Maria Grazia Bernengo

Cytotoxic/natural killer cell cutaneous lymphomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop.

Cutaneous lymphomas expressing a cytotoxic or natural killer (NK) cell phenotype represent a group of lymphoproliferative disorders for which there is currently much confusion and little consensus regarding the best nomenclature and classification.

microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C

Malignant melanoma is fatal in its metastatic stage. It is therefore essential to unravel the molecular mechanisms that govern disease progression to metastasis. MicroRNAs (miRs) are endogenous non‐coding RNAs involved in tumourigenesis. Using a melanoma progression model, we identified a novel pathway controlled by miR‐214 that coordinates metastatic capability. Pathway components include TFAP2C, homologue of a well‐established melanoma tumour suppressor, the adhesion receptor ITGA3 and multiple surface molecules. Modulation of miR‐214 influences in vitro tumour cell movement and survival to anoikis as well as extravasation from blood vessels and lung metastasis formation in vivo. Considering that miR‐214 is known to be highly expressed in human melanomas, our data suggest a critical role for this miRNA in disease progression and the establishment of distant metastases.

Prognostic Factors in Primary Cutaneous B-Cell Lymphoma: The Italian Study Group for Cutaneous Lymphomas

PURPOSE Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors. PATIENTS AND METHODS The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification. RESULTS Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94% and 85%, respectively. Compared with FCL/MZL, DLBCL, leg type, was characterized by statistically significant lower complete response rates, higher incidence of multiple cutaneous relapses and extracutaneous spreading, shorter time to progression, and shorter OS rates. The only variable with independent prognostic significance on the OS was the clinicopathologic diagnosis according to the WHO-EORTC classification (DLBCL, leg-type, showed a significantly worse prognosis v FCL and MZL; P < .001), whereas the only variable with independent prognostic significance on disease-free survival was the presence of a single cutaneous lesion (P = .001). CONCLUSION Our study identifies a possible PCBCL subclassification and the extent of cutaneous involvement as the two most relevant prognostic factors in PCBCL. These data can be considered reasonably as the clinical background for an appropriate management strategy.

Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients.

Based on the activity of gemcitabine in heavily pretreated patients with cutaneous T‐cell lymphoma (CTCL), the objective of the current study was to determine the role of gemcitabine in the treatment of patients with advanced, untreated CTCL.

T-cell receptor gamma gene rearrangement by multiplex polymerase chain reaction/heteroduplex analysis in patients with cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome) and benign inflammatory disease: correlation with clinical, histological and immunophenotypical findings.

Background  A dominant T‐cell clone can be detected by polymerase chain reaction (PCR) in 40–90% of cutaneous samples from patients with cutaneous T‐cell lymphoma (CTCL).

Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study

BACKGROUND The clinical features and the prognostic relevance of vitiligo lesions in melanoma patients are still controversial. This prospective observational study was designed to characterise the clinical features of melanoma-associated vitiligo, to analyse the association with other autoimmune manifestations and to ascertain whether the development of vitiligo lesions carries a prognostic relevance on the clinical course of melanoma. MATERIALS AND METHODS A total of 2954 consecutive patients have been included; multivariate analyses of distant metastasis-free survival (DMFS) and overall survival (OS) were carried out to ascertain the independent prognostic role of vitiligo as a time-dependent covariate. RESULTS Vitiligo was demonstrated in 83 of 2954 melanoma patients (2.8%). A significantly higher percentage of autoimmune diseases was demonstrated in vitiligo patients (7 of 83) with respect to patients without vitiligo (80 of 2871) (P = 0.004). Multivariate analyses selected the time-dependent covariate vitiligo as the favourable independent prognostic variable associated to a longer DMFS in stage III and a higher OS in both stage III and stage IV. CONCLUSION Melanoma-associated vitiligo should be considered as a distinct clinical entity, separate from vitiligo vulgaris, and identifies a subgroup of patients characterised by a high prevalence of immune-mediated diseases and by a favourable prognosis.

Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial.

