Hubert Pehamberger

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.

Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group

PURPOSE Chemotherapy resistance in melanoma has been linked to antiapoptotic effects mediated by Bcl-2 protein. We evaluated whether targeting Bcl-2 using an antisense oligonucleotide (oblimersen sodium) could improve the efficacy of systemic chemotherapy in patients with advanced melanoma. PATIENTS AND METHODS We randomly assigned chemotherapy-naïve patients with advanced melanoma to treatment with dacarbazine (1,000 mg/m2) alone or preceded by a 5-day continuous intravenous infusion of oblimersen sodium (7 mg/kg/d) every 3 weeks for up to eight cycles. Patients were stratified by Eastern Cooperative Oncology Group performance status, liver metastases, disease site, and serum lactate dehydrogenase (LDH). The primary efficacy end point was overall survival. RESULTS Among 771 patients randomly assigned, the addition of oblimersen to dacarbazine yielded a trend toward improved survival at 24-month minimum follow-up (median, 9.0 v 7.8 months; P = .077) and significant increases in progression-free survival (median, 2.6 v 1.6 months; P < .001), overall response (13.5% v 7.5%; P = .007), complete response (2.8% v 0.8%), and durable response (7.3% v 3.6%; P = .03). A significant interaction between baseline serum LDH and treatment was observed; oblimersen significantly increased survival in patients whose baseline serum LDH was not elevated (median overall survival, 11.4 v 9.7 months; P = .02). Neutropenia and thrombocytopenia were increased in the oblimersen-dacarbazine group; however, there was no increase in serious infections or bleeding events. CONCLUSION The addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes in patients with advanced melanoma and increased overall survival in patients without an elevated baseline serum LDH.

In vivo epiluminescence microscopy of pigmented skin lesions. I. Pattern analysis of pigmented skin lesions

The importance of recognizing early melanoma is generally accepted. Because not all pigmented skin lesions can be diagnosed correctly by their clinical appearance, additional criteria are required for the clinical diagnosis of such lesions. In vivo epiluminescence microscopy provides for a more detailed inspection of the surface of pigmented skin lesions, and, by using the oil immersion technic, which renders the epidermis translucent, opens a new dimension of skin morphology by including the dermoepidermal junction into the macroscopic evaluation of a lesion. In an epiluminescence microscopy study of more than 3000 pigmented skin lesions we have defined morphologic criteria that are not readily apparent to the naked eye but that are detected easily by epiluminescence microscopy and represent relatively reliable markers of benign and malignant pigmented skin lesions. These features include specific patterns, colors, and intensities of pigmentation, as well as the configuration, regularity, and other characteristics of both the margin and the surface of pigmented skin lesions. Pattern analysis of these features permits a distinction between different types of pigmented skin lesions and, in particular, between benign and malignant growth patterns. Epiluminescence microscopy is thus a valuable addition to the diagnostic armamentarium of pigmented skin lesions at a clinical level.

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.

Epiluminescence microscopy : a useful tool for the diagnosis of pigmented skin lesions for formally trained dermatologists

BACKGROUND AND DESIGN Epiluminescence microscopy (ELM) is a noninvasive technique that, by employing the optical phenomenon of oil immersion, makes subsurface structures of the skin accessible for in vivo examination and thus provides additional criteria for the clinical diagnosis of pigmented skin lesions. At present, almost all studies about the value and clinical importance of ELM are based on data derived from ELM experts (ie, dermatologists specifically trained in this technique). In the present study, we attempt to determine whether the clinical diagnosis of pigmented skin lesions is significantly improved using ELM and whether ELM-trained individuals and dermatologists not trained in this technique profit equally from this technique. Randomly selected histologically proven pigmented skin lesion specimens, photographed with (ELM) and without oil immersion (surface microscopy) were presented by slide projection to six ELM experts and 13 ELM nonexperts (ie, dermatologists not formally trained in ELM) for diagnosis. To evaluate the diagnostic performance of ELM experts and nonexperts with and without the oil immersion technique (ie, ELM vs surface microscopy), the following parameters were obtained: intraobserver and interobserver agreement by kappa statistics and sensitivity and specificity of diagnostic performance. RESULTS Our results show that by using the ELM technique the ELM experts reach a substantially better intraobserver agreement than nonexperts (median kappa, 0.56 vs 0.36). The interobserver agreement was markedly increased in the ELM experts group (average gain, 7%) but decreased in the ELM nonexperts group (average loss, 6%). The sensitivity of diagnosis was significantly increased in the ELM experts group (average gain, 10%), but decreased in the nonexperts group (average loss, 10%). Finally, the specificity of diagnosis was excellent in the ELM experts group, both with and without oil immersion (0.91) and was somewhat improved by ELM in the nonexperts group (0.77 vs 0.85). CONCLUSIONS We conclude that the ELM technique increases sensitivity in formally trained dermatologists, but may decrease the diagnostic ability in dermatologists not formally trained in the ELM technique. Consequently, formal broad-based training in ELM should be offered to the dermatologic community.

