Evaluation of mortality, prognostic parameters, and treatment efficacy in mycosis fungoides.

BACKGROUND AND OBJECTIVES: Mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, is characterized by a variable clinical course, presenting either as indolent disease or showing fatal progression due to extracutaneous involvement. Importantly, the lack of prognostic models and predominantly palliative therapy settings hamper patient care. Here, we aimed to define survival rates, disease prediction accuracy, and treatment impact in MF. PATIENTS AND METHODS: Hundred-forty MF patients were assessed retrospectively. Prognosis and disease progression/survival were analyzed using univariate Cox proportional hazards regression model and Kaplan-Meier estimates. RESULTS: Skin tumors were linked to shorter progression-free, overall survival and a 3.48 increased risk for disease progression when compared to erythroderma. The Cutaneous Lymphoma International Prognostic Index identified patients at risk in early-stage disease only. Moreover, expression of Ki-67 >20%, CD30 >10%, CD20+, and CD7- were associated with a significantly worse outcome independent of disease stage. Only single-agent interferon-α and phototherapy combined with interferon-α or retinoids/bexarotene achieved long-term disease control in MF. CONCLUSIONS: Our data support predictive validity of prognostic factors and models in MF and identified further potential parameters associated with poor survival. Prospective studies on prognostic indices across disease stages and treatment modalities are needed to predict and improve survival.

Comparison of Permethrin-Based Treatment Strategies against Scabies in Infants and Young Children.

OBJECTIVE: To optimize the permethrin-based therapies for scabies infestations in infants and young children, the efficacies of 3 different regimens were evaluated. STUDY DESIGN: The retrospective analysis encompassed 85 infants and children aged <4 years with scabies. The children had received either topical permethrin 5% on the entire body on days 1/8, on days 1/8/15, on days 1/8/15 plus interim applications restricted to hands and feet on days 2/3/4//9/10/11, or alternative treatments. RESULTS: The intensified regimen, consisting of full-body permethrin applied on days 1/8/15 and hands/feet on days 2/3/4//9/10/11, resulted in cure of scabies in 73.5% of the cases. The cure rates were significantly greater compared with full-body permethrin given on days 1/8, which led to eradication in 44%, and were greater compared with the clearance in children who had received full-body permethrin on days 1/8/15 (53.8%) or alternative treatments (60%). For patients in whom permethrin had previously been applied, the intensified regimen resulted in eradication of scabies in 71.4% of the cases, compared with 30% and 55.6% after full-body permethrin on days 1/8 and 1/8/15, respectively. CONCLUSIONS: The intensified regimen of full-body permethrin plus interim applications on hands/feet, which aims at reducing the number of mites present on the frequently heavily infested palmoplantar sites in addition to the standard entire body application, appears efficacious in curing scabies in young children.

Human dirofilariosis in Austria: the past, the present, the future.

BACKGROUND: Dirofilariosis is a vector-borne parasitosis caused by filarial nematodes of the genus Dirofilaria. In humans, who represent accidental hosts, dirofilariosis is mostly caused by Dirofilaria repens and Dirofilaria immitis. In Austria, the first reported case occurred in 1978. Since then, several (case) reports have been published. METHODS: A systematic and retrospective review of collected published cases and new, unpublished confirmed cases of human dirofilariosis occurring in Austria was performed. A nematode was extracted from the eyelid of a previously unreported case and subsequently characterized histologically and using molecular biology techniques. RESULTS: Data on a total of 39 cases of human dirofilariosis in Austria occurring between 1978 and 2020 are summarized. Over the past four decades the incidence has markedly increased, in particular after 1998. Of the 39 patients, men and women were equally affected, and the mean age was 47.1 years. The area most frequently affected was the head (38.5% of cases). Confined ocular involvement was observed in 23.1% of cases, and nematodes were isolated from the neck/trunk, extremities and the genito-inguinal area in 25.6, 15.4 and 15.4% of patients, respectively. Microfilariae were detected in two cases. Of the 39 patients, only 73.9% tested positive for anti-filarial antibodies and 56.3% for eosinophilia, despite successful isolation of a nematode; consequently, these measures did not represent reliable markers for dirofilariosis. Most patients had a travel history to countries endemic for Dirofilaria species. One patient who had not traveled abroad represented the only autochthonous case recorded to date. Dirofilaria repens was the predominant species, identified in 89.7% of cases. In the newly reported case of subcutaneous dirofilariosis, a live non-gravid Dirofilaria repens adult female of 12 cm length was isolated from the eyelid of the patient, and a video of the extraction is provided. CONCLUSIONS: The incidence of human dirofilariosis cases has increased strikingly over the last four decades in Austria. More cases can be expected in the foreseeable future due to changes in human behavior and (travel) activities as well as climate changes and the associated alterations in the availability of the natural reservoir, the vectors and the intrinsic characteristics of the parasite.

Long-term Therapeutic Success of Intravenous Rituximab in 26 Patients with Indolent Primary Cutaneous B-cell Lymphoma.

