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Adjuvant treatment with interferon-α (IFN-α) for patients with malignant melanoma can improve relapse-free and overall survival, but IFN-associated side effects may reduce patient's quality of life. The aim of the study was to prospectively evaluate health-related quality of life (HRQoL) in patients with melanoma before and during Low-Dose IFN-α therapy. In a prospective multicenter trial conducted by the Dermatologic Cooperative Oncology Group, 850 patients with cutaneous stage II malignant melanoma received a standard Low-Dose of IFN-α-2a. We evaluated HRQoL using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 questionnaire at baseline and after 3, 6, and 12 months of IFN-α treatment in 282 patients. Nine of 15 subscales showed significant poorer results after 3 months of adjuvant IFN treatment. Symptoms included reduced physical functioning, reduced cognitive functioning, fatigue, nausea, pain, dyspnea, insomnia, diarrhea, and loss of appetite. We did not find a significant change over time for role, emotional, or social functioning. Only cognitive functioning and dyspnea continuously worsened through the twelfth month. At baseline women had significantly lower scores for physical and emotional functioning and for fatigue compared with men. During treatment, women scored significantly poorer on physical functioning, emotional functioning, fatigue, pain, and constipation subscales. Patients who reported having a bad or very bad QoL before treatment were 5.8 times more likely to discontinue treatment early because of psychiatric problems. We conclude that adjuvant low-dose IFN treatment is associated with significant deterioration of HRQoL. Specific psychosocial care should be offered especially for patients who report lower HRQoL and emotional problems before treatment to prevent early discontinuation.

Nerve injury leads to sensitization mechanisms in the peripheral and central nervous system which involve transcriptional and post-transcriptional modifications in sensory nerves. To assess protein regulations in the spinal cord after injury of the sciatic nerve in the Spared Nerve Injury model (SNI) we performed a proteomic analysis using 2D-difference gel electrophoresis (DIGE) technology. Among approximately 2300 protein spots separated on each gel we detected 55 significantly regulated proteins after SNI whereof 41 were successfully identified by MALDI-TOF MS. Out of the proteins which were regulated in the DIGE analyses after SNI we focused on the carboxypeptidase A inhibitor latexin because protease dysfunctions contribute to the development of neuropathic pain. Latexin protein expression was reduced after SNI which could be confirmed by Western Blot analysis, quantitative RT-PCR and in-situ hybridisation. The decrease of latexin was associated with an increase of the activity of carboxypeptidase A indicating that the balance between latexin and carboxypeptidase A was impaired in the spinal cord after peripheral nerve injury due to a loss of latexin expression in spinal cord neurons. This may contribute to the development of cold allodynia because normalization of neuronal latexin expression in the spinal cord by AAV-mediated latexin transduction or administration of a small molecule carboxypeptidase A inhibitor significantly reduced acetone-evoked nociceptive behavior after SNI. Our results show the usefulness of proteomics as a screening tool to identify novel mechanisms of nerve injury evoked hypernociception and suggest that carboxypeptidase A inhibition might be useful to reduce cold allodynia., (© 2011 Kühlein et al.)

The purpose of the present study was to evaluate the incidence, spectrum and extent of psychiatric symptoms in patients with malignant melanoma (MM) before and during adjuvant treatment with interferon-alpha (IFN-alpha). 850 patients with cutaneous MM of > or =1.5 mm tumor thickness received standard low-dose IFN-alpha 2a in this prospective multicenter trial of the Dermatologic Cooperative Oncology Group (DeCOG). Psychiatric symptoms were evaluated at baseline and after 3, 6, and 12 months with the Beck Depression Inventory (BDI) and the Symptom Check List 90-Revised (SCL 90-R). In all, 282 patients completed all questionnaires. Mean BDI depression scores increased significantly during the first 6 months of IFN-alpha treatment (P < or =0.001), followed by a mild but not significant decrease. Also mean SCL 90-R scores increased significantly during the first 3 months of adjuvant treatment with IFN-alpha (P< or =0.001) and remained elevated until month 12 (P< or =0.001). Only 5% developed BDI scores >10, indicating a clinically significant depressive syndrome and only 1.4% reached a BDI score > or =18, indicating a moderate to severe depressive syndrome. Patients, who dropped-out early from psychiatric reasons, had significantly increased BDI and SCL-90R scores at baseline. Women scored higher in both scales before and during treatment if compared with men. In conclusion, adjuvant treatment with IFN-alpha was associated with a significant increase of BDI- and SCL 90-R scores. A higher pretreatment depression score was found to be a risk factor for an early drop-out during therapy. Pretreatment screening and an interdisciplinary care of the patients is recommended.

