Granulocyte turnover in advanced Hodgkin's disease

In 30 adult patients with III and IV Hodgkin's disease the studies of granulocytic turnover were performed. Bone marrow storage pool was measured by hydrocortisone test. Total blood granulocyte pool was judged by the estimation of muramidase activity and serum unsaturated vitamin B12 binding capacity. The epinephrine test was used for the marginated granulocyte pool determination. The circulating granulocyte pool was calculated from the count of granulocytes in the samples of venous blood. The tissue mobilization of granulocytes was measured by Senn's et al. method. After hydrocortisone application the releasing of the mature granulocytes from the bone-marrow was significantly lower in patients with Hodgkin's disease than in controls. The circulating and marginated pools of granulocytes in Hodgkin's disease did not differ from the normal persons. The tissue migration of granulocytes was decreased in patients with Hodgkin's disease. It is concluded that these abnormalities of granulocytic turnover in advanced Hodgkin's disease may be considered to be an additional cause of the defence mechanism in this disease.     

Hodgkin''s-like disease of the thymus. Clinical, surgical and morphological correlations

The histogenesis and relationship of so-called "granulomatous thymoma" to Hodgkin's disease is still a matter of controversy. Three of these lesions were selected from 43 thymomas and their clinico-pathological patterns are described. Two cases were diagnosed as Hodgkin's disease of the mediastinum because of the absence of epithelial structures of thymic origin. In one case, together with the morphological aspects of Hodgkin's disease, we noticed epithelial structures indicating a primary neoplastic lesion in the thymus. Accordingly we conclude that the term "Hodgkin's disease of the thymus" must be limited only to those lesions of the mediastinum in which structures of thymic origin are present. Other mediastinal Hodgkin's lesions, even in the presence of clinical, radiological and surgical evidence of thymic origin but in which it is not possible to observe such thymic structures, must be classified as Hodgkin's disease localized to the anterior mediastinum.     

Hodgkin's disease presenting with a bronchoesophageal fistula

Bronchoesophageal fistula is a rare complication of Hodgkin's disease. We report a case of Hodgkin's disease presenting with a bronchoesophageal fistula that was successfully treated with bipolar esophageal exclusion and substernal gastric bypass. Direct invasion from mediastinal lymph nodes was the probable cause. Although bronchoesophageal fistula can result as a complication during the course of treatment for Hodgkin's disease, it rarely occurs as the presenting feature. Early recognition and surgical treatment are key aspects of management.     

Hodgkin's disease: a cytokine-producing tumor--a review

Cytokines and hematopoietic growth factors are actively involved in regulation of proliferation, differentiation, and cellular functions of various cell lineages. Each cytokine exhibits pleiotropic biological functions on different target cells and subfamilies of cytokines often have redundant biological effects on the same target cell. Hodgkin's disease represents one of the most common human lymphoma entities, the molecular pathogenesis of which is not well understood. Hodgkin's disease is characterized by the presence of typical, presumed malignant Hodgkin and Reed-Sternberg cells in a hyperplastic background of normal reactive lymphocytes, plasma cells, histiocytes, neutrophils, eosinophils, and stromal cells. The histopathological presentation and characteristic clinical features of Hodgkin's disease correlate with an unbalanced production of multiple cytokines. Hodgkin and Reed-Sternberg cells express mRNA and proteins of various cytokines, growth factors, and cytokine receptors, implying a predominant role for cytokines in the pathophysiology of Hodgkin's disease as a tumor of cytokine-producing cells.     

