The Role of Stem Cells Derived From the Mesenchyme of the Umbilical Cord in Reducing Immunosuppressive Drug Doses Used in Allogenic Transplantations.

BACKGROUND: This study evaluated the potential of Wharton's jelly mesenchymal stem cells with high tolerogenic properties in reducing immunosuppressive dosage and related adverse effects. METHODS: A 4- to 6-week-old, 30-40 g weight, male inbred CD57BL/6 mice were used as skin allograft donors, whereas Balb/c mice with similar characteristics were used as recipients. Wharton's jelly stem cells were obtained from a commercial kit sourced from human umbilical cord. Skin allografts were performed from CD57Bl6 to Balb/c mice (day 0). Group 1 (control) received no treatment. Group 2 received 15 mg/kg cyclosporin A on days 0 to 30. Group 3 received 5.7 × 10 6 and 10.3 × 10 6 cell/kg Wharton's jelly stem cells on days 0 and 3, respectively. Groups 4, 5, and 6 received a combination of 15, 10, and 5 mg/kg per day cyclosporine A (days 0 to 30) with the same stem cell dose with group 3, respectively. Graft rejection was evaluated with digital photography and thermal imaging, histopathology (Banff grading, epithelialization scores, dermoepidermal dissociation), immunochemistry (Ki-67 and Bcl-2), and biochemical methods (interleukin 10, interleukin 2, interferon γ, tumor necrosis factor α) (day 10). Cumulative adverse effects of cyclosporin A occurring in the groups were revealed by histopathological evaluation of kidney and liver (a modified semiquantitative method of infiltration of inflammatory cells around the portal area and lobular region in liver; modification of the Banff rating of proximal tubules and hypertrophia of juxtaglomerular apparatus cells in kidney) (day 30). RESULTS: There was no rejection in groups 2, 4, and 5 until the end of study. These were statistically different versus groups 1 (day 10 ± 0.71), 3 (day 11 ± 0.82), and 6 (day 11 ± 0.58) (all P 's < 0.05). Groups 4 and 5 have exhibited statistically similar findings in histopathological (4 epithelization score: 3.7 ± 1.3; 5 epithelization score: 3.5 ± 0.5; 4 Banff grading score: 0.8 ± 0.6; 5 Banff grading score: 1.0 ± 0.5; both P 's = 1.00), immunohistochemical (4 Bcl-2 score: 3.5 ± 0.5, P = 0.618; 5 Bcl-2 score: 3.4 ± 0.5, P = 1.00; 4 Ki-67 score: 3.7 ± 0.4, P = 1.00; 5 Ki-67 score: 3.5 ± 0.5, both P 's = 1.00), and levels of cytokines (both P 's = 1.00) versus group 2. Adverse effects on kidneys and liver were lowest and statistically similar in groups 3, 5, and 6 (all P 's = 00) versus group 1. CONCLUSIONS: Wharton's jelly mesenchymal stem cells alter bioavailability of cyclosporine, albeit at much lower doses and with fewer systemic adverse effects.

Effects of Adipose-Derived Stem Cells and Platelet-Rich Plasma for Prevention of Alopecia and Other Skin Complications of Radiotherapy.

BACKGROUND: Radiotherapy (RT) involves the use of ionizing radiation in treating malignancies and benign disorders. However, RT damages target and healthy surrounding tissues in a dose-dependent manner. This effectively reduces patient compliance and quality of life, thereby warranting the prevention of RT-induced adverse effects on skin. Adipose-derived stem cells (ASCs) are used to treat RT-induced damage and platelet-rich plasma (PRP) provides a scaffold that potentiates the effects of ASCs. Thus, the aim of this study was to determine the mechanism employed by ASCs and PRP in protecting against RT-induced adverse effects. METHODS: We have established an immunodeficient mouse transplantation model using which human hair follicular units were implanted. When the follicular units were macroscopically and microscopically mature and anagenic, we administered localized RT. Subsequently, the mice were randomly divided into 4 groups based on the subcutaneous injection of the following to the irradiated transplantation site: saline, PRP, ASCs, and a combination of ASCs and PRP. Next, we used macroscopic and microscopic analyses to determine the protective effects of the injected solutions on skin and hair follicles. RESULTS: Adipose-derived stem cells reduced RT-induced adverse effects, such as impaired wound healing, alopecia, skin atrophy, and fibrosis by suppressing inflammation, dystrophy, degeneration, connective tissue synthesis, and apoptosis and increasing cellular proliferation, differentiation, and signaling. Moreover, these effects were augmented by PRP. CONCLUSIONS: Thus, co-administering ASCs with PRP in mice prevented RT-induced adverse effects and can be tested for use in clinical practice.

