Atypical methotrexate ulcerative stomatitis with features of lymphoproliferative like disorder: report of a rare ciprofloxacin-induced case and review of the literature

Methotrexate (MTX) is an established immunomodulating agent used in low doses (LDMTX) to treat several autoimmune diseases. Ulcerative stomatitis (US) may be observed as a long-term LDMTX adverse effect showing a wide histopathologic spectrum. A 73-year old female presented with painful oral ulcers of 5 days duration. The patient had been under treatment for rheumatoid arthritis with LDMTX, while one week before presentation she was prescribed ciprofloxacin for a urinary infection. Histopathologic examination of a lingual ulcer revealed a polymorphous lymphohistiocytic proliferation with scattered binucleated atypical lymphocytes. Immunohistochemically, most cells were of T-cell lineage while the EBER test was negative and a diagnosis of MTX-induced reactive ulceration was rendered. MTX cessation resulted in complete resolution of the ulcers with no recurrences reported so far. The clinical and histopathologic features of MTX-induced oral ulcers are not always diagnostic and a detailed history and an extensive clinicopathologic investigation may be needed to exclude a lymphoproliferative disorder

The role of CXC-chemokine receptor CXCR2 and suppressor of cytokine signaling-3 (SOCS-3) in renal cell carcinoma

BACKGROUND: Chemokine receptor signaling pathways are implicated in the pathobiology of renal cell carcinoma (RCC). However, the clinical relevance of CXCR2 receptor, mediating the effects of all angiogenic chemokines, remains unclear. SOCS (suppressor of cytokine signaling)-3 is a negative regulator of cytokine-driven responses, contributing to interferon-α resistance commonly used to treat advanced RCC with limited information regarding its expression in RCC. METHODS: In this study, CXCR2 and SOCS-3 were immunohistochemically investigated in 118 RCC cases in relation to interleukin (IL)-6 and (IL)-8, their downstream transducer phosphorylated (p-)STAT-3, and VEGF expression, being further correlated with microvascular characteristics, clinicopathological features and survival. In 30 cases relationships with hypoxia-inducible factors, i.e. HIF-1a, p53 and NF-κΒ (p65/RelA) were also examined. Validation of immunohistochemistry and further investigation of downstream transducers, p-JAK2 and p-c-Jun were evaluated by Western immunoblotting in 5 cases. RESULTS: Both CXCR2 and IL-8 were expressed by the neoplastic cells their levels being interrelated. CXCR2 strongly correlated with the levels of HIF-1a, p53 and p65/RelA in the neoplastic cells. Although SOCS-3 was simultaneously expressed with p-STAT-3, its levels tended to show an inverse relationship with p-JAK-2 and p-c-Jun in Western blots and were positively correlated with HIF-1a, p53 and p65/p65/RelA expression. Neither CXCR2 nor SOCS-3 correlated with the extent of microvascular network. IL-8 and CXCR2 expression was associated with high grade, advanced stage and the presence/number of metastases but only CXCR2 adversely affected survival in univariate analysis. Elevated SOCS-3 expression was associated with progression, the presence/number of metastasis and shortened survival in both univariate and multivariate analysis. CONCLUSIONS: Our findings implicate SOCS-3 overexpression in RCC metastasis and biologic aggressiveness advocating its therapeutic targeting. IL-8/CXCR2 signaling also contributes to the metastatic phenotype of RCC cells but appears of lesser prognostic utility. Both CXCR2 and SOCS-3 appear to be related to transcription factors induced under hypoxia

