A randomized, controlled trial of oral propranolol in infantile hemangioma.

BACKGROUND: Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited. METHODS: We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs. RESULTS: Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol. CONCLUSIONS: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).

Use of cryopreserved autologous cells for extracorporeal photochemotherapy: clinical applications.

BACKGROUND: Using autologous cryopreserved mononuclear cells (MNCs) for extracorporeal photochemotherapy (ECP) offers several advantages, such as treating patients from geographically distant care centers or maintaining ECP schedule while dramatically reducing number of apheresis sessions. We previously reported that cryopreserved cells retain their immunomodulatory properties when exposed to UVA and psoralen. To date, there are no clinical data on the use of cryopreserved MNCs for ECP ("cryo-ECP"). CASE REPORTS: Three patients were treated by cryo-ECP for refractory dermatomyositis, juvenile localized scleroderma, and acute graft-versus-host disease. For the first two patients, cryo-ECP aimed to reduce the number of apheresis sessions. Each cell product was split into three equal fractions: one was infused, and the other two were frozen for later infusion. The third patient was referred to our center from a hospital 700 km away. Fifteen apheresis procedures were performed during his stay: 12 were immediately treated and infused while three were cryopreserved. After discharge, the three cryopreserved bags were thawed, ECP-treated, and then sent back to the patient. CONCLUSION: In all three patients, cryo-ECP was safe and feasible. These cases illustrate promising clinical applications of the technique, opening perspectives for making ECP much more acceptable to patients while extending its indications.

Fetal microchimeric cells participate in tumour angiogenesis in melanomas occurring during pregnancy.

Melanoma is a major malignancy in younger individuals that accounts for 8% of all neoplasias associated with gestation. During pregnancy, a small number of fetal cells enter the maternal circulation. These cells persist and then migrate to various maternal tissues where they may engraft and differentiate, particularly if there is organ damage, adopting the phenotype of the host organ. To understand the relationship between melanoma and pregnancy, we analyzed these tumors in both humans and mice. Fetal cells were detected in 63% of human primary melanomas versus 12% in nevi during pregnancy (P = 0.034) and in 57% of B16 melanomas in pregnant mice but never in normal skin (P = 0.000022). More than 50% of these fetal cells expressed the CD34, CD31, or von Willebrand factor endothelial cell markers. In addition, the Lyve-1 lymphatic antigen was expressed by more than 30% of fetal cells in mice. In conclusion, we show that melanomas during pregnancy frequently harbor fetal cells that have an endothelial phenotype. Further studies are needed to assess whether the fetal contribution to lymphangiogenesis may alter the prognosis of the maternal tumor.

Primary cutaneous diffuse large B-cell lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases.

OBJECTIVES: To describe clinicopathologic features and to identify prognostic factors in a large series of primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL LT), as defined in the recent World Health Organization-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas. DESIGN: Retrospective multicenter study from the French Study Group on Cutaneous Lymphomas. SETTING: Nineteen departments of dermatology in 10 regions of France. PATIENTS: Sixty patients with a PCLBCL LT included in the registry of the French Study Group on Cutaneous Lymphomas. MAIN OUTCOME MEASURES: Age, sex, outcome, therapy, B symptoms, cutaneous extent, number of lesions, location (leg vs nonleg), serum lactate dehydrogenase level, and MUM-1 and Bcl-2 expression were recorded. Disease-specific survival was used as the main end point. Prognostic factors were identified using a Cox proportional hazards model. RESULTS: Primary cutaneous diffuse large B-cell lymphoma, leg type is characterized by a predilection for the leg (72%), a high proportion of Bcl-2 expression (85%), an advanced age at onset (mean age, 76 years), and frequent relapses and extracutaneous dissemination. The overall 5-year disease-specific survival rate was 41%. Location on the leg and multiple skin lesions were predictive of death in multivariate analysis. Although no variable related to therapy was significantly associated with survival, patients recently treated with combinations of anthracycline-containing chemotherapies and rituximab had a more favorable short-term outcome. CONCLUSIONS: Primary cutaneous diffuse large B-cell lymphoma, leg type is a distinct entity with a poor prognosis, particularly in patients with multiple tumors on the legs. Despite the advanced age of many patients, the prognosis could be improved with combinations of anthracycline-containing chemotherapies and rituximab.

Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study.

