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BACKGROUND: This phase Ib study evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed. PATIENTS AND METHODS: Pemetrexed 500 mg/m(2) with folic acid and vitamin B(12) was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1-15 without initial loading dose and 250 mg b.i.d. on days 16-30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d. RESULTS: Sixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (C(av,ss)) decreased by approximately 25% in the presence of pemetrexed. Enzastaurin C(av,ss) were approximately 40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST. CONCLUSIONS: Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.

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PURPOSE: To assess the efficacy, tolerability and safety of MTX-HSA (methotrexate (MTX) covalently linked to human serum albumin (HSA)) combined with cisplatin as first line therapy for advanced bladder cancer. METHODS: Patients (pat) were treated with a loading dose of 110 mg/m(2) of MTX-HSA followed by a weekly dose of 40 mg/m(2) starting on day 8. Cisplatin was given on day 2 of each 28 day cycle at a dose of 75 mg/m(2). RESULTS: Tumor response evaluation was possible in 7 patients. Complete response (CR) and partial response (PR) was observed in 1 patient each (overall response rate: 29%). Key toxicities included CTC Grade (G) 3/4 stomatitis in 6 patients, vomiting G3 in 1 patient, fatigue G3 in 1 patient and thrombocytopenia G3 in 3 patients. CONCLUSION: The combination of MTX-HSA with cisplatin is feasible and shows antitumor activity against urothelial carcinomas combined with an acceptable toxicity profile.

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A 46-year-old man presented with circumscribed inflammatory poikilodermatic lesions of loose skin on the upper arm. Histologic examination disclosed a heavy lymphocytic infiltrate of the whole dermis and the upper part of the subcutaneous fat tissue with a predominant T-helper phenotype and about 10% of Mac 387-positive macrophages and some scattered multinucleated giant cells. Lymphocytic cells were aligned along the epidermal basement membrane and showed focal epidermotropism. In part these cells had multilobular nuclei. The diagnosis of granulomatous mycosis fungoides versus early granulomatous slack skin was made. The patient was treated with a combination of radiotherapy (total dose 36 Gy) and interferon-alpha as a maintenance treatment which resulted in complete remission and disease-free survival of 27 months up to now.

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Owing to their relevance for growth regulation and cell adhesion monitoring the expression of galectins (endogenous beta-galactoside-binding lectins) and their binding sites has relevance for tumor biology. Using galectin-type-specific reagents (non-crossreactive antibodies for proto-type galectin-1, chimera-type galectin-3 and tandem-repeat-type galectins-4 and -8, and labeled galectins-1, -3, and -4) we determined galectin expression in cutaneous T cell lymphomas (CTCL) and controls. In addition to commonly studied galectins-1 and -3, tandem-repeat-type galectins could be detected, i.e., galectin-8 in six from 15 cases and galectin-4 in one of 15 cases. In view of relevant ligands such as bcl-2 or integrins the presence of galectins-3 and -8 seems to be possibly related to loss of proliferation control and change in cell adhesion properties that are involved in clonal expansion and epidermal spread of malignant T cell clones. Successful chemotherapy of CTCL alters galectin expression selectively as shown for liposomal doxorubicin.

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PURPOSE: Matrix metalloproteinases (MMPs) are a family of structurally related zinc-dependent endopeptidases that are able to degrade extracellular matrix components. MMPs play a role in tumor invasion and tumor metastasis. MMP-2 (also known as gelatinase A) is expressed in human melanoma cells. METHODS: In this study, we measured MMP-2 in 337 serum probes of 166 melanoma patients with a recently developed enzyme immunoassay and compared these data with the tumor stage, presence of metastases, and the levels of S100beta and soluble intracellular adhesion molecule-1 (sICAM-1) in serum. RESULTS: The mean levels were (189.2 +/- 50.8) ng/ml for MMP-2, (263.2 +/- 74.1) ng/ml for sICAM-1, and (0.424 +/- 1.568) U/ml for S100beta. There was a statistical significant correlation of MMP-2 with sICAM-1 (P=0.05) and Sl00beta (P=0.01). The mean MMP-2 levels (in ng/ml) in patients with metastatic melanoma were 196.4 +/- 54.0 versus 182.6 +/- 46.9 in non-metastasizing melanoma (P=0.037). However, there was no significant difference in MMP-2 levels between the different tumor stages. CONCLUSION: Determination of MMP-2 serum levels is of limited value as a tumor marker in melanoma, though there are higher levels in the more advanced disease.