Low-grade oligodendroglioma of the pineal gland: a case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Gliomas are a very rare subtype of pineal region tumours, whereas oligodendrogliomas of the pineal region are exceedingly rare, since there have been only 3 cases of anaplastic oligodedrogliomas reported this far.</p> <p>Methods-Results</p> <p>We present a case of a low-grade oligodendroglioma arising in the pineal gland of a 37 year-old woman. The patient presented with diplopia associated with a cystic pineal region mass demonstrated on MRI. Total resection was performed and histological examination showed that the cystic wall consisted of tumour cells with a central nucleus a perinuclear halo and minimal pleomorphism. Immnunohistochemical analysis showed that these cells were diffusely positive for CD57, and negative for GFAP, CD10, CD99, cytokeratins, neurofilaments and synaptophysin. FISH analysis was performed in a small number of neoplastic cells, which were not exhausted after immunohistochemistry and did not reveal deletion of 1p and 19q chromosome arms. However, the diagnosis of a low grade oligodendroglioma of the pineal gland was assigned.</p> <p>Conclusion</p> <p>Although the spectrum of tumours arising in the pineal gland is broad, the reports of oligodendrogliomas confined to this location are exceedingly rare, and to the best of our knowledge there is no report of a low-grade oligodendroglioma. However, they should be added in the long list of tumours arising in the pineal gland.</p

Gastrointestinal stromal tumor

<p>Abstract</p> <p>Background</p> <p>GISTs are a subset of mesenchymal tumors and represent the most common mesenchymal neoplasms of GI tract. However, GIST is a recently recognized tumor entity and the literature on these stromal tumors has rapidly expanded.</p> <p>Methods</p> <p>An extensive review of the literature was carried out in both online medical journals and through Athens University Medical library. An extensive literature search for papers published up to 2009 was performed, using as key words, GIST, Cajal's cells, treatment, Imatinib, KIT, review of each study were conducted, and data were abstracted.</p> <p>Results</p> <p>GIST has recently been suggested that is originated from the multipotential mesenchymal stem cells. It is estimated that the incidence of GIST is approximately 10-20 per million people, per year.</p> <p>Conclusion</p> <p>The clinical presentation of GIST is variable but the most usual symptoms include the presence of a mass or bleeding. Surgical resection of the local disease is the mainstay therapy. However, therapeutic agents, such as Imatinib have now been approved for the treatment of advanced GISTs and others, such as everolimus, rapamycin, heat shock protein 90 and IGF are in trial stage demonstrate promising results for the management of GISTs.</p

