Rafał Czajkowski

Novel Approaches to Treatment of Advanced Melanoma: A Review on Targeted Therapy and Immunotherapy

The incidence of malignant melanoma is increasing. The majority of patients are diagnosed in early stages when the disease is highly curable. However, the more advanced or metastatic cases have always been a challenge for clinicians. The poor prognosis for patients with melanoma is now changing as numerous of promising approaches have appeared recently. The discovery of aberrations of pathways responsible for intracellular signal transduction allowed us to introduce agents specifically targeting the mutated cascades. Numerous clinical studies have been conducted to improve effectiveness of melanoma treatment. From 2011 until now, the U.S. FDA has approved seven novel agents, such as BRAF-inhibitors (vemurafenib 2011, dabrafenib 2013), MEK-inhibitors (trametinib 2013), anti-PD1 antibodies (nivolumab 2014, pembrolizumab 2014), anti-CTLA-4 antibody (ipilimumab 2011), or peginterferon-alfa-2b (2011) intended to be used in most advanced cases of melanoma. Nevertheless, clinicians continue working on new possible methods of treatment as resistance to the novel drugs is a commonly observed problem. This paper is based on latest data published until the end of January 2015.

Current aspects of vitiligo genetics

Vitiligo is a common acquired depigmentation disorder of the skin manifested by the presence of white macules. The disease occurs at a frequency of approximately 1–4% of the world population. Currently, the most popular theory of vitiligo development is a multifactorial hypothesis according to which genetic conditions predispose vitiligo macules to occur as a result of specific environmental factors. According to the genetic hypothesis, vitiligo inheritance is multigenic. Genetic studies conducted so far concern patients with non-segmental vitiligo. There are three basic techniques of genetic studies: candidate gene association studies, genomewide linkage studies and genome-wide association studies (GWAS). The GWAS are the “gold standard” for detecting susceptibility genes. Up to now, approximately 36 convincing non-segmental vitiligo susceptibility loci have been identified. Approximately 90% of them encode immunoregulatory proteins, while approximately 10% encode melanocyte proteins. The existence of various associations between vitiligo and other autoimmune diseases may provide new knowledge on the causes of many disorders. Examples include the inverse relationship between vitiligo and melanoma and association of vitiligo with other autoimmune diseases. The main goal of all researches is to find new, optimal therapeutic strategies for vitiligo and other autoimmune diseases.

Chemoprevention of skin melanoma: facts and myths.

Melanoma is the most dangerous type of skin cancer. Despite the rise of public awareness, the incidence rate among the white population has been rising constantly for several decades. Systematic improvement in knowledge about the biology of pigment cells and molecular mechanisms of their neoplastic transformation has enhanced the possibility of melanoma chemoprevention. Hence, chemopreventive agents that prevent, inhibit, or reverse melanoma development are being investigated intensively. Among synthetic compounds, especially well studied are lipid-lowering drugs and cyclooxygenase inhibitors. Substances found in everyday diet, such as genistein, apigenin, quercetin, resveratrol, and curcumin may also have potential chemopreventive qualities. However, studies examining the chemopreventive activity of these compounds have shown widely varying results. Early reports on the possible chemopreventive activity of statins and fibrates were not proved by the results of randomized clinical trials. Similarly, case–control studies examining the influence of NSAIDs on the risk of melanoma do not confirm the antitumor activity of cyclooxygenase inhibitors. Further clinical trials involving carefully selected target populations as well as the identification of specific biomarkers of prognostic and predictive value seem to be essential for the evaluation of the chemopreventive activity of the studied substances.

Cell cycle in sporadic melanoma

Sporadic melanoma is a neoplasm whose etiology has not been fully investigated. Contemporary achievements in molecular biology have made it possible to localize the genes whose damage can contribute to the initiation of neoplastic transformation of melanocytes and lead to a progression of the disease. The majority of these genes are responsible for the correct progression of phase G1 of the cell cycle. Phase G1 of the cell cycle is subject to control by many protooncogenes and antioncogenes, which constitute the pRb or p53 pathway, damage to which can lead to the development of malignant melanoma. The present paper discusses disorders in the control of phase G1 of the cell cycle in sporadic melanoma.

