CCL20-CCR6 axis directs sperm-oocyte interaction and its dysregulation correlates/associates with male infertility‡.

The interaction of sperm with the oocyte is pivotal during the process of mammalian fertilization. The limited numbers of sperm that reach the fallopian tube as well as anatomic restrictions indicate that human sperm-oocyte encounter is not a matter of chance but a directed process. Chemotaxis is the proposed mechanism for re-orientating sperm toward the source of a chemoattractant and hence to the oocyte. Chemokines represent a superfamily of small (8-11 kDa), cytokine-like proteins that have been shown to mediate chemotaxis and tissue-specific homing of leukocytes through binding to specific chemokine receptors such as CCRs. Here we show that CCR6 is abundantly expressed on human sperms and in human testes. Furthermore, radioligand-binding experiments showed that CCL20 bound human sperm in a specific manner. Conversely, granulosa cells of the oocyte-surrounding cumulus complex as well as human oocytes represent an abundant source of the CCR6-specific ligand CCL20. In human ovaries, CCL20 shows a cycle-dependent expression pattern with peak expression in the preovulatory phase and CCL20 protein induces chemotactic responses of human sperm. Neutralization of CCL20 in ovarian follicular fluid significantly impairs sperm migratory responses. Conversely, analyses in infertile men with inflammatory conditions of the reproductive organs demonstrate a significant increase of CCL20/CCR6 expression in testis and ejaculate. Taken together, findings of the present study suggest that CCR6-CCL20 interaction may represent an important factor in directing sperm-oocyte interaction.

[Aesthetic Filler Injections and the Management of Side Effects]. / Ästhetische Behandlungen mit Fillern und das Management von Nebenwirkungen.

Over the past years aesthetic procedures have been evolving as an important part of daily dermatological practice. Herein, fillers represent an integral component of a modern, multimodal aesthetic treatment approach. Advances in the understanding of the aging face and modern fillers offer a broad variety of indications ranging from augmentation to hydration or collagen-induction. At the same time the range of available injection materials, products and techniques has grown to mere unmanageable dimensions. Finally, dermatologists are frequently confronted with the consequences of improper filler treatments or late side effects of early filler materials which have already disappeared from the market and even the experienced injector may encounter treatment-associated side effects. Here, we review the most important current and historic filler materials, including indications, injection techniques, adverse effects and the respective management recommendations.

Treatment of onychomycosis using a 1064-nm diode laser with or without topical antifungal therapy: a single-center, retrospective analysis in 56 patients.

BACKGROUND: Currently available treatment options for onychomycosis such as topical and systemic antifungals are often of limited efficacy, difficult to administer or associated with relevant side effects. Non-ablative laser therapy is proposed to represent a safe alternative without the disadvantages of drugs. Yet, to date, the efficacy of laser therapy for onychomycosis is discussed controversially. Against this background, we performed a systematic retrospective analysis of our clinical experience of 4 years of onychomycosis treatment applying a long-pulsed 1.064-nm diode laser. METHODS: We retrospectively evaluated the records of 56 patients with microscopic and culturally proven onychomycosis affecting a toenail of the hallux and other toes, who had been treated with a long-pulsed 1.064-nm diode laser (FOX, A.C.R. Laser GmbH, Nuremberg) during the time period of July 2013-December 2016 with or without concomitant topical antifungals. Thereof, 27 patients received laser treatment and 29 patients received laser treatment in combination with local antifungals. We conducted a mean of 3.9 laser treatments at 2-6-week intervals. The primary endpoint of our analysis was clinical improvement; secondary endpoints were complete remission of fungal pathogens in fungal culture and in microscopy. RESULTS: Clinical improvement was achieved in 56% of patients treated with laser only after a mean of 4.5 treatments and in 69% of patients treated with laser in combination with topical antifungals after a mean of 3.6 treatments. Cultural healing was detected in 63% of patients treated with laser only after a mean of 5.4 treatments, vs. 86% of patients treated with laser and concomitant topical antifungals after a mean of 4.8 treatments. Microscopic healing (complete healing) with the absence of fungal pathogens was achieved in 11% of patients after a mean of 4.7 treatments with laser only, vs. 21% of patients treated with laser and concomitant topical antifungals after a mean of 4 treatments. No relevant adverse effects were observed. CONCLUSIONS: The 1.064-nm diode laser is an effective and safe option for the treatment of onychomycosis. Of note, the combination with topical antifungals will increase overall treatment efficacy and reduce the time to healing. Particularly, patients with contraindications against systemic antifungals may benefit from this multimodal therapeutic approach. Our data, moreover, suggest that treatment efficacy is positively correlated with the total number of laser treatments.

