The Role of EGFR Inhibitors in the Treatment of Metastatic Anal Canal Carcinoma: A Case Series

Anal cancer patients who have exhibited disease progression after having received all approved drugs pose a major therapeutic challenge. In addition to cytotoxic agents, novel targeted agents are being developed and have an established role in the treatment of many solid tumors, including colon cancer. However, their role in anal cancer is yet to be determined. Most anal malignancies are squamous cell carcinomas often strongly expressing epidermal growth factor receptors (EGFRs). Targeting the latter seems to result in favorable changes in tumor growth. We present three cases of refractory anal cancers, treated with EGFR inhibitors, after having received the recommended chemotherapy regimens. We conclude that EGFR inhibitors may play a vital role in the treatment of anal cancer and we suggest that large trials are be conducted in order to clarify their efficacy and to improve therapeutic management

Secretory activity of subcutaneous abdominal adipose tissue in male patients with rheumatoid arthritis and osteoarthritis -association with clinical and laboratory data

Abstract Introduction: Adipose tissue exerts widespread effects on the metabolism and immune system, but its activity differs between the genders. In the general population low-grade adipose tissue inflammation contributes to development of diseases of affluence. Little is known about the systemic impact of peripheral fat tissue in osteoarthritis (OA) and rheumatoid arthritis (RA), characterized by chronic, low-and high-grade systemic inflammation, respectively. To clarify this we evaluated the secretory activity of subcutaneous abdominal adipose tissue (SAAT) obtained from male patients affected with RA (n = 21) and OA (n = 13), and assessed its association with body mass and composition, demographic, clinical and laboratory data. Material and methods: Basal and interleukin (IL)-1β-triggered secretion of selected adipocytokines from SAAT explants was measured by specific enzyme-linked immunosorbent assays (ELISA). Patients' body composition was evaluated by bioelectric impendence technique. Results: Rheumatoid SAAT secreted more adiponectin and macrophage migration inhibitory factor (MIF) than respective osteoarthritis tissue. In both RA and OA patient groups, stimulation of SAAT explants with IL-1β (1 ng/ml/100 mg tissue) significantly up-regulated release of pro-(IL-6, IL-8, tumor necrosis factor -TNF) and anti-inflammatory (IL-10) cytokines but had no effect on the secretion of adiponectin, leptin, MIF and hepatocyte growth factor (HGF). Compared with RA, patients with OA were more obese. In RA patients SAAT-released adiponectin and TNF inversely correlated with body mass index (BMI) and visceral fat rating (FVSC). In addition, SAAT-secreted adiponectin and leptin positively correlated with DAS28 and disease duration, respectively. In the OA group tissue-released TNF positively correlated with patients' age. Conclusions: We conclude that in RA male patients adipocytokines originating from SAAT are of clinical importance because: (i) adiponectin and TNF may contribute to maintenance of normal body composition and mass, (ii) in addition adiponectin may play a pathogenic role. Moreover, in both RA and OA male patients secretory activity of SAAT may vary with time

Patogeneza reumatoidalnego zapalenia stawów. Część I – odpowiedź nabyta, uwarunkowania genetyczne i środowiskowe

Kliniczny początek reumatoidalnego zapalenia stawów (RZS)poprzedza faza bezobjawowa, podczas której inicjowana jestodpowiedź autoimmunizacyjna o różnej swoistości, a najbardziejcharakterystycznym komponentem jest reaktywność limfocytówT i B na białka cytrulinowane. Rozwój nabytej odpowiedzi jestdeterminowany przez czynniki genetyczne i środowiskowe. Genetycznepodłoże RZS tworzy polimorficzny gen HLA-DRB1, kodującycząsteczki DR zawierające „wspólny epitop” i prezentujące autoantygeny,oraz liczne geny związane z odpowiedzią nabytą. Spośródczynników środowiskowych główną rolę przypisuje się tym,które zwiększają cytrulinację białek, tj. paleniu tytoniu i zakażeniomwywołanym przez Porphyromonas gingivalis. Odpowiedźautoimmunizacyjna per se jest niewystarczająca do rozwoju RZS,ale stanowi istotną składową procesów patogennych, ponieważautoprzeciwciała i aktywowane limfocyty biorą udział w inicjacjii podtrzymywaniu odpowiedzi zapalnej i procesach destrukcyjnych.W artykule omówiono te zagadnienia, opierając się na najnowszychosiągnięciach badawczych i w sposób zbiorczyprzedstawiono graficznie (ryc. 1). Znaczenie układu odpornościwrodzonej, cytokin i procesów destrukcyjnych w patogenezie RZSbędzie przedmiotem następnych opracowań

