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Biomedical subjects

H Pehamberger

Publications and source records attributed to H Pehamberger.

At least 19 recordsLinked to original sources
PubMed2006

Jun and Fos family protein expression in human breast cancer: correlation of protein expression and clinicopathological parameters.

OBJECTIVES: The activator protein-1 (AP-1) is a dimeric transcription factor formed by members of the Jun and Fos protein family. AP-1 plays a role in a variety of physiological functions including cell proliferation and differentiation, although both c-Jun and c-Fos have also been implicated in oncogenic transformation and tumor progression. To further elucidate the role of AP-1 in breast cancer, we have investigated the expression of the AP-1 proteins c-Jun, JunB, JunD, phosphorylated c-Jun, c-Fos, Fral, Fra2 and the tumor supressor protein p53. METHODS: Protein expression was evaluated on a breast cancer tissue microarray with 58 lymph node positive or negative breast cancer specimens, 29 corresponding lymph node metastases, and 11 tissue samples from surrounding tumor-free tissue, each cored as triplicate. Jun and Fos protein family expression was evaluated by immunohistochemistry and was correlated with clinicopathological parameters. RESULTS: High expression levels were observed for c-Jun, JunD, c-Fos and Fra2, whereas JunB and Fral exhibited lower staining. c-Jun protein expression was correlated to Fral staining (p = 0.007, Kendall's Tau) and Fral was further associated with c-Fos (p < 0.001), JunD (p = 0.001) and Fra2 (p = 0.011) expression. JunD expression correlated with c-Fos (p < 0.001), JunB (p = 0.035) and c-Jun (p = 0.05). Activated c-Jun correlated with c-Fos expression (p = 0.041). JunB was negatively correlated to tumor stage, (p = 0.093, corr coeff. = -0.293, Spearman's correlation) but was significantly increased in nodal negative tumors (p = 0.004, Mann Whitney test). In addition, increased Fral expression showed a trend towards an increased overall survival (p = 0.077, RR = 0.534, Cox regression). CONCLUSION: Our results suggest an important role for JunB and Fral in the biological behavior of malignant breast tumors.

Biomarkers, Tumor↗
PubMed2005

Sentinel node status in melanoma patients is not predictive for overall survival upon multivariate analysis.

Sentinel lymph node biopsy (SLNB) has become a widely accepted standard procedure in the staging of patients with cutaneous melanoma and absence of clinical lymph node metastases, although there is no final proof that SLNB influences overall survival in these patients. This study investigated the accuracy of SLNB and the clinical outcome of patients after a mean follow-up of 22 months. Between 1998 and 2003, SLNB was performed in 309 consecutive patients. Patients with one or more positive sentinel lymph nodes (SLNs) were subjected to selective lymphadenectomy (SL). Survival analyses were performed using the Kaplan-Meier approach. A Cox proportional-hazard analysis was used for univariate and multivariate analysis to explore the effect of variables on survival. Sentinel lymph nodes were identified in 299 of 309 patients (success rate: 96.8%). Of these, 69 (23%) had a positive SLN. The false-negative rate was 9.2%. Recurrence of disease to the regional lymph node basin (3.0%) and to the locoregional skin (2.6%) was rare in SLN-negative patients in contrast to SLN-positive patients (7.2 and 17.4%, respectively). The 3-year overall survival was 93 and 83% for SLN-negative and SLN-positive patients, respectively. Upon multivariate analysis, SLN status (P<0.001), Breslow thickness (P<0.02) and ulceration (P<0.026) were all found to be independent prognostic factors with respect to disease-free survival, whereas Breslow thickness proved to be the only significant factor with respect to overall survival.

Adult↗
PubMed2005

Alternative splicing of IL-24 in melanocytes by deletion of exons 3 and 5.

