Isinsu Kuzu

Bone marrow microvessel density (MVD) in adult acute myeloid leukemia (AML): therapy induced changes and effects on survival.

Based on the strong evidence in favor of an increase in microvessel density (MVD) in hematological malignancies, we evaluated VEGF immunoreactivity and MVD measurement in bone marrow biopsies of 36 AML patients at diagnosis and following therapy. MVD assessment was based on CD31, CD34 expressing vessels. The values were calculated for only one marker if the other vascular marker was positive on blasts, otherwise both markers were used. VEGF immunoreactivity was also scored. Comparison of MVD values of 36 AML patients with 18 non-malignant controls showed a significantly higher MVD in AML (CD31: P = 0.004, CD34: P < 0.001), which is independent of other variables such as cellularity or blast percentage. Following induction chemotherapy, the responders showed a significant decrease in blast counts (P < 0.001), cellularity (P = 0.001) and MVD (P = 0.050) quantification with CD31. Higher baseline MVD (CD34) values were associated with shorter overall survival (P = 0.0027). These results are encouraging for inclusion of MVD enumeration in bone marrow examinations of AML patients at diagnosis as an additional prognostic factor.

Role of integrins and intracellular adhesion molecule-1 in lung injury after intestinal ischemia-reperfusion

BACKGROUND We tested the hypothesis that lung injury after intestinal ischemia-reperfusion (IR) requires the activation of CD11/CD18 glycoprotein complex and its ligand, intracellular adhesion molecule-1 (ICAM-1), on pulmonary endothelial surface. METHODS Rats were assigned to one of six groups including sham operation, intestinal IR (60/120 min) and IR plus treatment with one of the following monoclonal antibodies against CD11a, CD11b, CD18, and ICAM-1. Pulmonary microvascular permeability, neutrophil accumulation, and expression of adhesion molecules were evaluated. RESULTS Intestinal IR resulted in lung injury characterized by a marked increase in microvascular permeability, neutrophil accumulation and upregulated expression of leukocyte integrins and ICAM-1. The increase in pulmonary microvascular permability and neutrophil accumulation elicited by intestinal reperfusion was effectively prevented by administration of blocking antibodies against ICAM-1, CD11, and CD18. CONCLUSIONS These results indicate that adhesion molecules contribute to the lung injury after intestinal IR. Immunoneutralization of certain of these adhesion molecules may prevent intestinal IR-induced lung injury.

An unusual presentation of helicobacter pylori infection: so-called “Russell body gastritis”

Helicobacter pylori (H. pylori) is a “slow” bacterial pathogen, which induces several gastroduodenal diseases. Varying degrees of inflammation can be present in the gastric mucosa of patients infected with H. pylori. The case presented here is a male patient suffering from dyspepsia and nausea. His upper gastrointestinal endoscopy revealed pan gastritis. Histological examination of multiple gastric biopsies taken from the body and antrum showed a rare morphological expression of H. pylori gastritis characterized by diffuse plasma cell infiltration with extensive Russell body formation. Diffuse infiltration of plasma cells with Russell bodies in gastric mucosa can cause difficulties in differentiation from neoplastic processes. However, immunohistochemically, the infiltrating cells in the gastric mucosa stained negatively with cytokeratins while they expressed both kappa and lambda light chains showing their polyclonal nature. The presence of diffuse plasma cells with Russell bodies in the gastric mucosa may represent a different presentation of H. pylori gastritis. There are only two case reports of similar presentation and both have been called “Russell body gastritis”.

Barrett's esophagus: Prevalence and its relationship with dyspeptic symptoms

Background and Aim:  Barretts metaplasia is a premalign condition which plays a pivotal role in the development of esophageal adenocarcinoma. It is considered a complication of chronic gastroesophageal reflux disease. Although esophageal adenocarcinoma is an uncommon cancer, its incidence is rapidly increasing. The aims of the present study were to determine the prevalence of Barretts metaplasia in outpatients referred for gastroscopy for upper gastrointestinal symptoms, and to clarify the relationship between Barretts metaplasia and upper gastrointestinal symptoms.

Early lesions in lymphoid neoplasia: Conclusions based on the Workshop of the XV. Meeting of the European Association of Hematopathology and the Society of Hematopathology, in Uppsala, Sweden

The increasing use of immunophenotypic and molecular techniques on lymphoid tissue samples without obvious involvement of malignant lymphoma has resulted in the increased detection of ‘early’ lymphoid proliferations which show some, but not all, of the criteria necessary for a diagnosis of malignant lymphoma. In most instances, these are incidental findings in asymptomatic individuals, and their biological behaviour is uncertain. In order to better characterize these premalignant conditions and to establish diagnostic criteria, a joint workshop of the European Association for Haematopathology and the Society of Hematopathology was held in Uppsala, Sweden, in September 2010. The panel reviewed and discussed more than 130 submitted cases and reached consensus diagnoses. Cases representing the nodal equivalent of monoclonal B cell lymphocytosis were discussed, as well as the ‘in situ’ counterparts of follicular lymphoma (FL) and mantle cell lymphoma, topics that also stimulated discussions concerning the best terminology for these lesions. The workshop also addressed the borderland between reactive hyperplasia and clonal proliferations such as paediatric marginal zone lymphoma and paediatric FL, which may have very limited capacity for progression. Virus-driven lymphoproliferations in the grey zone between reactive lesions and manifest malignant lymphoma were covered. Finally, early manifestations of T cell lymphoma, both nodal and extranodal, and their mimics were addressed. This workshop report summarizes the most important conclusions concerning the diagnostic features, as well as proposals for terminology and classification, of early lymphoproliferations and tries to give some practical guidelines for diagnosis and reporting.

