Tim Graefe

Treatment of relapsing or recalcitrant cutaneous T-cell lymphoma with pegylated liposomal doxorubicin☆☆☆★

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-Hodgkins lymphoma. Although pegylated liposomal doxorubicin is currently used in the treatment of Kaposis 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.

Pegylated doxorubicin for primary cutaneous T-cell lymphoma: a report on ten patients with follow-up

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.

Angiosarcoma of the scalp: treatment with liposomal doxorubicin and radiotherapy

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.

Galectin fingerprinting by immuno- and lectin histochemistry in cutaneous lymphoma

Abstract. Owing to their relevance for growth regulation and cell adhesion monitoring the expression of galectins (endogenous β-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.

Muir-Torre Syndrome – Treatment with Isotretinoin and Interferon Alpha-2a Can Prevent Tumour Development

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-α2a) s.c. 3 × 106 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.

Erythema multiforme-like drug eruption with oral involvement after intake of leflunomide.

Leflunomide is an antirheumatic agent of the type of a ‘disease-modifying antirheumatic drug’. In rare cases, severe skin reactions up to the extreme expression of toxic epidermal necrolysis have been observed. A female patient with rheumatoid arthritis had been treated with systemic steroids and methotrexate for 2 years. Five weeks prior to admission to our hospital methotrexate was replaced by leflunomide. Three weeks after initiation of leflunomide therapy a progressive generalized erythema with blistering formation occurred accompanied by increase of body temperature, chills and erosive lesions on the lips and oral mucosa. The palmar and plantar surfaces revealed edema, erythema and pulpitis with epidermolysis. On histologic examination necrotic keratinocytes and epidermal spongiosis were observed. After administration of high-dose prednisolone and topical treatment the patient recovered within 14 days. This is one of the few cases of severe drug reaction after intake of leflunomide. Therefore, the indication of this relatively new drug should be considered carefully.

Botulinum toxin A for focal hyperhidrosis in leg amputees: a case report.

Sir, Among the side-effects arising with a prosthesis, ®tting problems and dermatological complaints are the most frequent. The importance of prevention or early recognition of skin problems cannot be overemphasized to avoid bed rest and other handicaps (1). One major problem in leg amputees is stump hyperhidrosis. The use of silicone pads and other rather occlusive materials in prostheses aggravates hyperhidrosis, leading to lubrication. Whereas occlusion alone can cause hydration of the stratum corneum, the combination of lubrication with occlusion initiates prolonged disturbance of the skins barrier function (2). Hyperhidrosis is linked to discomfort and a number of skin complaints including malodour, folliculitis and other bacterial and mycological skin disease, and the development of irritant and allergic contact dermatitis (1). Several attempts have been made to treat hyperhidrosis including topical astringent agents and tap water iontophoresis (3). Recently, botulinum toxin A (BTXA) has been used to treat focal hyperhidrosis (4, 5). BTXA is a zinc endopeptidase. The toxin is internalized by endocytosis at the axon terminal and becomes fully activated by disulphide reduction once inside the cell. BTXA targets SNAP-25 involved in acetylcholine release (6). We report a patient with leg amputation and hyperhidrosis of the stump treated successfully with BTXA for stump hyperhidrosis. A 58-year-old man, with a lower leg amputation due to osteomyelitis in 1962, was referred to the Department of Dermatology because of suspected contact dermatitis. He suffered from diabetes mellitus, stump hyperhidrosis, and nummular microbial eczema. On examination we found a lower leg amputation stump with a suction stocking prosthesis. The itching, malodorous, exudating, hyperhidrotic skin showed erythematous scaling lesions and mild distal veruccous hyperplasia. Laboratory investigations, including differential blood count, creatinine, urea, bilirubin, serum enzymes, urine analysis, total IgE, and protein electrophoresis, were normal. Several swabs were taken from the exudating skin lesions. A mixed bacterial culture was found including aerobic (Acinetobacter iwof®, Corynebacterium spp., Sphingomonas paucimobilis and saprophytic staphylococci) and anaerobic species (Camphylobacter rectus, Propionibacteria, Peptostreptococci and Bacteroides spp.). Patch testing was performed according to the German Contact Dermatitis Research Group (7). No type-IV sensitization was found against the most common allergens of the standard test, textile colours, rubbers, topical ointments and conservatives, and materials of his own prosthesis. We performed topical treatment of the microbial eczema including a povidone-iod based disinfectant and topical corticosteroid creme (initially amcinonide; later on prednicarbat). Eczema and pruritus disappeared. After informed consent we treated his stump hyperhidrosis with BTXA. Hyperhidrotic areas were identi®ed by Minors iodineÐstarch test (8). As shown in Fig. 1, they were found on both the distal and the lateral part of the stump. For treatment, 100 U of BTXA (Botox; Allergan, Irvine, CA, USA; distributed by Merz Pharma Germany) were diluted with 4.0 ml 0.9% sterile physiological saline without preservative. The toxin was injected in amounts of 0.05 ± 0.1 ml (5 ± 10 U) strictly intracutaneous using a 30 gauge needle. Analgesic therapy was not necessary. The effect was evaluated by Minors iodineÐstarch test 3 days later (Fig. 2). The patient had a consultation 3 months later. He was still satis®ed with the anhidrotic effect. There was no relapse of the microbial eczema. The development of functional and aesthetic leg prostheses is a great advantage for amputees. The ongoing use of the prosthesis, however, may account for some discomfort and skin problems. Sweating inside the socket is annoying and Fig. 1. Identi®cation of hyperhidrotic areas after Minors sweat test.

Large B-Cell Lymphoma of the Leg – Complete Remission with Perilesional Interferon Alpha

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 α2a 3 × 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.

Serum matrix metalloproteinase-2 in patients with malignant melanoma.

Abstract. 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 S100beta (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.

Pegylated Doxorubicin for Primary Cutaneous T Cell Lymphoma

Cutaneous T cell lymphomas (CTCLs) are neoplasias of malignant T lymphocytes that usually possess the helper/inducer phenotype. The prognosis of advanced stages is poor. No systemic therapy cures patients with CTCL. Anthracyclines are among the most active and widely used antineoplastic agents. Doxorubicin has been used successfully in non-Hodgkin lymphomas as a part of the CHOP regimen or its modifications. On the other hand, the therapeutic index of doxorubicin is low, and hematotoxicity is a common and dose-dependent side effect. Severe neutropenia develops in almost all patients with >120 mg m-2. Gastrointestinal side effects, palmoplantar erythrodysesthesia, and reversible alopecia are common. Anthracyclineinduced cardiomyopathy may lead to congestive heart failure.1 With the development of polyethyleneglycol-modified (pegylated) liposome carriers for doxorubicin (PEG-DOXO), reduced toxicity and improved efficacy have been demonstrated for AIDS-related Kaposi’s sarcoma and selected solid tumors.2,3 Recently, first data on the efficacy and safety of PEG-DOXO have been published for patients with CTCL.4 The present report on 10 patients provides data on safety, efficacy, and the disease-free interval of PEG-DOXO in relapsing or recalcitrant CTCL.