Two novel interleukin-24 (IL-24) splice variants were identified in normal human melanocytes by sequencing cloned polymerase chain reaction (PCR) products that are not expressed in metastatic melanoma. These gene products have been generated by differential skipping of exons 3 (IL-24 delE3) and 5 (IL-24 delE5). IL-24 delE3 has limited sequence identity to the IL-24-interacting protein mda-7s, and IL-24 delE5 is homologous to IL-24.

Alternative Splicing↗
PubMed2004

Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.

PURPOSE: To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma. PATIENTS AND METHODS: Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days). RESULTS: Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms. CONCLUSION: ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.

Adult↗
PubMed2004

Selective immunohistochemical staining shows significant prognostic influence of lymphatic and blood vessels in patients with malignant melanoma.

Few data on the influence of lymphatic microvessel density (LMVD) on survival in patients with melanoma are available. The aim of this study was to assess LMVD and blood microvessel density (MVD) in tissue samples from 120 patients with melanoma. LMVD was stained with an antibody staining for podoplanin, and blood MVD was assessed by CD31 (PECAM-1)-immunostaining. Survival was determined using univariate and multivariate analysis. A significant association between a high CD31 MVD (but not LMVD) and the presence of lymph node metastases (P=0.007) was observed. Patients with a high LMVD had a significant shorter overall (OS) (P=0.0436) and disease-free survival (DFS) (P=0.0249) in univariate analysis. The survival analysis showed CD31 MVD was a strong prognostic factor for OS and DFS in both uni-and multivariate analyses. Our results demonstrate LMVD as a prognostic factor in malignant melanoma, although its prognostic relevance is much smaller compared with blood MVD.

Adult↗
PubMed2004

Temozolomide and interferon alpha 2b in metastatic melanoma stage IV.

BACKGROUND: A multicentre, centrally randomized, open-labelled study with temozolomide and interferon (IFN)-alpha 2b was carried out to study the therapeutic effect in patients with metastatic melanoma stage IV. OBJECTIVES: The response rate, efficacy, side-effects, reasons for discontinuation of therapy and survival rate of 47 patients treated with temozolomide in combination with two different dosing regimens of IFN-alpha 2b were documented. PATIENTS/METHODS: Twenty-nine male and 18 female patients (mean age 57.6 years, range 34-74) were centrally randomized to two different arms: 20 patients received a treatment schedule with temozolomide 150 mg m(-2) on days 1-5 orally every 28 days in combination with IFN-alpha 2b 10 MIU m(-2) every other day and 27 patients received temozolomide 150 mg m(-2) on days 1-5 every 28 days in combination with IFN-alpha 2b in a fixed dose of 10 MIU every other day. RESULTS: We observed an overall response rate of 27.6% comprising five complete remissions (10.6%: one patient group A, four patients group B), in two of these five patients at the last follow-up in the study (4.3%, both in group B); and eight partial remissions (17%: six patients in group A, two patients in group B), in three of these eight patients at the last follow-up in the study (6.4%, two patients in group A, one patient in group B). Three patients showed stable disease (6.4%: one patient in group A, two patients in group B). Mean survival was 14.5 months [95% confidence interval (CI) 10-19] with no significant differences between treatment groups. However, there was a significant correlation with response after three cycles (log rank test, P < 0.03). Within the 32 patients who completed at least three cycles of therapy, seven patients (three in group A and four in group B) with a partial or complete response showed a significantly better mean survival of 30.6 months (95% CI 19.1-42) compared with 25 patients who did not respond (13.7 months 95% CI 9.2-18.3). In total, patients with at least one complete remission showed the longest survival (37.1 months 95% CI 26.3-47.9), followed by patients with at least one partial response (17.4 95% CI 10.9-23.9). Major side-effects of the treatment were nausea, vomiting, headache, leucopenia, thrombopenia, elevation of liver function parameters and neurological symptoms. In five patients, the side-effects led to a discontinuation of treatment: neurological symptoms (two patients), sepsis (one patient), brain haemorrhage (one patient) and exanthema (one patient). There were no treatment-related deaths. CONCLUSIONS: The combination of temozolomide and IFN-alpha 2b can easily be administered and shows tolerable toxicity. When an objective response occurs after three cycles, it indicates a significant survival advantage.