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We present the case of an 85-year-old woman with cutaneous and subcutaneous nodules on the lower and upper leg showing the characteristic histological features of a large B-cell lymphoma of the leg. Investigations for non-Hodgkin's lymphoma with the prognostic markers matrix metalloproteinase 2 and soluble intercellular adhesion molecule 1 revealed an increased serum level of the latter. Monotherapy with perilesional interferon alpha(2a) 3 x 9 million units/week was well tolerated. The final outcome was a complete remission after 14 months with an overall survival of more than 17 months.

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We report on a 57 year old women with a long-standing course of severe rheumatoid arthritis, developing acute febrile neutrophilic dermatosis (Sweet's syndrome) in an active phase of the arthritis. Sweet's syndrome has been reported with hematologic and solid malignancies, infections and several autoimmunopathies, but in only three cases is there a coincidence with rheumatoid arthritis. We review Sweet's syndrome with regard to pathogenesis and associated disorders.

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PURPOSE: Angiosarcoma of the scalp and face is a rare malignant endothelial tumor arising mainly in elderly people. The prognosis is poor. Effective and safe treatments are warranted. METHODS: A 79-year-old woman with an angiosarcoma of the scalp larger than 5 cm in diameter was treated with intravenous liposomal doxorubicin, 20 mg per square meter body surface (i.e., 30 mg) once per month followed by radiotherapy. RESULTS: After 12 infusions of liposomal doxorubicin, we observed a partial remission with a > 50% decrease of affected area and disappearance of ulceration. After 21 infusions, however, there was no further improvement. We decided to discontinue chemotherapy but move on with radiotherapy with an electron beam using fractionated doses of 2 Gy five times per week for up to a total of 40 Gy. To ensure a maximum dose in the upper layer of the dermis a bolus technique was used. Radiotherapy was terminated due to a temporary circumscribed epidermolysis. At the end of treatment a remarkable regression of the cutaneous lesion was noted. During the subsequent 24 months she has not developed any metastatic spread. CONCLUSION: Sequential therapy of bad prognosis angiosarcoma with liposomal doxorubicin followed by radiotherapy showed a marked clinical improvement and prolonged relapse-free survival in this patient.

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Pseudoainhum is a rare disorder characterized by digital constrictions leading to autoamputation. We report a bilateral pseudoainhum of all fingers in a 64-year-old fair-skinned woman with breast cancer, systemic scleroderma, and primary biliary cirrhosis. The overlap between scleroderma and primary biliary cirrhosis with antimitochondrial antibodies M2 is also known as Reynolds' syndrome. Although pseudoainhum has been associated with many conditions, this particular association is exceptional and has yet not been described.

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PURPOSE: Pegylated liposomal doxorubicin (PEG-DOXO) was found to be effective in primary cutaneous T-cell lymphomas (CTCL). The present observation reports on follow-up and relapse-free interval in patients with CTCL. METHODS: Ten patients (one female, nine male) aged 50-78 years (mean 66.7 years) with relapsing or recalcitrant CTCL, stage I b (n = 3), II a (2), II b (3), IV a (1), and IV b (1) were treated with PEG-DOXO 20 mg m(-2) once a month with an upper limit of 400 mg or eight infusions to induce a clinical response. There was one drop out after a single infusion because of a capillary leak syndrome. RESULTS: In nine patients with PEG-DOXO the best response was a complete response (CR) in five patients and a partial response (PR) in four patients. The final outcome was CR in six, PR in two, stable disease (SD) in one, and progressive disease (PD) in another patient. The overall response rate (CR + PR) was 80% (of ten patients). The follow-up was 2-22 months (mean 12.8+/-7.1 months). The overall survival was calculated as 19.8+/-7.4 months with eight out of ten patients still alive. Response duration was 15.2+/-3.9 months, disease-free survival 13.3+/-6.1 months, event-free survival 16.7+/-9.0 months, and progression-free survival 18.2+/-6.5 months. Four patients (stage I b and II b) achieved 12-19 months of disease-free survival. The follow-up after the first course with PEG- DOXO was 2-22 months (mean 12.8+/-7.1 months). The survival rate after 12 months of follow-up was 80% (n = 5). One patient free of relapse died after 12 months because of pulmonary embolism not related to disease or treatment. Another patient died 1 month after a second course of PEG-DOXO in an advanced tumor stage of CTCL. The most frequent side effects of treatment were anemia and lymphopenia without the need of supportive treatment or dose-reduction. Only one patient developed toxicity of grade 4 (anemia). CONCLUSIONS: These results indicate that patients with relapsing or recalcitrant CTCL can achieve an 80% response rate with PEG-DOXO and long-term remissions.

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Graft-versus-host disease (GVHD) is a major complication of stem cell transplantation. Here we report a 40-year-old woman who developed an acute GVHD 30 months after transplantation. Late and very late appearance of acute GVHD has only been described in rare cases.