Slide agglutination test for the diagnosis of pulmonary and extra-pulmonary tuberculosis

Nasal polyposis can be defined as a chronic inflammatory disease of the paranasal sinus mucosa, leading to a protrusion of benign edematous polyps from the meatus into the nasal cavities. Nasal polyps are histologically characterized by massive edema and accumulation of eosinophils. IgE-mediated allergy seems to play only a minor role in eosinophil accumulation, leaving the place for a new concept of non-allergic rhinitis with eosinophilia. The central question still remains, however, why eosinophils accumulate into nasal polyposis tissue. Some initial data show that tissue structural cells, i.e. epithelial cells or fibroblasts, could produce cytokines (GM-CSF) and play a role in eosinophil accumulation (micro-environmental theory). However, further studies showed, that GM-CSF was mainly produced by eosinophils themselves (autocrine theory), leading to the hypothesis of an intrinsic eosinophilic inflammatory process. Eosinophils may contribute to nasal polyp formation and growth not only through inflammation but also by exerting their effects on extracellular matrix including stimulation of collagen synthesis. Another feature associated with nasal polyposis is aspirin sensitivity. Some preliminary data indicate that eosinophils could also be involved in aspirin-sensitivity mechanisms.     

Burkitt's lymphoma-leukemia in patients treated for Hodgkin's disease

We reviewed all reported cases of Burkitt's lymphoma and/or Burkitt's leukemia (BLL) occurring following therapy for Hodgkin's disease. In addition to the case described in this report, a total of 19 patients have been previously reported. The male/female ratio was 3.75. Treatment for Hodgkin's disease included chemotherapy combined with radiation therapy in 15 patients, chemotherapy in 3 patients, and radiation therapy alone in 1 patient. Median interval between Hodgkin's disease and the diagnosis of BLL was 97 months. Patient characteristics are similar to those with de novo BLL. Bone marrow, abdomen, central nervous system, as well as extranodal organs were commonly involved. Typical cytogenetic translocations seen in patients with primary BLL were found in 6 patients, but 5 of these patients had additional cytogenetic abnormalities. Only 2 patients achieved complete remission after chemotherapy. The mechanism for the development of BLL after treatment for Hodgkin's disease is unknown. Although the majority of cases have been seen in patients treated with combined-modality therapy, the role of previous therapy in causing this complication cannot be assessed in this study.     

Telomerase activity in Hodgkin's disease

Telomere maintenance executed by the action of telomerase seems to be a prerequisite for immortalization. Telomerase is found in most cell lines and malignant tumors. A telomerase-independent mechanism for telomere maintenance in Hodgkin's disease has been proposed in the absence of detectable telomerase activity. In this study, telomerase activity was detected in 31 of 77 Hodgkin's disease samples and a strong correlation between eosinophilia and absence of detectable telomerase activity was found. Purified eosinophils and specifically eosinophil-derived neurotoxin and eosinophilic cationic protein, both ribonucleases, were found to degrade telomerase. Purified neutrophils also exhibited weak telomerase degradative activity. Reanalysis of previously telomerase-negative Hodgkin's disease samples with eosinophilia using ribonuclease inhibitors resulted in the detection of telomerase activity. Ribonuclease-containing cells in vivo thus have a considerable impact on the detectability of telomerase. In Hodgkin's disease samples without eosinophilia, 24 of 27 exhibited telomerase activity at decreased levels compared with non-Hodgkin's lymphomas and at increased levels compared with reactive nodes indicative of a telomerase positive tumor component in Hodgkin's disease. Telomerase positivity of the Hodgkin's and Reed-Sternberg cells in vivo was also supported by high levels of telomerase expression in Hodgkin's disease cell lines. Based on our data, Hodgkin's lymphomas are potential targets for antitelomerase therapy.     

A simple strategy to look back on posttransfusion hepatitis B in a multitransfused patient

The diagnosis of Hodgkin's disease by fine-needle aspiration (FNA) can be problematic. A case of Hodgkin's disease, lymphocyte depleted subtype, sample by FNA biopsy is presented. We describe the cytomorphologic features present in this unusual subtype of Hodgkin's disease and discuss the differential diagnosis. Immunohistochemical and morphologic findings of a subsequent biopsy specimen supported the diagnosis. Although FNA is an increasingly used diagnostic modality to evaluate tumors including malignant lymphomas, Hodgkin's disease remains, as in this case, a difficult diagnosis by FNA.     

