Integrating multi-disciplinary discussion in clinical practice

Interstitial lung diseases are very heterogeneous. We present a case of usual interstitial pneumonia pattern on high resolution computed tomography of the chest that was diagnosed successfully after multi-disciplinary discussion. Pulmonologists should be aware of the pitfalls in the diagnostic management of interstitial lung diseases, especially in cases with atypical clinical presentation and systemic signs and symptoms

The immune microenvironment of cancer of the uterine cervix

While several treatment choices exist for cervical cancer, such as surgical therapy, chemotherapy, and radiotherapy, some patients will still show poor prognosis. HPV infection is a principal factor for cervical cancer development, from early inflammation to proliferation, angiogenesis, and neoplastic growth. While HPV T-cell responses exist, the tumor seems to evade the immune system upon its tolerance. The latter suggests the existence of a confluent tumor microenvironment responsible for the evasion tactics employed by the neoplasm. Therefore, novel biomarkers governing prognosis and treatment planning must be developed, with several studies tackling the significance of the tumor microenvironment in the genesis, development, proliferation, and overall response of cervical cancer during neoplastic processes. This review aims to analyze and contemplate the characteristics of the tumor microenvironment and its role in prognosis, progression, evasion, and invasion, including therapeutic outcome and overall survival

Plasmablastic Lymphoma with Coexistence of Chronic Lymphocytic Leukemia in an Immunocompetent Patient: A Case Report and Mini-Review

Background. Plasmablastic lymphoma (PBL) is a rare, aggressive B-cell lymphoma with poor prognosis usually found in the oral cavity of HIV-positive patients. Chronic lymphocytic leukemia (CLL) is an indolent B-cell lymphoma with a variable clinical course. Transformation of CLL to PBL as Richter’s syndrome is rare while coexistence of CLL and PBL at diagnosis is even rarer. Case Report. We describe a case of a male immunocompetent patient with an ileum-cecum valve mass and a soft tissue mass at the left humerus with histologic evidence of PBL with coexistence of CLL in the bone marrow and peripheral blood. Amputation of the patient’s left arm was inevitable, and the patient was started on bortezomib and dexamethasone. However, prolonged hospitalization was complicated by aspiration pneumonia, and the patient passed away. Conclusions. No standard of care exists for patients with PBL, and prognosis remains dismal. Concomitant presentation of hematological malignancies becomes increasingly recognized, and further insight is needed in order to delineate whether they originate from the same clone or from different ones

Can ReGeneraTing Agents Improve Functional Recovery of Transected Peripheral Nerve through a Nerve Gap Bridged with an Artery Graft

Background The purpose of this study was to use artery grafts filled with CACIPLIQ20 and see if they promote nerve regeneration. Methods Sixty male Wistar rats were used. The rats were randomly divided into four experimental groups (n = 15): transected control group (negative control group [NCG]), sham-operated group (positive control group [SO]) artery graft group filled with saline (AG/NS), and CACIPLIQ20-treated group (AG/CACIPLIQ20). Fifteen rats were used as artery graft donors. In the SO group, the sciatic nerve was dissected from the surrounding tissues and left intact. In the NCG, AG/NS and AG/CACIPLIQ20) groups, a 10-mm gap was created in the left sciatic nerve. In the NCG group, the gap was not bridged with a graft. In the AG/NS group, the gap was bridged with a graft filled with saline. In the AG/CACIPLIQ20 group, the graft was filled with CACIPLIQ20. Walking track analysis was performed at 4, 8, 12, and 16 weeks after surgery. At 16 weeks postoperatively, the rats were sacrificed, nerve sections were harvested for histopathology analysis, and the weight ratio of the gastrocnemius muscle was measured. Results There was no significant difference in myelin sheath thickness between the AG/NS and AG/CACIPLIQ20 groups. Muscle weight in the AG/CACIPLIQ20 group was higher but not statistically significant (p = 0.168) compared with the AG/NS group. Also, AG/CACIPLIQ20 mean was better than AG/NS mean, although there was no statistically significant difference (p = 0.605). Conclusion There could be an indication that CACIPLIQ20 improves functional recovery of a transected peripheral nerve through a nerve gap bridged with an artery graft

