Marek Jankowski

Interleukin-27: Biological Properties and Clinical Application

Interleukin (IL)-27 is a novel cytokine secreted by stimulated antigen-presenting cells. Initial studies on the biology of IL-27 provided evidence for its role in the initiation of TH1 responses; however, subsequent work has indicated that IL-27 has broad inhibitory effects on TH1, TH2, and TH17 subsets of T cells as well as the expansion of inducible regulatory T cells. The involvement of IL-27 in the regulation of angiogenesis and antiviral response has also recently been reported. The aim of this review is to highlight the potential areas of IL-27 clinical application, especially the management of neoplastic and viral diseases as well as autoimmune disorders, including rheumatoid arthritis and multiple sclerosis. The review will also serve to elaborate on the molecular mechanisms involved in the expression of this cytokine and signaling from the IL-27 receptor.

Merkel cell carcinoma: is this a true carcinoma?

Recent years have brought an enhanced understanding of Merkel cell carcinoma (MCC) biology, especially with regard to the Merkel cell polyoma virus as a causative agent. Differences between Merkel cell polyomavirus‐positive and Merkel cell polyomavirus‐negative MCC in morphology,, gene expression, miRNA profiles and prognosis have been reported. Origin of MCC is controversial. Presence of neurosecretory granules has suggested that these carcinomas originate from one of the neurocrest derivatives, most probably Merkel cells; the name Merkel cell carcinoma is now widely accepted. Expression of PGP 9.5, chromogranin A and several neuropeptides, initially regarded as specific markers for neural and neuroendocrine cells, has recently been shown in a subset of lymphomas. MCC commonly expresses terminal deoxynucleotidyl transferase and PAX5. Their co‐expression under physiologic circumstances is restricted to pro/pre‐B cells and pre‐B cells. These findings lead to the hypothesis by zur Hausen et al. that MCC originates from early B cells. This review was intended to critically appraise zur Hausens hypothesis and discuss the possibility that MCC is a heterogenous entity with distinct subtypes.

Coexistence of psoriasis vulgaris and vitiligo with bullous pemphigoid: a case report.

underlying mechanisms for the occurrence of this phenomenon. In our patient, zosteriform cutaneous involvement was the first clinical sign of an undiagnosed primary breast carcinoma. The unusual zosteriform distribution of cutaneous metastases, in conjunction with the relatively low incidence of breast malignancies in males, may result in delayed diagnosis, inadequate management, and prolonged morbidity in this group of patients. Increased awareness among physicians of the significance of such findings and the early recognition of cutaneous metastases are mandatory for the provision of an optimal treatment strategy.