Systemic monotherapy with rituximab is a well-known treatment approach for primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone lymphoma. Both have excellent prognosis despite high relapse rates. To investigate the long-term effectiveness and clinical outcome of intravenous rituximab at a dose of 375 mg/m2 once weekly, data for 26 patients (17 primary cutaneous follicle centre lymphoma and 9 primary cutaneous marginal zone lymphoma) were analysed retrospectively. Complete remissions occurred in 20 (77%) and partial remissions in 6 patients (23%), demonstrating an overall response rate of 100%. The relapse rate was 52.9% in primary cutaneous follicle centre lymphoma and 88.9% in primary cutaneous marginal zone lymphoma. Ongoing complete remissions after therapy with rituximab were observed in 9 patients (34.6%) with a median progression-free survival of 161 months (13.4 years). These results confirm that intravenous rituximab is an effective and well-tolerated treatment with durable responses in a relevant percentage of patients at a median follow-up of 148 months (12.3 years).

Patients' Illness Perception as a Tool to Improve Individual Disease Management in Primary Cutaneous Lymphomas.

The Revised Illness Perception Questionnaire (IPQ-R) has been shown to assess illness perception reproducibly in primary cutaneous T-cell lymphomas (CTCL). Illness perception reflects patients' individual concepts of understanding and interpretation of the disease, influencing illness behaviour and health-related quality of life (HRQOL). This study investigated the clinical relevance of the relationships between illness perception, illness behaviour, and HRQOL in CTCL and cutaneous B-cell lymphomas (CBCL). A total of 92 patients completed the IPQ-R, the Scale for the Assessment of Illness Behavior (SAIB), and a skin-specific HRQOL tool (Skindex-29). Data on illness behaviour were not evidently related to illness perception, whereas illness perception was significantly associated with HRQOL. Both, IPQ-R and HRQOL results correlated with disease entity, stage, and socio-demographics. Only IPQ-R results provided practical information on patients' needs to train personal coping strategies. IPQ-R assessment in CTCL and CBCL might be a useful instrument to improve individual disease management.

High expression of Dicer reveals a negative prognostic influence in certain subtypes of primary cutaneous T cell lymphomas.

BACKGROUND: Aberrant expression of microRNAs (miRNAs) has been implicated in oncogenesis of various tumors and primary cutaneous T cell lymphomas. Dicer, a ribonuclease III-like enzyme is essential for miRNA processing. OBJECTIVE: We initiated a retrospective study to characterize the alterations in the expression profile of Dicer in patients with primary cutaneous T cell lymphomas (CTCL). METHODS: A total of 50 consecutive patients with primary CTCL were studied, with the majority having mycosis fungoides (n=34). Five patients had primary cutaneous CD 30+ anaplastic large cell lymphoma, four patients each had lymphomatoid papulosis and primary cutaneous CD4-positive small/medium T-cell lymphoma, one primary cutaneous γδ T cell lymphoma, one Sézary syndrome and another subcutaneous panniculitis-like T cell lymphoma of αß-phenotype. Immunohistochemistry was performed on paraffin sections using a commercially available antibody against Dicer. Intensity of expression was correlated with clinical parameters including disease specific survival (DSS) and time to progression (TTP). RESULTS: After a median follow-up of 74 months (range: 1-271), 12/50 patients (24%) have died. Univariate and multivariate analysis for disease-specific survival showed Dicer expression and stage as a negative predictive factor in the sole group of MF patients (n=34) as well as in the heterogeneous group of patients (n=50), but not gender, histological subtype, primary localization of disease, age and recurrence of lymphoma (p>0.05). CONCLUSION: Our data suggest Dicer expression as a possible molecular marker in patients with MF and apparently indicate that miRNA(s) might be of clinical relevance in CTCL.

Molecular cytogenetic evidence of t(14;18)(IGH;BCL2) in a substantial proportion of primary cutaneous follicle center lymphomas.

In contrast to nodal follicular lymphoma, limited data exist on genetic changes in primary cutaneous follicular lymphoma (primary cutaneous follicle center lymphoma according to WHO-EORTC). The detection rate of the BCL2 rearrangement, representing the characteristic t(14;18)(q32;q21) underlying follicular lymphoma, by polymerase chain reaction (PCR) has been reported to vary over a wide range (0%-41%), and only a few cases have been studied by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). In this study, 27 primary cutaneous follicle center lymphomas were analyzed by FISH and the results compared with those obtained by PCR. FISH demonstrated translocations affecting the immunoglobulin heavy chain locus (IGH) in 14 of 27 cases (52%): a t(14;18)(q32;q21) involving BCL2 was found in 11 cases (41%), a t(3;14)(q27;q32) affecting BCL6 in 2 cases (7%), and in 1 case the partner gene of IGH could not be identified. Interestingly, PCR did not detect BCL2 rearrangement in any case. These data suggest that the t(14;18)(q32;q21) frequently occurs in primary cutaneous follicular lymphoma. The reason(s) why BCL2 rearrangements escape the detection by PCR is (are) not clear but could be due to BCL2 mutations, breakpoints outside the amplified DNA, or a high load of somatic mutations.

