Clear Cell Carcinoma of the abdominal wall.

BACKGROUND: Clear cell carcinoma in scars after cesarean section is extremely rare, with only 22 cases reported in the literature. Management of this condition needs to be further explored. Here, we report of a patient with clear cell carcinoma of the abdominal wall that developed 35 years after cesarean section. CASE REPORT: The material of the study was a group of 61 patients divided into two groups. Group I - 35 deaf or with profound sensorineural hearing loss children (the pupils of the deaf and hard of hearing school), aged 5-17 years (average 9,2 years), 14 males, 21 females, II - control group comprised 26 normal hearing patients, aged 5-16 years (average 10,4 years), 14 males, 12 females (patients of Department of Pediatric Otolaryngology, Audiology and Phoniatrics, Medical University of Lodz). In both groups, exon 2 sequencing of GJB2 gene was performed. RESULTS: A 58-year-old woman was admitted to our department due to abdominal pain and a progressively growing mass in the abdominal wall. Based on biopsy, a preliminary diagnosis of clear cell carcinoma was made. A wide surgical excision of the tumor with clear margins, hysterectomy with bilateral salpingo-oophorectomy, and abdominal wall reconstruction using synthetic mesh were performed. The patient was discharged in good condition after fifteen days of hospitalization. The patient remained recurrence-free 6 months after the treatment. CONCLUSIONS: T Lack of standardized management of rare malignant transformations hinders patient care. Due to a growing number of cesarean deliveries, we can expect clear cell carcinoma prevalence of the abdominal wall to increase. Therefore, patients and clinicians should attend to any pain, itching, or change in the size of abdominal wall scars.

Kaposi Sarcoma in the Genital Area in a Kidney Transplant Patient: A Case Report and Literature Review.

BACKGROUND: Kaposi sarcoma (KS) is a cancer with an incidence in patients after transplantation (Tx) that is 500 times greater than that in the healthy population. The risk of KS increases significantly during therapy, especially when immunosuppressive therapy with cyclosporine A (CsA) is used. Most cases of KS develop during the first 2 years after transplantation. After a KS diagnosis, it is recommended to reduce the doses of immunosuppressive medications. Conversion of immunosuppressive treatment into mammalian target of rapamycin (m-TOR) inhibitors is strongly suggested. PATIENTS AND METHODS: We present the case of a 65-year-old man with end-stage renal disease (ESRD) of unknown etiology, who had kidney transplantation in 2008. Immunosuppressive protocol was based on CsA, mycophenolate mofetil (MMF) and prednisolone (PRE). In 2011, during the dermatological consultation, on the penis glans a purple stain of uneven surface was noted. Histology study revealed the presence of KS. The treatment was modified. The patient was converted from CsA to everolimus. Before converting, the creatinine concentration was 1.79 mg/dl and proteinuria less than 0.3 g/day. RESULTS: The change in the scheme of immunosuppresion from CsA to everolimus was performed to treat the Kaposi sarcoma. Gradually, within a year, the KS was cured. However, the graft function deteriorated, and the graft was lost in one-years' time. CONCLUSION: We present the first documented case of KS in the genital area of a kidney patient. The reduction in the strength of immunosuppression, and the introduction of an m-TOR inhibitor, may have contributed to the deterioration of kidney function, however it was substantial in the treatment of KS.

The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors.

Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumors. Using a primary human in vitro model for Merlin-deficient tumors, we report that the Ras/Raf/mitogen-activated protein, extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) scaffold, kinase suppressor of Ras 1 (KSR1), has a vital role in promoting schwannomas development. We show that KSR1 overexpression is involved in many pathological phenotypes caused by Merlin loss, namely multipolar morphology, enhanced cell-matrix adhesion, focal adhesion and, most importantly, increased proliferation and survival. Our data demonstrate that KSR1 has a wider role than MEK1/2 in the development of schwannomas because adhesion is more dependent on KSR1 than MEK1/2. Immunoprecipitation analysis reveals that KSR1 is a novel binding partner of Merlin, which suppresses KSR1's function by inhibiting the binding between KSR1 and c-Raf. Our proteomic analysis also demonstrates that KSR1 interacts with several Merlin downstream effectors, including E3 ubiquitin ligase CRL4(DCAF1). Further functional studies suggests that KSR1 and DCAF1 may co-operate to regulate schwannomas formation. Taken together, these findings suggest that KSR1 serves as a potential therapeutic target for Merlin-deficient tumors.

Integrin α11ß1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer.