Merkel cell carcinoma: an illustrative case and review

Merkel cell carcinoma (MCC) was first described by Toker in 1972, as trabecular carcinoma [1, 2]. It is a primary cutaneous tumor of neuroendocrine origin characterized by aggressive course and poor prognosis [3–5]. Agelli and Clegg in 2007 showed that the incidence of MCC in the U.S. was 0.24/100000 per year [6]. Merkel cell carcinoma has a high propensity for local recurrence, lymphatic spread and distal metastases. Metastases are usually found in the skin (28%), liver (13%), bones (10%), and brain (6%). Typically, at the time of diagnosis, local or distant metastases are present. Merkel cell carcinoma affects mainly the elderly, more often men, usually between 65 and 85 years of age. Primary lesions are frequently localized in sun-exposed areas. In 29–40% of cases it is the head and neck region, followed by extremities (21–38%), trunk (7–23%), and other skin regions (3.4–12%) [7]. Merkel cell carcinoma often arises in the setting of immunodeficiency (post-transplant immunosuppression or HIV infection), autoimmune connective tissue diseases and neoplasm, particularly Hodgkins disease, B-cell lymphoma, chronic lymphocytic leukemia, breast and ovary cancer [8, 9]. Established risk factors for MCC development are UV radiation, immunosuppression and Merkel cell polyomavirus infection [7, 10]. Clinically MCC appears as an indolent, rapidly growing blue-red nodule often with telangiectasias. Histological findings are: monomorphous indistinct bluish cells, often arranged in trabeculae or strands with numerous mitotic figures, apoptotic cells and occasionally necrosis. Lymphocyte intra- and peritumoral infiltration is common. Routine histological examination may be of limited diagnostic value. Immunohistochemical staining, particularly against cytokeratin 20 (CK20) or chromogranin A, increase the effectiveness of MCC diagnosis [11]. Therapeutic management of choice is wide surgical excision or Mohs micrographic surgery of the tumor with sentinel lymph node biopsy. Adjuvant radiotherapy or chemotherapy is administered according to the clinical staging of disease. Metastases are treated with protocols similar to small-cell lung carcinoma management [12, 13]. A 74-year-old woman presented to our clinic with blue-red colored, well-demarcated skin tumors ranging from 0.5 cm to 2.0 cm in diameter located on the left lower extremity. Lesions were hard and painful on palpation (Figure 1). The enlarged inguinal lymph nodes were present bilaterally. Additionally the patient had a history of arterial hypertension, type 2 diabetes, rheumatoid arthritis and post-thrombotic syndrome. Figure 1 Blue-red colored, hard and painful to the touch skin tumors of the left lower leg diagnosed as MCC Lesions appeared 2 years ago, initially they would remit spontaneously. One year after the first occurrence, a nodular, ulcerated lesion located in the proximity of the left medial malleolus was biopsied. Histopathological examination of skin biopsy revealed positive staining for chromogranin A and CD56 as well as positive staining for cytokeratin 7 and cytokeratin 20 with a dot-like pattern. Deep surgical margin was positive. During current hospitalization skin biopsy was repeated revealing nests of small undifferentiated cells with round nuclei and scant cytoplasm. Numerous mitotic figures and apoptotic cells were present with occasional necrosis. Abundant peritumoral lymphocyte infiltration was observed. Immunohistochemical stainings were positive for CK20 (with a characteristic dot-like pattern), CD56, epithelial membrane antigen (EMA, MUC1), neuron-specific enolase (NSE, focal expression). Leukocyte common antigen (LCA) expression was positive only in peritumoral infiltrate (Figure 2). Adjacent muscular tissue was infiltrated with tumor cells. Based on clinical appearance and histology, MCC was diagnosed. Figure 2 Merkel cell carcinoma. A, B – Hematoxylin and eosin staining. The obtained result of the histopathological examination found within the dermis area is low-differentiated small cancer cells with scanty cytoplasm and round nuclei with small grains. ... Routine laboratory blood and urine tests, X-ray and computed tomography (CT) scans of the thorax, chest examination, USG of the abdomen and histology of enlarged inguinal lymph nodes were normal. The patient was staged IIC T4 N0 M0, where IIC is for primary tumors > 2 cm in size with extracutaneous invasion, T4 stands for primary tumor invading the bone, muscle, fascia, or cartilage; N0 – no regional lymph node metastasis and M0 – no distant metastases. The patient has undergone two surgeries with skin grafting. Due to local spread of the tumor, the 2nd and 1st fingers with metatarsal head were amputated. Currently adjuvant chemotherapy is considered. Merkel cell carcinoma is a rare neuroendocrine skin tumor occurring in the elderly, more often in men (70%). Common localization is the head and neck area and limbs, several cases of MCC in the anogenital area and on the mucosae have been reported [14]. Clinical appearance of MCC is heterogeneous. It frequently presents as an asymptomatic, reddish, bluish, or purple tumor of the skin. The size at the time of the first consultation is usually smaller than 2 cm, although rapid growth is characteristic [15, 16]. Merkel cell carcinoma pathogenesis remains largely unknown, but ultraviolet radiation and immunosuppression may play a significant role in the development of this cancer. In recent years, the relationship between Merkel cell polyomavirus infection and the development of the tumor was observed [17]. In the patient presented in this report, the incidence of tumors on both legs and the history of spontaneously resolving nodules may indicate MCC metastases without an apparent primary tumor. Spontaneous regression of the primary MCC tumor is not uncommon, with a dozen of cases described in medical literature [18]. Enlarged inguinal lymph nodes in our patient could indicate changes in tumor spread via lymphatic vessels. Cases of micro-metastases in the lymph nodes without clinical lymphadenopathy have been reported as well. Therefore, the sentinel lymph node biopsy and chest and abdomen imaging are necessary. Ulceration is uncommon in MCC. We believe that coexistence of MCC with post-thrombotic syndrome in our patient may explain ulceration of MCC tumor in this case. Merkel cell carcinoma derives from neuroendocrine cells and typically has appearance of ‘blue-cell tumor’ comprised of small, monomorphous cells with scant cytoplasm. Cancer cells are usually restricted to the dermis and subcutaneous tissue with a little propensity to invade epidermis. Differential diagnosis should consider basal cell carcinoma, squamous cell carcinoma, lymphoma, melanoma, metastatic neuroblastoma and neuroendocrine carcinoma. Useful diagnostic features are a positive dot-like pattern of staining for CK20 and sometimes other cytokeratins as well as positive staining for chromogranin A, somatostatin, gastrin characteristic of cells of neuroendocrine origin. Merkel cell carcinoma cells also exhibit a positive reaction with CD117, CD99, but negative with LCA and S-100 protein and of TTF-1. In our case, MCC was positive for cytokeratin 7, CK20 chromogranin A and MUC1. The prognosis in MCC is usually poor. The size of the primary tumor below 2.0 cm is associated with better prognosis, unfortunately, because of the very rapid proliferation of tumor cells, and diagnostic difficulties delaying diagnosis, in most cases, patients are diagnosed with MCC at the stage when the primary lesion exceeds 2.0 cm [19]. The classification of TMN American Joint Committee on Cancer (AJCC) proposed a clinical staging of MCC (0 to IV) [20]. According to this classification, the estimated 5-year survival rate for patients with stage IIC T4 N0 M0 is 50%. Merkel cell carcinoma lesions are considered highly malignant, hence a combination of surgery, radiotherapy in stages IA to IIIB of the disease is recommended [21–24]. Because of a rapid progression of the disease, adjuvant chemotherapy is frequently administered [2]. One can consider both the chemotherapy and radiotherapy in order to reduce the tumor mass prior to surgery in stages IIC to IIIB. In our patient, due to the presence of coexisting diseases and general condition, only surgical treatment was applied. In the IV stage of disease, the treatment of choice is palliative chemotherapy with the assessment of response to therapy and toilet surgery or radiotherapy of the bone, central nervous system and extensive skin metastases. Because of its similarity to small lung cancer, recommended chemotherapy protocols are cisplatin with etoposide or doxorubicin and cyclophosphamide or ifosfamide. The value of adjuvant radiotherapy has been confirmed with meta-analysis [25–27].

