[Side effects of novel cancer immunotherapies]. / Nebenwirkungen neuer onkologischer Immuntherapien.

Systemic treatment with immune checkpoint inhibitors (ICI) has revolutionized the treatment of hematological and oncological diseases in recent years. The mechanism of action hinges on enhancing the natural ability of the immune system to eliminate malignant cells. The most important substances in this arena include inhibitors of PD­1, PD-L1 and CTLA­4. As a consequence, the spectrum of treatment-associated adverse reactions is shifting away from classical cytotoxic effects (e.g. pancytopenia and polyneuropathy) towards novel entities of immune-mediated complex diseases. These so-called immune-related adverse events (irAEs) can involve any organ system and mimic known classical autoimmune conditions. Timely recognition of irAEs is the key for rapid initiation of a suitable treatment and is especially challenging in the clinical routine as it requires an intensive interdisciplinary management. Nephrologists are particularly confronted with this kind of problem due to the highly interdisciplinary nature of their work. This article summarizes the broad spectrum of currently known renal and more frequently occuring non-renal forms of irAEs and aims to prime the reader on diagnostic and therapeutic options.

The alpha-herpesviridae in dermatology : Herpes simplex virus types I and II.

This review on herpes simplex virus type I and type II (HSV­I, HSV­II) summarizes recent developments in clinical manifestations and treatment interventions for primary and recurrent orolabial and genital herpes, as well as those regarding vaccination issues. Among the clinical presentations, the relationship between pyogenic granuloma and chronic HSV­I infection; HSV-related folliculitis; verrucous HSV­I and HSV­II lesions; the role of recurrent HSV­I infection in burning mouth syndrome; HSV­I and HSV­II infection of the periareolar area; zosteriform HSV; the "knife-cut sign"; and the preferential colonization and infection of preexisting dermatoses by HSV­I or HSV­II are discussed. The usual antiviral treatment regimens for primary and recurrent orolabial and genital herpes are compared to short-term and one-day treatment options. New anti-HSV­I and anti-HSV­II agents include amenavir, pritelivir, brincidofovir, valomaciclovir, and FV-100. Therapeutic or preventive vaccination against HSV­I and HSV­II infections still remains a highly desirable treatment aim, which, unfortunately, has no clinically relevant applications to date.

[The alpha-herpesviridae in dermatology : Herpes simplex virus types I and II. German version]. / Alpha-Herpesviridae in der Dermatologie : Herpes-simplex-Virus Typ I und II.

This review on herpes simplex virus type I and type II (HSV-I, HSV-II) summarizes recent developments in clinical manifestations and treatment interventions for primary and recurrent orolabial and genital herpes, as well as those regarding vaccination issues. Among the clinical presentations, the relationship between pyogenic granuloma and chronic HSV-I infection; HSV-related folliculitis; verrucous HSV-I and HSV-II lesions; the role of recurrent HSV-I infection in burning mouth syndrome; HSV-I and HSV-II infection of the periareolar area; zosteriform HSV; the "knife-cut sign"; and the preferential colonization and infection of preexisting dermatoses by HSV-I or HSV-II are discussed. The usual antiviral treatment regimens for primary and recurrent orolabial and genital herpes are compared to short-term and one-day treatment options. New anti-HSV-I and anti-HSV-II agents include amenavir, pritelivir, brincidofovir, valomaciclovir, and FV-100. Therapeutic or preventive vaccination against HSV-I and HSV-II infections still remains a highly desirable treatment aim, which, unfortunately, has no clinically relevant applications to date.

[Buschke-Lowenstein tumors]. / Buschke-Löwenstein-Tumor.

BACKGROUND: A giant condyloma acuminatum which shows destructive growth but lacking invasion is designated as a Buschke-Lowenstein tumor (BLT). OBJECTIVES: Classification of the BLT and therapeutic guidelines are provided. MATERIALS AND METHODS: A MEDLINE literature search from 2006-2016 was performed. RESULTS: Induction through low-risk mucosotropic human papillomavirus (HPV) infection separates BLT from verrucous carcinoma. In the last 10 years, slightly more than 100 new cases have been described. Invasion as a true sign of malignancy was described in 12% of cases. HIV infection was observed in 14%. As invasion often occurs only focally and may only be detected after complete resection, BLT must be treated and considered as a low grade in situ epithelial cancer that evolves from condylomata acuminata. Diagnosis is confirmed by HPV detection and typical histology. CT scans are recommended to rule out deeper invasion. Organ preservation surgery remains the recommended therapy. CONCLUSIONS: Buschke-Lowenstein tumors represent low grade epithelial in situ carcinomas which evolved from condylomata acuminata. Focal invasion is frequent but metastases occur only rarely. Organ preservation surgery is recommended.