[Seasonal and Perennial Allergic Rhinoconjunctivitis]. / Die saisonale und perenniale allergische Rhinokonjunktivitis.

Seasonsal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) as well as intermittent and persistent allergic rhinitis are widespread diseases. Because a combined occurrence of ocular and nasal symptoms is very common the summarising term allergic rhinoconjunctivitis is frequently used. SAC and PAC representing the two acute forms of allergic conjunctivitis account for more than 90% of all cases of allergic conjunctivitis. Compared to the chronic forms of allergic conjunctivitis their course of disease is milder. Nevertheless because of their high prevalence and the proven influence on patients' quality of life they possess clinical and socioeconomic relevance. Allergic rhinoconjunctivitis is caused by a type 1 IgE-mediated hypersensitivitity reaction that is provoked by aeroallergens in the majority of cases. The pathognomonic sign is itching. Besides, typical ocular findings are chemosis, conjunctival injection,watery secretion and lid swelling. Otorhinolaryngologists' findings include rhinorrhea, postnasal drip and sneezing. Problems in breathing through the nose resulting from nasal obstruction can cause impaired nighttime sleep and daytime somnolence. In addition to a reduction of allergen exposure by modification of environment and life style factors, in mild forms of SAC and PAC artificial tears are recommended. Topical antihistamines can generate rapid relief from acute symptoms and itching. Topical mast cell stabilisers however provide long-term effects. Dual action drugs that combine antihistamines and mast cell stabilisers show increased patient compliance due to reduced application frequency. Use of topical steroids should be cautious and only temporary. For prolonged treatment periods unpreserved anti-allergic eye-drops should be preferred. Combined topical antihistamines and new-generation topical nasal steroids often used by otorhinolaryngologists demonstrate a good safety profile without systemic side effects. In summary, allergic rhinoconjunctivitis represents a common disease pattern that can be treated effectively. Once it is diagnosed correctly targeted treatment results in improved patients' quality of life quickly.

A novel native collagen dressing with advantageous properties to promote physiological wound healing.

OBJECTIVE: Chronic hard-to-heal wounds generate high costs and resource use in western health systems and are the focus of intense efforts to improve healing outcomes. Here, we introduce a novel native collagen (90 %):alginate (10 %) wound dressing and compare it with the established oxidised dressings Method: Matrices were analysed by atomic force microscopy (AMF), scanning electron microscopy (SEM), and immunoelectron microscopy for collagen types I, III and V. Viability assays were performed with NIH-3T3 fibroblasts. Matrix metalloproteinase (MMP) binding was analysed, and the effect of the wound dressings on platelet-derived growth factor B homodimer (PDGF-BB) was investigated. RESULTS: Unlike oxidised regenerated cellulose (ORC)/collagen matrix and ovine forestomach matrix (OFM), the three-dimensional structure of the native collagen matrix (NCM) was found to be analogous to intact, native, dermal collagen. Fibroblasts seeded on the NCM showed exponential growth whereas in ORC/collagen matrix or OFM, very low rates of proliferation were observed after 7 days. MMP sequestration was effective and significant in the NCM. In addition, the NCM was able to significantly stabilise PDGF-BB in vitro. CONCLUSION: We hypothesise that the observed microstructure of the NCM allows for an effective binding of MMPs and a stabilisation and protection of growth factors and also promotes the ingrowth of dermal fibroblasts, potentially supporting the re commencement of healing in previously recalcitrant wounds. DECLARATION OF INTEREST: This work was supported by BSN Medical, Hamburg, Germany.