Study of signaling pathways involved in cell cycle and apoptosis regulation of diffuse large b-cell lymphomas

The Jun family includes c-Jun, JunB and JunD that are components of the activator protein-1 (AP-1) transcription factor complex involved in cell proliferation and apoptosis. Recent evidence suggests that c-Jun and JunB are expressed in classical Hodgkin lymphomas and CD30-positive non-Hodgkin lymphomas. The STAT family are important transcription factors that have been implicated in cell differentiation, cycle and death. STAT can be activated via the JAK-STAT pathway. Therefore, the immunohistochemical expression of Jun family proteins was studied in relation to: 1) the CD30 expression, 2) the proliferation profile (cyclin A, B1, D2, D3, E and Ki-67) and 3) B cell differentiation markers (CD10, Bcl-6, MUM-1/IRF4) and phenotype in 130 de novo DLBCL. In a subset of cases with low JunB expression, we performed MSP (methylation specific PCR) in order to investigate whether methylation of the JunB promoter correlates with silencing of the gene. Expression of phospho(ph)-c-Jun, JunB, JunD and ph-STAT3 was found in 59/103 (67%), 100/103 (97%), 94/98 (97%) and 41/61 (67%) cases of DLBCL, respectively. The expression of JunB was positively associated with Ki-67 (p=0.032), cyclin A (p=0.042), cyclin B1 (p=0.016), cyclin D2 (p=0.037), cyclin E (p=0.001), CD30 (p<0.001), MUM-1/IRF-4 (p<0.001) and non-GC phenotype (p=0.006) and negatively with CD10 (p<0.001). Moreover, the expression of JunD was positively associated with Ki-67 (p=0.01), cyclin E (p=0.007) and Bcl-6 (p=0.03) as well as the expression of ph-c-Jun with MUM-1/IRF-4 (p=0.03). Cases were also assigned to a high (52 cases) and a low (77 cases) proliferation cluster by K-means clustering based on the combined expression levels of the proteins Ki-67 and cyclin A, B1, D2, D3 and E. These classification variables were ordered by ANOVA according to their statistically significant contribution to the derived clustering from highest to lowest, as follows: Ki-67, cyclin A, cyclin D3, cyclin E and cyclin B1. Cyclin D2 was the only classification variable with statistically non-significant separation ability. Analysis of the differences in mean values between the two clusters by T-tests, showed significantly higher expression levels of the Ki-67, cyclin A, cyclin B1, cyclin D3, cyclin E, bcl6 (all p<0.001), JunB (p=0.033), JunD (p=0.027) and MUM-1/IRF-4 (p=0.006) in the high expression cluster. Methylation of the JunB promoter was found in 17/20 of the cases with low JunB expression. The proteins of Jun family expressed in DLBCL. The association between JunB and JunD and high proliferation cluster