Prospective International Cohort Study Demonstrates Inability of Interim PET to Predict Treatment Failure in Diffuse Large B-Cell Lymphoma

The International Atomic Energy Agency sponsored a large, multinational, prospective study to further define PET for risk stratification of diffuse large B-cell lymphoma and to test the hypothesis that international biological diversity or diversity of healthcare systems may influence the kinetics of treatment response as assessed by interim PET (I-PET). Methods: Cancer centers in Brazil, Chile, Hungary, India, Italy, the Philippines, South Korea, and Thailand followed a common protocol based on treatment with R-CHOP (cyclophosphamide, hydroxyadriamycin, vincristine, prednisolone with rituximab), with I-PET after 2–3 cycles of chemotherapy and at the end of chemotherapy scored visually. Results: Two-year survivals for all 327 patients (median follow-up, 35 mo) were 79% (95% confidence interval [CI], 74%–83%) for event-free survival (EFS) and 86% (95% CI, 81%–89%) for overall survival (OS). Two hundred ten patients (64%) were I-PET–negative, and 117 (36%) were I-PET–positive. Two-year EFS was 90% (95% CI, 85%–93%) for I-PET–negative and 58% (95% CI, 48%–66%) for I-PET–positive, with a hazard ratio of 5.31 (95% CI, 3.29–8.56). Two-year OS was 93% (95% CI, 88%–96%) for I-PET–negative and 72% (95% CI, 63%–80%) for I-PET–positive, with a hazard ratio of 3.86 (95% CI, 2.12–7.03). On sequential monitoring, 192 of 312 (62%) patients had complete response at both I-PET and end-of-chemotherapy PET, with an EFS of 97% (95% CI, 92%–98%); 110 of these with favorable clinical indicators had an EFS of 98% (95% CI, 92%–100%). In contrast, the 107 I-PET–positive cases segregated into 2 groups: 58 (54%) achieved PET-negative complete remission at the end of chemotherapy (EFS, 86%; 95% CI, 73%–93%); 46% remained PET-positive (EFS, 35%; 95% CI, 22%–48%). Heterogeneity analysis found no significant difference between countries for outcomes stratified by I-PET. Conclusion: This large international cohort delivers 3 novel findings: treatment response assessed by I-PET is comparable across disparate healthcare systems, secondly a negative I-PET findings together with good clinical status identifies a group with an EFS of 98%, and thirdly a single I-PET scan does not differentiate chemoresistant lymphoma from complete response and cannot be used to guide risk-adapted therapy.

Recipient-derived hepatocytes in sex-mismatched liver allografts after liver transplantation: Early versus late transplant biopsies

Background. The presence of microchimerism in transplanted tissues is well defined; however, the timeframe of appearance and disappearance of engraftment in liver allograft is unknown. The aims of this study were to analyze for the presence of “recipient-derived cells” in sex-mismatched individuals after liver transplantation, comparing the frequency of “recipient-derived cell repopulation” in early versus late transplant biopsies and to evaluate the relationship between “recipient-derived cell repopulation” and the severity of graft injury. Methods. Paraffin-embedded liver biopsy samples of 18 recipients were reviewed. Sixteen of them were obtained from recipients with sex-mismatched donors. The remaining two were obtained from recipients with sex-matched donors and were used as controls. Immunohistochemistry and fluorescence in situ hybridization double-labeling method were performed on pretreated slides using anti-human hepatocyte antibody to identify hepatocytes, a mouse anti-human cytokeratin-7 to identify ductal epithelial cells, and using CEPX/Y DNA probes for visualizing X and Y chromosomes. The double-labeled slides were examined systematically using an image analyzer system. Results. The mean time from transplantation to biopsy was 8.1 months. Eleven of the 16 samples obtained from recipients with sex-mismatched grafts demonstrated “recipient-derived hepatocyte repopulation,” comprising a mean of 2.1% of the hepatocytes. In the control biopsies, none of the cells demonstrated different nuclear signals from the donor’s sex origin. The presence and proportion of “recipient-derived hepatocyte repopulation” rate were significantly higher in early transplant biopsies than in late transplant biopsies (P<0.05). Conclusion. Some hepatocytes of sex-mismatched liver grafts were replaced by “recipient-derived cells” during injury. Such repopulation is more common in the early liver-graft biopsies. The severity of acute cellular rejection appears to have no effect on the rate of recipient-derived repopulation.