Immunotherapy with imiquimod and interferon alfa for metastasized Merkel cell carcinoma.

Merkel cell carcinoma (mcc) is a highly aggressive neuroendocrine tumour of the skin. Remission rates are high with chemotherapy in patients with metastasis, but without any improvement in overall survival. We present the case of a 90-year-old woman with facial mcc. After radiation and surgery, the mcc recurred with widespread cutaneous and regional lymph node metastases. The metastases were treated with weekly intralesional injections of 1-2×10(6) IU interferon alfa-2a, accompanied by topical imiquimod 5% cream 3 times weekly. After partial regression, subcutaneous pegylated interferon alfa-2b was added at a dose of 30 µg weekly, which was then increased to 50 µg weekly. At 4 months after the start of immunotherapy, all cutaneous metastases and the intralesionally treated lymph node metastases receded. Interruption or reduction of systemic interferon application resulted in locoregional relapses that were successfully treated with surgery or intralesional interferon injections. The patient remains alive 30 months after initiation of immunotherapy, suggesting that locally metastasized mcc might be able to be controlled with local and systemic immunotherapy.

[Extensive fibromata pendulantia. Hydrosurgery as a therapy option using the Versajet technique]. / Flächenhafte Fibromata pendulantia. Hydrochirurgie als Therapieoption mittels Versajet-Technik.

Fibromata pendulantia often appear as small filiform skin tags with a narrow pedicle in the neck, axilla and groin areas. Hitherto, extensive fibromata pendulantia were resected either surgically (curette, scissors, scalpel) or by laser. The present case study of an adipose patient with disseminated fibromata pendulantia in the axillary region in the setting of pseudoacanthosis nigricans introduces the Versajet hydrosurgery technique as an alternative method. It is able to remove tissue and rinse the wound simultaneously by means of a high-pressure water jet.

[Cutaneous cytotoxic T-cell lymphoma]. / Kutanes zytotoxisches T-Zell-Lymphom.

Cutaneous cytotoxic T-cell lymphoma is a rare variant of cutaneous T-cell lymphoma, which shows immunoreactivity for CD56+. We report on an 83-year old woman with numerous skin infiltrates and nodules mainly on her face and trunk. Histopathologic criteria lead to the diagnosis of cutaneous cytotoxic T-cell lymphoma. Bexarotene was not tolerated because of cardiac insufficiency, but treatment with methotrexate (7.5 mg once weekly) led to prompt regression of all lesions.

[Clinical algorithm of cutaneous extragenital wart treatment]. / Klinischer Algorithmus zur Therapie von kutanen, extragenitalen HPV-induzierten Warzen.

Various human papillomavirus of the genera α-, ß-, γ-, µ- and η-papillomavirus induce type-specific extragenital warts. Plantar, common and plane warts are the most common types. The closely related Alpha-papillomaviruses HPV 2, 27 and 57 are responsible for the majority of therapy-resistant common warts. A wide armamentarium of surgical, physical, chemical or drug therapies is available but no modality cures all patients. In order to avoid overtreatment it is mandatory to differentiate between indolent warts which will spontaneously resolve, warts which cause acute discomfort and warts without any tendency to heal spontaneously. HPV type, wart type, localization, size, disease duration as well as age and immune status are parameters influencing self-healing and should be considered when choosing the appropriate wart therapy.

[Pagetoid reticulosis in a patient with mycosis fungoides. Successful therapy with localized electron beam irradiation]. / Pagetoide Retikulose bei einem Patienten mit Mycosis fungoides. Erfolgreiche Therapie mit lokalisierter Elektronenbestrahlung.

Pagetoid reticulosis is a mycosis fungoides subtype. It is characterized by a prominent epidermotropism, localized lesions, slow progression and benign prognosis. We report on a 67-year-old patient with a history of classic mycosis fungoides, who developed pagetoid reticulosis on the right heel. Local electron beam therapy induced a complete remission, with no recurrence over three months of follow-up.

[Primary cutaneous CD30+ ALK(-) anaplastic large cell T-cell lymphoma]. / CD30(+) ALK(-) anaplastisch grosszelliges primär kutanes T-Zell-Lymphom.

