A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up.

Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

Clarithromycin stops lung function decline in airway-centered interstitial fibrosis.

Airway-centered interstitial fibrosis (ACIF) is a distinct type of lung interstitial fibrosis characterized by lesions centered on the airways. Several cases reported in the literature showed little to no effect of corticosteroids and a high mortality rate in the absence of lung transplantation. No other efficient approach is described for the treatment of this type of fibrosis. We report for the first time the case of a 44-year-old patient diagnosed with ACIF on surgical lung biopsy and stabilized with clarithromycin after failure of systemic corticosteroids. We need to confirm this benefit in other patients to ascertain the anti-inflammatory effect of macrolides, which are far less harmful compared to corticosteroids or immunosuppressant drugs.

Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS.

BACKGROUND: There is no consensual first-line chemotherapy for elderly patients with mantle cell lymphoma (MCL). The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang) group previously developed the (R)VAD+C regimen (rituximab, vincristine, doxorubicin, dexamethasone and chlorambucil), which appeared as efficient as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisone) while less toxic. Based on this protocol, we now added bortezomib (RiPAD+C: rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil) given its efficacy in relapsed/refractory MCL patients. The goal of the current phase II trial was to evaluate the feasibility and efficacy of the RiPAD+C regimen as frontline therapy for elderly patients with MCL. PATIENTS AND METHODS: Patients between 65 and 80 years of age with newly diagnosed MCL received up to six cycles of RiPAD+C. RESULTS: Thirty-nine patients were enrolled. Median age was 72 years (65-80). After four cycles of RiPAD+C, the overall response rate was 79%, including 51% complete responses (CRs). After six cycles, CR rate increased up to 59%. After a 27-month follow-up, median progression-free survival (PFS) is 26 months and median overall survival has not been reached. Four patients (10%) discontinued the treatment because of a severe toxicity and seven patients (18%) experienced grade 3 neurotoxicity. CONCLUSION: The bortezomib-containing RiPAD+C regimen results in high CR rates and prolonged PFS with predictable and manageable toxic effects in elderly patients with MCL.

Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey.

BACKGROUND: Invasive aspergillosis is an opportunistic infection that occurs mainly among patients with prolonged neutropenia. Few data are available on invasive aspergillosis in nonneutropenic patients. METHODS: The aim of this survey was to compare neutropenic and nonneutropenic patients who had received a diagnosis of invasive aspergillosis at our institution during a 6-year period. RESULTS: Among the 88 cases of invasive aspergillosis analyzed here, 12 were histologically proven, 52 were probable, and 24 were possible. Forty-seven percent of cases were diagnosed in the intensive care unit, and 40% were diagnosed in hematology units. Neutropenia was a risk factor for 52 patients (59%), most of whom had hematological or solid malignancies. Among the 36 nonneutropenic patients (41%), the main underlying conditions were steroid-treated chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, giant-cell arteritis, and microvascular disorders; 10 patients were recipients of solid-organ transplants, and 1 patient was seropositive for human immunodeficiency virus. The distribution of proven and probable invasive aspergillosis was similar for neutropenic and nonneutropenic patients. The mortality rate was 71.5% overall and was significantly higher among nonneutropenic patients than among neutropenic patients (89% vs. 60%; P<.05). Compared with neutropenic patients, nonneutropenic patients were significantly less likely to have symptoms of invasive aspergillosis and more likely to have frequent intercurrent pneumonia due to another microorganism. The sensitivity of mycological examination of bronchoalveolar lavage fluid specimens was higher for nonneutropenic patients than for neutropenic patients (85% vs. 58%; P<.05), whereas the sensitivity of antigenemia was the same for the 2 populations (65% vs. 64%). Findings on thoracic computed tomographs were similar, except that segmental areas of consolidation occurred more frequently among neutropenic patients. CONCLUSION: This survey at a whole institution underlines the high number of cases of invasive aspergillosis among nonneutropenic patients, with an overall mortality rate that was significantly higher than that for neutropenic patients.

TIMP-1 is a key factor of fibrogenic response to bleomycin in mouse lung.