Cell cycle control and urothelial bladder cancer

Background: The transition from the various restrictions points of the mammalian cell cycle is coordinated by cyclin-dependent kinases (CDKs), which are devoid of enzymatic activity unless bound to their cyclin partners. The D-type Cyclins (D1, D2, D3) serve as growth factors which, in conjunction with CDK4 and CDK6 operate in mid to late G1 phase to promote progression through the G1/S restriction point, thus contributing to cell’s commitment to replicate its genome. Replication protein A (RPA) is a heterotrimer complex composed of three tightly associated subunits of 70, 32 and 14 kDa, designated as RPA1 (RPA70), RPA2 (RPA32), and RPA3 (RPA14) respectively. Current evidence appears to document RPA’s involvement in DNA damage checkpoints and also its role as a hyperphosphorylation-dependent downstream checkpoint effector for regulation of DNA metabolic pathways and all major types of DNA repair, including nucleotide excision, base excision, mismatch and double strand break repairs. Methods: Paraffin-embedded tissue from 157 patients with bladder UC was immunostained for cyclins D1, D2 and D3 as well as RPA1 and RPA2 proteins. Statistical analysis was performed in order to elucidate possible correlations with clinicopathological data and survival. Results: Cyclin D1 expression positively correlated with D2 and negatively with D3. Cyclin D1 expression decreased with increasing grade (p=0.0001) and tumour T-category in the entire cohort and in muscle-invasive carcinomas (p=0.0001 and p=0.0033). Cyclin D2 correlated with grade (p=0.0005) and T-category (p=0.0078), a relationship which remained significant in muscle-invasive (p=0.0135). Cyclin D3 immunoreactivity increased with histologic grade and T-category in the entire cohort (p=0.0001 in both relationships), in superficial (p=0.0034) and in muscle-invasive carcinomas (p=0.0036 respectively). Survival analysis in superficial tumours showed that higher cyclin D1 (p=0.0001) and higher cyclin D3 levels (p=0.0032) implied a lesser probability of survival. In muscle-invasive tumours lower cyclin D1 (p=0.0234), and D2 (p=0.0424) and higher cyclin D3 (p=0.0322) correlated with shortened survival. In multivariate analysis in superficial tumours only cyclin D3 expression remained significant. Cyclin D3 expression also retained its adverse significance in muscle-invasive tumours. RPA1 expression decreased with increasing histological grade (p= 0.0007) and T-category in the entire cohort and in muscle-invasive carcinomas (p= 0.0078 and p= 0.0135). RPA2 expression also displayed an inverse relationship with histological grade (p=0.0001) and T-category in the entire cohort and in muscle-invasive carcinomas (p=0.0001 and p=0.0120). RPA1 expression was positively correlated with RPA2 (R=0.3089, p=0.0001). Both RPA1 and RPA2 expressions were positively correlated with cyclin D1 expression (R=0.3535, p<0.0001 and R= 0.9340, p<0.0001). Survival analysis in the entire cohort showed that decreased RPA2 and RPA1 correlated with a lesser probability of survival (p<0.0001 and p=0.0181). In non muscle-invasive tumours (Ta-T1) only lower RPA2 (p=<0.0001) was proven to be correlated with shortened survival, whereas in muscle-invasive tumours (T2-T4) decreased RPA2 and RPA1 were shown to be adversely correlated with prognosis (p=0.0351 and p=0.0424). In multivariate survival analysis in the entire cohort and in non-muscle invasive cases RPA2 expression remained significant, even when adjustment for Cyclin D1 expression was applied. Conclusion: Cyclin D1 overexpression seems to be more important during early stages of bladder carcinogenesis, whereas cyclin D3 is implicated in the acquisition of a more aggressive phenotype. Cyclin D3 overexpression emerges as an independent adverse prognostic marker in both superficial and muscle-invasive tumours. Cyclin D1 is an independent indicator of shortened survival only in muscle-invasive tumours. RPA1 and RPA2 overexpression seems to be more important during early T-categories of bladder carcinogenesis. Showing similar kinetics with cyclin D1. RPA2 expression emerges as a valuable marker of favourable prognosis in the entire cohort and in non-muscle invasive tumours, supplementing the imformation obtained by standard clinicopathological prognosticators.