Expression of galectin-3 in adenoid cystic carcinoma of the head and neck and its relationship with distant metastasis.

PURPOSE: Adenoid cystic carcinoma (ACC) is one of the most common malignant tumours of the salivary glands characterized by multiple recurrences and distant metastasis resulting in significantly worsening prognosis. Galectin-3, a member of the beta-galactoside-binding lectin family, has been implicated in tumour progression, metastasis, and found to have prognostic value. The aim of the study was to determine galectin-3 expression in ACC and correlate it with clinicopathological features and patient survival. METHODS: Galectin-3 expression was investigated in paraffin sections of 35 ACC of the head and neck. Patients were divided into two groups based on a threshold of 5% positivity in the tumour cell population. The mean follow-up period for all patients was 90.1 months (range 3-300.1 months). RESULTS: Seventeen (48.6%) tumour specimens were considered galectin-3-positive. Galectin-3 reactivity was significantly associated with regional and distant metastasis (P=0.045 and P<0.001, respectively). There was no statistical significance in the correlation of galectin-3 expression and disease-free survival and overall survival rate (P=0.095 and 0.102, respectively). CONCLUSION: Galectin-3 may be used as an indicator in the prediction of metastatic spread in ACC.

Growth pattern and distribution of follicular dendritic cells in mantle cell lymphoma: a clinicopathological study of 96 patients.

Mantle cell lymphoma (MCL) is an aggressive lymphoma with accepted risk factors such as proliferation markers. To date, the different follicular dendritic cell (FDC) patterns have never been analyzed in comparison with the overall survival time. Lymph node biopsy specimens from 96 patients were analyzed by conventional morphology and immunohistochemistry with antibodies against cluster differentiation (CD)20, CD5, CD23, cyclin D1, and FDC (Ki-M4P). Two groups can be distinguished with different FDC patterns: a nodular pattern in 79 cases and a diffuse pattern in 17 cases. A Kaplan-Meier analysis revealed significantly better survival for the nodular group (p=0.0312). This group was subdivided into a group with a nodular FDC pattern similar to the FDC distribution in primary follicles (PF-nodular in 72 cases) and one with a nodular FDC pattern resembling the colonization of germinal centers (GCs) by tumor cells (GC-nodular in seven cases). A Kaplan-Meier analysis showed that patients with MCL with a PF-nodular FDC pattern had a significantly better clinical outcome than patients with the other two patterns (p=0.0033). If only cases with classical cytology (n=79) were analyzed (blastoid types excluded), patients with a PF-nodular FDC pattern had a better clinical outcome (p=0.0008). The distribution of FDC in MCL is a diagnostic tool for identifying patients with a better clinical prognosis.

[Acute gastrointestinal bleeding]. / Akute obere gastrointestinale Blutung.

Acute gastrointestinal bleeding is a common major emergency (Internal medical or gastroenterological or medical), approximately 85 % of which occur in the upper GI tract. It is estimated that about a half of upper GI bleeds are caused by peptic ulcers. Upper GI bleeds are associated with more severe bleeding and poorer outcomes when compared to middle or lower GI bleeds. Prognostic determinants include bleeding intensity, patient age, comorbid conditions and the concomitant use of anticoagulants. A focused medical history can offer insight into the bleeding intensity, location and potential cause (along with early risk stratification). Initial measures should focus on rapid assessment and resuscitation of unstable patients. The oesophagogastroduodenoscopy (OGD) is the gold standard method for localizing the source of bleeding and for interventional therapy. Bleeding as a result of peptic ulcers is treated endoscopically with mechanical and / or thermal techniques in combination with proton pump inhibitor (PPI) therapy. When variceal bleeding is suspected, pre-interventional use of vasopressin analogues and antibiotic therapies are recommended. Endoscopically, the first line treatment of esophageal varices is endoscopic ligature therapy, whereas that for gastric varices is the use of Histoacryl injection sclerotherapy. When persistent and continued massive hemorrhage occurs in a patient with known or suspected aortic disease the possibility of an aorto-enteric fistula must be considered.