[Seasonal and perennial allergic rhinoconjunctivitis]. / Die saisonale und perenniale allergische Rhinokonjunktivitis.

Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) as well as intermittent and persistent allergic rhinitis are widespread diseases. Because a combined occurrence of ocular and nasal symptoms is very common the summarising term allergic rhinoconjunctivitis is frequently used. SAC and PAC representing the two acute forms of allergic conjunctivitis account for more than 90 % of all cases of allergic conjunctivitis. Compared to the chronic forms of allergic conjunctivitis their course of disease is milder. Nevertheless because of their high prevalence and the proven influence on patients' quality of life they possess clinical and socioeconomic relevance. Allergic rhinoconjunctivitis is caused by a type 1 IgE-mediated hypersensitivity reaction that is provoked by aeroallergens in the majority of cases. The pathognomonic sign is itching. Besides, typical ocular findings are chemosis, conjunctival injection, watery secretion and lid swelling. Otorhinolaryngologists' findings include rhinorrhea, postnasal drip and sneezing. Problems in breathing through the nose resulting from nasal obstruction can cause impaired nighttime sleep and daytime somnolence. In addition to a reduction of allergen exposure by modification of environment and life style factors, in mild forms of SAC and PAC artificial tears are recommended. Topical antihistamines can generate rapid relief from acute symptoms and itching. Topical mast cell stabilisers however provide long-term effects. Dual action drugs that combine antihistamines and mast cell stabilisers show increased patient compliance due to reduced application frequency. Use of topical steroids should be cautious and only temporary. For prolonged treatment periods unpreserved anti-allergic eye-drops should be preferred. Combined topical antihistamines and new-generation topical nasal steroids often used by otorhinolaryngologists demonstrate a good safety profile without systemic side effects. In summary, allergic rhinoconjunctivitis represents a common disease pattern that can be treated effectively. Once it is diagnosed correctly targeted treatment results in improved patients' quality of life quickly.

Long-term outcome after neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer and predictive factors for a pathologic complete remission : results of a multivariate analysis.

BACKGROUND: An earlier published series of neoadjuvant radiochemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15 years. Long-term outcome data and predictive factors for pathologic complete response (pCR) were analyzed. PATIENTS AND METHODS: During 1991-1998, 315 LABC patients (cT1-cT4/cN0-N1) were treated with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or-in case of breast conservation-a 10-Gy interstitial boost with (192)Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow-up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX, and the time interval between end of RT and surgery were examined in multivariate terms with pCR and overall survival as end point. RESULTS: The total pCR rate after neoadjuvant RT-CHX reached 29.2%, with LABC breast conservation becoming possible in 50.8% of cases. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1.17 [95% CI 1.05-1.31], p < 0.01). However, in large tumors (T3-T4) a significantly reduced pCR rate (HR 0.89 [95% CI 0.80-0.99], p = 0.03) was obtained. Importantly, pCR was the strongest prognostic factor for long-term survival (HR 0.28 [95% CI 0.19-0.56], p < 0.001). CONCLUSION: pCR identifies patients with a significantly better prognosis for long-term survival. However, a long time interval to surgery (> 2 months) increases the probability of pCR after NRT-CHX.

Trimodal therapy in squamous cell carcinoma of the esophagus.

Patients with ESCC (squamous cell carcinoma of the esophagus) are most commonly diagnosed with locally advanced tumor stages. Early metastatic disease and late diagnosis are common reasons responsible for this tumor's poor clinical outcome. The prognosis of esophageal cancer is very poor because patients usually do not have symptoms in early disease stages. Squamous cell carcinoma of the esophagus frequently complicates patients with multiple co-morbidities and these patients often require interdisciplinary diagnosis and treatment procedures. At present time, neoadjuvant radiation therapy and chemotherapy followed by surgery are regarded as the international standard of care. Meta-analyses have confirmed that this approach provides the patient with better local tumor control and an increased overall survival rate. It is recommended that patients with positive tumor response to neoadjuvant therapy and who are poor surgical candidates should consider definitive radiochemotherapy without surgery as a treatment option. In future, EGFR antibodies may also be administered to patients during therapy to improve the current treatment effectiveness. Positron-emission tomography proves to be an early response-imaging tool used to evaluate the effect of the neoadjuvant therapy and could be used as a predictive factor for the survival rate in ESCC. The percentage proportions of residual tumor cells in the histopathological analyses represent a gold standard for evaluating the response rate to radiochemotherapy. In the future, early response evaluation and molecular biological tests could be important diagnostic tools in influencing the treatment decisions of ESCC patients.