Five-year follow-up after transepicardial implantation of autologous bone marrow mononuclear cells to ungraftable coronary territories for patients with ischaemic cardiomyopathy

OBJECTIVE Cell therapy for patients with ischaemic cardiomyopathy (IC) is still an open issue. We aimed to assess the long-term safety and therapeutic potency of autologous bone marrow mononuclear cell (ABMMNC) implantation into ungraftable coronary artery (UCA) territories in patients with IC. METHODS Bone marrow was aspirated from the iliac crest, and transepicardial ABMMNC implantation (n=25, 24 men, aged 57+/-7 years) as an adjunct to coronary artery bypass grafting (CABG) was performed into an area of reversible ischaemia within the territory of UCA (1.29+/-0.09 x 10(9) ABMMNCs). Control group (n=25, 23 men, aged 59+/-7 years) underwent incomplete CABG due to poor target vessel graftability. The study protocol consisted of coronary angiography, stress echocardiography, nuclear imaging and Holter monitoring at baseline and follow-up. The mean follow-up time was 988+/-423 days. RESULTS There was no difference between the groups regarding postoperative complications and outcome. Overall 5-year survival for the ABMMNC group was 79+/-10%, and 71+/-12% for the controls (p=0.48). Left ventricular ejection fraction (LVEF) at baseline was 24.8+/-3.7 versus 25.9+/-3.1 in the ABMMNC group and the controls, respectively. After 6 months, mean global LVEF increased to 36.3+/-7.4 (p<0.001) versus 31.4+/-4.1 (p=0.001), respectively. A significant difference was noted in delta LVEF between the groups (p<0.001, 95% confidence interval (CI): 3.4-8.9) at 6 months, and (p=0.001, 95% CI: 2.0-7.4) at 1 year. Accordingly, perfusion scores in UCA segments detected by single-photon emission computed tomography (SPECT) improved with ABMMNC therapy to 18.0+/-24.4 from 7.1+/-25.7 (p=0.001 vs control UCA segments). CONCLUSION Cellular therapy for IC within UCA could augment myocardial perfusion and contractility but does not improve overall survival. No adverse events were detected after cell therapy at mid-term follow-up.

The usefulness of chromoendoscopy with methylene blue in Barrett’s metaplasia and early esophageal carcinoma

BackgroundBarrett’s esophagus is a condition that is premalignant for adenocarcinoma of the esophagus and the esophagogastric junction. Early detection of Barrett’s metaplasia and dysplasia is very important to decrease the mortality and morbidity from esophageal adenocarcinoma cancer. This study aimed to evaluate the effectiveness of methylene blue–targeted biopsies in the differential diagnosis of intestinal metaplasia, dysplasia, and superficial esophageal carcinoma.MethodsA total of 109 patients (43 women and 66 men; average age, 62.32 ± 10.61 years; range, 33–82 years) were enrolled for the study. Four groups were designed before endoscopic examinations. The patients for these groups were selected at the conventional endoscopy, and then chromoendoscopy was performed. The esophagus was stained with methylene blue, after which six biopsies were taken from stained and unstained areas.ResultsConventional and chromoendoscopic assessments were compared with histopathologic examination. The sensitivity of chromoendoscopy for Barrett’s epithelium was superior to that of conventional endoscopy (p < 0.05). However, there was no statistical difference between the two methods in the diagnosis of esophagitis or esophageal carcinoma (p > 0.05). Stained biopsies were superior to unstained biopsies in terms of sensitivity for Barrett’s epithelium and esophageal carcinoma (p < 0.001).ConclusionChromoendoscopy is useful for delineating Barrett’s epithelium and for indicating the correct location for securing biopsies where dysplasia or early esophageal cancer is suspected.

The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing

Plasmacytic differentiation may occur in almost all small B cell lymphomas (SBLs), although it varies from being uniformly present (as in lymphoplasmacytic lymphoma (LPL)) to very uncommon (as in mantle cell lymphomas (MCLs)). The discovery of MYD88 L265P mutations in the vast majority of LPLs has had a major impact on the study of these lymphomas. Review of the cases contributed to the 2014 European Association for Haematopathology/Society for Hematopathology slide workshop illustrated how mutational testing has helped refine the diagnostic criteria for LPL, emphasizing the importance of identifying a clonal monotonous lymphoplasmacytic population and highlighting how LPL can still be diagnosed with extensive nodal architectural effacement, very subtle plasmacytic differentiation, follicular colonization, or uncommon phenotypes such as CD5 or CD10 expression. MYD88 L265P mutations were found in 11/11 LPL cases versus only 2 of 28 other SBLs included in its differential diagnosis. Mutational testing also helped to exclude other cases that would have been considered LPL in the past. The workshop also highlighted how plasmacytic differentiation can occur in chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, SOX11 negative MCL, and particularly in marginal zone lymphomas, all of which can cause diagnostic confusion with LPL. The cases also highlighted the difficulty in distinguishing lymphomas with marked plasmacytic differentiation from plasma cell neoplasms. Some SBLs with plasmacytic differentiation can be associated with amyloid, other immunoglobulin deposition, or crystal-storing histiocytosis, which may obscure the underlying neoplasm. Finally, although generally indolent, LPL may transform, with the workshop cases suggesting a role for TP53 abnormalities.