Pulmonary fibrosis is characterized by the excessive deposition of extracellular matrix in the interstitium, resulting in respiratory failure. The role of remodeling mediators such as metalloproteinases (MMPs) and their inhibitors (TIMPs) in the fibrogenic process remains misunderstood. We investigated MMP-9, MMP-2, TIMP-1, TIMP-2 and TIMP-3 in the fibrotic response to bleomycin of fibrosis prone C57BL/6J and fibrosis resistant BALB/c mice. Mice were administered with 0.1 mg bleomycin by intranasal administration. Either 24 h or 14 days after, the mice were anesthetized and underwent either bronchoalveolear lavage (BAL) or lung removal. Collagen deposition in lung tissue was determined by hydroxyproline measurement, MMP activity was analyzed by zymography, and other mediators were analyzed by ELISA. TIMP-1 was localized in lung sections by immunohistochemistry and real time PCR was performed to gene expression in lung. Non parametric Mann-Whitney and Spearman tests were used for statistical analysis. Fourteen days after bleomycin administration, hydroxyproline assay and histological study revealed that BALB/c mice developed significantly less fibrosis compared to C57BL/6J mice. At day 1, bleomycin enhanced TIMP-1, MMP-2 and MMP-9 protein levels in BALF, and induced corresponding genes in lung tissue of both strains. The rise of Timp-1, Mmp-9 and Mmp-2 gene levels were significantly stronger in lungs of C57BL/6J, whereas gelatinase activities of MMP-2 and MMP-9 were similar. Immunohistochemistry revealed that TIMP-1 macrophages and epithelial cells were prominent TIMP-1 producers in both strains. At day 14, neither MMP-2 nor MMP-9 levels exhibited strain-dependent protein level or gene expression, although TIMP-1 was strongly associated with fibrosis. Interestingly, bleomycin induced neither Timp-2 nor Timp-3 in lung tissue at any time of the study. The present study shows that early altered regulation of TIMP-1 following bleomycin administration may be involved in bleomycin-induced pulmonary fibrosis.

Blastic variant of mantle cell lymphoma: a rare but highly aggressive subtype.

The blastic variant (BV) form of mantle cell lymphoma (MCL) is considered to be a very aggressive subtype of non-Hodgkin's lymphoma (NHL). In order to determine its clinico-biological features and response to therapy we studied 33 patients (17%) out of 187 suffering from MCL who were diagnosed with a BV of MCL. Blastic variant was diagnosed according to histopathological patterns, immunophenotyping, and bcl1 gene rearrangement and/or cyclin D1 overexpression. Three patients initially diagnosed with large cell NHL were classified as BV. Patients received front-line therapy including CHOP-like regimen or CVP (n = 29), or chlorambucil (n = 4) and CHOP or ESAP as second-line therapy. High-dose intensification with stem cell transplantation (SCT) was performed in 11 cases (autoSCT, n = 8; alloSCT, n = 3). All but two patients were in complete remission (CR) at the time of transplant (CR1, n = 5; CR2, n = 4). Clinical and biological characteristics did not differ from those of the common form of MCL. The median age was 62 years (29-80), with a sex ratio (M/F) of 2.6:1. Of the 33 patients, 66% had extranodal site involvement, 85% had an Ann Arbor stage IV, and 82% had peripheral lymphadenopathy. Circulating lymphomatous cells were seen in 48% of cases. Twelve patients (36%) entered a CR1 with a median duration of 11 months. Fifteen patients (46%) failed to respond and rapidly died of progressive disease. Second-line therapy led to a 26% (6/23) CR2 rate. Nine patients relapsed after high-dose therapy. Twenty-two of the 33 patients (66%) died of refractory or progressive disease. Median overall survival (OS) time was 14.5 months for the 33 BV patients as compared to 53 months for the 154 patients with a common form of MCL, P <0.0001. In the univariate analysis, OS was influenced by age, extranodal site involvement, circulating lymphomatous cells, and international prognosis index (IPI). In the multivariate analysis, only IPI affected OS: patients with IPI > or =2 had 8 months median OS as compared to 36 months median OS for patients with IPI <2, P = 0.003. Blastic variant is one of the worst forms of NHL. An improved recognition of BV of MCL is required, particularly in high-grade CD5+ NHL using immunophenotyping and bcl1 molecular study. Standard therapy using anthracycline or even high-dose intensification produce poor results and an alternative treatment should be proposed to such patients.

Modulation of HLA-G antigens expression in myelomonocytic cells.