Do insulin-like growth factor associated proteins qualify as a tumor marker? Results of a prospective study in 163 cancer patients.

OBJECTIVE: Insulin-like growth factor (IGF)-1, -2 and Insulin like growth factor binding proteins (IGFBP) are involved in the proliferation and differentiation of cells. It has never been evaluated, if the IGF-system can serve as a tumor marker in neoplasms. METHODS: In our prospective study 163 patients with colorectal cancer (22), prostate cancer (21), head and neck tumors (17), lymphomas (20), lung cancer (34) and other entities (49) were analysed for their IGF and IGFBP serum levels at the beginning and the end of radiotherapy and compared to 13 healthy people. Subgroups of patients with local tumor disease versus metastatic disease, primary and recurrent therapy and curative versus palliative therapy were compared. RESULTS: The serum levels of IGF-2 were significantly elevated in patients with prostate and colorectal cancer. However, sensitivity and specificity were only 70%. IGFBP-2 serum levels were elevated in patients with head and neck tumors. Again sensitivity and specificity were only 73%. A difference between local disease and metastatic disease could not be found. A difference between IGF serum levels before and after radiotherapy could not be detected. CONCLUSION: The IGF-system cannot serve as a new tumor marker. The detected differences are very small, sensitivity and specificity are too low. IGF measurement is not useful for the evaluation of the success of radiotherapy in malignancies.

[Multimodal therapy in locally advanced gastric cancer]. / Multimodale Therapie beim lokal fortgeschrittenen Magenkarzinom.

Locally advanced gastric cancers are characterized by poor prognosis. Clinical outcome can be improved if surgery becomes part of a multimodal treatment approach. The purpose of neoadjuvant treatment includes downsizing of the primary tumor, improvement of the T- and N- categories, and early therapy of micrometastasis. Several controlled clinical trials showed that neoadjuvant chemotherapy as well as neoadjuvant combined radio-chemotherapy, especially for tumors of the gastroesophageal junction, can improve the rate of primary R0 resections, relapse-free survival, and overall survival. While patients with locally advanced tumors clearly benefit from this strategy, the approach is still controversial in patients with early stage disease. Nonresponders do not benefit from neoadjuvant therapy. Therefore, response evaluation and response prediction are of great importance. After successful neoadjuvant chemotherapy, patients should undergo gastrectomy with D(2)-lymphadenectomy because of a high probability of lymph node metastasis. This article summarizes current developments in this field.

The role of neoadjuvant and adjuvant treatment for adenocarcinoma of the upper gastrointestinal tract.

Both locally advanced adenocarcinoma of the stomach and gastro-esophageal junction are associated with poor prognosis due to the lack of effective treatment. Recently multimodal treatment consisting of neoadjuvant chemotherapy in combination with radiotherapy is reported to improve survival when compared to surgery alone. Neoadjuvant therapy in these locally advanced tumors allows for early tumor responses and the extent of tumor regression that can be achieved is considered a significant prognostic factor. This, in turn, increases the resectability of these tumors. Also due to the high frequency of lymph node metastasis, patients with locally advanced adenocarcinoma should undergo a D2 lymphadenectomy. Postoperative chemo?radiation and perioperative chemotherapy have been studied in gastric adenocarcinomas and showed a survival benefit. However, the surgical techniques used in these trials are no longer considered to be standard by today's surgical practice. In addition, there are no standard recommendations for adjuvant chemotherapy or chemoradiation after R0 resection and adequate lymph node dissection.

[Therapy with epidermal growth factor receptor inhibitors. Clinical spectrum of cutaneous adverse effects]. / Therapie mit Inhibitoren des epidermalen Wachstumsfaktorrezeptors. Spektrum kutaner Nebenwirkungen.