New aspects of spondyloarthritis pathogenesis. Part III – arthritis, pathological bone remodeling

Spondyloarthritis (SpA) is a form of chronic inflammatory arthritis affecting axial and peripheral joints, which may be initiated by inflammation of joint subchondral bone marrow or enthesitis. Invasive fibrous tissue which substitutes bone marrow, entheseal innate-like T lymphocytes and proinflammatory cytokines: tumor necrosis factor (TNF), interleukins 23, 17 and 22, all contribute to these local pathological processes. Joint inflammation, joint cartilage and bone destruction are mediated by mechanisms that are molecularly similar to rheumatoid arthritis. These pathologic processes are halted by effective anti-inflammatory therapy, including anti-TNF biological agents. By contrast, anti-TNF therapy fails to inhibit pathologic new bone formation, which is a unique hallmark of SpA and results, among others things, in syndesmophyte formation followed by spine ankylosis. The molecular mechanisms driving pathologic bone remodeling in SpA patients and interaction of this process with inflammatory pathways are not fully understood. Three hypotheses, discussed in the article, have been proposed to explain this issue

New aspects of spondyloarthritis pathogenesis. Part I. Genetic factors and role of HLA-B27 molecules

Recent data verify understanding of spondyloarthritis (SpA) pathogenesis by showing that there is the overlap between traditionally classified subtypes in terms of genetic background (HLA-B27 alleles, variants of IL-23R, ERAP1 and ERAP2 genes), which is discussed in this article. Moreover, there is also similarity in environmental factors and immunopathology, which will be the subject of next review articles. The view on the role of HLA-B27 molecules in SpA pathogenesis has also been changed. HLA-B27 molecules exist as canonical and non-canonical subtypes. The latter are formed by free heavy chains or heavy chain homodimers. Canonical HLA-B27 molecules present self and non-self antigens and thus initiate acquired immune response. By contrast, non-canonical HLA-B27 molecules trigger autoinflammatory response. This question is also discussed in this article

Adiponectin Isoforms and Leptin Impact on Rheumatoid Adipose Mesenchymal Stem Cells Function

Adiponectin and leptin have recently emerged as potential risk factors in rheumatoid arthritis (RA) pathogenesis. In this study we evaluated the effects of adiponectin and leptin on immunomodulatory function of adipose mesenchymal stem cells (ASCs) derived from infrapatellar fat pad of RA patients. ASCs were stimulated with leptin, low molecular weight (LMW) and high/middle molecular weight (HMW/MMW) adiponectin isoforms. The secretory activity of ASCs and their effect on rheumatoid synovial fibroblasts (RA-FLS) and peripheral blood mononuclear cells (PBMCs) from healthy donors have been analysed. RA-ASCs secreted spontaneously TGFβ, IL-6, IL-1Ra, PGE2, IL-8, and VEGF. Secretion of all these factors was considerably upregulated by HMW/MMW adiponectin, but not by LMW adiponectin and leptin. Stimulation with HMW/MMW adiponectin partially abolished proproliferative effect of ASC-derived soluble factors on RA-FLS but did not affect IL-6 secretion in FLS cultures. ASCs pretreated with HMW/MMW adiponectin maintained their anti-inflammatory function towards PBMCs, which was manifested by moderate PBMCs proliferation inhibition and IL-10 secretion induction. We have proved that HMW/MMW adiponectin stimulates secretory potential of rheumatoid ASCs but does not exert strong impact on ASCs function towards RA-FLS and PBMCs

