Monika Schindl

Expression of hypoxia-inducible factor-1α in oligodendrogliomas : Its impact on prognosis and on neoangiogenesis

BACKGROUND Hypoxia-inducible factor (HIF)1 alpha is considered to play a key role in the adaptation of cells to hypoxia by stimulating angiogenesis via regulation of vascular endothelial growth factor and by metabolic adaptation to O(2) deprivation. METHODS Expression of HIF-1 alpha protein and p53 was investigated by immunohistochemistry in 51 specimens of supratentorial pure oligodendrogliomas. Microvessels density (MVD) was determined by anti-CD34 immunostaining. The influence of HIF-1 alpha expression on survival was investigated using univariate and multivariate analysis. RESULTS Strong expression of HIF-1 alpha was observed in 12 (23.5%) specimens, moderate in 21 (41.2%) specimens, and weak in 8 (15.7%) cases, and no expression was found in 10 samples (19.6%). There was no correlation of HIF-1 alpha expression with histologic grading (P = 0.428, Mann-Whitney test). Hypoxia-inducible factor-1 alpha expression and MVD showed a strong correlation (P < 0.001, r = 0.735, Spearman coefficient of correlation). Overexpression of p53 was observed in only two cases. Patients with strong or moderate expression of HIF-1 alpha had a significantly shorter overall survival rate compared with those with low or no expression in univariate (P = 0.0434; log-rank test) and multivariate analysis (P = 0.0187). CONCLUSIONS Overexpression of HIF-1 alpha indicates a diminished prognosis in oligodendrogliomas, independent of p53 status. This finding may be explained by the strong vascularization of these tumors that prevents hypoxia and allows O(2) diffusion and henceforth tumor progression.

Overexpression of Id-1 is associated with poor clinical outcome in node negative breast cancer

Id‐1 is an important regulator of cellular growth and differentiation and controls malignant progression of breast cancer cells. The aim of our study was to assess the clinical impact of Id‐1 expression in breast cancer, i.e., its potential impact on prognosis and prediction of treatment response. Id‐1 protein expression was determined immunohistochemically in 191 patients with lymph‐node negative breast cancer, and univariate and multivariate survival analysis was carried out. Fifteen (7.9%) specimens showed strong expression, 75 (39.3%) moderate, 55 (28.8%) weak expression and 46 (24.1%) cases no expression of Id‐1. Patients with strong or moderate Id‐1 expression had a significant shorter overall (p = 0.003, Cox regression) and disease‐free survival (p = 0.01, Cox regression) compared to those with absent or low expression. Progesterone receptor density was significantly higher in breast cancers with absent/low Id‐1 expression compared to those with moderate/strong expression (p < 0.001, t‐test). Id‐1 expression was significantly stronger in cases positive for p16INK4a expression compared to those negative for p16 (p = 0.049, Mann‐Whitney test). The influence of Id‐1 on clinical outcome seems much stronger in patients with negative estrogen receptor status compared to those with positive status, who received receptor antagonists as adjuvant therapy in most cases. Overexpression of Id‐1 protein represents a strong independent prognostic marker in node negative breast cancer, and future therapies inhibiting Id‐1 expression might be beneficial for these patients. Our results also suggest that due to the apparent interaction of Id‐1 with the steroid‐receptor system in breast cancer, hormonal therapies might influence Id‐1 expression and its impact on clinical outcome.

Expression of hypoxia-inducible factor–1α in oligodendrogliomas

Hypoxia‐inducible factor (HIF)1α is considered to play a key role in the adaptation of cells to hypoxia by stimulating angiogenesis via regulation of vascular endothelial growth factor and by metabolic adaptation to O2 deprivation.

Elective cesarean section vs. spontaneous delivery: a comparative study of birth experience

Background.  To investigate birth experience and medical outcome in women with elective cesarean section (CS) compared with women with intended vaginal delivery.

Lymphatic microvessel density as a novel prognostic factor in early-stage invasive cervical cancer.