Integrin α11ß1 is a stromal cell-specific receptor for fibrillar collagens and is overexpressed in carcinoma-associated fibroblasts (CAFs). We have investigated its direct role in cancer progression by generating severe combined immune deficient (SCID) mice deficient in integrin α11 (α11) expression. The growth of A549 lung adenocarcinoma cells and two patient-derived non-small cell lung carcinoma (NSCLC) xenografts in these α11 knockout (α11(-/-)) mice was significantly impeded, as compared with wild-type (α11(+/+)) SCID mice. Orthotopic implantation of a spontaneously metastatic NCI-H460SM cell line into the lungs of α11(-/-) and α11(+/+) mice showed significant reduction in the metastatic potential of these cells in the α11(-/-) mice. We identified that collagen cross-linking is associated with stromal α11 expression, and the loss of tumor stromal α11 expression was correlated with decreased collagen reorganization and stiffness. This study shows the role of integrin α11ß1, a receptor for fibrillar collagen in differentiation of fibroblasts into CAFs. Furthermore, our data support an important role for α11 signaling pathway in CAFs, promoting tumor growth and metastatic potential of NSCLC cells and being closely associated with collagen cross-linking and the organization and stiffness of fibrillar collagen matrices.

Axl/Gas6/NFκB signalling in schwannoma pathological proliferation, adhesion and survival.

TAM family receptor tyrosine kinases comprising Tyro3 (Sky), Axl, and Mer are overexpressed in some cancers, correlate with multidrug resistance and contribute to tumourigenesis by regulating invasion, angiogenesis, cell survival and tumour growth. Mutations in the gene coding for a tumour suppressor merlin cause development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas occurring spontaneously or as part of a hereditary disease neurofibromatosis type 2. The benign character of merlin-deficient tumours makes them less responsive to chemotherapy. We previously showed that, amongst other growth factor receptors, TAM family receptors (Tyro3, Axl and Mer) are significantly overexpressed in schwannoma tissues. As Axl is negatively regulated by merlin and positively regulated by E3 ubiquitin ligase CRL4DCAF1, previously shown to be a key regulator in schwannoma growth we hypothesized that Axl is a good target to study in merlin-deficient tumours. Moreover, Axl positively regulates the oncogene Yes-associated protein, which is known to be under merlin regulation in schwannoma and is involved in increased proliferation of merlin-deficient meningioma and mesothelioma. Here, we demonstrated strong overexpression and activation of Axl receptor as well as its ligand Gas6 in human schwannoma primary cells compared to normal Schwann cells. We show that Gas6 is mitogenic and increases schwannoma cell-matrix adhesion and survival acting via Axl in schwannoma cells. Stimulation of the Gas6/Axl signalling pathway recruits Src, focal adhesion kinase (FAK) and NFκB. We showed that NFκB mediates Gas6/Axl-mediated overexpression of survivin, cyclin D1 and FAK, leading to enhanced survival, cell-matrix adhesion and proliferation of schwannoma. We conclude that Axl/FAK/Src/NFκB pathway is relevant in merlin-deficient tumours and is a potential therapeutic target for schwannoma and other merlin-deficient tumours.

Lymphangiogenesis is induced during development of periodontal disease.

Lymphangiogenesis, the formation of new lymphatics, is associated with chronic inflammation and tissue injury, and its role is to enhance lymphatic flow, immune cell transport, and antigen clearance. It is unknown if lymphangiogenesis takes place during periodontal disease development, and we hypothesized that growth of lymphatic vessels occurs in gingiva during development of periodontitis in mice. Inflammation was induced in gingiva with Porphyromonas gingivalis gavage, and bone resorption was verified after 42 days. Growth of lymphatic and blood vessels was measured after immunofluorescent staining with LYVE-1 and CD31. Expression of vascular endothelial growth factors and 2 inflammatory cytokines was investigated 10 days post-infection. Gingival lymphangiogenesis was found 10 days and 42 days post-infection, but proliferation of vessels was observed only in the shortest observation period. Epithelial expression of vascular growth factors (VEGF) A, C, and D was observed in gingiva, and increased numbers of immune cells expressing VEGF-C were found after infection, along with up-regulation of IL-1ß and TNF-α at protein levels. We conclude that lymphangiogenesis takes place in gingiva during periodontal disease development, and that up-regulation of vascular growth factor C in recruited immune cells is likely important for the growth of lymphatic vessels.

Interleukin (IL)-4, IL-13, and IL-17A differentially affect the profibrotic and proinflammatory functions of fibrocytes from asthmatic patients.