Nicotinamide N-methyltransferase overexpression may be associated with poor prognosis in ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer-related mortality in women. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme and there is growing evidence to suggest that it plays an important role in cancer progression. This is the first study to examine the expression of NNMT in serous ovarian cystadenomas, serous borderline tumours, low grade serous carcinomas (LGSC) and high grade serous carcinomas (HGSC) and investigate the potential independent association of NNMT expression with survival. Tissue samples were analysed immunohistochemically for NNMT expression. The stromal NNMT score was significantly higher in HGSC compared to serous cystadenomas and serous borderline tumours (p < .001, p < .043, respectively). The mean stromal NNMT score of patients with HGSC was significantly higher than patients with LGSC (p = .043). Patients with low expression of NNMT had a significantly higher mean recurrence-free survival than patients with high expression (p = .036). NNMT may support tumour progression in ovarian cancer by promoting desmoplastic stromal tumour reaction. NNMT overexpression may be associated with poor prognosis and can be a therapeutic target in ovarian cancer.IMPACT STATEMENTWhat is already known on this subject? Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that is overexpressed in many malignancies. Its overexpression was shown to lead to histone hypomethylation, which in turn can decrease and increase the expression of tumour suppressor proteins and onco-proteins, respectively. NNMT was also shown to play a role in epithelial-to-mesenchymal transition, which is critical in tumour progression and the stromal tumour reaction. The stromal tumour reaction was recently targeted with promising therapeutic results in ovarian cancer.What do the results of this study add? The expression of NNMT in various ovarian neoplasms including serous cystadenomas, borderline tumours and serous carcinomas has not been studied and independently associated with poor survival, previously. This study suggests that NNMT is progressively overexpressed in the stroma of ovarian neoplasms from benign cysts to HGSCs. NNMT overexpression appears to be independently associated with poor survival in ovarian cancer.What are the implications of these findings for clinical practice and/or further research? The implications of these findings are that NNMT may play an important role in the stromal tumour reaction, and therefore its overexpression may contribute to poor survival. NNMT overexpression may be an important target of ovarian cancer therapy.

Expression and Clinical Significance of Nicotinamide N-Methyltransferase in Cervical Squamous Cell Carcinoma.

Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme, overexpressed in various human malignancies. It is associated with cancer progression and resistance to treatment. The role of NNMT in cervical cancer has not been studied thus far. We aimed to evaluate expression of NNMT in cervical squamous cell carcinoma (SCC) and investigate its clinical significance. NNMT expression was assayed by use of immunohistochemistry in 61 cases of SCC, 11 cases of high-grade squamous intraepithelial lesion, 17 cases of low-grade squamous intraepithelial lesion, and 51 benign cervical tissues. NNMT immunoreactivity was scored based on staining intensity and percentage of positively stained cells. The expression of NNMT was significantly higher in SCC than in benign tissue, low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion (P<0.001). NNMT expression in benign tissue was significantly lower than in low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion. When stratified according to stage, NNMT expression was significantly higher in patients with stage III and IV than those in stage I and II disease (P=0.009). For all stages, patients with metastatic pelvic or para-aortic lymph nodes had significantly higher NNMT expression than patients without nodal involvement (P=0.001). Although preliminary, this is the first study to detect overexpression of NNMT in SCC and increased expression associated with advanced stage and metastatic lymph nodes. NNMT should be investigated further in cervical cancer as a potential therapeutic target and a prognostic indicator.