As trophoblast cells and macrophages share cellular characteristics, we investigated the expression of HLA-G antigens during the myelomonocytic differentiation. Analyses with the 87G and 16G1 monoclonal antibodies demonstrated that HLA-G was not expressed in peripheral blood monocytes, in in vitro differentiated dendritic cells and macrophages, and in resident mononuclear phagocytes infiltrating healthy tissues. Conversely, activated macrophages and dendritic cells localized in tumoral biopsies of some lung carcinomas expressed HLA-G antigens. Induction of HLA-G expression at the cell surface of the monohistiocytic cell line U 937 with different cytokines strongly suggests that cytokines secreted during inflammation may be involved in this specific upregulation. Bronchoalveolar macrophages collected from patients suffering from acute HCMV pneumonitis also expressed HLA-G molecules. In vitro, we thus demonstrated that HLA-G antigens are produced during viral reactivation in the macrophages generated after allogeneic stimulation of HCMV latently infected monocytes. Our data suggest that inflammatory processes in lung tissues, like tumoral transformation and HCMV acute infection, are likely to induce HLA-G molecules in infiltrating macrophages and dendritic cells. The expression of molecules capable of downregulating both the innate and adoptive immunity could be a mechanism that helps tumoral and HCMV infected cells to escape immune response.

Lung macrophages and dendritic cells express HLA-G molecules in pulmonary diseases.

HLA-G is selectively expressed in extravillous trophoblast of human placenta, which does not express classical HLA-A and -B molecules. Several studies report the role of HLA-G as a molecule involved in immune tolerance. By interacting with NK and T cells inhibitory receptors, HLA-G may downregulate their cytotoxicity functions. To appreciate the biologic and clinical relevance of HLA-G expression in lung diseases, HLA class I and HLA-G expression were analyzed in a panel of 36 ex vivo neoplastic tissues and 8 non-neoplastic lung tissues. Immunohistochemical analysis was performed using a pan-HLA class I antibody (W6/32) and three different specific anti-HLA-G antibodies (87G, MEMG/9 and 4H84). These findings demonstrated that HLA-G products were not expressed in pulmonary structural cells. However, HLA-G molecules were detected in activated macrophages and dendritic cells infiltrating lung carcinomas (33%) and nontumoral pulmonary diseases (25%). HLA-G expression was not correlated with classical HLA alterations. No statistical correlation was found between HLA-G expression and clinical or biologic parameters except high tumor size. The expression of HLA-G in myelo-monocytic cells infiltrating lung pathologic tissues could alter antigenic presentation and contribute to decrease immune response efficiency, subsequently favoring the progression of tumoral or inflammatory processes.

Primary central nervous system lymphomas in 72 immunocompetent patients: pathologic findings and clinical correlations. Groupe Ouest Est d'étude des Leucénies et Autres Maladies du Sang (GOELAMS)

We reviewed 72 primary central nervous system lymphomas occurring in immunocompetent patients. The cases were reviewed for clinical data, histology, immunophenotype, bcl-2 and p53 expression, and Epstein-Barr virus association. Follow-up was available for 40 patients included in the Groupe Ouest Est d'étude des Leucénies et Autres Maladies du Sang (GOELAMS) lymphomes cérébraux primitifs (LCP 88) trial. Each diagnosis, requiring a consensus among at least 3 pathologists, was performed according to the recent Revised European-American Lymphoma classification and equivalents in the updated Kiel classification. Tumors were predominantly classified as diffuse large B-cell lymphomas. There were 3 T-cell lymphomas and 1 Hodgkin lymphoma. The proteins bcl-2 and p53 were expressed in 35% and 16% of the tested cases, respectively. Epstein-Barr virus was not found by in situ hybridization except in the case classfied as a cerebral localization of Hodgkin disease. No significant association was found between subtypes, bcl-2 or p53 expression, and patient survival. From the standpoint of their biologic characteristics, primary central nervous system lymphomas are very similar to systemic diffuse large B-cell lymphomas. In contrast to AIDS-related primary central nervous system lymphomas, primary central nervous system lymphomas are rarely associated with Epstein-Barr virus and in immunocompetent patients they express bcl-2 at a relatively low rate.

Expression of Po66-CBP, a galectin-8, in different types of primary and secondary broncho-pulmonary tumors.