Εισαγωγή: Η πρόοδος του κυτταρικού κύκλου καθορίζεται σημαντικά από µια οµάδα ενζύµων, που ονοµάζονται κυκλινοεξαρτώµενες κινάσες και στην ενεργό τους µορφή σχηµατίζουν ετεροδιµερή µε τις κυκλίνες. Υπάρχουν αρκέτα είδη κυκλίνες μεταξύ των οποίων οι κυκλίνες D είναι τριών τύπων: η κυκλίνη D1, η κυκλίνη D2 και η κυκλίνη D3 οι οποίες λειτουργούν ως αυξητικοί παράγοντες και συνδυαζόμενες με τις αντίστοιχες κινάσες (CDK4 και CDK6) λειτουργούν στη μέση ως όψιμη περίοδο της G1 με σκοπό να ρυθμίσουν τη δίοδο μέσω του περιοριστικού σημείου G1/S. Η πρωτεΐνη αντιγραφής A (RPA) είναι ένα σύνθετο ετεροτριμερές που αποτελείται από 3 στενά συνδεδεμένες υπομονάδες 70, 32 and 14 kDa, που ονομάζονται RPA1 (RPA70), RPA2 (RPA32), and RPA3 (RPA14) αντίστοιχα. Πρόσφατα δεδομένα αναφέρουν ότι η πρωτεΐνη RPA συμμετέχει στον έλεγχο της ακεραιότητας του DNA στα σημεία ελέγχου του κυτταρικού κύκλου και στην επιδιόρθωση των βλαβών του DNA. Υλικά και μέθοδος: Μελετήθηκε η ανοσοϊστοχημική έκφραση των κυκλινών D1, D2 και D3 και δύο υπομονάδων (RPA1 και RPA2) της RPA πρωτεΐνης στο καρκίνωμα της ουροδόχου κύστης σε βιοπτικό υλικό 157 ασθενών με ουροθηλιακό καρκίνωμα ουροδόχου κύστης και έγινε μία προσπάθεια συσχέτισής τους με τα κλινικοπαθολογοανατομικά χαρακτηριστικά και με την επιβίωση των ασθενών. Αποτελέσματα: Η χρώση ήταν ομοιογενής και πυρηνική και στα πέντε μόρια που μελετήθηκαν. Η έκφραση της κυκλίνης D1 σχετιζόταν θετικά με την έκφραση της κυκλίνης D2 και αρνητικά με την κυκλίνη D3. Η έκφραση της κυκλίνης D1 ελαττωνόταν με την αύξηση του ιστολογικού βαθμού κακοηθείας (p=0.0001) και της κατηγορίας Τ σε όλο το δείγμα και στα νεοπλάσματα που διηθούν το μυϊκό χιτώνα (p=0.0001 και p=0.0033). Η έκφραση της κυκλίνης D2 σχετιζόταν επίσης αρνητικά με το βαθμό κακοηθείας (p=0.0005) και την κατηγορία Τ (p=0.0078), μία συσχέτιση που παρέμεινε σημαντική στα και στα νεοπλάσματα που διηθούν το μυϊκό χιτώνα (p=0.0135). Η έκφραση της κυκλίνης D3 αυξανόταν με την αύξηση του αύξηση του ιστολογικού βαθμού κακοηθείας (p=0.0001) και της κατηγορίας σε όλο το δείγμα (p=0.001), στα επιφανειακά (p=0.0034) και στα νεοπλάσματα που διηθούν το μυϊκό χιτώνα (p=0.0036). Η ανάλυση επιβίωσης στα επιφανειακά νεοπλάσματα έδειξε ότι η αυξημένη έκφραση της κυκλίνης cyclin D1 (p=0.0001) και της κυκλίνης D3 (p=0.0032) σχετιζόταν με χειρότερη πρόγνωση. Στα νεοπλάσματα που διηθούν το μυϊκό χιτώνα η μειωμένη έκφραση της κυκλίνης D1 (p=0.0234), και D2 (p=0.0424) και η αυξημένη έκφραση της κυκλίνης D3 (p=0.0322) σχετιζόταν με ελαττωμένη επιβίωση. Στην πολυπαραγοντική ανάλυση επιβίωσης στα επιφανειακά νεοπλάσματα μόνο η κυκλίνη D3 παρέμεινε στατιστικά σημαντική. Η κυκλίνη D3 επίσης διατήρησε τη στατιστική σημαντικότητά της και στα νεοπλάσματα που διηθούν το μυϊκό χιτώνα. Η έκφραση της RPA1 φαίνεται να σχετίζεται θετικά με την έκφραση της RPA2 R=0.3089, p=0.0001), ενώ και οι δύο σχετίζονται θετικά με την έκφραση της κυκλίνης D1 (R=0.3535, p<0.0001 και R= 0.9340, p<0.0001 αντίστοιχα). Η έκφραση της RPA1 και της RPA2 αυξάνει αντιστρόφως ανάλογα με το στάδιο και τη διαφοροποίηση του όγκου (p=0.0007 και p=0.0078 για την RPA1 και p=0.0001 σε αμφότερες τις περιπτώσεις για την RPA2). Κατά την πολυπαραγοντική ανάλυση επιβίωσης η έκφραση της RPA2 αναδεικνύεται ως ανεξάρτητος προγνωστικός παράγοντας σε όλο το δείγμα και στα επιφανειακά (pTa-pT1) νεοπλάσματα, ακόμη και μετά από στατιστική διόρθωση με την έκφραση της κυκλίνης D1. Συμπέρασμα: Η υπερέκφραση της κυκλίνης D1 φαίνεται να παίζει σημαντικό ρόλο στα πρώιμα στάδια της καρκινογένεσης του ουροθηλιακού καρκινώματος της ουροδόχου κύστης, ενώ η κυκλίνη D3 στα όψιμα στάδια. Η υπερέκφραση της κυκλίνης D3 προκύπτει ως ανεξάρτητος προγνωστικός παράγοντας τόσο στα επιφανειακά όσο και στα νεοπλάσματα που διηθούν το μυϊκό χιτώνα. Η κυκλίνη D1 αναδεικνύεται ως ανεξάρτητος προγνωστικός παράγοντας μόνο στα νεοπλάσματα που διηθούν το μυϊκό χιτώνα. Ακόμη, οι πρωτεΐνες RPA φαίνεται να σχετίζονται με την ογκογένεση του καρκίνου της ουροδόχου κύστης, παίζοντας ενδεχομένως σημαντικό ρόλο στα πρώιμα στάδια της ανάπτυξης του όγκου. Παρόμοια ευρήματα έχουν αναφερθεί προηγουμένως και για την κυκλίνη D1, γεγονός που σε συνδυασμό με τη θετική σχέση που αναδεικνύεται μεταξύ των δύο πρωτεΐνών αποτελεί ένδειξη ότι οι δύο πρωτεΐνες έχουν παρόμοια κινητική στην παθογένεση του καρκίνου της ουροδόχου κύστης. Ακόμη, η πρωτεΐνη RPA2 αναδεινύεται ως σημαντικός ευνοϊκός προγνωστικός παράγοντας