Melanocyte stem cells: Biology and current aspects

Summary Epidermal stem cells have become an object of intensive research. The epidermis constitutes one of the main sources of stem cells and is a tissue of choice for use in exploring their biology. Stratified squamous epithelium (epidermis) possesses the capacity for self-renewal and repair due to the presence of epidermal stem cells (ESC). They have been identified within basal layer of the interfollicular epidermis (IFE), in the “bulge” of the hair follicles of rodents, and also in the human follicular bulge. Melanocyte stem cells (MSC) from hair follicles (precisely from the bulge region, which also contains epidermal stem cells) provide an attractive model for the study of stem cells and their regulation at the niche. This review summarizes the rapidly developing field of epidermal stem cell research and their application in regenerative medicine, paying particular attention to melanocyte stem cells, their biology and some of the processes that occur during hair graying and regeneration of the pigmentary system, as well as discussing how aged-associated changes in the melanocyte stem cells compartment impact hair graying. This review also includes differentiation of human skin stem cells into functional epidermal melanocytes.

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.

Will Tissue-Engineered Urinary Bladders Change Indications for a Laparoscopic Cystectomy?

Radical open cystectomy is a treatment of choice for muscle invasive urinary bladder cancer. Laparoscopic radical cystectomy (LapRC) is surgically advanced and is an extremely difficult technique but presents many advantages. Urinary diversion (conduit, pouch or neobladder) when performed during laparoscopy necessitates a conversion to open procedure. Urinary diversion using an autologous bowel is associated with longer operative times and complications. The authors have analyzed the LapRC procedure and its 2 main parts—that is, bladder resection and urinary diversion. The emphasis was on the operative time and complications related to the urinary diversion procedure. A urinary diversion created in vitro could make the LapRC totally intracorporeal, and it could be completed within an acceptable time. Tissue engineering techniques used for urinary diversion after cystectomy shorten the operative time and help avoid serious complications related to bowel surgery. LapRC with tissue-engineered urinary diversion could become a management of choice for muscle invasive bladder cancer.

Filling Effects, Persistence, and Safety of Dermal Fillers Formulated With Stem Cells in an Animal Model

BACKGROUND Research is scarce regarding the effectiveness of dermal fillers containing autologous stem cells. OBJECTIVES The authors sought to determine the local and systemic effects of adipose-derived stem cells (ADSCs) as a component of dermal fillers in an animal model. METHODS Wistar rats were injected with 1 of the following dermal fillers: ADSCs combined with hyaluronic acid (ADSC-HA), ADSCs combined with fish collagen (ADSC-COL), HA alone (CONTROL-HA), or COL alone (CONTROL-COL). Fillers were injected into the glabella, dorsum, and chest of each animal. The ADSCs were labeled with PKH26 to assess cell migration. Filling effects (FEs) were measured immediately after injection and at 1.5 months and 3 months after injection. Skin specimens were stained with hematoxylin and eosin to assess localization and persistence of ADSCs. RESULTS Mean FEs in animals implanted with ADSCs were greater and persisted longer than those of controls. No inflammatory responses were observed in any group. Three months after injection, PKH26-positive cells comprised nearly 70% of cells at the injection site in animals treated with ADSC-HA. PKH26 fluorescence also was detected in the spleen but not in the brain, kidney, or lung. CONCLUSIONS Stem cells have the potential to improve the aesthetic effects and longevity of dermal fillers.

The concentration of thiobarbituric acid reactive substances (TBARS) and paraoxonase activity in blood of patients with osteoarthrosis after endoprosthesis implantation

Summary Background The aim of this study was to evaluate the concentration of malondialdehyde (MDA) in erythrocytes and in blood plasma and the activity of blood paraoxonase (PON1) of patients with osteoarthrosis (OA) submitted to endoprosthesis implantation for evaluating oxidative stress. Material/Methods Study was conducted on 55 patients with OA and on 54 total movement-efficient volunteers. The material for the study was venous blood plasma, serum and erythrocytes. Results Increased concentration of MDAe before surgery was observed in the group of men and in patients with a degenerative process affecting hip joints. After an implantation of endoprosthesis, MDAe decreased to the level observed in the control groups. In the study group MDA concentration in plasma was slightly lower before surgery, and after an operation it reached the value of the parameter of the reference groups. Regardless of sex or age, paraoxonase activity was almost twice as high in almost all subgroups as in the reference group. A positive correlation between PON 1 activity and MDAe concentration was demonstrated both before and after surgery in the group of men. Conclusions The increase of PON1 activity in patients’ serum in relation to the control groups indicates a probable pathogenic role of the increased formation of reactive oxygen species in the course of OA and may suggest acute inflammation of the synovial joint. The high level of PON 1 activity after endoprosthesis implantation indicates that surgical treatment may additionally stimulate ROS generation. MDAe concentration indicate more intensive process of lipid peroxidation in the elderly.