Symptoms and signs of an acute myocardial ischemia caused by chemotherapy with Paclitaxel (Taxol) in a patient with metastatic ovarian carcinoma.

INTRODUCTION: Paclitaxel (Taxol) is an anticancer agent used for the treatment of breast and ovarian cancer. The major side effects are bone marrow suppression, alopecia, polyneuropathy and cardiac toxicity like bradycardia, myocardial infarction, congestive heart failure and cardiac death. SETTING: Intensive care unit (ICU) of a university hospital. PATIENT: We report on a 58-years-old woman with a metastatic ovarian carcinoma who had chest pain, nausea and collapse during their first Taxol infusion. The infusion was stopped and the patient was submitted to the intensive care unit (ICU) to exclude an acute coronary syndrome. RESULTS: The electrocardiography (ECG) showed a third-degree heart block and ST elevation in II, III and avF. In the initial and in the control laboratory investigation values of cardiac enzymes (creatininkinase and Troponine T) remained normal. The control ECG after 30 minutes turned back to normal. After one day the patient was submitted back to a normal ward. CONCLUSION: Symptomatic bradyarrhythmia and clinical sign of an myocardial infarction are rare but important cardiac side effects in patients treated with Taxol. Those patients should be under intensive care unit until patients conditions improve and acute myocardial ischemia has been excluded.

Transforming growth factor beta in chronic obstructive sialadenitis of human submandibular gland.

BACKGROUND: The exact pathomechanism of inflammation progress and fibrosis in chronic obstructive sialadenitis is unknown. The aim of the present study was to assess whether there is an association between transforming growth factor beta (TGF-beta) and fibrogenic process of chronic sialadenitis. METHODS: Tissue samples of 12 patients with chronic sialadenitis and 4 normal tissue samples of the submandibular gland were examined immunohistochemically for identification of TGF-beta. TGF-beta1 messenger RNA (mRNA) expression was analysed semiquantitatively using reverse transcription polymerase chain reaction and gel electrophoresis to correlate its expression levels with stages of the disease. RESULTS: TGF-beta positive cells could be found in the secretory duct system of all examined samples. However, an intense TGF-beta immunoreactivity was observed in inflamed salivary glands. With progress of disease TGF-beta1 mRNA expression increases significantly. CONCLUSION: Expression of TGF-beta in chronic sialadenitis and its apparent increase in advanced stages of the disease, suggests that this growth factor may play a role in glandular fibrosis.

Extracellular matrix molecules in chronic obstructive sialadenitis: an immunocytochemical and Western blot investigation.

The exact pathomechanism of inflammation progress and fibrosis in chronic sialadenitis is unknown. Connective tissue growth factor (CTGF), matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in the pathogenesis of various fibrotic conditions. These factors are thought to be essential in the regulation of extracellular matrix turnover and the development of tissue fibrosis. In the present study, the expression of CTGF, MMP-2, -3, -9, -13 and TIMP-3 was examined in chronic obstructive sialadenitis. Tissue samples of 13 patients with chronic sialadenitis of the submandibular gland associated with sialolithiasis and 4 normal tissue samples of the submandibular gland were analyzed immunohistochemically and by Western blot analysis. An intense CTGF immunoreactivity was observed in the ductal system of inflamed salivary glands, whereas in normal glands no reactivity or a very low CTGF immunoreactivity was present. Immunohistochemical studies revealed a low to strong reactivity of MMP-2, -3, -9, -13, and TIMP-3 in the ductal system, in acinar cells and in lymphomonocytic infiltrates in normal and inflamed tissues. The expression of MMP-2, -3, -9, -13, and TIMP-3 was confirmed by Western blotting in all cases. Over-expression of CTGF in chronic obstructive sialadenitis suggests that this factor may play a role in glandular fibrosis. However, the physiological role of MMP-2, -3, -9, -13, and TIMP-3 in normal glands, as well as their possible role in inflammation progress and fibrosis in chronic obstructive sialadenitis, remains to be elucidated.