Anaplastic large cell lymphomas (ALCL) are characterized by large, pleomorphic cells with a strong expression of cytokine receptor CD 30. We present a 71-year-old patient with several nodules on the right temple extending to his right ear. Based on clinical, histological and immunophenotypic criteria, the diagnosis of a primary cutaneous CD30(+) ALK(-) anaplastic large cell lymphoma was made. After local excision and adjuvant radiotherapy no relapse occurred during a follow-up period of three months.

[Eccrine adenocarcinoma in a patient with familial breast carcinoma]. / Ekkrines Adenokarzinom bei einer Patientin mit familiärem Mammakarzinom.

A 67-year-old patient developed a subcutaneous, non-tender nodule in her left groin over a period of about seven years. The patient underwent surgery and 4 procedures were required to obtain complete excision. The histopathologic findings showed eccrine adenocarcinoma, a member of the heterogeneous group of sweat gland tumors which occur primarily in adults with a peak of 50-60 years of age. Sweat gland carcinomas are extremely rare neoplasms of the skin and exhibit a slow growth rate with a rather high local recurrence rate. The tumor has a disposition to metastasize and shows a poor response rate to adjuvant therapy regimens. Therefore wide, deep surgical excision with an excision margin of 2-3 cm is the treatment of choice. Nevertheless there are some case reports on successful therapy of a metastasized sweat gland carcinoma with 5-fluorouracil and tamoxifen. Here further studies are needed to achieve a better survival rate for patients with metastatic disease.

Molecular analysis of the effect of topical imiquimod treatment of HPV 2/27/57-induced common warts.

Imiquimod is effective in the treatment of genital warts and clinical studies suggest activity against common warts as well. We have analyzed the effect of topical imiquimod on gene expression and virus load in human papilloma virus (HPV) 2/27/57-induced common warts. mRNA was extracted from keratinocyte culture, from normal skin, from three untreated common warts and from three common warts treated topically with 5% imiquimod cream twice daily. Differential gene expression was demonstrated by RT-PCR and by cDNA microarray hybridization. We further analyzed viral DNA content in scales from three superficially pared imiquimod-treated warts by real-time PCR. Comparison of normal skin with wart tissue revealed that HPV 2/27/57 infection led to an induction of IL-6, IL-10 and interferon-gamma inducible protein (IP10) and to an up-regulation of TGF-beta. We could further detect expression of PCTAIRE-3, WNT2B, frizzled-3, notch-2, notch-4 and BRCA2 in normal skin and common warts. Analysis of imiquimod-treated warts demonstrated that imiquimod enhanced IL-6 expression and induced IL-8, GM-CSF, MRP-8 and MRP-14. It could also be shown that imiquimod led to an infiltration of wart tissue with macrophages and to a strong decrease of viral copy number in warts within 3 months of treatment. Our data thus provide molecular proof of principle for imiquimod treatment of cutaneous common warts.

[Unilateral facial edematous granulomatosis. Initial symptom of basalioma]. / Unilaterale faziale ödemgebundene Granulomatose. Initialsymptom eines Basalioms.

A seventy-year-old woman presented with persistent edema of the left lower eyelid and induration in the inner angle of her left eye. Histological examination revealed granulomatous blepharitis of the lower eyelid as well as a solid basal cell carcinoma with partial calcification in the inner angle of the eye. The edema of the lower eyelid resolved upon complete surgical removal of the tumor.

[Mollusca contagiosa in an infant with atopic eczema. A therapeutic challenge]. / Mollusca contagiosa bei einem Kleinkind mit atopischer Dermatitis. Eine therapeutische Herausforderung.

Molluscum contagiosum is a viral disease frequently observed in children and adolescents with atopic dermatitis, in whom it poses a special therapeutic challenge. A 3-year-old girl presented with atopic eczema and disseminated molluscum contagiosum on her buttocks and upper legs. Topical application of 0.05% tretinoin resulted in a steady regression of the lesions. Other therapeutic options include topical anti-viral agents, cryosurgery, laser treatment, and curettage. Further, the therapeutic outcome is highly dependent on an adequate therapy of the concomitant atopic eczema.

Topical 5% imiquimod long-term treatment of cutaneous warts resistant to standard therapy modalities.