Purpose: In vitro sensitivity assays are promising tools to predict the individual outcome of different chemotherapy regimens. However, a direct association between in vitro and in vivo chemosensitivity has to be shown by clinical studies. This multicenter phase II trial was aimed to investigate the efficacy of a sensitivity-directed, first-line chemotherapy in metastasized melanoma patients, and to prove an association between in vitro sensitivity and therapy outcome., Patients and Methods: The primary study end point was objective response; secondary end points were safety, overall survival, and progression-free survival. Viable tumor cells obtained from metastatic lesions were tested for chemosensitivity to seven single drugs and five drug combinations using an ATP-based luminescence viability assay., Results: Out of 82 recruited patients (intention-to-treat), 57 received assay-directed chemotherapy and 53 were evaluable for all study end points (per protocol). The drug combinations used were gemcitabine+treosulfan, paclitaxel+cisplatin, paclitaxel+doxorubicin, and gemcitabine+cisplatin. The per protocol population could be divided into 22 (42%) chemosensitive and 31 (58%) chemoresistant patients by an arbitrary chemosensitivity index. Objective response was 36.4% in chemosensitive patients compared with 16.1% in chemoresistant patients (P=0.114); progression arrest (complete response+partial response+stable disease) was 59.1% versus 22.6% (P=0.01). Chemosensitive patients showed an increased overall survival of 14.6 months compared with 7.4 months in chemoresistant patients (P=0.041)., Conclusion: In vitro chemosensitivity testing may be worthy of further exploration to see if it could be a useful tool to predict the outcome of melanoma patients treated with a sensitivity-directed chemotherapy. Therefore, these preliminary results will be evaluated by a planned phase III trial using a randomized, standard-regimen controlled setting.

Purpose: Temozolomide (TMZ) has shown efficacy in metastatic melanoma equal to that of dacarbazine (DTIC), the standard chemotherapeutic agent for melanoma. As the combination with interferon-alfa (IFN-alpha) appears superior to single-agent DTIC regarding response rates, the purpose of this study was to compare TMZ alone and TMZ plus IFN-alpha in terms of objective response (OR), overall survival, and safety in a prospective, randomized, multicenter trial., Patients and Methods: Two hundred ninety-four patients with untreated stage IV metastatic melanoma (American Joint Committee on Cancer staging system) were randomly assigned to receive either oral TMZ alone (200 mg/m2/day; days 1 through 5 every 28 days) or in combination with subcutaneous IFN-alpha (5 MU/m2; days 1, 3, and 5 every week)., Results: Two hundred eighty-two patients were eligible for an intent-to-treat analysis, 271 patients were treated per protocol. In the TMZ + IFN-alpha arm, 33 (24.1%) of 137 patients responded to therapy (partial or complete remission) whereas in the monotherapy arm, in 18 (13.4%) of 134 patients, a response was evident. Thus, the response rate was significantly higher in the combination arm (P = .036). Median survival time was 8.4 months for patients treated with TMZ (95% CI, 7.07 to 9.27) and 9.7 months for those treated with the combination (95% CI, 8.26 to 11.18; P = .16). Dose modifications and interval prolongations due to hematologic toxicity were significantly more frequent in the TMZ + IFN-alpha arm (P < .001)., Conclusion: In metastatic melanoma treatment with TMZ + IFN-alpha leads to a significantly superior OR rate compared to treatment with TMZ alone, which did not translate into prolonged survival in our study population.