Inflammatory bowel disease-related arthritis – clinical evaluation and possible role of cytokines

Objectives: I n inflammatory bowel disease (IBD), characterized by chronic mucosal inflammation, rheumatic abnormalities ranging from arthralgia to spondyloarthritis (SpA) are the most common extraintestinal manifestations. The pathogenesis of IBD-related arthritis is unclear. In this study, we search for clinical and immunological differences between patients with IBD-associated spondyloarthritis and IBD patients without SpA symptoms. Material and methods : Patients with an established diagnosis of IBD, suffering from Leśniowski-Crohn disease (L-CD, n = 24) or ulcerative colitis (UC, n = 27), were enrolled in the study. Clinical evaluation of patients, based on medical history, blood tests, physical and radiological examinations, allowed two subgroups of patients to be established. One subgroup comprised patients fulfilling criteria for both IBD and SpA (IBD + SpA, n = 29), while the other included IBD patients with arthralgia only (IBD, n = 22). Serum concentrations of interleukins (IL-6, IL-10, IL-21, IL-22, IL-23) and interferon  (IFN-) were measured by specific enzyme-linked immunosorbent assays (ELISA). Results : Patients with IBD + SpA were characterized by shorter disease duration (3 vs. 9 years), higher frequency of HLA-B27 positivity (60.7% vs. 4.5%) and uveitis (20.7% vs. 0%), compared with the IBD subgroup. The serum concentrations of C-reactive protein (CRP) and tested cytokines did not differ between IBD + SpA and IBD patients, or between L-CD and UC groups. However, in the IBD + SpA subgroup there was weak to moderate positive correlation between serum concentrations of CRP and several cytokines (IL-6, IL-21, IFN-), and additional moderate positive correlation between serum concentrations of IL-23 and clinical activity of SpA. By contrast, in IBD subgroup a strong inverse correlation between serum concentrations of Interleukin 23 and CRP was found. Conclusions : IBD-related spondyloarthritis occurs relatively early, affects mostly HLA-B27(+) individuals, and is often accompanied by ocular involvement. In these patients several circulating cytokines are associated with systemic inflammation. IL-23 seems to be protective in IBD while detrimental in IBD-related spondyloarthritis

Inhibition of Allogeneic and Autologous T Cell Proliferation by Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients

Background. In ankylosing spondylitis (AS), accompanied by chronic inflammation, T cell expansion plays a pathogenic role; the immunoregulatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) are impaired, while functional characteristics of their adipose tissue-derived counterparts are (ASCs) unknown. Methods. We evaluated the antiproliferative activity of AS/ASCs, obtained from 20 patients, towards allogeneic and autologous T lymphocytes, using ASCs from healthy donors (HD/ASCs) as the reference cell lines. The PHA-activated peripheral blood mononuclear cells (PBMCs) were cocultured in cell-cell contact and transwell conditions with untreated or TNF + IFNγ- (TI-) licensed ASCs, then analyzed by flow cytometry to identify proliferating and nonproliferating CD4+ and CD8+ T cells. The concentrations of kynurenines, prostaglandin E2 (PGE2), and IL-10 were measured in culture supernatants. Results. In an allogeneic system, HD/ASCs and AS/ASCs similarly decreased the proliferation of CD4+ and CD8+ T cells and acted mainly via soluble factors. The concentrations of kynurenines and PGE2 inversely correlated with T cell proliferation, and selective inhibitors of these factors synthesis significantly restored T cell response. AS/ASCs exerted a similar antiproliferative impact also on autologous T cells. Conclusion. We report for the first time that despite chronic in vivo exposure to inflammatory conditions, AS/ASCs retain the normal capability to restrain expansion of allogeneic and autologous CD4+ and CD8+ T cells, act primarily via kynurenines and PGE2, and thus may have potential therapeutic value. Some distinctions between the antiproliferative effects of AS/ASCs and HD/ASCs suggest in vivo licensing of AS/ASCs