Unraveling the Immune Microenvironment of Thymic Epithelial Tumors: Implications for Autoimmunity and Treatment

Thymic Epithelial Tumors (TETs) represent a rare tumor family, originating from the epithelial component of the thymus gland. Clinicopathologically, they are segregated into six major subtypes, associated with distinct histological features and clinical outcomes. Their emergence and evolution are accompanied by the generation of a complex tumor microenvironment (TME), dominated by phenotypically and functionally divergent immune cellular subsets, in different maturation states and in analogies that vary significantly among different subtypes. These heterogenous leukocyte populations exert either immune-permissive and tumor-suppressive functions or vice versa, and the dynamic equilibrium established among them either dictates the tumor immune milieu towards an immune-tolerance state or enables the development of a productive spontaneous tumoricidal response. The immunologically &ldquo;hot&rdquo; microenvironment, defining a significant proportion of TETs, makes them a promising candidate for the implementation of immune checkpoint inhibitors (ICIs). A number of phase I and II clinical trials have already demonstrated significant, type-specific clinical efficacy of PD-L1 inhibitors, even though substantial limitations in their utilization derive from their immune-mediated adverse effects. Moreover, the completed clinical studies involved relatively restricted patient samples and an expansion in the enrolled cohorts is required, so that more trustworthy conclusions regarding the benefit from ICIs in TETs can be extracted

SOX11 and Epithelial-Mesenchymal Transition in Metastatic Serous Ovarian Cancer

Background: Ovarian cancer is the leading cause of death from gynecological malignancies, with serous carcinoma being the most common histopathologic subtype. Epithelial–mesenchymal transition (EMT) correlates with increased metastatic potential, whereas the transcription factor SRY-box transcription factor 11 (SOX11) is overexpressed in diverse malignancies. Methods: In the present study, we aimed to evaluate the potential role of the immunohistochemical expression of SOX11 in 30 serous ovarian carcinomas in association with E-cadherin and vimentin expression as well as with patients’ clinicopathological data. Results: Most of the examined cases showed concurrent expression of E-cadherin and vimentin, whereas SOX11 was expressed in a minority of the cases (26.7%). Interestingly, the positive cases more frequently had a metastatic disease at the time of diagnosis compared with the negative cases (p = 0.09), an association, however, of marginal significance. Moreover, there was a negative correlation between E-cadherin and SOX11 expression (p = 0.0077) and a positive correlation between vimentin and SOX11 expression (p = 0.0130). Conclusions: The present work, for the first time, provides preliminary evidence of a possible implication of SOX11 overexpression in the promotion of EMT in metastatic serous ovarian cancer, thereby endorsing tumor metastasis