Nicotinamide N-methyltransferase expression and its association with phospho-Akt, p53 expression, and survival in high-grade endometrial cancer

Background/aim: Nicotinamide N-methyltransferase (NNMT) is an enzyme that is overexpressed in malignancies. NNMT expression has not been previously studied in endometrial cancer (EC). Increased phospho-Akt (pAkt) levels in response to NNMT overexpression have been reported in in vitro studies of different cancer types. We assayed NNMT expression in primary and metastatic high-grade EC and investigated the relationship of NNMT with p53, pAkt, and survival. Materials and methods: NNMT, pAkt, and p53 expressions were assayed in 100 tissue samples of benign endometria, primary EC, and metastatic EC by immunohistochemistry. Results: The NNMT immunoreactivity score was significantly higher in primary high-grade EC than benign endometrial tissue (P = 0.001). NNMT expression in metastatic tissue was significantly higher than in primary cancer (P < 0.001). Metastatic stromal NNMT expression was significantly higher than that of the adjacent tumor and stroma adjacent to the primary tumor. p53 expression in the primary tumor showed a significant positive correlation with omental NNMT and pAkt expression. NNMT expression was also correlated with pAkt expression in metastatic tissue. NNMT overexpression in metastatic tissue was associated with decreased survival (P = 0.039). Conclusion: This study suggests that NNMT may promote cancer progression and that NNMT overexpression is associated with aberrant p53 expression, pAkt, and poor survival. NNMT's role in cancer progression could make it a target of EC therapy.

Infantile Eosinophilic Pustular Folliculitis: A Case Report.

BACKGROUND: Infantile eosinophilic pustular folliculitis (I-EPF) is a rare disease characterized by pruritic vesicles and sterile pustules on the erythematous surface of the scalp and facial localization, usually seen in the neonatal period. It is essential to show the presence of dense eosinophils in the diagnosis of pustules. Histopathological examination of the hair follicles by eosinophils infiltration is determined. AIM: Here, we reported a 5-month-old baby boy diagnosed infantile eosinophilic pustular folliculitis. PATIENT: A 5-month-old baby boy was consulted to our polyclinic by his family because of pustules on the scalp, face, and neck developing in two week after birth. In dermatological examination, the pustular lesions of 1-2 mm in diameter on the scalp, face, and neck on an erythematous background were determined. RESULTS: There was no growth in the culture taken from the pustule. In the laboratory tests of the patient; upon detection of eosinophilia in the hemogram. The eosinophil count at the patient's first admission was 1.48 K/µl. (0.05 0.50). Eosinophil count was 0.02 K/µl after treatment. It was decreased. The patient was evaluated for other pustular dermatoses. In the differential diagnosis of the patient; causing bacterial/non-bacterial pustulosis were included. Bacterial culture was negative. CONCLUSION: Eosinophilic folliculitis defines as a group of papulopustular diseases with unknown etiology characterized histologically by eosinophilic infiltrates. First, Ofuji reported a female patient with recurrent follicular pustules and peripheral eosinophilia as a variant of folliculitis in 1965. Its etiopathogenesis is not clearly known. In the differential diagnosis of EPF includes the other pustular lesions of the newborn such as erythematoxicum neonatarum, transient neonatal pustular dermatosis, infantile acropustulosis, scabies, dermatophytosis, and langerhans cell histiocytosis. Treatment options includes topical corticosteroids and calcineurin inhibitors, antihistamines, systemic antibacterial and anti-inflammatory agents, and dapson.

Aggressive treatment for urothelial cancer-complete urinary tract extirpation: Operative feasibility in two cases.

Bladder cancer (BC), the most common malignancy of the urinary tract, accounts for 90-95% of all urothelial carcinomas (UCs), while upper urinary tract UC (UUTUC) accounts for only 5-10%. Radical nephroureterectomy with excision of bladder cuff, and radical cystectomy with pelvic lymph node dissection and a urinary diversion (UD) are the gold standard treatments for UUTUC and muscle-invasive bladder cancer (MIBC), respectively. These two treatments can be performed simultaneously when a bilateral or unilateral UUTUC is present with a MIBC, and are called complete urinary tract extirpation (CUTE) and hemi-CUTE, respectively. This complex surgery can help the patient by avoiding multi-staged surgeries, repeated anesthesia, and delay in completion of treatment. Herein, we report the first cases of a hemi-CUTE and CUTE in our department and share our experience with this aggressive and complex surgical treatment.

First experience with a new form of orthotopic ileal neobladder (Leuven N-Pouch) following radical cystectomy.

Bladder cancer is the most common malignancy of the urinary tract. Radical cystectomy with pelvic lymph node dissection and a urinary diversion (UD) is the gold standard treatment of non-metastatic muscle-invasive bladder cancer (MIBC). Although ileal conduit is the standard and most commonly performed type of UD, more number of centers have recently started to perform orthotopic ileal neobladder (OIN). A novel OIN has been described in 2005 as the so-called "Leuven N-pouch", which combines the features of the commonly used Hautmann and Studer neobladders. Herein, we report our first experience with a case of Leuven N-pouch in our department, which was performed for a male patient with MIBC.