Fibrocytes contribute to the fibrotic changes most frequently observed in forms of asthma where inflammation is driven by T helper type 2 (Th2) cells. The mechanisms that regulate the profibrotic function of asthmatic fibrocytes are largely unknown. We isolated circulating fibrocytes from patients with allergen-exacerbated asthma, who showed the presence of fibrocytes, together with elevated concentrations of interleukin (IL)-4 and IL-13 and slightly increased concentrations of the Th17 cell-derived IL-17A, in induced sputum. Fibrocytes stimulated with IL-4 and IL-13 produced high levels of collagenous and non-collagenous matrix components and low levels of proinflammatory cytokines. Conversely, fibrocytes stimulated with IL-17A proliferated and released proinflammatory factors that may promote neutrophil recruitment and airway hyperresponsiveness. IL-17A also indirectly increased α-smooth muscle actin but not collagen expression in fibrocytes. Thus, fibrocytes may proliferate and express a predominant profibrotic or proinflammatory phenotype in asthmatic airways depending on the local concentrations of Th2- and Th17-derived cytokines.

The alpha11beta1 integrin has a mechanistic role in control of interstitial fluid pressure and edema formation in inflammation.

OBJECTIVE: Collagen-binding integrins may be involved in controlling interstitial fluid pressure (Pif), transcapillary fluid flux, and tissue fluid volume. Our aim was to explore whether the newly discovered collagen binding alpha11beta1 integrin has a mechanistic role in inflammatory edema formation. METHODS AND RESULTS: In collagen matrices seeded with a mixture of mast cells and fibroblasts, fibroblasts lacking the alpha11 integrin subunit (alpha11(-/-)) contracted collagen gels less efficiently than control fibroblasts, suggesting that the alpha11beta1 integrin is able to mediate tensile force in connective tissues. In alpha11(-/-) mice, control Pif in skin did not differ from the pressure found in wild-type mice. Whereas a reduction in Pif was found in control mice after inducing inflammation, thereby contributing to fluid extravasation and edema formation, such a reduction was not seen in alpha11(-/-) mice. That this effect is mediated through the extracellular compartment is suggested by a similar plasma protein extravasation ratio in alpha11(-/-) and wild-type mice. CONCLUSIONS: Our data suggest that alpha11beta1 integrins on dermal fibroblasts mediate collagen lattice remodeling and have a mechanistic role in controlling Pif in inflammation and thereby fluid extravasation and edema formation in vivo.

A role for alpha11beta1 integrin in the human periodontal ligament.

We previously demonstrated a role for alpha11beta1 integrin in periodontal ligament (PDL)-driven tooth eruption in the mouse. To explore a possible role for alpha11beta1 in the human periodontium, we have characterized the expression and function of alpha11 in human PDL tissue, in human PDL fibroblasts (hPDLF), and in human gingival fibroblasts (hGF). alpha11 expression was detected in PDL tissue, in hPDLF, and in hGF cells. Platelet-derived growth factor-BB and insulin-like growth factor II stimulated contraction of collagen lattices by both types of fibroblasts. alpha2 integrin blocking antibodies and the use of alpha11 siRNA demonstrated a role for both alpha2beta1 and alpha11beta1 in collagen lattice remodeling. Analysis of the proximal ITGA11 promoter from persons with chronic periodontal disease failed to reveal any polymorphism. Analysis of our data shows that alpha11beta1 is a major collagen receptor on cultured human PDL cells and implies that it is also functionally important in the PDL in vivo.

Mast cells tryptase in patients after renal transplantation.

Mast cells (MC) are involved in the pathogenesis of interstitial fibrosis, acute renal transplant rejection, and chronic allograft nephropathy. The aim of this study was to evaluate MC tryptase concentrations in the sera of 58 renal transplant recipients at various times after surgery in relation to graft function. We observed that kidney transplantation patients showed much higher serum tryptase concentrations than healthy controls. We demonstrated a positive correlation between serum tryptase concentration and hemoglobin, hematocrit, red blood cell count, and hepatic cell damage. We were not able to show any direct correlation between serum tryptase concentration and graft function. The clinical relevance of these findings demand further investigation.

Brain abscess as a rare complication in a hemodialysed patient.

BACKGROUND: Infections remain among the most common morbid events and are an important cause of death in end stage renal disease. They have reduced immune response and increased hazard of infections due to repeated puncture of an arterio-venous fistula, formation of haematoma at the site of cannulation and central vein catheterisation. CASE REPORT: We report a case of brain abscess in chronically haemodialysed patient admitted to our department due to haedache, vomiting, accelerated hypertension and fever. The clinical examination revealed narroving of the right palpebral slit, weeping and right oral angle hanging loose. He had mild microcytic anaemia and high level of g-globulin. Ophtalmologic examination showed normal oculi fundi. The computed tomography revealed heterogenous mass marginally enhanced with contrast agent in the right frontal cerebral lobe. The right fronto-temporal craniotomy was performed and the right frontal lobe abscess was found and totally excised. The postoperative course was uneventful besides of seizures which were effectively treated with carbamazepine. After bilateral nephrectomy the patient undervent succesfull kidney transplantation and is in good condition without any neurological defect. A probable cause of his brain abscess was peridontal abscess recognized 3 month earlier or bilateral vesicoureteral refluxes. CONCLUSIONS: 1. Uremic patients have a reduced immunocapacity and are a high risk group for infections of various etiology. 2. Prompt eradication of all sources of infection is essential in hemodialysed patients.