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BACKGROUND: Calciphylaxis is a rare syndrome developing predominantly in female patients suffering from end-stage renal disease (ESRD) with secondary hyperparathyroidism. Skin lesions begin as superficial patches that quickly progress to painful necrotic ulcers. Histopathological findings are calcification of small arteries and arterioles and infarction of subcutis and skin. The prognosis of calciphylaxis is poor due to an increased risk of systemic infection. METHODS: We report on a 50-year-old woman suffering from calciphylaxis. Initial treatments were not tolerated due to pain and therefore the patient was treated with maggot therapy and 800 mg/day of oral pentoxyfillin. RESULTS: Over a period of 6 months a complete remission of her skin lesions was achieved. CONCLUSION: Patients suffering from ulcers due to calciphylaxis may benefit from the use of maggot therapy, which cleanses ulcers and prevents systemic infection.

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Because the primary aim of adjuvant therapy for melanoma is not curative, all the possible aspects of quality of life have to be considered. One aspect of increasing importance is fertility. The effect of adjuvant interferon alpha-therapy for malignant melanoma on male fertility has not been systematically investigated. In the present study, twelve male patients with primary cutaneous melanoma (pT3, 4; N0; M0) who were taking adjuvant low-dose interferon alpha2b (3 x 3 mio U/week) for one year were included. Inhibin B--an established marker of male fertility-was measured with an immunosorbent assay before and after one year of interferon alpha-therapy to investigate whether this treatment has any influence on fertility. The results were compared with those from normal controls (n=40). The mean serum inhibin B concentration in melanoma patients before interferon therapy was 225.4 +/- 112.5 pg/mL; after treatment the level was 229.6 +/- 82.0 pg/mL. This difference was not statistically significant (p>0.05). The serum inhibin B concentration in controls was 201.5 +/- 17.1 pg/mL, which was not statistically different from either untreated or interferon-treated melanoma patients (p>0.05). We conclude that low-dose interferon alpha does not have a significant (negative) effect on inhibin B or male fertility.

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Muir-Torre syndrome is a genodermatosis in which multiple internal malignancies are associated with cutaneous sebaceous tumours and kerato-acanthomas. A 57-year-old man presented with multiple sebaceous tumours, kerato-acanthomas, verrucous carcinoma of the nose, renal cell and transitional cell carcinomas of the left kidney, adenoma of the colon and a positive family history of colon carcinoma. He was treated with interferon (IFN-alpha2a) s.c. 3 x 10(6) U three times a week along with 50 mg isotretinoin daily as well as topical isotretinoin gel. During a follow-up of 29 months, only 1 sebaceous skin tumour developed and was removed, whereas more than 30 such skin tumours had been surgically removed during the last 3 years. No evidence of internal tumour development or recurrence was found. The combination of IFN with retinoids seems to be of promise to prevent tumour development in Muir-Torre syndrome.

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BACKGROUND: Pegylated liposomes are stable, long-circulating carriers useful for delivering doxorubicin to tumor sites with a lower toxicity than the free drug. Free doxorubicin is used in several treatment protocols for non-Hodgkin's lymphoma. Although pegylated liposomal doxorubicin is currently used in the treatment of Kaposi's sarcoma, no data are available for tumors, such as primary cutaneous T-cell lymphomas (CTCLs). OBJECTIVE: Our purpose was to determine the efficacy and toxicity of pegylated liposomal doxorubicin in patients with relapsing or recalcitrant CTCL. The cumulative dose was limited to 320 mg. METHODS: A prospective pilot study was performed. Six patients (1 woman and 5 men) aged 59 to 78 years with relapsing or recalcitrant CTCL of the mycosis fungoides type, stage (Ib/IIb), were treated with pegylated liposomal doxorubicin to induce a clinical response. The drug was administered at a dosage of 20 mg m(-2) once a month. Four patients received 8 doses, and 2 patients received 6 doses. RESULTS: The best response was a complete response in 4 patients and a partial response in 2 patients. The final outcome was a complete response in 4, a partial response in 1, and progressive disease in 1 patient (overall response rate, 83%). The responders showed a decrease of lymphocytic infiltrates and activated T lymphocytes in skin biopsy specimens. Side effects were seen temporarily, ranging from grade 0 to grade 3. The most frequent side effects were mild anemia and lymphopenia. There was no need of additional therapy because of side effects. CONCLUSION: These results indicate that patients with relapsing or recalcitrant CTCL can achieve a high response rate with pegylated liposomal doxorubicin and that a monthly dose is a well-tolerated regimen.

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