BACKGROUND: Long-lasting cutaneous warts may represent an unbearable stigma to patients and therefore pose a singular challenge for the physician. Generally, these warts are induced by human papillomavirus (HPV) 2, HPV-27 or HPV-57. OBJECTIVES: The present study was conducted to evaluate the efficacy and safety of long-term treatment with imiquimod 5% cream applied to long-lasting (mean duration 6.3 years) common warts, which had been resistant to previous therapeutic interventions. PATIENTS AND METHODS: Imiquimod cream was self-applied by the patients twice daily. Assessment of response and occurrence of side-effects was performed every 4 weeks until clinical cure or up to a maximum of 24 weeks. A total of 37 patients were recruited. RESULTS: 31 out of 37 patients completed the treatment. 10 out of 37 patients experienced a total clearance of their warts (27%). The mean duration to clearance was 19.2 weeks. 18 patients (49%) showed a reduction of more than 50% and 5 patients (14%) a reduction of less than 50%. CONCLUSION: Our data demonstrate that the long-term topical application of imiquimod 5% cream is an effective treatment for otherwise therapy-resistant cutaneous warts without causing any meaningful side-effects.

High dose inhalation interleukin-2 therapy for lung metastases in patients with malignant melanoma.

BACKGROUND: The lungs are a frequent site of metastasis in patients with melanoma, and this may cause respiratory problems in the terminal phase of the illness. Inhalation interleukin (IL)-2 therapy to the lung has been piloted and appears to be well tolerated. METHODS: Twenty-seven patients were treated with single agent dacarbazine and concurrent high dose inhalation IL-2 36 million IU per day). The patients previously had progressed on chemotherapy, predominately dacarbazine-based regimens. Patients included those with American Joint Committee on Cancer Stage IV melanoma, predominately those with lung metastases, but patients with extrapulmonary metastases also were allowed on the study. RESULTS: Five of the 27 patients experienced a complete pulmonary remission. Eight patients achieved a partial pulmonary remission, and 5 patients experienced stabilization of their disease. Eight patients developed pulmonary metastases. One patient was not evaluable. Four of the five patients who achieved a complete response and seven of the eight patients who achieved a partial response previously were treated with dacarbazine and progressed. There were no responses in extrapulmonary metastases. Side effects of treatment were minimal. The complete responses all were durable with a follow-up of 12 months, whereas patients with partial responses and stable disease progressed when IL-2 was discontinued. CONCLUSIONS: Inhalation therapy with IL-2 for pulmonary metastases from melanoma appears to be safe. The current preliminary study suggests efficacy although concurrent chemotherapy was given, thus confounding results to some extent. Therefore, these results need to be reproduced without concomitant chemotherapy. In addition, a strategy comprised of therapy with IL-2 inhalation until disease progression may prolong responses.

Analysis of tumor cell evolution in a melanoma: evidence of mutational and selective pressure for loss of p16ink4 and for microsatellite instability.

Tumorigenesis and tumor progression can be considered an evolutionary process. In order to deduce information on the mutational and selective pressures during melanoma progression we performed microsatellite analysis at 42 autosomal and two X-linked loci in a microdissected primary melanoma and its nine metastases. Loss of heterozygosity at locus D9S259 was the only genetic change observed in all metastases. The pattern of loss of heterozygosity at loci D9S162 and D9S171 within the region of common loss on chromosome 9p21 which encompasses the tumor suppressor gene p16ink4 enabled the distinction of four genetically different tumor cell populations. Three cell lineages showed homozygous loss of the p16ink4 gene, which evolved independently in each tumor cell population within the primary tumor. Additional allele losses could be demonstrated at markers D14S53 and DXS998. The fourth lineage did not demonstrate loss of heterozygosity at loci D9S162 and D9S171 and contained the wild type p16ink4 gene but was characterized by abundant microsatellite instability. The evolutionary approach towards tumorigenesis and tumor progression used in this study thus confirms the role of p16ink4 inactivation for melanoma progression but not for melanoma initiation; it suggests the existence of additional putative tumor suppressor genes located on 9p as well as on the long arm of chromosome 14 and shows that microsatellite instability may represent an alternative pathway of tumor cell evolution in malignant melanoma.

HPV 18-induced pigmented bowenoid papulosis of the neck.

We describe the case of a 53-year-old man in whom pigmented bowenoid papulosis developed on the skin of the neck. By polymerase chain reaction with general primers for genital human papillomaviruses (HPV) and subsequent restriction enzyme cleavage we could demonstrate HPV 18-related DNA in two biopsy specimens of the pigmented papules. To our knowledge, this report represents the first case of HPV 18-induced extragenital bowenoid papulosis of the neck.