BACKGROUND Panobinostat is a potent, oral pan-deacetylase inhibitor (pan-DACi) that increases the acetylation of proteins involved in multiple oncogenic pathways. Here, panobinostat is studied in bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS Patients with CTCL subtypes mycosis fungoides and Sézary syndrome who received ⩾2 prior systemic therapy regimens received panobinostat (20mg) three times every week. The primary objective was overall response rate (ORR) as determined by a combined evaluation of skin disease and involvement of lymph node and viscera. Disease progression was defined as an unconfirmed, ⩾25% increase in modified Severity Weighted Assessment Tool (mSWAT) compared with nadir. RESULTS Seventy-nine bexarotene-exposed and 60 bexarotene-naïve patients were enrolled. Reductions in baseline mSWAT scores were observed in 103 patients (74.1%). The ORR was 17.3% in all patients in the primary analysis (15.2% and 20.0% in the bexarotene-exposed and -naïve groups, respectively). The median progression-free survival was 4.2 and 3.7 months in the bexarotene-exposed and -naïve groups, respectively. The median duration of response was 5.6 months in the bexarotene-exposed patients and was not reached at data cutoff in the bexarotene-naïve patients. Additional responses were observed when less-stringent progression criteria were used. The most common adverse events were thrombocytopenia, diarrhoea, fatigue and nausea. Thrombocytopenia and neutropenia were the only grade 3/4 adverse events in >5% of patients and were manageable. CONCLUSION Despite a very conservative definition of disease progression, panobinostat demonstrated activity with a manageable safety profile in bexarotene-exposed and -naïve CTCL patients. ClinicalTrials.gov Identifier: NCT00425555.

The Sézary syndrome: hematologic criteria

The hematologic criteria for Sézary syndrome that were recently proposed by the International Society on Cutaneous Lymphomas are critically evaluated. Based on the experience at two institutions, revisions to the definition for Sézary syndrome are proposed.

CD56-positive cutaneous lymphoma: a poorly recognized entity in the spectrum of primary cutaneous disease.

CD56‐positive (CD56+) lymphomas, characterized by the expression of the neural cell adhesion molecule on pathological lymphocytes, share a frequent extranodal involvement and a generally aggressive course. Five CD3‐ CD56+ lymphoma patients presenting with nodular lesions were identified among 180 immunophenotyped cutaneous lymphomas. All the patients were men, with ages ranging from 55 to 78 years. After staging, two patients were diagnosed as having primary cutaneous lymphomas: the remaining three had the secondary cutaneous type. The clinical course was aggressive and four patients died within 8 months from diagnosis. The remaining patient is still alive after a 17‐month follow‐up. The histological diagnosis was immunoblastic lymphoma in two patients, and medium and large cell pleomorphic lymphoma in three. The angiocentric infiltrate was located mainly in the dermis: azurophilic granules were present in three of the five patients. Immunogenotypic analyses suggested the natural killer cell origin of these neoplasias: all cases exhibited a CD56+ CD3‐ CD5‐ T‐cell receptor (TCR) silent phenotype, and Southern blot analysis showed a germline configuration of the TCR β‐chain gene.

VEGF-165 serum levels and tyrosinase expression in melanoma patients: correlation with the clinical course.

Vascular endothelial growth factor (VEGF) is known to play a crucial role in the growth and metastatization of solid tumours. In cancer patients, high VEGF serum levels correlate with tumour status and prognosis, but to date few data have been reported concerning VEGF in melanoma patients. In the present study, immunoenzymatic and reverse transcription-polymerase chain reaction (RT-PCR) techniques were used to detect VEGF-165 serum levels and the presence of tyrosinase mRNA, respectively, in the peripheral blood of a cohort of 155 melanoma patients at different clinical stages (30 stage I, 40 stage II, 40 stage III and 45 stage IV; AJCC classification). Data were compared with both the extent of the disease and the clinical course. The aim was to assess the relationship between VEGF serum levels, the presence of detectable circulating melanoma cells and melanoma progression. A significant increase in VEGF serum levels was found in melanoma patients, in particular in those with metastatic disease; a higher incidence of relapses was found in stage I–III disease-free patients who showed an increase in VEGF during follow-up. VEGF serum levels were significantly higher in patients with detectable circulating melanoma cells than in those with negative tyrosinase mRNA expression. The finding of both an increase in VEGF and the presence of detectable melanoma cells during follow-up was associated with a relapse rate of 81%. The relapse rate was significantly lower when either of the two parameters were present separately. Multivariate analysis of both overall survival and time-to-progression selected baseline tyrosinase expression in peripheral blood but not VEGF serum levels as an independent prognostic factor.