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study

BACKGROUND This phase II study evaluated the safety and activity of ipilimumab, a fully human mAb that blocks cytotoxic T-lymphocyte antigen-4, in patients with advanced melanoma. PATIENTS AND METHODS Patients with previously treated, unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. The primary end point was best overall response rate (BORR) using modified World Health Organization (WHO) criteria. We also carried out an exploratory analysis of proposed immune-related response criteria (irRC). RESULTS BORR was 5.8% with a disease control rate (DCR) of 27% (N = 155). One- and 2-year survival rates (95% confidence interval) were 47.2% (39.5% to 55.1%) and 32.8% (25.4% to 40.5%), respectively, with a median overall survival of 10.2 months (7.6-16.3). Of 43 patients with disease progression by modified WHO criteria, 12 had disease control by irRC (8% of all treated patients), resulting in a total DCR of 35%. Adverse events (AEs) were largely immune related, occurring mainly in the skin and gastrointestinal tract, with 19% grade 3 and 3.2% grade 4. Immune-related AEs were manageable and generally reversible with corticosteroids. CONCLUSION Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.

Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group.

PURPOSE Patients with primary cutaneous melanoma with a Breslow thickness > or = 1.5 mm have only a 30% to 70% probability of survival after surgery, and no adjuvant therapy has so far improved this outcome. Since interferon alfa-2a (IFNalpha2a) exhibits antitumor activity in metastatic melanoma, we investigated whether adjuvant IFNalpha2a diminishes the occurrence of metastases and thus prolongs disease-free survival in melanoma patients after excision of the primary tumor. PATIENTS AND METHODS In a prospective randomized study, 311 melanoma patients with a Breslow thickness > or = 1.5 mm were assigned to either adjuvant IFNalpha2a treatment (n = 154) or observation (n = 157) after excision of the primary tumor. IFNalpha2a was given daily at a dose of 3 mIU subcutaneously (s.c.) for 3 weeks (induction phase), after which a dose of 3 mIU s.c. three times per week was given over 1 year (maintenance phase). RESULTS Prolonged disease-free survival was observed in patients treated with IFNalpha2a versus those who underwent surgery alone. This difference was significant (P = .02) for all patients enrolled onto the study (intention-to-treat analysis) at a mean observation time of 41 months. Subgroup analysis showed that Breslow tumor thickness had no influence on treatment results in the groups of patients investigated. CONCLUSION Adjuvant IFNalpha2a treatment diminishes the occurrence of metastases and thus prolongs disease-free survival in resected primary stage II cutaneous melanoma patients.

Influenza Virus NS1 Protein Counteracts PKR-Mediated Inhibition of Replication

ABSTRACT The availability of an influenza virus NS1 gene knockout virus (delNS1 virus) allowed us to establish the significance of the biological relationship between the influenza virus NS1 protein and double-stranded-RNA-activated protein kinase (PKR) in the life cycle and pathogenicity of influenza virus. Our results show that the lack of functional PKR permits the delNS1 virus to replicate in otherwise nonpermissive hosts, suggesting that the major function of the influenza virus NS1 protein is to counteract or prevent the PKR-mediated antiviral response.

New common variants affecting susceptibility to basal cell carcinoma

In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 × 10−9). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 × 10−9), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 × 10−10). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.

In vivo epiluminescence microscopy of pigmented skin lesions. II. Diagnosis of small pigmented skin lesions and early detection of malignant melanoma.

Pattern analysis by epiluminescence microscopy of pigmented skin lesions was tested in a study of 318 small pigmented skin lesions that were diagnostically equivocal when examined with the naked eye. An improvement of clinical diagnosis was achieved by epiluminescence microscopy for practically all lesions, both benign and malignant, and was equally impressive for melanocytic and nonmelanocytic lesions. Improvement in diagnostic accuracy was as follows: for small nodular melanomas, from 50% to 70%; for superficial spreading melanoma in situ, from 46% to 80%; for invasive superficial spreading melanoma, from 64% to 90%; and for early lentigo maligna and lentigo maligna melanoma, from 67% to 88%. Conversely, the diagnosis of pigmented Spitz nevi improved from 46% to 93% and of pigmented basal cell carcinomas from 60% to 90%, which appears equally important because most of these lesions had clinically been considered to represent melanomas. The use of epiluminescence microscopy also resulted in considerable improvement in the diagnosis of dysplastic nevi, which was particularly helpful in making therapeutic decisions. Epiluminescence microscopy greatly expands the diagnostic armamentarium available for pigmented skin lesions at a clinical level and thus increases the chances of detecting or ruling out melanoma in its earliest stages.