Few data on the influence of lymphatic microvessel density (MVD) on survival in cancer are available since until recently there was no reliable immunohistological marker for lymphatic endothelium. Using an antibody staining podoplanin, a novel marker for lymphatic endothelium, lymphatic MVD in tissue samples of 85 patients with cervical cancer classification pT1b treated by radical hysterectomy was investigated. Survival was determined using univariate and multivariate analyses. Lymphatic MVD was also compared to MVD assessed by immunostaining against factor VIII–related antigen, which is considered a marker for blood vessels. Patients with >5 lymphatic microvessels/0.25 mm2 field had significantly better overall survival (mean 91.8 months) than those with ≤5 lymphatic microvessels/field in univariate analysis (mean 113 months) (p = 0.0105, log‐rank test). In multivariate analysis, lymphatic node involvement (p =0.0183), vessel infiltration (p =0.0158) and lymphatic MVD (p =0.0269) remained independent prognostic factors. No correlation between lymphatic MVD and various clinical and histopathological parameters was observed. Correlation between lymphatic MVD and MVD assessed by immunostaining against factor VIII was only weak (p = 0.004, r = 0.312, Spearmans coefficient of correlation). Our results suggest that increased lymphatic MVD is associated with favorable prognosis in early‐stage cervical cancer.

The citalopram challenge test in patients with major depression and in healthy controls

Neuroendocrine challenge tests in depressed patients have revealed a blunted hormonal reaction to serotonergic stimuli. In the present study, citalopram was chosen as the serotonergic agent for neuroendocrine stimulation. Compared to earlier challenge agents, citalopram has the advantage of serotonergic selectivity, its application is well tolerated and the possibility of intravenous application reduces pharmacokinetic interference. Sixteen patients suffering from an acute episode of major depression and 16 healthy controls underwent the stimulation procedure with 20 mg of citalopram and placebo. Whereas significant differences in the secretion of prolactin and cortisol between citalopram and placebo challenge were observed in the control group, no differences were found in the group of depressed patients. Comparison of depressed patients and controls showed a significantly blunted prolactin secretion in patients. Differences in cortisol secretion following serotonergic stimulation with citalopram did not become significant. The stimulation procedure was well tolerated in all subjects, although a higher number of side effects was observed in the control group. The amount of side effects did not correlate with the hormone responses. These results are in line with the hypothesis of serotonergic hypofunction in depressed patients. In conclusion, the 20-mg citalopram challenge test is thought to be a promising tool for further investigation of serotonergic function in psychiatric illness.

Induction of complete wound healing in recalcitrant ulcers by low‐intensity laser irradiation depends on ulcer cause and size

Chronic skin ulcers still represent a therapeutic challenge in dermatology. Among the various non‐invasive treatment modalities used for the improvement of impaired wound healing, low‐intensity laser irradiations are gaining an increasing body of interest. We used low‐intensity laser irradiations delivered by a 30 mW helium‐neon laser at an energy density of 30 J/cm2 three times weekly for the induction of wound healing in ulcers of diverse causes. Twenty patients with the same number of ulcers, which had previously been treated by conventional wound care for a median period of 34 weeks (range: 3–120 weeks) without any significant evidence of healing, were included in the study. Concerning the underlying disorders, patients were divided into four groups: diabetes, arterial insufficiency, radio damage and autoimmune vasculitis. In all ulcers, complete epithelization could be induced by laser therapy. No amputation or any other surgical intervention was necessary and no adverse effects of any kind were noted during low‐intensity laser treatment. Regarding the different diagnoses, a statistically significant difference was noted (P=0.008): ulcers due to radio damage healed significantly faster than those caused by diabetes (6 weeks [range: 3–10 weeks] vs. 16 weeks [range: 9–45 weeks], P=0.005). Wound healing in autoimmune vasculitis (24 weeks [range: 20–35 weeks]) required longer than in radiodermitis, although the difference was not significant.

Signal-amplified colorimetric in situ hybridization for assessment of human papillomavirus infection in cervical lesions.