Calcified fibrous pseudotumor with Castleman disease.

Simultaneous calcified fibrous pseudotumor (CFT) and Castleman disease (CD) is an extremely rare association. CD is an uncommon lymphoproliferative disease that can arise in various sites of the body, while CFT is a rare type of benign fibrous lesion that frequently affects children and young adults, occurring as solitary or multiple lesions throughout the human body. Both entities are rare and exhibit typical and diverse histomorphological features. We report the case of a 15-year-old female patient, who, at the age of 13 had a biopsy performed at an external medical center; however, after 4 months the lesion had regrown. This lesion was removed with a surgical operation; however, it regrew 2 years later and was removed a third time. The results of the latter two biopsies were the same: CFT accompanying CD. The histologic examination of the excised lymph node and the surrounding tissue showed hyalinized fibrous tissue containing dystrophic and psammomatous calcification. In this case, the hyaline vascular type of CD was found to be intertwined with a CFT, which hampered the differentiation of whether both entities emerged within the lymph node or if the CFT developed from the soft tissue and then involved the lymph node. Future studies involving larger case series will provide a more precise insight, which should serve to resolve the current uncertainty.

Neurothekeoma in childhood: a benign tumor mimicking malignant disease.

Neurothekeoma (NT) sometimes extends to subcutaneous adipose tissue, skeletal muscle or epidermis, and thus may imitate some malignant situations. A 17-year-old female patient was admitted to another medical center with a swelling at her waistline. Plexiform fibrous histiocytoma was diagnosed, and she was referred to our clinic. Total re-excision was performed. The new pathology report indicated features of atypical NT. A case of atypical NT, which can be misdiagnosed as a malignant mesenchymal tumor, is discussed in this paper.

Pilomatrixoma in childhood.

CONTEXT: Pilomatrixoma is a benign tumor of the skin. Malignant transformation can be seen rarely in the small percentage. AIM: The aim of the following study is to attract attention to this tumor in the differential diagnosis because if it is not kept in mind it leads to both unnecessary interventions and treatments for the patient. PATIENTS AND METHODS: From January 2006 to December 2012, 8 patients with pilomatrixoma were evaluated retrospectively. RESULTS: A total of 8 pediatric pilomatrixoma patients' charts were reviewed retrospectively. None of the patients had familial feature. Of 8 patients 4 (50%) were male and 4 (50%) were female. The patients' age ranged from 2-18 years with a median age 11.5 years. All of the patients were admitted with the complaint of swelling at the lesion site. Two patients have multiple lesions, one of them has two and other has three lesions. A total of 11 lesion were detected in our 8 patients that 5 of them were located upper extremities (46%), 3 of them cervical region (27%), 2 of them on occipital region (18%) and 1 of them in the sacral region (9%). All lesions were excised completely. Until now, no patient had evidence of recurrence or malignant disease. CONCLUSION: As a result pilomatrixoma is a benign tumor, with atypical forms and unfortunately, no tumor-specific diagnostic feature except of a careful histopathological examination is available.

Calcified fibrous pseudotumor with Castleman disease

Simultaneous calcified fibrous pseudotumor (CFT) and Castleman disease (CD) is an extremely rare association. CD is an uncommon lymphoproliferative disease that can arise in various sites of the body, while CFT is a rare type of benign fibrous lesion that frequently affects children and young adults, occurring as solitary or multiple lesions throughout the human body. Both entities are rare and exhibit typical and diverse histomorphological features. We report the case of a 15-year-old female patient, who, at the age of 13 had a biopsy performed at an external medical center; however, after 4 months the lesion had regrown. This lesion was removed with a surgical operation; however, it regrew 2 years later and was removed a third time. The results of the latter two biopsies were the same: CFT accompanying CD. The histologic examination of the excised lymph node and the surrounding tissue showed hyalinized fibrous tissue containing dystrophic and psammomatous calcification. In this case, the hyaline vascular type of CD was found to be intertwined with a CFT, which hampered the differentiation of whether both entities emerged within the lymph node or if the CFT developed from the soft tissue and then involved the lymph node. Future studies involving larger case series will provide a more precise insight, which should serve to resolve the current uncertainty.