Tumor sclerosis but not cell proliferation or malignancy grade is a prognostic marker in advanced-stage follicular lymphoma: the German Low Grade Lymphoma Study Group.

PURPOSE: Follicular lymphoma is an indolent lymphoma with a long median overall survival. However, a considerable number of patients die within the first 2 years after the onset of the disease. Because the treatment options vary with respect to antitumor effect and potential toxic adverse effects, the identification of high-risk patients would be helpful in directing therapeutic decisions in individual patients. Several histopathologic biomarkers for risk stratification have been suggested, but most markers have not been validated in patients treated in prospective trials. PATIENTS AND METHODS: We report a comprehensive approach to evaluate histopathologic biomarkers, including WHO grade, histology, and proliferation and quantitation of immune bystander cells, in 158 patients with nodal advanced-stage follicular lymphoma treated first line within a randomized trial. RESULTS: Tumor sclerosis was a significant prognostic marker of poor overall survival that was independent of the Follicular Lymphoma International Prognostic Index (FLIPI). WHO grade, proliferation, and total T-cell or macrophage content were not associated with overall survival. CONCLUSION: The presence of sclerosis within the lymphoma is a marker of poor overall survival that is independent of the FLIPI. The quantification of macrophage or absolute T-cell content, grading, and proliferation are of no help in predicting the outcome of FL. Future studies need to identify surrogate markers for the prognostic immune signatures identified by gene expression profiling. Most importantly, new prognostic markers need to be confirmed in patients treated within prospective trials.

Quantitative assessment of molecular remission after high-dose therapy with autologous stem cell transplantation predicts long-term remission in mantle cell lymphoma.

To evaluate the prognostic impact of minimal residual disease (MRD), quantitative real-time polymerase chain reaction (RQ-PCR) of clonal IGH rearrangements was performed in 29 patients with mantle cell lymphoma (MCL) treated with high-dose radiochemotherapy and autologous stem cell transplantation (ASCT). Fourteen of 27 patients evaluable for MRD after ASCT achieved complete clinical and molecular remission, whereas 13 patients had detectable MRD within the first year after ASCT. Molecular remission after ASCT was strongly predictive for improved outcome, with a median progression-free survival (PFS) of 92 months in the MRD-negative group compared with 21 months in the MRD-positive group (P < .001). Median overall survival (OS) was 44 months in the MRD-positive group and has not been reached in the MRD-negative group (P < .003). In multivariate analysis, molecular remission and bulky disease were independent prognostic factors for PFS (P = .001 and P = .021, respectively). While cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP)-like cytoreduction had only modest influence, ara-C-containing mobilization and myeloablative radiochemotherapy significantly reduced MRD. Quantitative MRD measured in the stem cell products of 27 patients was not predictive for molecular remission. We conclude that sequential quantitative monitoring of residual disease after ASCT is a powerful indicator for treatment outcome in MCL and defines subgroups of patients with a significantly different prognosis.

Repp86: a new prognostic marker in mantle cell lymphoma.

OBJECTIVES: Proliferation indices are important prognostic factors for the clinical outcome of patients with mantle cell lymphoma (MCL). We investigated whether the expression of repp86 (restrictedly expressed proliferation-associated protein 86 kDa), a new proliferation specific marker expressed in the cell cycle phases G(2), S and M, but not in G(1), correlates with the clinical course in patients with MCL. PATIENTS AND METHODS: Biopsy specimens from 94 untreated patients enrolled in two multicenter trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, and repp86 (Ki-S2). RESULTS: Patients with 0-1% repp86 expression had a median overall survival time of 71.0 months, compared with 38.2 months for patients with 1-5% positive cells and 25.4 months for patients with 5-10% positive tumor cells. Patients with repp86 expression of more than 10% showed the shortest survival (median: 15.0 months). Kaplan-Meier analysis revealed a significant difference in the overall survival time between patients with very high (>10%) and very low (0-1%) repp86 expression (P < 0.0001) in the tumor cells. The multivariate analysis revealed repp86 expression to be superior to other clinical characteristics as a prognostic factor (P = 0.0016). CONCLUSION: Based on these findings, repp86 expression is a new important prognostic factor in MCL.