in DLBCL, suggests that increased JunB and JunD expression may be involved in their pathogenesis by favoring tumor cell proliferation. The association between JunB and non-GC phenotype may reflect NFκB control of JunB in view of previous findings that JunB is under NFκB control in classical Hodgkin lymphomas and NFκB is activated in non-GC DLBCL. The association between JunD and Bcl-6 expression is in line with data that JunD is a major enhancer molecule of Bcl-6 in mouse GC B-cells. Aberrant methylation of the JunB promoter may be the underlying mechanism in the cases with low JunB expression.Η οικογένεια των πρωτεϊνών Jun που περιλαμβάνει τους μεταγραφικούς παράγοντες c-Jun, JunB και JunD, αποτελεί μέλος του συμπλέγματος του μεταγραφικού παράγοντα της ενεργοποιητικής πρωτεΐνης-1 (AP-1, activator protein-1) και εμπλέκεται στον κυτταρικό πολλαπλασιασμό και στην απόπτωση. Αποτελέσματα μελετών έδειξαν ότι οι πρωτεΐνες c-Jun και JunB εκφράζονται στο κλασικό Hodgkin λέμφωμα και σε CD30-θετικά μη-Hodgkin λεμφώματα. Η οικογένεια των πρωτεϊνών STAT είναι σημαντικοί μεταγραφικοί παράγοντες που εμπλέκονται στην κυτταρική διαφοροποίηση, στον πολλαπλασιασμό και την απόπτωση. Η οικογένεια STAT ενεργοποιείται μέσω του JAK/STAT μονοπατιού μεταγωγής σήματος. Μελέτη της έκφρασης της οικογένειας των πρωτεϊνών Jun και ph-STAT3 σε DLBCL δεν έχει δημοσιευθεί στη διεθνή βιβλιογραφία, από όσο τουλάχιστον γνωρίζουμε.Σκοπός της παρούσας μελέτης ήταν η διερεύνηση της ανοσοϊστοχημικής έκφρασης των πρωτεϊνών ph(phospho)-c-Jun, JunB, JunD και ph-STAT3 σε 130 περιπτώσεις διάχυτων Β-λεμφωμάτων από μεγάλα κύτταρα (DLBCL, Diffuse Large B-Cell Lymphoma) σε σχέση με: 1) την ανοσοϊστοχημική έκφραση της πρωτεΐνης ενεργοποίησης CD30, 2) το πρότυπο του κυτταρικού πολλαπλασιασμού (κυκλίνες A, B1, D2, D3 και E και Ki-67), 3) την ανοσοϊστοχημική έκφραση πρωτεϊνών Β-κυτταρικής διαφοροποίησης (CD10, Bcl-6 και MUM-1/IRF4) και 4) τους ιστογενετικούς/ανοσοφαινοτυπικούς υπότυπους [ομοιάζοντος με αυτόν των Β-κυττάρων του βλαστικού κέντρου (Germinal Center, GC) και του μη ομοιάζοντος (non-GC)], όπως αυτοί καθορίζονται από την έκφραση των πρωτεϊνών Β-κυτταρικής διαφοροποίησης. Σε ορισμένες περιπτώσεις με χαμηλά και υψηλά επίπεδα έκφρασης της πρωτεΐνης JunB πραγματοποιήθηκε αλυσιδωτή αντίδραση πολυμεράσης ειδικής της μεθυλίωσης (MSP, methylation specific PCR), με σκοπό να διερευνηθεί εάν η μεθυλίωση του εκκινητή του γονιδίου JunB σχετίζεται με σιγή του γονιδίου.