Hemorrhagic shock activates mast cells in the rat stomach wall.

The activation of mast cells (MC) and liberation of their mediators can play an essential role in initiating and controlling inflammatory processes in the wall of the gastrointestinal tract (GIT) due to ischemia. The role of MC in changes induced by hemorrhagic shock (HS) remains unknown. Heparin provided by MC seems to inhibit local inflammation and prevent DIC. The aim of this study was to evaluate the morphometric changes and biochemical activity of MC in the stomach wall after 75 minutes of hemorrhagic shock. The MC in mucosal, submucosal, muscular and serosal compartments of the various stomach wall regions were examined in shocked rats and in the control group. Additionally, the contents of glycosaminoglycans (GAG), measured as uronic acids concentration, as well as anticoagulative activity in the stomach wall were assessed. HS resulted in an evident increase in the number of mast cells detected in the stomach mucosa and serosa, in slight alterations in number of MC in the submucosal and muscular layers, a significant increase in size and changes of the shape of the MC. The elevation of the width, area, and circular shape of MC in all layers were noted. No clear and significant differences between various stomach regions in MC numbers and MC sizes could be shown. No reaction of other inflammatory cells at this stage of shock was observed. Highly significant increases in GAG concentration, and anticoagulative activity in the stomach wall due to shock were noted. The morphometric and biochemical data may indicate MC activation, especially in mucosa and serosa. The shock-induced migration of MC settled in the stomach wall seems to be possible. The results suggest an essential role of MC reaction in the stomach wall in the early phase of hemorrhagic shock.

[Morphology of mast cells in experimental pulmonary fibrosis induced with bleomysin]. / Morfologia komórek tucznych w doswiadczalnym wlóknieniu pluc wywolanym przez bleomycyne.

Bleomycin induces local inflammatory process with subsequent pulmonary fibrosis. An unknown chemoattractant induces the mast cell (MC) migration to the injured lung tissue. Aim of this study was evaluation of the number, topography and ultrastructure (TEM) of the MC in rat lungs with bleomycin-induced fibrosis. The bleomycin was administered once intratracheally (3.6 mg/kg). The animals were sacrificed on 7th. 14th and 21st day of experiment. MC were stained with Csaba's method. An evident increase in MC number related to the phase of experiment and stage of lung fibrosis was observed: 520, 1200, 4745 per cm2 section on the 7th, 14th and 21st day respectively. In control the MC number was 163 per cm2 section (p < 0.001). On the 7th day the MC were rich in red granules (mature granules with preponderance of heparin). They were located mainly in pleura and around the blood vessels, as in control. On the 14th and 21st day the majority of MC was situated in places of active fibrosing. They contained exclusively blue granules (the young granules with preponderance of biogenic amines), mixture of increased secretory function of the MC in the fibrotic lungs. Some of the MC granules showed fusion and altered matrix contents, other were emptied in piecemeal manner. A net of microtubules connected the granules was observed. Degranulation of MC may release heparin and cytokines able to stimulate synthesis of extracellular matrix. It has been suggested that heparin contributes to the fibrotic process and angiogenesis, stimulating directly or indirectly collagen synthesis by binding, stabilization and activation of fibroblast growth factor (FGF) and cell adhesion glycoproteins.

Mast cells in the gastrointestinal tract.

The morphology and functions of gastrointestinal mast cells (MCs) under physiological and pathological conditions were described. Special attention was paid to the MCs origin, differentiation and morphological and biochemical aspects of their degranulation. Mast cells are important component of normal architecture of the gastrointestinal tract. Many substances released from MCs during degranulation are biologically active and mediate numerous processes: blood flow regulation, epithelial and endothelial permeability, mucosal secretion, gastrointestinal tract motility, immunological events related to the antigens of various origin, angiogenesis, cancer development. Thus MC is often considered as an important agent in pathogenesis of many gastrointestinal diseases. The gastrointestinal diseases which was described in this paper are following: bacterial and parasitic infections, peptic ulcer, ulcerative colitis, Lesniowski-Crohn's disease, inflammatory polyps, intestinal graft-versus-host reaction, neoplastic tumors, mastocytosis, intestinal ischemia.