New blood vessel formation is essential for the growth and metastasis of many cancers. As a result, antitumor activities of various angiogenesis inhibitors have been intensely explored in various tumors. Recent preclinical studies suggest that certain conventional cytotoxic agents can function as antiangiogenic drugs when administered at comparatively low doses on a continuous or very frequent schedule. Such antiangiogenic 'metronomic' scheduling of chemotherapy without extended rest periods has been shown to exert significant therapeutic antitumor efficacy with very limited toxicity in different tumor models. Combining metronomic low-dose chemotherapy regimens with specific angiogenesis inhibitors further increases efficacy. Based on the promising preclinical studies, it is anticipated that metronomic chemotherapy in combination with angiogenesis inhibitors will prove effective in clinical trials in terms of survival prolongation. While considerable progress may derive from larger randomized clinical studies, only joint efforts between basic and clinical research will ultimately advance the new paradigm of long-term metronomic antiangiogenic chemotherapy, which carries the prospect of turning cancer into a more controllable chronic disease at minimal toxicity.

Purpose: The safety and efficacy of oral metronomic low-dose treosulfan chemotherapy in combination with the cyclooxygenase-2 (COX-2) inhibitor rofecoxib as a compound with antiangiogenic potential, a therapeutic regimen optimally targeting endothelial cells instead of tumor cells, were assessed in pretreated advanced melanoma patients., Methods: Endothelial cells were analyzed for proliferation, apoptosis and cytotoxicity in response to increasing concentrations of treosulfan, either in the absence or presence of COX-2 inhibitor, to determine whether inhibition of COX-2 enhanced the effect of treosulfan on cell function. In a clinical pilot study, 12 consecutive patients with pretreated advanced melanoma, meeting the eligibility criteria were enrolled. Patients received combined daily treosulfan chemotherapy (500 mg) with rofecoxib (25 mg). Metastatic lesions were assessed every 12 weeks. Patients with responsive or stable disease were eligible for a further 12-week treatment period. Response criteria according to the WHO handbook for reporting results of cancer treatment were applied. Side effects were classified according to the National Cancer Institute's Common Toxicity Criteria v2.0., Results: At noncytotoxic concentrations, treosulfan inhibited endothelial cell proliferation in a dose-dependent fashion. Simultaneous inhibition of COX-2 significantly increased the extent to which treosulfan suppressed cell proliferation, without inducing cytotoxicity. In the pilot study in which 12 patients were treated, toxicity was mild; only hematologic toxicity of grade II was seen. An objective response was noted in one patient, and four patients showed stabilization of their disease for 24 weeks (one) and 36 weeks (three). The patient who had a partial response subsequently showed stable disease for 48 weeks. The median survival time was 13 months., Conclusions: As increases in response rates following polychemo- or biochemotherapy have not been shown to correlate with prolongation in overall survival, more durable control of metastatic melanoma represents an attractive therapeutic goal. Thus, regimens scheduled to primarily target endothelial cells may potentially provide a palliative alternative that preserves quality of life in the absence of significant treatment-related toxicity.

Transmembrane signaling of the CXC chemokine stromal cell-derived factor-1 (SDF-1) is mediated by CXCR4, a G protein-coupled receptor initially identified in leukocytes and shown to serve as a coreceptor for the entry of HIV into lymphocytes. Characterization of SDF-1- and CXCR4-deficient mice has revealed that SDF-1 and CXCR4 are of vital developmental importance. To study the role of the SDF-1/CXCR4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cDNA encoding SDF-1 of the lower vertebrate Xenopus laevis (xSDF-1). Recombinant xSDF-1 was produced in insect cells, purified, and functionally characterized. Although xSDF-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)SDF-1alpha in terms of activating both X. laevis CXCR4 and hCXCR4. Thus, both xSDF-1 and hSDF-1alpha promoted CXCR4-mediated activation of heterotrimeric G(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells. Analysis of the time course of xSDF-1 mRNA expression during Xenopus embryogenesis revealed a tightly coordinated regulation of xSDF-1 and X. laevis CXCR4. xSDF-1 mRNA was specifically detected in the developing CNS, incipient sensory organs, and the embryonic heart. In Xenopus, CXCR4 mRNA appears to be absent from the heart anlage, but present in neural crest cells. This observation suggests that xSDF-1 expressed in the heart anlage may attract cardiac neural crest cells expressing CXCR4 to migrate to the primordial heart to regulate both septation of the cardiac outflow tract and differentiation of the myocardium during early heart development.