Στην παρούσα μελέτη έκφραση των πρωτεϊνών ph-c-Jun, JunB, JunD και ph-STAT3 ανιχνεύθηκε στις 59/103 (67%), 100/103 (97%), 94/98 (97%) και 41/61 (67%) περιπτώσεις DLBCL, αντίστοιχα. Η έκφραση της JunB συσχετίστηκε θετικά με την έκφραση των πρωτεϊνών Ki-67 (p=0.032), κυκλίνης A (p=0.042), κυκλίνης B1 (p=0.016), κυκλίνης D2 (p=0.037), κυκλίνης E (p=0.001), CD30 (p<0.001) και MUM-1/IRF-4 (p<0.001), καθώς και με τον non-GC ιστογενετικό ανοσοφαινότυπο (p=0.006) και αρνητικά με την έκφραση της πρωτεΐνης CD10 (p<0.001). Η έκφραση της JunD συσχετίστηκε θετικά με την Ki-67 (p=0.01), την κυκλίνη E (p=0.007) και την Bcl-6 (p=0.03) και η ph-c-Jun θετικά με την MUM-1/IRF-4 (p=0.03). Μεθυλίωση του JunB εκκινητή ανιχνεύτηκε σε 17 από τις 20 περιπτώσεις με χαμηλή ανοσοϊστοχημική έκφραση της πρωτεΐνης JunB που εξετάσθηκαν.Οι περιπτώσεις των DLBCL διαχωρίστηκαν σε συστάδες (cluster) υψηλού (52 περιπτώσεις) και χαμηλού (77 περιπτώσεις) κυτταρικού πολλαπλασιασμού με την μέθοδο k-μέσων τιμών συστάδων (k-means clustering), βάσει των επιπέδων συνδυασμένης έκφρασης των πρωτεϊνών του κυτταρικού κύκλου Ki-67 και των κυκλινών A, B1, D2, D3 και E. Επιπρόσθετα, οι πρωτεΐνες αυτές ιεραρχήθηκαν με τη δοκιμασία ANOVA σύμφωνα με τη συμβολή της καθεμιάς στο διαχωρισμό των περιπτώσεων των DLBCL σε συστάδες υψηλού και χαμηλού κυτταρικού πολλαπλασιασμού. Η σειρά της στατιστικής σημαντικής ικανότητας διαχωρισμού των πρωτεϊνών αυτών ήταν: Ki-67, κυκλίνη A, κυκλίνη D3, κυκλίνη E και κυκλίνη B1. H κυκλίνη D2 ήταν η μόνη πρωτεΐνη ταξινόμησης που δεν παρουσίασε στατιστικώς σημαντική ικανότητα διαχωρισμού. Η ανάλυση των διαφορών των μέσων τιμών έκφρασης των πρωτεϊνών που μελετήθηκαν μεταξύ των δύο συστάδων κυτταρικού πολλαπλασιασμού έδειξε σημαντικά υψηλότερα επίπεδα έκφρασης των πρωτεϊνών: Ki-67, κυκλίνη A, κυκλίνη B1, κυκλίνη D3, κυκλίνη E και bcl6 (όλα p<0.001), JunB (p=0.033), JunD (p=0.027) και MUM-1/IRF-4 (p=0.006) στην συστάδα υψηλού κυτταρικού πολλαπλασιασμού (T-test). Συμπερασματικά, στην παρούσα μελέτη διαπιστώθηκε ότι οι πρωτεΐνες της οικογένειας Jun και η πρωτεΐνη ph-STAT3 εκφράζονται σε DLBCL. Η συσχέτιση της έκφρασης των πρωτεϊνών JunB και JunD με τη συστάδα των DLBCL υψηλού κυτταρικού πολλαπλασιασμού υποδεικνύει ότι η αυξημένη έκφραση τους μπορεί να εμπλέκεται στη παθογένεση των DLBCL, επάγοντας τον κυτταρικό πολλαπλασιασμό. Η συσχέτιση μεταξύ JunB και non-GC ανοσοφαινότυπου ίσως να οφείλεται στην ρύθμιση της JunB από τον NFκB, δεδομένου ότι στο κλασικό λέμφωμα Hodgkin η JunB βρίσκεται υπό τον έλεγχο του NFκB και είναι γνωστό ότι ο NFκB είναι ενεργοποιημένος στον ανοσοφαινοτυπικό υπότυπο των non-GC DLBCL. Η συσχέτιση των πρωτεϊνών JunD and Bcl-6 συμφωνεί με το εύρημα ότι η JunD ενισχύει την έκφραση του Bcl-6 των Β-κυττάρων του βλαστικού κέντρου του ποντικού. Η ανώμαλη μεθυλίωση του εκκινητή του γονιδίου JunB πιθανώς να είναι ο υποκείμενος μηχανισμός στις περιπτώσεις με χαμηλή έκφραση της JunB πρωτεΐνης