Adult↗
PubMed2003

Compact, broad-bandwidth fiber laser for sub-2-microm axial resolution optical coherence tomography in the 1300-nm wavelength region.

A novel, compact, user friendly fiber laser with a broad emission bandwidth (MenloSystems, lambdac = 1375 nm, deltalambda = 470 nm, Pout = 4 mW) was used to achieve unprecedented sub-2-microm axial resolution optical coherence tomography (OCT) in nontransparent biological tissue in the 1300-nm wavelength region. Fresh human skin and arterial biopsies were imaged ex vivo with approximately 1.4-microm axial and approximately 3-microm lateral resolution and 95-dB sensitivity, demonstrating the great potential for clinical OCT applications of this stable, low-cost, and turn-on-key fiber laser.

Arteries↗
PubMed2003

Equine melanoma in a population of 296 grey Lipizzaner horses.

REASONS FOR PERFORMING STUDY: Equine melanomas occur most commonly in grey horses at age 5 years or more. Generally, benign and malignant melanomas are distinguished by microscopy, but a more distinct classification would be helpful. OBJECTIVES: The objectives of this study were to gain further evidence concerning the occurrence of melanotic tumours, and to evaluate the impact of heredity on melanoma development. METHODS: A clinical study was conducted on a defined population of 296 grey horses of Lipizzaner breed. Individuals were classified according to their stage of disease using a 0-5 scale. Heritability was estimated on a sample of 296 grey horses with pedigrees traced back as far as 32 generations. RESULTS: Of the 296 horses, dermal melanomas were present in 148 horses (50%), 68 of which were more than age 15 years; 51 of these were melanoma-bearing. In 75.6% of cases, melanotic tumours were detected underneath the tail. Although melanoma-bearing grey horses were encountered up to stage 4, none of the affected individuals suffered any severe clinical effect or was handicapped in performance. Statistical analysis revealed highly significant effects of stud and age (P < 0.0001), explaining 28% of the total variability. CONCLUSIONS: In contrast to melanomas in solid-coloured horses characterised by early metastases, melanomas in grey horses showed less malignancy. Affected individuals often had encapsulated nodules or structures similar to human blue nevi. Grey horse-specific genetic factors inhibiting metastatic processes may be responsible for this phenomenon. POTENTIAL CLINICAL RELEVANCE: Although the obtained heritability estimate of 0.36 with a standard error of 0.11 indicates a strong genetic impact on the development of melanoma in ageing grey horses, a possible influence of the genes with large effects was also suggested. Therefore, further analysis is required of melanoma development in the ageing grey horse.

Age Distribution↗
PubMed2002

Diagnostic accuracy of dermoscopy.

The accuracy of the dinical diagnosis of cutaneous melanoma with the unaided eye is only about 60%. Dermoscopy, a non-invasive, in vivo technique for the microscopic examination of pigmented skin lesions, has the potential to improve the diagnostic accuracy. Our objectives were to review previous publications, to compare the accuracy of melanoma diagnosis with and without dermoscopy, and to assess the influence of study characteristics on the diagnostic accuracy. We searched for publications between 1987 and 2000 and identified 27 studies eligible for meta-analysis. The diagnostic accuracy for melanoma was significantly higher with dermoscopy than without this technique (log odds ratio 4.0 [95% CI 3.0 to 5.1] versus 2.7 [1.9 to 3.4]; an improvement of 49%, p = 0.001). The diagnostic accuracy of dermoscopy significantly depended on the degree of experience of the examiners. Dermoscopy by untrained or less experienced examiners was no better than clinical inspection without dermoscopy. The diagnostic performance of dermoscopy improved when the diagnosis was made by a group of examiners in consensus and diminished as the prevalence of melanoma increased. A comparison of various diagnostic algorithms for dermoscopy showed no significant differences in their diagnostic performance. A thorough appraisal of the study characteristics showed that most of the studies were potentially influenced by verification bias. In conclusion, dermoscopy improves the diagnostic accuracy for melanoma in comparison with inspection by the unaided eye, but only for experienced examiners.