The monoclonal antibody Po66 is an IgG1 immunoglobulin isolated from a human bronchial squamous carcinoma and directed against a carbohydrate binding protein, Po66-CBP, belonging to the galectin family involved in neoplastic processes. This Po66 antibody has been shown to be useful for immunoscintigraphic detection of squamous cell carcinoma metastasis. We examined the expression of Po66-CBP in a wider range of primary or secondary malignant tumors of the lung of various histological types. We studied 52 specimens of broncho-pulmonary tumors including 41 primary squamous, glandular or neuro-endocrine tumors and 11 secondary tumors of glandular, connective tissue, melanocytic or germinal origin as well as 9 extra-pulmonary primary tumors with histological types similar to lung metastases. An immunohistochemical study was performed using an amplification system on paraffin-embedded sections. All histological types were positive for Po66 antibody, the cell origin giving no influence on the expression of Po66-CBP. There was however a relation between Po66-CBP expression and the degree of differentiation notably for squamous cell cancer and neuro-endocrine tumors. The metastatic character of the tumor tissue did not affect Po66-CBP expression.

Expression of Po66-CBP, a type-8 galectin, in different healthy, tumoral and peritumoral tissues.

UNLABELLED: A monoclonal antibody, Po66, recognized an antigen named Po66 carbohydrate binding protein (PO66-CBP), which was homologous to the galectin-8 protein. Two additional isoforms previously not described were characterized. The aim of this study was to compare the expression of Po66-CBP and its isoforms in different healthy, tumoral and peritumoral tissues and at last to determine the localization of the protein in tumors and distant tissues. MATERIALS AND METHODS: Reverse transcriptase PCR of Po66-CBP was performed on total RNA extract from eleven healthy and eleven tumoral and peritumoral tissue specimens. Antibody Po66 was used to localize the protein in the tumors and distant tissues by an immunohistochemistry method. RESULTS: Po66-CBP was expressed by half of the healthy tissues. One of the isoforms, the last often present in healthy tissues, was found in all tumoral and peritumoral tissues studied. Immunohistochemistry evidenced a gradient of protein expression in normal cells depending on the vicinity of tumoral tissue. Po66-CBP expression was modified in cancerous tissue, suggesting the implication of galectins in carcinogenesis.

Sodium butyrate induces growth inhibition and modulates galectin-8 expression in human lung carcinoma cells.

Galectins are animal lectins, which may play a role in neoplastic transformation. Po66-Carbohydrate Binding Protein (Po66-CBP) belongs to the galectin-8 family and is expressed in lung tumor cells but not in normal ones. Recent studies showed that galectin-8 could be used for human lung squamous cell carcinoma radioimmunotherapy. To optimize this method of treatment, we attempted to increase galectin-8 expression in human lung tumor cells. A human lung squamous (SK-MES-1) or adeno (A 549) carcinoma cell line was grown with or without sodium butyrate. Cell growth, morphology, transcriptional, expression translational expression and cellular localization of galectin-8 were studied. 3 mM of sodium butyrate inhibited the two cell lines' growth after 48 hours of treatment, but only in SK-MES-1 cells galectin-8 expression is modulated without any secretion and cellular localization modifications, apoptosis or necrosis. Sodium butyrate could be an interesting tool in optimizing the radioimmunotherapy of human lung squamous carcinoma, but not of adenocarcinoma.

Alveolar haemorrhage revealing epithelioid haemangioendothelioma.

Epithelioid haemangioendothelioma of the pulmonary vessels is a rare neoplasm which usually has a minimal clinical expression. The present case report describes an exceptional case with severe inaugural alveolar haemorrhage which led to death by acute respiratory failure within a few weeks.

Immunohistochemical expression of the intracellular component of galectin-8 in squamous cell metaplasia of the bronchial epithelium in neoplastic and benign processes.

Specified galectins are known to play a role in regulating cell proliferation, differentiation, adhesion and migration. Po66, a mouse IgG1 monoclonal antibody produced by immunization against squamous cell cancer, reacts against a carbohydrate-binding protein (Po66-CBP), recently shown to be a member of the galectin family with a strong homology with galectin-8 (PCTA-1), identified as a human tumor-associated antigen. We studied Po66 in squamous metaplasia of the bronchi in order to determine whether it could be specifically involved in neoplastic conditions and if so, if it would be helpful in distinguishing metaplasia at risk of cancer. Twenty-eight formalin-fixed, paraffin-embedded archival tissues of 17 metaplasias with SCC, 3 metaplasia with distant neoplastic disease and 8 metaplasias with an inflammatory process, were immunostained using a streptavidin biotin peroxydase method. The squamous metaplasias were positively stained in non-neoplastic disease as well as in neoplastic processes. Expression was also observed in stromal and normal cells. Po66-CBP was not associated with a pre-neoplastic character. We discussed the expression of this intra-cellular component of galectin-8 according to the functions of galectins in cellular differentiation, host reaction against tumor, and inflammation.