Blastoid variant of mantle cell lymphoma: late progression from classical mantle cell lymphoma and quantitation of minimal residual disease.

OBJECTIVES: Classical mantle cell lymphoma (MCL) and its blastoid variant (MCL-BV) are characterized by an extremely poor prognosis. Long-time survivors are rare, only very few patients with an overall survival over 10 years have been reported. We present a case of a 41-year-old male with a 12 yr history of MCL stage I to show, that very late relapses in MCL are possible and may present as a transformation into an aggressive blastoid variant and to illustrate the value of quantitative minimal residual disease (MRD) monitoring for treatment guidance. METHODS: Diagnostic lymph node and bone marrow samples were investigated by immunohistochemistry. Clonality analysis was performed by immunoglobulin heavy chain gene (IGVH) and t(11;14) PCR. The MRD assessment was done by real-time quantitative PCR (RQ-PCR) on available follow-up samples. RESULTS: By histologic review and sequencing of the clonal IGVH and t(11;14) PCR products we demonstrated a common clonal origin of the leucemic MCL-BV and the classical MCL diagnosed 12 yr earlier. Quantitative MRD assessment revealed significant MRD levels after intensive conventional chemotherapy including Rituximab. Therefore, treatment was early intensified by myeloablative radio-chemotherapy and allogeneic peripheral stem cell transplantation from an unrelated HLA-identical donor. This did not translate into a sustained remission as reflected by persisting MRD levels after transplantation and the patient died from rapid progressive disease 3.5 months after transplant. CONCLUSION: This report presents a rare case of long-term survivor of MCL with a progression of the original MCL cell clone to MCL-BV and demonstrates the clinical value of quantitative MRD assessment for optimized therapeutic management.

AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping.

This study was undertaken to analyze the differentiation profiles assessed by immunophenotyping in AIDS-related B-cell lymphoma (ARL) and their relation to the clinical course. Paraffin-embedded sections of 89 ARL cases during 1989 to 2004 were stained immunohistochemically with antibodies to CD3, CD10, CD20, CD38, CD138/Syndecan-1 (Syn-1), multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4), B-cell lymphoma protein-2 (BCL-2), BCL-6, latent membrane protein-1 (LMP-1), and Ki-67. Expression of CD10 and CD20 were associated with better overall survival (OS; P = .009 and P = .04, respectively). Expression of CD20 was associated with longer disease-free survival (DFS; P = .03), whereas expression of CD138/Syn-1 was associated with shorter DFS (P = .03). OS and DFS were worse in patients with immunophenotypic profiles related to post-germinal center (GC) differentiation (BCL-6 and CD10 negative, MUM1/IRF4 and/or CD138/Syn-1 positive) when compared with GC differentiation (P = .01). When controlled for age-adjusted International Prognostic Index (IPI), prior AIDS-defining illness (ADI), and year of ARL diagnosis, a post-GC differentiation remained significantly associated with poor OS and DFS. Expression of CD10 was associated with a preserved immunocompetence, whereas CD20 was less frequent in patients developing ARL while on highly active antiretroviral therapy (P = .04). In summary, lack of CD20 or CD10 expression and a post-germinal center signature are associated with a worse prognosis in ARL.

Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network.