We here report an uncommon association of Sweet's syndrome with non-Hodgkin lymphoma, in which the skin symptoms led to a diagnosis of the underlying disease. Association with the disease was implied by resolution of skin lesions during chemotherapy and reappearance of skin symptoms after renewed progression of the non-Hodgkin lymphoma.

Background: The etiopathology of chronic eczematous lesions of the palms and/or soles remains elusive in a considerable proportion of patients. Accumulating evidence suggests that a rare variant of mycosis fungoides (MF)-type cutaneous T cell lymphoma (CTCL) restricted to the palms and/or soles may mimic common palmoplantar dermatoses., Objective: In the present study, we analyzed the clinical and histological characteristics of 3 adult patients with preexisting nonclassified chronic palmoplantar eczema poorly responding to standard therapies. Palmar and/or plantar MF was eventually diagnosed., Methods: The course of the disease, response to previous therapies and dermatological features are described, results of histochemical and immunohistochemical analyses are reported, including T cell receptor gamma gene rearrangement where obtainable., Results: Onset of cutaneous lesions with broad clinical variation was experienced 2-10 years prior to diagnosis; conventional therapies led to short-time or partial remission only; except for 1 patient, the epidermotropic infiltrate was predominantly composed of CD4-positive cells; topical photochemotherapy seems to result in more durable responses., Conclusion: As therapeutic strategies for this disease variant differ from symptomatic standard treatment regimens, awareness of MF-type CTCL as a relevant differential diagnosis of palmoplantar eczema should be expanded to prevent delay in diagnosis and adequate therapy., (Copyright 2002 S. Karger AG, Basel)

Background: Autologous hair transplantation and its combination with flap or reduction procedures is a common surgical approach to cover defects in cicatricial alopecias. Due to the poor recipient conditions present in scar tissue, it is crucial to minimize the trauma exerted on implantation holes in order to achieve good transplantation results., Objective: We sought to evaluate the "cold"-ablative properties of the Er:YAG laser for the generation of recipient holes in cicatricial alopecia., Methods: Patients with cicatricial alopecia of diverse etiology were treated with Er:YAG laser-assisted hair transplantation. Mini- or micrografts were inserted into recipient holes ablated with a pulse energy of 900-1200 mJ and a spot size of 1.0-1.6 mm., Results: A fluence of 80-120 J/cm2 and 8-12 pulses gave an almost ideal combination of minimal thermal damage and tissue ablation down to the subcutis. With an apparent mini- and micrograft survival of 95% we achieved good cosmetic results after two to five transplant sessions in all patients., Conclusion: The Er:YAG laser is a novel effective tool to ablate recipient holes for autologous hair transplantation in cicatricial alopecia.

Background: The efforts to treat localized scleroderma, including therapies with potentially hazardous side effects, are often unsatisfactory. Recently, PUVA-bath photochemotherapy has been proven highly effective in the treatment of localized scleroderma. Another form of topical PUVA therapy, 8-methoxypsoralen (8-MOP) containing cream or gel preparations, has been proven to be as effective as PUVA-bath therapy for palmoplantar dermatoses., Objective: We sought to assess the efficacy of PUVA-cream photochemotherapy in patients with localized scleroderma., Methods: Four patients with localized scleroderma were included in the study. Diagnosis was confirmed by 20 MHz ultrasound assessment as well as pretreatment skin biopsy specimens from lesional skin. PUVA-cream therapy was performed 4 times a week; all patients received 30 treatments., Results: PUVA-cream photochemotherapy induced significant clinical improvement or clearance of localized scleroderma in all patients. Clearance was documented by clinical features as well as by 20 MHz ultrasound and histopathologic analysis., Conclusion: PUVA-cream phototherapy can be highly effective in patients with localized scleroderma even if previous therapy was unsuccessful.

When size and location of a keratoacanthoma along with patient-related factors argue against surgical treatment, intralesional methotrexate shows to be an effective, easy and inexpensive alternative. The case report presented validates this treatment modality., (Copyright 2000 S. Karger AG, Basel)