[Vertebrate galectins: structure and function, role in tumoral process]. / Les galectines animales: structure et fonctions, rôle dans les processus tumoraux.

Galectins are proteins structurally related to the lectin family. They share, with lectins, the ability to bind carbohydrate residues. Galectins are suspected to mediate several biological functions such as embryonic development growth, immune response and apoptosis. Their role is similar to that of adhesion molecules in cell to cell or to matrix interactions. Their contribution to human carcinogenesis has been suggested from experimental studies. In clinical research, they could be used as a differentiation marker, particularly in thyroid carcinomas and in certain lymphomas.

[An uncommon tumor of the urinary bladder: the small cell carcinoma]. / Une tumeur vésicale rare: le carcinome à petites cellules.

Primary small cell carcinoma of the urinary bladder is an uncommon tumor, compared to the frequency of urothelial tumors. Fifty percent of cases are combined with a non endocrine carcinomatous component. We report six new cases of this tumor, three of pure, and three associated with an urothelial carcinoma. Diagnosis is easy established by the immunohistochemical study which show the neuro-endocrine differentiation of these aggressive tumors. Pathologist needs to look for a neuro-endocrine part in all bladder cancer, as its presence modify the treatment. Chemotherapy is used in these cancers, due to their high metastatic power. Places of radical surgery and radiotherapy need to be specified.

[Primary T-cell lymphoma of the common bile duct]. / Lymphome T primitif de la voie biliaire principale.

Involvement of the gastrointestinal tract is frequently reported among the extranodal sites of non-Hodgkin's lymphoma, but primary lymphoma of the common bile duct is extremely rare. We report the case of a 29-year-old man who presented with obstructive jaundice, leading to the diagnosis of high-grade primary non Hodgkin's T-cell lymphoma, originating from the extrahepatic biliary tract, and confirmed by endosonography and magnetic resonance cholangiography. This patient was treated by sequential chemotherapy without resection and remained in complete remission after one year.

[Crohn's disease complicated by multiple and recurrent aseptic splenic abscesses]. / Maladie de Crohn compliquée d'abcès aseptiques multiples et récidivants de la rate.

We report a case of multiple aseptic splenic abscesses occurring in a woman with Crohn's disease for three years. All microbiological samples were negative. The diagnosis was suspected on abdominal echography and CT scan and confirmed on histologic examination of the splenectomy specimen. The evolution was marked by recurrence of fever and inflammatory syndrome, associated to transitory morphological abnormalities of the accessory spleen. Aseptic splenic abscesses recurrence was suspected. This case allows us to consider aseptic splenic abscesses as an extra-intestinal manifestation and not as a splenic localisation of Crohn's disease.

[Tracheobronchial amyloidosis: apropos of 2 cases]. / Amylose trachéobronchique: à propos de deux cas.

INTRODUCTION: Tracheo-bronchial amyloidosis is an uncommon localized form of amyloidosis. We report two new cases. EXEGESIS: Two patients had developed expiratory dyspnea for several months. CT-scan and flexible bronchoscopy confirmed tracheal narrowing and a diagnosis of tracheo-bronchial amyloidosis was made by tissue biopsies. The immunohistochemical type was AL in one case, undetermined in the other case. There was no argument for systemic involvement. The two patients benefited from bronchoscopic dilatation. This treatment improved clinical symptoms and pulmonary function tests with a follow up of 12 and 18 months respectively. CONCLUSION: Tracheo-bronchial amyloidosis is a localised form of amyloidosis with various respiratory symptoms. Diagnosis is made by CT-scan and flexible bronchoscopy that allows biopsies. Immunohistochemical type is more often AL. Recurrence, respiratory insufficiency and tracheo-bronchial metaplasia are the most important complications. Treatment consists of bronchoscopic dilatation or excision, and bronchoscopic laser-YAG. Pulmonary function testing allows precise follow-up.

[Primary pulmonary rhabdomyosarcoma: a case report]. / Rhabdomyosarcome pulmonaire primitif: à propos d'une observation.

We report a case of primary pulmonary rhabdomyosarcoma in a 52-year-old woman. The diagnosis was established after radical right pneumonectomy, mainly based on immunohistochemistry and electron microscopy findings. This type of tumor is rare in adults. Its primary origin is suggested when a pulmonary meta-stasis of rhabdomyosarcoma from another site or a component of a mixed tumor are ruled out. The best treatment is surgery. The prognosis is poor.