Mantle cell lymphoma (MCL) is a distinct lymphoma subtype with a particularly poor clinical outcome. The clinical relevance of the morphological characteristics of these tumours remains uncertain. The European MCL Network reviewed 304 cases of MCL to determine the prognostic significance of histopathological characteristics. Cytomorphological subtypes, growth pattern and markers of proliferation (mitotic and Ki-67 indices) were analysed. In addition to the known cytological subtypes, classical (87.5%), small cell (3.6%), pleomorphic (5.9%) and blastic (2.6%), we identified new pleomorphic subgroups with mixtures of cells (classical + pleomorphic type; 1.6%) or transitions (classical/pleomorphic type; 1.6%), which, however, did not differ significantly in overall survival time. Exactly 80.5% of cases displayed a diffuse growth pattern, whereas 19.5% of cases had a nodular growth pattern, which was associated with a slightly more favourable prognosis. A high proliferation rate (mitotic or Ki-67 indices) was associated with shorter overall survival. Cut-off levels were defined that allowed three subgroups with different proliferation rates to be discriminated, which showed significantly different clinical outcomes (P < 0.0001). Based on this large clinicopathological study of prospective clinical trials, multivariate analysis confirmed the central prognostic role of cell proliferation and its superiority to all other histomorphological and clinical criteria.

Characterization of lymphoid infiltrates in chronic obstructive sialadenitis associated with sialolithiasis.

BACKGROUND: Chronic obstructive sialadenitis is characterized by acinar atrophy, lymphocytic infiltrates and progressive fibrosis. The immunological mechanisms involved in the pathogenesis of this disease are, for the most part, unknown. The aim of the present study was to characterize the lymphocytic infiltrates in chronic obstructive sialadenitis associated with sialolithiasis. METHODS: Paraffin-embedded tissue samples from 23 affected submandibular glands were immunostained for T-cells (CD3, CD4, CD8), cytotoxic T-cells (granzyme B), B-cells (CD20), plasma cells (CD38) and macrophages (Ki-M1P). RESULTS: CD4-positive subsets were the predominant cells, and they were located mainly periductally. Isolated intraepithelial CD8-positive cytotoxic T-cells associated with ductal epithelial cell destruction were observed in all cases. B lymphocytes were restricted to lymphoid follicles located periductally and around intralobular ducts. In early stages of the disease, a large number of CD38-positive plasma cells were distributed diffusely in the periacinar area. With progression of the disease, conspicuous clusters of plasma cells were located especially between atrophic acini adjacent to fibrotic tissue. An intimate relation between the lymphocytic infiltrates and the ductal epithelium, the target of the inflammatory process, was observed. CONCLUSION: The composition and distribution of inflammatory cells suggest that intraepithelial infectious agents may be the cause of the inflammatory reaction and the progressive fibrosis in this disease.

Chronic sclerosing sialadenitis of the submandibular gland is mainly due to a T lymphocyte immune reaction.

The aim of our study was to investigate the role of immunopathological processes in the pathogenesis of chronic sclerosing sialadenitis of submandibular glands (Küttner tumor). For this purpose, biopsy specimens from submandibular glands of 22 patients with the histological diagnosis of chronic sclerosing sialadenitis were analyzed. Paraffin-embedded tissues were immunostained for T-lymphocyte subsets (CD3, CD4, CD8), cytotoxic T cells (granzyme B), B cells (CD20, Ki-B3), and macrophages (Ki-M1P). Polymerase chain reaction and capillary electrophoresis were used to detect rearrangements of the T-cell receptor gamma chain and the CDRIII region of the immunoglobulin heavy chain. In all cases, abundant cytotoxic T cells were found, especially in close association with ducts and acini. T-cell receptor gamma chain rearrangements showed a monoclonal pattern in 6 cases (27.3%), an oligoclonal pattern in 8 (36.4%), and a polyclonal pattern in 8 (36.4%). The B-cell reaction was less pronounced and largely restricted to lymph follicles. Molecular analysis of immunoglobulin heavy chain revealed a polyclonal rearrangement in 17 cases (77.3%). In conclusion, there is an intimate relationship between the T-cell-dominated inflammatory infiltrate and acinar and duct cells. This, together with the frequent demonstration of monoclonal and oligoclonal populations of cytotoxic T cells and their histopathological behavior, suggests that chronic sclerosing sialadenitis may be the result of an immune process triggered by intraductal agents.