Enhanced expression of Fas Ligand (FasL) in the lower airways of patients with fibrotic interstitial lung diseases (ILDs).

The exact role of FasL, and particularly its soluble and membrane-bound forms, in the development of chronic ILDs and lung fibrosis has not been extensively explored. We aimed at analyzing membrane-bound FasL expression on alveolar macrophages (AM) and lymphocytes (AL) as well as soluble FasL (sFasL) levels in bronchoalveolar lavage (BAL) from ILDs patients, incl. pulmonary sarcoidosis (PS), hypersensitivity pneumonitis (HP), silicosis, asbestosis, idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), and healthy subjects (n = 89, 12, 7, 8, 23, 6, 17, respectively). In IPF, significantly increased percentage of AM FasL(+) and CD8(+)FasL(+) cells as well as sFasL levels in BAL were found. Increased sFasL levels were also observed in HP. NSIP and asbestosis were characterized by higher AM FasL(+) relative number; CD8(+)FasL(+) population was expanded in asbestosis only. There was a significant decline in AL FasL(+) percentage in PS and HP. Vital capacity was negatively correlated with sFasL levels, AM FasL(+) and CD8(+)FasL(+) cell relative count. CD4(+)FasL(+) and CD8(+)FasL(+) percentage strongly correlated with BAL neutrophilia, an unfavorable prognostic factor in lung fibrosis. The concurrent comparative BAL analysis of FasL expression indicates that FasL(+) AM and AL (mainly Tc cells) comprise an important element of the fibrotic process, mostly in IPF. FasL might play a crucial role in other fibrosis-complicated ILDs, like NSIP and asbestosis.

Swimming pools and fungi: An epidemiology survey in Polish indoor swimming facilities

Environmental conditions for swimming facilities may support fungal growth and also may represent a biological risk for users. However, since previously published studies both cleaning procedures and sanitary regulations are likely to have been improved. The aim of the study was to examine whether attendance to public swimming pools was still a risk factor for fungal infection of the skin in Poland. We investigated the occurrence of mycotic species, in a sample from Polish swimming pools. Detection and identification of isolated species were achieved by cultural and morphological methods. Study revealed high incidence of yeast and yeast‐like fungi. Candida spp. and Rhodotorula rubra were commonly detected, followed by Aspergillus spp. and Trichophyton mentagrophytes. Surprisingly, the prevalence of clinically important species isolated from swimming pool environments did not reflect prevalence of those species in Polish population. The present results are in agreement with previous research and support that swimming pools remain an important reservoir of clinically important fungi, yet the exposure associated with swimming pools may not be a major source of dermatophytic infection in Poland.