Dermatology↗
PubMed2002

Protein kinase C isoforms in normal and transformed cells of the melanocytic lineage.

Enzymes belonging to the protein kinase C (PKC) family represent one of the major mediators of signal transduction in melanocytes. To identify PKC isoforms that may be associated with the process of malignant transformation and metastasis, we investigated the expression pattern of 11 different PKC isoforms (alpha, beta I, beta II, gamma, delta, epsilon, eta, theta, zeta, lambda, and iota) in melanoma lymph node metastases, in cell lines established from these metastases, in primary cell cultures from normal melanocytes, and in permanent cell lines established from spontaneously transformed melanocytes. PKC alpha, beta I, beta II, delta, epsilon, eta, zeta, lambda and iota were found to be expressed in total lysates from melanoma metastases. In permanent cell lines established from these metastases, the expression levels of PKC beta I, beta II, delta, epsilon, and eta were lower or undetectable when compared with initial expression in tumour lysates. In normal primary melanocyte cultures, the PKC isoforms beta II, delta, epsilon, eta and iota were undetectable. PKC gamma and theta isoforms were undetectable in all melanocytic cell types examined. PKC iota was the only isoform exclusively detected in tumour lysates, in spontaneously transformed melanoma cells and melanoma cell lines, but not in normal melanocytes, and may therefore be associated with the transformed phenotype in human melanoma in vitro and in vivo.

3T3 Cells↗
PubMed2001

A genetically engineered influenza A virus with ras-dependent oncolytic properties.

The NS1 protein of influenza virus is a virulence factor that counteracts the PKR-mediated antiviral response by the host. As a consequence, influenza NS1 gene knockout virus delNS1 (an influenza A virus lacking the NS1 open reading frame) fails to replicate in normal cells but produces infectious particles in PKR-deficient cells. Because it is known that oncogenic ras induces an inhibitor of PKR, we addressed the question of whether the delNS1 virus selectively replicates in cells expressing oncogenic ras. We show that upon transfection and expression of oncogenic N-ras, cells become permissive for productive delNS1 virus replication, suggesting that the delNS1 virus has specific oncolytic properties. Viral growth in the oncogenic ras-transfected cells is associated with a reduction of PKR activation during infection. Moreover, treatment of s.c. established N-ras-expressing melanomas in severe combined immunodeficiency mice with the delNS1 virus revealed that this virus has tumor-ablative potentials. The delNS1 virus does not replicate in nonmalignant cell lines such as melanocytes, keratinocytes, or endothelial cells. The apathogenic nature of the delNS1 virus combined with the selective replication properties of this virus in oncogenic ras-expressing cells renders this virus an attractive candidate for the therapy of tumors with an activated ras-signaling pathway.

Animals↗
PubMed2001

Penetration of dacarbazine and its active metabolite 5-aminoimidazole-4-carboxamide into cutaneous metastases of human malignant melanoma.