Recently, inhibitors of the epidermal growth factor receptor (EGFR), such as erlotinib, gefitinib, cetuximab or panitumumab, have been successfully established in the therapy of a variety of solid tumors. Cutaneous adverse effects are the most frequent side-effects of these so-called targeted cancer drugs and occur in 45-100% of patients. In addition to a characteristic papulo-pustular rash, adverse effects include painful paronychia, xerosis cutis, pruritus, alopecia or alterations of the hair structure. These often stigmatizing side-effects represent a serious threat to the patients' quality of life and compliance and may lead to dose-reduction or even cessation of the antineoplastic therapy. Considering the steadily growing numbers of patients who receive EGFR-targeting therapy, these medicament-associated cutaneous adverse effects are becoming increasingly more important in the routine clinical practice of dermatologists and oncologists.

Evaluation of the tissue toxicity of antiseptics by the hen's egg test on the chorioallantoic membrane (HETCAM).

BACKGROUND: Antiseptics are frequently used for the prophylaxis and treatment of local infections of chronic wounds. Whereas local antiseptics in general have a positive effect on wound healing an uncritical use may impair wound healing due to toxic side effects. OBJECTIVE: We sought to assess the vascular irritation potential of different antiseptic solutions and ointments commonly used for short and long term application as a measure of tissue toxicity. METHOD: The vascular irritation was evaluated by the hen's egg test (HET) on the chorioallantoic membrane (CAM). The effects on the vessels of a mucous membrane were directly assessed by stereomicroscopic observation in vivo. RESULTS: Severe CAM irritation was observed after short-term applications of 1% octenidin-2HCl (Octenisept), 72% isopropanol (Cutasept), 0.35% chloroxylenol (Dettol) and 10% PVP-I ointment (Betaisodona). Medium irritations were observed for 10% PVP-I solution (Betaisodona), 3% lysosomal PVP-I ointment (Repithel), 1.8% cadexomer-iodine ointment (Iodosorb) and 1% cadexomer-iodine pellets (Iodosorb). Finally, slight irritations were observed for 1% PVP-I solution (Betaisodona), 0.1% polyhexanid plus betain (Prontosan) and 1% silver-sulfadiazine ointment (Flammazine), whereas 0.04% polyhexanid solution (Lavanid), washings from sterile maggots of Lucilia sericata and filtrated enzymes from Clostridium histolyticum (Iruxol-N) showed no effects of irritation. In the long-term approaches, no vascular irritations were found for polyhexanid, washings from Lucilia sericata and enzyme filtrations from Clostridium histolyticum. CONCLUSION: The vascular injuries caused by the studied antiseptics are an indirect indicator of their tissue toxicity. Strikingly, even therapeutic substances, which have been regarded as safe in their application for the treatment of chronic wounds in clinical studies, showed severe irritations on the CAM. We suggest that agents with no or low irritation potential on the CAM should be preferred in the clinical practice in order to obtain optimal results.

[Merkel cell carcinoma. Viral genesis and new therapeutic options?]. / Merkel-Zell-Karzinom. Virale Genese und neue Therapieoptionen?

Merkel cell carcinoma (cutaneous neuroendocrine carcinoma) is a rare, highly malignant, neuroendocrine tumor of the skin with predominance in older patients. The tumor is most often located in the sun-exposed skin of the head, the neck and -as in our patient - the extremities. Notably, the tumor bears a high risk of an early regional lymph node as well as distant metastases. Clinically, only a presumptive diagnosis of Merkel cell carcinoma can be established. The definite diagnosis is made by histological and immunohistological methods. Surgical excision with a safety margin should be combined with sentinel lymph node biopsy. In advanced tumor stages (lymph node or visceral metastasis), a remission can be achieved by different chemotherapy schedules in combination with radiation. Recently, a previously unknown polyomavirus, named Merkel cell polyomavirus (MCV or MCPyV), has been identified in 80% of Merkel cell carcinomas. In the near future, these novel findings could be utilized to distinguish Merkel cell carcinoma from small round cell cancers and could lead to the development of new therapeutic options.