Unraveling the Immune Microenvironment in Classic Hodgkin Lymphoma: Prognostic and Therapeutic Implications

Classic Hodgkin lymphoma (cHL) is a lymphoid neoplasm composed of rare neoplastic Hodgkin and Reed–Sternberg (HRS) cells surrounded by a reactive tumor microenvironment (TME) with suppressive properties against anti-tumor immunity. TME is mainly composed of T cells (CD4 helper, CD8 cytotoxic and regulatory) and tumor-associated macrophages (TAMs), but the impact of these cells on the natural course of the disease is not absolutely understood. TME contributes to the immune evasion of neoplastic HRS cells through the production of various cytokines and/or the aberrant expression of immune checkpoint molecules in ways that have not been fully understood yet. Herein, we present a comprehensive review of findings regarding the cellular components and the molecular features of the immune TME in cHL, its correlation with treatment response and prognosis, as well as the potential targeting of the TME with novel therapies. Among all cells, macrophages appear to be a most appealing target for immunomodulatory therapies, based on their functional plasticity and antitumor potency

CD5-Positive Primary Cutaneous Diffuse Large B-Cell Lymphoma-Leg Type

Most primary cutaneous B-cell lymphomas (PCBCL) are CD5 negative, and only a few cases were found to express CD5. We report the first well-documented CD5+ primary cutaneous diffuse large B-cell lymphoma-leg type (PCDLBCL-LT). A 71-year-old woman with a history of Multiple Sclerosis was admitted because of a nodule at the left thigh. Histological examination of the skin biopsy disclosed a diffuse dermal infiltration by large lymphoid cells. Immunohistochemistry revealed that these large cells were positive for CD5, CD20, CD79a, MUM1/IRF4, Bcl6, Bcl2, and cytoplasmic IgM/λ, whereas CD3, CD56, CD23, CD21, CD10, CD30, cyclin D1, CD68, lysozyme, myeloperoxidase, and CD34 were not detected. Thus, the diagnosis of a CD5+ PCDLBCL-LT was made. Despite treatment, the patient died 11 months after initial diagnosis

Expression Patterns of GATA3 in Classical Hodgkin Lymphoma: A Clinico-Pathological Study

GATA3 is a transcription factor involved in T-cell maturation and has been previously shown to be aberrantly overexpressed in malignant Hodgkin and Reed–Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). However, the immunophenotypes of the cell types expressing GATA3 have not been precisely characterized so far in cHL tissues. In this single-center retrospective cohort study we analyzed the expression patterns of GATA3 alone and in combination with B, T, NK or macrophage-associated markers in 73 cases with newly diagnosed cHL and investigated for a possible correlation with clinical and laboratory parameters. Immunohistochemistry (single and double) was performed using GATA3 alone and in combination with CD20, CD3, CD56, CD68, CD30 or CD15. Clinical and laboratory parameters were collected and correlated with the expression of GATA 3. GATA3 nuclear expression was found in HRS cells in 39/73 (54%) cases of cHL. The Nodular Sclerosis (NS) subtype showed the highest positivity rate (35/56, 63%), followed by mixed cellularity (MC; 4/14, 29%) and lymphocyte rich (LR; 0/3). Double immunostainings showed that GATA3 was expressed by CD30+ or CD15+ HRS cells and a few CD3+ T-cells, whereas GATA3 expression was not detected in CD20, CD56 or CD68+ cells. GATA3-negative cHL was significantly associated with unfavorable prognostic factors such as older age at diagnosis and increased levels of serum β2-microglobulin. The heterogenous expression patterns of GATA3 in HRS cells that were observed in a substantial proportion of cHL, mainly in the NS subtype, further support the biological heterogeneity of cHL

Unraveling the Immune Microenvironment in Diffuse Large B-Cell Lymphoma: Prognostic and Potential Therapeutic Implications

Diffuse large B cell lymphoma (DLBCL) is a multifaceted condition characterized by significant diversity in its molecular and pathological subtypes and clinical manifestation. Despite the progress made in the treatment of DLBCL through the development of novel drugs, an estimated one-third of patients encounter relapse or acquire refractory disease. The tumor microenvironment (TME) of DLBCL, a complex network consisting of cellular and noncellular components that engage in interactions with the tumor, is a parameter that is gaining increasing attention. The TME comprises both the immune and nonimmune microenvironments. The immune microenvironment comprises natural killer (NK) cells, dendritic cells (DCs), tumor-associated macrophages (TAMs), neutrophils, myeloid-derived suppressor cells (MDSCs), and T and B lymphocytes. The nonimmune microenvironment consists of the extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells, and other molecules that are secreted. Despite ongoing research, the exact impact of these components and their interaction on the progression of the disease remains elusive. A comprehensive review of significant discoveries concerning the cellular and noncellular constituents, molecular characteristics, and treatment response and prognosis of the TME in DLBCL, as well as the potential targeting of the TME with novel therapeutic approaches, is provided in this article