BACKGROUND: Dacarbazine has been on the market for approximately 3 decades but remains the most effective single agent available for the therapy of metastatic malignant melanoma (MMM). Most MMMs, however, respond poorly to dacarbazine therapy. Apart from tumor resistance at a molecular level, several studies support the notion that therapeutic failure in tumor therapy also might be attributed to an impaired transcapillary drug transfer. METHODS: On the basis of this hypothesis, the authors measured intratumor transcapillary transfer rates of dacarbazine and its active metabolite 5-aminoimidazole-4-carboxamide (AIC) by in vivo microdialysis after intravenous administration of dacarbazine at doses of 200 mg/m(2) to 1000 mg/m(2) (n = 7) in patients suffering from MMM. RESULTS: For all doses, area under the concentration curve (AUC) values for dacarbazine and AIC were not significantly different between plasma and tumor interstitium with AUC(tumor)/AUC(plasma) ratios of 0.97 +/- 0.08 (mean +/- standard error of the mean) for dacarbazine and 0.76 +/- 0.22 for AIC. AUC(0-240) values for dacarbazine and AIC measured in plasma correlated closely with corresponding AUC(0-240)values measured in the interstitium of MMMs with values of r(s) = 0.82 (P = 0.042) and r(s) = 0.90 (P = 0.037), respectively. CONCLUSIONS: The results of this study indicate favorable tumor penetration characteristics of dacarbazine and its active metabolite AIC. The relative lack of response to antineoplastic therapy with dacarbazine, thus might be explained by resistance of melanoma cells at a molecular level rather than by an inability of dacarbazine and AIC to penetrate into the interstitium of MMM.

Aged↗
PubMed2001

A ten-year analysis of demographic trends for cutaneous melanoma: analysis of 2501 cases treated at the University Department of Dermatology in Vienna (1990-1999).

BACKGROUND: The aim of the study is to provide recent demographic data on cutaneous melanoma in Austria. PATIENTS AND METHODS: Patients with primary cutaneous melanoma diagnosed between January 1, 1990 and December 31, 1999 were included in the analysis. Data were retrieved from the melanoma registry of the University Department of Dermatology in Vienna. RESULTS: In the observation period, 2501 cutaneous melanomas were diagnosed in 2427 patients (mean age: 55.4 yrs; 51.2% females). A total of 267 (10.7%) cutaneous melanomas were in situ, and 2234 (89.3%) were invasive. The median invasion thickness according to Breslow for invasive melanomas was 0.98 mm (25%-75% percentiles: 0.55-2.00 mm). We observed a significant trend towards thicker tumors with increasing age (p < 0.001). In patients less than fifty years of age, a significantly higher Breslow thickness was observed in men than in women (0.90 mm versus 0.80 mm, p = 0.03). The median Breslow thickness of invasive melanoma decreased from 1.20 mm in 1990 to 0.92 mm in 1999 (p for trend, < 0.001). Compared to women, men had melanomas more frequently on the back (43.8% versus 24.4%, p < 0.001). In women, melanomas were more frequently found on the lower legs than in males (21.5% versus 6.7%, p < 0.001). In a multivariate model, invasion thickness according to Breslow was the single most important predictor of survival. CONCLUSION: Our data confirm recent reports from other European countries with regard to the decline in tumor thickness of cutaneous melanoma. Our data also demonstrate a need for improving early diagnosis, particularly in certain subgroups of patients.

Adult↗
PubMed2001

Compliance with follow-up and prognosis among patients with thin melanomas.

The aim of this study was to report on the compliance with follow-up among patients with thin melanomas. We also examined the prognosis of patients with recurrent disease and whether there were any differences in prognosis associated with the time between the last follow-up examination and the onset of recurrence. A retrospective analysis of the records of 513 consecutive patients (50.3% males, mean age: 52.8+/-16.9 years) with thin melanomas (<1.5 mm Breslow thickness) was carried out. The estimated cumulative proportion of patients who still continued their follow-up examinations 5 years after diagnosis of the primary tumour was 55.3% (95% Confidence Interval (CI): 50.4--60.2%). The mean annual drop-out rate was 11.2%. The drop-out rate was similar for males and females and was not influenced by the patients' age or the tumour thickness. Among 263 patients who continued follow-up, 50.2% (n=132) were not compliant with the time schedule. 20 patients presented with recurrent disease after a median of 35.9 months (25--75% percentiles: 16.7--46.5 months). Six patients who did not have a follow-up examination within 1 year before the onset of recurrence presented with more advanced disease and had a worse prognosis (median survival: 12.5 months, hazard ratio: 3.5, 95% CI: 1.1--17.1, P=0.04), than those patients, who had a recent follow-up examination before the onset of recurrence (n=14, median survival: 22.3+ months). In the majority of recurrent cases with good prognosis, metastatic disease was confined to the regional lymph nodes and the presumptive diagnosis of metastatic disease was either made by palpation or by sonography of the regional lymph nodes. The observed drop-out rate of patients during the first 5 years of follow-up is substantial and does not depend on the patients' age, sex or on the tumour thickness. Although the frequency of recurrences among patients with thin melanomas is low, regular follow-up examinations including physical examination, as well as palpation and sonography of the regional lymph nodes, are essential.