Detection and typing of human papillomavirus (HPV) infection may have a major impact in cervical-screening and follow-up. In this study various commercially available techniques for the detection of HPV were evaluated. HPV-status was determined in 86 samples of cervical cancer by PCR and direct sequencing, catalyzed signal amplified colorimetric DNA in situ hybridization (CSAC- ISH) (GenPoint system, DAKO), immunohistochemistry (IHC) and in 12 selected cases also by conventional, non-amplified ISH. Twenty-one samples of cervical intraepithelial neoplasias grade III (CIN III) were investigated by CSAC-ISH, conventional ISH and by IHC, in corresponding PAP smears HPV-detection and typing was performed by CSAC-ISH and Hybrid Capture test II (HC). In additional 20 PAP smears HPV typing was performed using HC and a novel immunocytochemical system for HPV detection and-typing. CSAC-ISH showed good correlation with PCR analysis in cervical cancers: In 87% of PCR positive cases, HPV infection was also detected by CSAC- ISH (66/76). HPV 16 was detected in 75% of PCR-positive cases (44/59), HPV 18 in 71% of PCR positive cases (5/7). CSAC-ISH detected HPV 31 in only 29% of PCR positive cases (2/7), and HPV 33 in 64% of PCR-positive cases (23/36). Nevertheless, CSAC-ISH- false negative cases for HPV 31 or 33 were nearly always combined infections with other HPV types, which were detectable by CSAC-ISH in most cases. CSAC-ISH revealed HPV infection in 20 of 21 HC-positive cervical smears, while in corresponding biopsies (CIN III) CSAC-ISH detected 100% of HPV infections. Conventional, non-amplified ISH showed significantly lower sensitivity compared with CSAC-ISH, and immunocyto- and -histochemistry were of very low sensitivity for detection of HPV. CSAC-ISH is an easy-to-handle method for detection and typing of cervical HPV infection, and shows sufficient sensitivity for clinical practice.

Increased microvessel density in adenomyosis uteri

OBJECTIVE To investigate microvessel density in adenomyosis compared to the endometrium in patients with adenomyosis and in normal controls. DESIGN Uterine paraffin-embedded histologic specimens were immunostained for CD34. The area with the highest microvessel density in adenomyosis and in the endometrium was evaluated. All microvessels in a specific field of view (x200 magnification) were counted. SETTING The Department of Gynecological Endocrinology and the Institute of Clinical Pathology, Department of Gynecopathology, in an university hospital. PATIENT(S) Specimens of 53 patients with adenomyosis, who had undergone hysterectomy. Endometrial specimens of 17 women without uterine pathology were investigated as normal controls. MAIN OUTCOME MEASURE(S) Microvessel density in adenomyosis and in the endometrium. RESULT(S) The mean microvessel density was significantly higher in adenomyosis than in the endometrium of the same patients (33.5 +/- 14.6 vs. 19.5 +/- 12.5 microvessels/field; P<.001 sign test). No significant difference between the endometrium of patients and of normal controls was observed (P=.805). CONCLUSION(S) Adenomyosis exhibits angiogenic properties. However, the endometrium of patients with adenomyosis is not more prone to express angiogenic activity compared to the endometrium of normal controls.

Low intensity laser irradiation in the treatment of recalcitrant radiation ulcers in patients with breast cancer--long-term results of 3 cases.

Radiotherapy can be followed by recalcitrant skin ulcers. As low intensity laser irradiation has been demonstrated to have a beneficial effect on impaired wound healing, we investigated its efficacy and safety in three patients with chronic radiation ulcers. The three patients, previously mastectomized due to breast cancer, with recalcitrant radiation ulcers of the skin were treated with a 30 mW helium‐neon laser (wavelength: 632.8 nm, intensity: 3 mW/cm2, dose: 30 J/cm2) three times weekly. In all patients, complete wound closure was achieved within a period of 7, 5, and 8 weeks. One patient died 6 weeks after laser treatment due to tumor cachexia. Neither of the other patients showed recurrence of radiation ulcers or neoplasm during a follow‐up of 36 months. Low intensity helium‐neon laser irradiation has been shown to be effective in the induction of wound healing in radiotherapy‐induced ulcers in three patients with breast cancer.