OBJECTIVE: To determine if a therapeutic regimen of twice-weekly applications of mechlorethamine hydrochloride and betamethasone dipropionate cream is effective in the treatment of early-stage mycosis fungoides while increasing cutaneous tolerance. DESIGN: Prospective nonrandomized study conducted from November 1999 to November 2002. SETTING: Eleven university or hospital dermatology departments in France. PATIENTS: Sixty-four consecutive patients with newly diagnosed early-stage mycosis fungoides (stage IA, n = 33; stage IB, n = 26; stage IIA, n = 5). INTERVENTIONS: Patients were treated with twice-weekly applications of a 0.02% aqueous solution of mechlorethamine followed by an application of betamethasone cream during a 6-month period. MAIN OUTCOME MEASURES: The primary end point was the rate of complete response during the treatment. Secondary end points were mean delay to achieve complete response, rate of severe cutaneous reactions of intolerance, and rate of relapse after achieving complete response. RESULTS: Thirty-seven patients (58%) had a complete response after a mean +/- SD treatment duration of 3.6 +/- 2.5 months: 20 (61%) of 33 patients with stage IA disease, 15 (58%) of 26 patients with stage IB disease, and 2 (40%) of 5 patients with stage IIA disease. Eighteen patients (28%) developed severe cutaneous reactions of intolerance that necessitated treatment discontinuation. Relapse was observed in 17 patients (46%) after a mean +/- SD time of 7.7 +/- 6.5 months. CONCLUSIONS: A regimen of twice-weekly applications of mechlorethamine and betamethasone cream is an effective treatment for early-stage mycosis fungoides. The decreased frequency of applications provides an advantage to the patient by being easy to use with limited adverse effects.

Downregulation of BRCA1 in A375 melanoma cell line increases radio-sensitivity and modifies metastatic and angiogenic gene expression.

The participation of BRCA1 (breast cancer 1) in DNA repair is well established, especially in mammary and ovarian cells. Our purpose was to develop a new in vivo radio-sensitizing therapy for melanoma. We therefore investigated the effect of downregulation of BRCA1 on irradiated melanoma cells using an anti-BRCA1 ribozyme. Our results show that BRCA1 downregulation increased radio-sensitivity of the A375 cell line, suggesting that BRCA1 could act as a caretaker in melanoma; however, as BRCA1 functions are not limited to maintaining genomic integrity but also regulate transcription and the cell cycle, we confirmed that the proliferative rate of BRCA1 downregulated clones did not change. We also demonstrate that: (1) among the major pro-angiogenic genes, FGF-2 was not increased before or after irradiation and vascular endothelial growth factor strongly inhibited after irradiation; (2) expression of two important metalloproteinases, matrix metalloproteinase 2 and 9, involved in melanoma metastasis were decreased before and after irradiation; (3) expression of their major inhibitor, tissue inhibitor of metalloproteinase, was mainly upregulated; and (4) that invasion of BRCA1 downregulated cells was modified. Together these data suggest that BRCA1 downregulation in melanoma cells did not make them more aggressive and could lead to new therapeutic strategies for this tumor, which is so difficult to control once metastasized.

Ichthyosiform mycosis fungoides.

Malignancy-associated acquired ichthyosis is well known, but the ichthyosiform subset of mycosis fungoides (MF) is rarely reported. We report on two patients with a clinical presentation for whom diagnosis of mycosis fungoides was established on histological grounds. In both cases, long term remission was obtained with non aggressive therapies. This rare condition must be added to newly described forms of MF with epidermal hyperplasia such as keratosis lichenoides chronica like MF and pilotropic MF.

Soluble IL-2 receptor: a biomarker for assessing myositis activity.

OBJECTIVE: To evaluate the clinical significance of serum soluble IL-2R (sIL-2R) in inflammatory myopathies. METHODS: Serum sIL-2R and CK levels were determined in 27 patients with IM during periods of disease exacerbation and inactive disease and were compared to 20 healthy controls and 23 controls with noninflammatory elevated CK. The performance of sIL-2R and CK tests for assessing disease activity was compared. RESULTS: sIL-2R levels were increased in patients with IM. Significantly higher sIL-2R levels were detected in patients with disease exacerbation than in patients with inactive disease. In patients with IM, the sIL-2R levels correlated with the CK levels. Based on ROC analysis, diagnostic accuracy of sIL-2R and CK tests for disease activity was similar. However, when the CK threshold was defined by the upper limit of the normal, the specificity for the CK test dropped to 58%. CONCLUSION: Serum sIL-2R level could be useful to distinguish disease exacerbation from damage in IM, especially in patients with persistent elevated CK levels when a clinical muscular worsening is noted. For discrimination of the disease activity, CK testing requires the use of a different threshold than the upper limit of the normal.