Adult↗
PubMed2001

Perilesional injection of r-GM-CSF in patients with cutaneous melanoma metastases.

Based on evidence that granulocyte-macrophage colony stimulating factor (GM-CSF) induces a potent systemic antitumor immunity, we tested recombinant GM-CSF in advanced melanoma. Seven patients with histologically confirmed cutaneous melanoma metastases were treated with perilesional intracutaneous injections of recombinant GM-CSF and observed for a follow-up time of 5 y. All but two patients had a decrease in the total number of metastases. At the end of the 5 y follow-up three of the seven patients are still alive with only one patient receiving other than surgical therapy, and one patient died tumor free at the age of 93. The remaining three patients died from progressive melanoma. Perilesional intradermal GM-CSF therapy resulted in a mean survival time of 33 mo. The treatment was well tolerated and no side-effects other than local erythema at the injection sites and mild drowsiness were seen. Immunohistochemical analysis with staining for CD14 and GM-CSF receptor demonstrated an increased infiltration of monocytes into both injected and noninjected cutaneous melanoma metastases compared with lesions excised prior to the initiation of therapy. The same was true for CD4- and CD8-positive lymphocytes. This phenomenon, together with GM-CSF-induced leukocyte counts of more than 20,000 during therapy, support the possible impact of a systemic over a locally induced reaction by GM-CSF. To our knowledge this is the first report that intracutaneously injected GM-CSF results in long-lasting reduction of melanoma metastases.

Aged↗
PubMed2001

Differential expression levels of Par-4 in melanoma.

The pro-apoptotic prostate apoptosis response-4 gene product Par-4 sensitizes prostate cells to the induction of programmed cell death. In this study we examined Par-4 expression in human melanoma cell lines and melanoma metastases. The heterogeneous expression detected prompted us to investigate the biological relevance of Par-4 in a human melanoma xenotransplantation model. Overexpression of Par-4 by transfection decreased tumour development in xenotransplanted A375-C6 melanoma cells in SCID mice and correlated to an increase in tumour cell apoptosis. These data suggest that high expression of the pro-apoptotic protein Par-4 could qualify as a prognostic marker in human melanoma.

Animals↗
PubMed2001

Elevated procaspase levels in human melanoma.

In this study procaspase expression levels were investigated by Western blotting in a panel of established melanoma cell lines, transformed melanocytic cell lines and normal primary melanocytes. Upstream caspases such as procaspase-8 that contain a death effector domain were found to be overexpressed in transformed melanocytes and melanoma cell lines compared with melanocytes. Heterogeneous levels of procaspase-8 were seen in melanoma cells, including one cell line that completely lacked procaspase-8 expression. Procaspase-10 is generally overexpressed in transformed melanocytes and melanoma cell lines. Expression of the downstream procaspases-3 and -7 was increased in melanoma cells compared with normal melanocytes. Procaspases containing caspase recruitment domains such as procaspase-2 were expressed at similar levels in nearly all the cell lines investigated. Reduced levels of procaspase-1 compared with normal melanocytes were detected in transformed melanocytes and melanoma cell lines. These data indicate that procaspase levels in general increase during the malignant transformation of melanocytic cells.

Blotting, Western↗