Identification of a melanoma marker derived from melanoma-associated endogenous retroviruses.

We previously described the expression of melanoma-associated endogenous retrovirus (MERV) proteins and viral particles in human melanomas and metastases. The objective of the present study was to determine whether a humoral immune response to MERV proteins occurs in melanoma. Candidate B-cell epitopes on MERV proteins were predicted using bioinformatic screening. The reactivity of MERV peptides corresponding to the predicted epitopes with antibodies prevalent in sera of melanoma patients was analyzed. An immunodominant peptide located in the env protein of MERV was identified. Subsequent analyzes using 81 samples from stage I to stage IV melanoma patients and 95 sera from healthy subjects revealed statistically significant differences in seroprevalence of antibodies in melanoma sera samples when compared with reference samples from healthy subjects. The prevalence of anti-MERV antibodies in melanoma patient sera was confirmed by immunofluorescence on env-transfected cells. These data indicate the potential of this candidate peptide as target for diagnosis and immunotherapy.

Somatostatin receptor scintigraphy with 111In-DOTA-lanreotide and 111In-DOTA-Tyr3-octreotide in patients with stage IV melanoma: in-vitro and in-vivo results.

The overexpression of somatostatin receptors (SST-Rs) on various tumour cells provides the molecular basis for the successful use of radiolabelled SST analogues in clinical oncology. The objective of the study was to evaluate the tumour binding of In-1,4,7,10-tetraazacyclo-dodecane-N,N',N'',N'''-tetraacetic acid-lanreotide (In-DOTA-LAN) and In-DOTA-tyrosine-octreotide (In-DOTA-Tyr-OCT) in patients with stage IV melanoma. In addition, we evaluated the potential antiproliferative effect of SST analogues, together with an assessment of the functionality of SST-Rs, on four melanoma cell lines. Twenty-three patients with advanced metastatic melanoma underwent scintigraphy. Thirty-eight of 61 lesions (62%) were positively imaged with In-DOTA-LAN, whereas 23 (37%) were negative. With In-DOTA-Tyr-OCT, 10 of the 23 documented lesions (43%) were positive and 13 (56%) were negative. In vitro, cell lines showed no growth inhibition in the presence of SST analogues and no influence on cell cycle distribution was found with the addition of SST analogues to cultured cells. In addition, no functional surface SST-Rs could be demonstrated on these cell lines. Taken together, our results demonstrate the visualization of metastatic melanoma in a high percentage of patients, probably due to binding of SST analogues to SST-Rs on tumour vessels or infiltrating immune cells. Judging from our data, however, there is no evidence of functional SST-R expression on melanoma cells.

Randomized phase II study of irinotecan plus mitomycin C vs. oxaliplatin plus mitomycin C in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer.

INTRODUCTION: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs might act synergistically with mitomycin C, a randomized study using a 'pick the winner' design was undertaken to determine the effectiveness and tolerance of these two combination schedules in patients with fluoropyrimidine/leucovorin-pretreated advanced colorectal cancer. PATIENTS AND METHODS: Sixty-four patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin were enrolled onto this study. They were randomly assigned to treatment with irinotecan 120 mg/m2 on days 1 + 15 plus mitomycin C 8 mg/m2 on day 1 (arm A) or oxaliplatin 85 mg/M2 on days 1 + 15 plus mitomycin C 8 mg/m2 on day 1 (arm B). In both treatment arms, courses were repeated every 4 weeks. RESULTS: The objective response rate in arm A is 7/33 (21.2%; 95% confidence interval, 9.0-38.9%) as compared to 5/31 in arm B (16.1%; 95% CI, 5.5-34.7%). Stable disease was noted in 48.5 vs. 45.2%, whereas the tumor progressed in 30.3 vs. 38.7%, respectively. Similar to the recorded response activities, the difference of the two combination regimens in terms of median time to progression (7.0 vs. 5.2 months) and overall survival (12.0 vs. 11.2 months) was only minor and clincally insignificant. The tolerance of treatment was acceptable in both arms, though severe adverse reactions requiring dose reductions (30 vs. 16%) and treatment delays (22 vs. 13% of courses) were more commonly noted with irinotecan/mitomycin C. The most common toxicities in arm A were neutropenia (85%; WHO grade 3/4 in 33%), thrombocytopenia (52%), diarrhea (45%), emesis (52%) and alopecia (92%). In arm B, common toxicities included neutropenia (68%; grade 3/4 in 13%), thrombocytopenia (81%), emesis (52%), and peripheral neutropathy (48%). CONCLUSIONS: Both mitomycin C combination regimens seem to provide an acceptable therapeutic index in patients with fluoropyrimidine/leucovorin-pretreated metastatic colorectal cancer. In view of the increasing need for a broader chemotherapeutic armentarium for second-line therapy of this common malignant disease, both regimens may be worthwhile to undergo further clinical investigation.