Second-line chemotherapy of disseminated malignant melanoma with cystemustine at 60 mg/m2: a phase II trial.

Nitrosoureas possess some anti-tumor activity as a single agent in metastatic melanoma (MM). In a phase II trial, we evaluated the anti-tumor effects of cystemustine chemotherapy, a new nitrosourea, as a second-line treatment. Patients were required to have histologic evidence of disseminated MM and had failed in first-line chemotherapy. Treatment comprised cystemustine given at a dose of 60 mg/m every 2 weeks by a 15-min infusion. From February 1997 to September 1999, 22 patients (median age 66 years) were enrolled and were assessable. Two complete responses, one partial response, three stable diseases and 16 progressions were observed, giving an overall response rate of 13.6%. Median duration of response was 10 months (range 4-63). Median survival of responders and non-responders was 11 and 4 months, respectively. However, hematological toxicity, particularly thrombopenia, was a limiting factor for one-third of patients. We conclude that cystemustine at 60 mg/m is active in patients who progressed after one line of chemotherapy in advanced disease, and offers the possibility of complete responses and long durations of these responses.

123I-N-(2-diethylaminoethyl)-2-iodobenzamide: a potential imaging agent for cutaneous melanoma staging.

Melanoma is a neoplasia of dramatically increasing incidence that has a propensity to spread rapidly. Early detection is fundamental and patient management requires reliable, sensitive and reproducible staging methods, such as a single examination by planar scintigraphy or single-photon emission tomography (SPET) using a radiopharmaceutical with selectivity for melanoma tissue. Among iodobenzamides reported to possess an affinity for melanoma, a new compound, N-(2-diethylaminoethyl)-2-iodobenzamide (BZA(2)), was selected for a clinical trial in view of its pharmacokinetic experimental profile in melanoma-bearing mice. Planar whole-body scintigraphy using (123)I-BZA(2) was performed in 25 patients with histologically proven cutaneous melanoma. Performance was evaluated in two groups of patients with one or more documented secondary lesions ( n=13) or with no known secondary lesions ( n=12), and results were compared with those of conventional investigation techniques. No adverse clinical or biological events were recorded. Lesions were imaged by increased tracer uptake, and good quality images were obtained 4 h after administration. After a follow-up of more than 1 year, the overall results of (123)I-BZA(2) scintigraphy on a per patient basis showed a sensitivity of 100%, a specificity of 95%, a positive predictive value of 86% and a negative predictive value of 100%. The proven secondary lesions were imaged with a sensitivity of 100% and a specificity of 91%. In seven patients with suspected metastases, the absence of (123)I-BZA(2) uptake was confirmed as true negative, and in one patient without suspected metastases, (123)I-BZA(2) scintigraphy revealed a gastric lesion. Hence eight diagnoses would have been modified by (123)I-BZA(2) scintigraphy data. (123)I-BZA(2) allowed discrimination between benign and malignant lesions and, in the case of malignancies, between those of melanomatous origin and others. This compound, which is selective for melanoma tissue, appears promising for the staging and restaging of melanoma.

The kinetics of the visible growth of a primary melanoma reflects the tumor aggressiveness and is an independent prognostic marker: a prospective study.

Primary melanoma (MM) could be a good model to test an intuitive concept: a cancer that is growing fast in its early phase is likely to have a high aggressiveness. Since MMs are visible tumors, many patients can provide information to indirectly assess the kinetics of their lesion. A prospective study was designed to assess if the kinetics of the visible growth of a primary MM, as described by the patient, could be a noninvasive prognostic marker. The ratio of MM thickness to delay between MM appearance and MM removal was used as a surrogate value for the kinetics of the MM growth. To assess the delay between MM appearance and removal, 362 patients with self-detected invasive MM fulfilled a detailed questionnaire, which provided 2 types of estimations of this delay and thus 2 melanoma kinetics indexes (MKI and MKI*). After a median follow-up of 4 years, univariate and multivariate analyses assessed whether relapse-free survival was linked to MKI or MKI*. MKI was significantly predictive of relapse-free survival (HR = 1.84 [1.51-2.25]) and relapse at 1 year (RR = 2.93 [1.84-4.69]), independently from Breslow thickness. MKI was retained in multivariate prognostic models, just after thickness and before other usual markers. MKI* was also a significant independent risk marker, although less predictive. In this model, the initial growth kinetics of a cancer reflects its aggressiveness and a high index predicts a short-term relapse. The "subjective" data obtained from patients about their MM history, although usually neglected, can thus provide a better prognostic marker than many "objective" tests.