining. Additionally mRNA analysis was performed by Northern blotting. Whereas hyperthermia inhibited the proliferation of thyroid cells, it significantly increased the expression of hsp72, thyroglobulin, CD54 and HLA-DR (P < 0.05). Our results suggest that hyperthermia may suppress growth while supporting differentiation and immune recognition in thyroid cancer. It may therefore be beneficial as a treatment for patients with thyroid carcinoma.

Retrobulbar T cells from patients with Graves' ophthalmopathy are CD8+ and specifically recognize autologous fibroblasts.

Graves' ophthalmopathy is an autoimmune condition characterized by T cell infiltration of the retrobulbar tissue. Phenotypic and functional analysis of these infiltrating cells may provide insight into the pathogenesis of the disease. IL-2-responsive cells were therefore grown out of the retrobulbar tissue from two patients with severe Graves' ophthalmopathy undergoing orbital decompression surgery, and six T cell lines were established and characterized. They consisted predominantly of CD8 + CD45RO+ cells and secreted IL-4, IFN-gamma, and IL-10 upon activation. When screened for their antigen reactivity, all lines proliferated in response to stimulation with autologous retrobulbar fibroblasts in an HLA class I-restricted manner, but did not recognize autologous peripheral blood mononuclear cells, crude eye muscle extract, allogeneic cells, or purified protein derivate of Mycobacterium tuberculosis. In contrast, PBMC from the same patients responded readily to purified protein derivate of Mycobacterium tuberculosis and allogeneic PBMC, but did not recognize autologous fibroblasts. Interestingly, only one of the six retrobulbar T cell lines displayed cytotoxicity towards its specific target cell population. These results suggest that the retrobulbar fibroblasts are a major T cell target in Graves' ophthalmopathy. Pronounced cytokine production in the absence of target cell cytotoxicity may explain fibroblast proliferation, glycosaminoglycan secretion, and secondary eye muscle enlargement in this condition.

Interferon gamma and iodide increase the inducibility of the 72 kD heat shock protein in cultured human thyroid epithelial cells.

The 72 kD heat shock protein (hsp 72) has been postulated to play a role in the development of autoimmune disease and has been shown to be overexpressed in the Graves' disease thyroid gland. The expression and modulation of the 72 kD heat shock protein were therefore studied in cultured human thyroid epithelial cells (TEC). TEC from normal thyroid tissue as well as from non-toxic goitres, thyroid adenomas and Graves' disease thyroids were analysed by Western blotting. Potential modulatory effects of heat shock treatment, TSH, IFN gamma, different serum supplements, sodium iodide and sodium selenite were investigated. Hsp 72 was detectable in cells from all tissue types under basal culture conditions and, at increased concentrations, after heat shock treatment. Quantitative evaluation of Western blotting results by densitometer scanning revealed that hsp 72 concentrations were identical in TEC from normal and diseased thyroids. IFN gamma increased the expression of hsp 72 under basal culture conditions as well as after heat shock treatment. TSH had no effect. Sodium iodide did not affect hsp 72 under basal culture conditions, but augmented the susceptibility of TEC to the effect of heat shock treatment. In contrast, sodium selenite had no effect on the expression of hsp 72. These results demonstrate that local as well as environmental factors may facilitate the induction of hsp 72 in TEC. This may be an important factor for the initiation and progression of thyroid autoimmunity. The stimulatory effect of iodide on hsp induction may also provide an explanation for the frequent occurrence of thyroid autoimmune diseases after iodine exposure.

Do heat shock proteins play a role in Graves' disease? Heat shock protein-specific T-cells from Graves' disease thyroids do not recognize thyroid epithelial cells.

Thyroid-derived T-cells from patients with Graves' disease were analyzed for their reactivity to recombinant heat shock proteins (hsp) and autologous thyroid epithelial cells (TEC). Five of six uncloned T-cell lines responded to stimulation with recombinant mycobacterial 71-kilodalton (kDa) hsp and cross-reacted with the corresponding amoebial and human proteins. Only one line reacted with recombinant 65-kDa hsp. Thyroid-derived T-cell lines also showed a proliferative response to TEC, which could be increased in four of the lines, when hsp expression was induced in thyroid cells by heat stress before the initiation of coculture. Clonal specificity analysis of thyroid-derived T-cell clones, however, demonstrated that distinct T-cells were responsible for the recognition of recombinant hsp and TEC. None of the clones responsive to recombinant hsp recognized TEC, whereas TEC-responsive clones did not react with recombinant hsp. Interestingly, the response of the majority of TEC-reactive clones could be dramatically increased when heat-shocked TEC were used as stimulator cells. These results suggest that T-cells specific for hsp of the 70- or 60-kDa families do not recognize TEC in the autoimmune thyroid gland. Heat shock-inducible proteins may, however, still play a role in the autoimmune process by facilitating the presentation of thyroid-specific autoantigen(s) to autoreactive T-cells.

[Accurate assessment of myocardial viability: complementation of Thallium-201 scintigraphy with a subsequent reinjection study]. / A szívizom életképességének pontosabb megítélése: a terheléses thallium-201 szcintigráfia kiegészítése késöi, illetve reinjekciós vizsgálattal.

Persistent myocardial thallium perfusion defects 3 to 4 hours after stress do not represent irreversible ischemia in every case. In many instances signs of reversibility show up 8-72 hours later or after rest reinjection. Authors performed additional investigations of redistribution in 64 patients with persistent defects. Rest reinjection was given to 11 patients and delayed redistribution was followed in the others. Persistent perfusion defects improved or disappeared in 13 percent of myocardial segments and 38 percent of patients. In 18% of segments late reverse redistribution was observed. The assessment of patients' state was significantly influenced by the results of the additional investigations in 19% of cases. Authors suggest that important information can be obtained about the viability of the myocardium by the extended studies even with the common planar method.

The effect of TSH and TSI on the thyroglobulin expression of cultured human thyroid cells.

Human thyroid cells in culture stimulated by TSH and TSI were used in order to detect thyroglobulin expression. After three days stimulation the cells were incubated with monoclonal thyroglobulin antibody and FITC-conjugated antiglobulin. Fluorescent index (the intensity of fluorescence related to hundred analysed cells) was estimated for each experimental group. The most effective stimulation of the thyroglobulin expression was detected after TSH stimulation at the concentration of 0.1 mU/ml. TSI from active Graves' patients provoked the highest expression of thyroglobulin at concentration of 1.0 mg/ml, but the fluorescence index was lower than after TSH stimulation. The thyroglobulin expression was intracellular, large, partly confluent granules were detectable mainly in the perinuclear area. Antigen expression on the surface of cultured thyroid cells could not be detected. The morphology of thyroglobulin expression as detected by immunofluorescence, was the same after TSH and TSI stimulation. It is concluded, that both stimulating factors, i.e. TSH and TSI, are involved in the thyroglobulin expression of human thyroid cells.