Stevens-Johnson syndrome/toxic epidermal necrolysis presumably induced by norfloxacin

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare mucocutaneous, unpredictable, life-threatening drug side reactions. A very rare case of norfloxacin-induced SJS/TEN overlap with uncommon clinical presentation in a patient with a suspected urinary tract infection is reported. The SJS/TEN management with possible treatment capabilities are discussed. In spite of only two previous reports of norfloxacin-induced SJS and TEN we believe that awareness of norfloxacin adverse reactions needs to be raised among prescribers.

Novel KRT14 mutation causing epidermolysis bullosa simplex with variable phenotype

About 75% of cases of epidermolysis bullosa simplex result from mutations in KRT5 and KRT14 genes. Here, we report a family with a novel heterozygous missense mutation p.Leu418Gln in the KRT14 gene causing EBS of phenotype varying from EBS‐loc to EBS‐gen intermed. To the best of our knowledge, the family reported by us is the largest one in which two different phenotypes can be distinguished. The molecular dynamics simulations show that p.Leu418Gln mutation results in clear disruption of intermolecular π‐stacking between KRT14:Tyr415 and KRT5:Tyr470, which in turn may affect putative phosphorylation site at KRT14:Thr414. This study further supports the importance of the EIATYR/KLLEGE motif in maintaining structural stability of KRT14:KRT5 heterodimer and indicates that physical properties of introduced amino acid can modulate the disease severity. The results obtained indicate further need of genotype–phenotype studies in EBS. In conclusion, genotype‐based prognosis should be given to patients with caution.

Low-level laser therapy (LLLT) does not reduce subcutaneous adipose tissue by local adipocyte injury but rather by modulation of systemic lipid metabolism.

Low-level laser (light) therapy (LLLT) has been applied recently to body contouring. However the mechanism of LLLT-induced reduction of subcutaneous adipose tissue thickness has not been elucidated and proposed hypotheses are highly controversial. Non-obese volunteers were subject to 650nm LLLT therapy. Each patient received 6 treatments 2-3 days apart to one side of the abdomen. The contralateral side was left untreated and served as control. Subjects’ abdominal adipose tissue thickness was measured by ultrasound imaging at baseline and 2 weeks post-treatment. Our study is to the best of our knowledge, the largest split-abdomen study employing subcutaneous abdominal fat imaging. We could not show a statistically significant reduction of abdominal subcutaneous adipose tissue by LLLT therapy. Paradoxically when the measurements of the loss of fat thickness on treated side was corrected for change in thickness on non treated side, we have observed that in 8 out of 17 patients LLLT increased adipose tissue thickness. In two patients severe side effect occurred as a result of treatment: one patient developed ulceration within appendectomy scar, the other over the posterior superior iliac spine. The paradoxical net increase in subcutaneous fat thickness observed in some of our patients is a rationale against liquefactive and transitory pore models of LLLT-induced adipose tissue reduction. LLLT devices with laser diode panels applied directly on the skin are not as safe as devices with treatment panels separated from the patient’s skin.

IL-27: A Key Player in Immune Regulation

Interleukin-27 plays an important role in the regulation of immune response. IL-27 signaling mediated by its heterodimeric IL-27Rα/gp130 receptor activates multiple signaling cascades, including STAT1 and STAT3, Akt/mTOR, ERK, and p38 MAPK pathways. Up- and downregulation of both receptor subunits and cross talk between immune cell populations regulate the magnitude of signal transduction. Transduction of IL-27 stimulatory signal is also limited through a reciprocal feedback loop involving SOCS3. Initial studies focused on proinflammatory activities of IL-27. IL-27 induces expression of T-bet and hence promotes Th1 cell differentiation and augments CD8+ T cell- and NK cell-mediated cytotoxicity. Simultaneously, IL-27 limits inflammation through its ability to negatively regulate GATA-3 and ROR-γt, key transcription factors of Th2 and Th17 cells, respectively. In contrast, Tr1 cell differentiation is positively stimulated by IL-27 through upregulation of c-Maf and Ahr further contributing to the limitation of the inflammation. Here, we have discussed the downstream signaling from the IL-27 receptor and its main molecular targets in immune cell subsets including Th1, Th2, Th17, Treg, Tr1, and Tfh cell population as well as B cells, DCs, and macrophages.