Numerical chromosomal aberrations in Hodgkin's disease detected by in situ hybridisation on routine paraffin sections

AIMS: To visualise directly numerical chromosomal aberrations and polyploidy in both Hodgkin and Reed Sternberg (HRS) cells and background cells from cases of Hodgkin's disease using in situ hybridisation. METHODS: Non-isotopic DNA in situ hybridisation was applied to interphase cell nuclei of Hodgkin's disease within routine paraffin embedded tissue sections. Two a satellite DNA probes, specific for chromosomes 3 and 12, were used to evaluate the feasibility of this approach. Double labelling with immunocytochemical detection of the CD30 antigen was used to identify HRS cells. Cytogenetic normal diploid and triploid placental tissue served as controls. RESULTS: The eight cases of Hodgkin's disease investigated displayed frequent polysomy, while the majority of background cells showed disomy signals. CONCLUSIONS: Numerical chromosomal aberrations were detected in HRS cells from eight cases of Hodgkin's disease by in situ hybridisation. These data show that in Hodgkin's disease HRS cells frequently display polyploidy compared with background cells and are, therefore, probably the only neoplastic component in this disease. Correlations between polysomy and tumour type or grade could not be made from these data owing to the limited number of cases examined and to problems with interpreting data from truncated nuclei.     

Cytogenetics of Hodgkin's disease

Cytogenetic studies over the past 35 years have made a major contribution towards the understanding of the nature of Hodgkin's disease by demonstrating unequivocally the consistent presence of a clonal population of cells that have the cardinal features of malignancy e.g. more or less gross aneuploidy, frequently with complex chromosomal changes and showing considerable variation from case to case, thus comparable to the findings in carcinomas and other solid cancers. The mode is frequently in the triploid-tetraploid region, as we found in 17 of 27 cases studied in this laboratory by Feulgen microspectrophotometry, compared to only 10 cases with neardiploid modes. It is disappointing that no specific change, such as a translocation that could give a clue to the chromosomal location of a gene or genes involved in the etiology of Hodgkin's disease, has yet been found. Nevertheless it is clear that a number of nonrandom changes, including several that are also common in other malignancies including the non-Hodgkin's lymphomas, are frequently present, e.g., deletions of 1p, 6q, and 7q. Interestingly, deletions of 4q, with loss of 4q25 --> q27, that have also been reported may show some specificity for Hodgkin's disease.     

Epstein-Barr virus and Hodgkin's disease: further evidence for the three disease hypothesis

The epidemiology of Hodgkin's disease suggests that it is a heterogeneous condition comprising more than one disease entity. The Epstein-Barr virus (EBV) is present in the Reed-Sternberg cells of a proportion of cases and is likely to play a role in the pathogenesis of these cases. In this study we show that EBV association rates vary with age at diagnosis. We suggest that Hodgkin's disease can be divided into three disease entities on the basis of EBV association and age, thereby providing biological support for the multiple aetiology hypothesis proposed by MacMahon (Cancer Res 1966; 26: 1189-1290).     

Multifactor evaluation of the determinants of ischemic electrocardiographic response to maximal treadmill testing in coronary disease

Peripheral blood lymphocytes from patients with all stages of untreated Hodgkin's disease and from normal healthy adults were shown to synthesize and release ferritin in vitro. Ferritin synthesis was confirmed by immunoelectrophoresis, double immunodiffusion and autoradiography. Hodgkin's disease lymphocytes synthesized ferritin 4.2 times faster and released it 2.4 times faster than did normal lymphocytes, whereas total protein synthesis was faster in normal lymphocytes. Patients with nodular sclerosis and perhaps those with absence of fever had the highest synthetic rates; however no relationship was observed between relative rates of lymphocyte ferritin synthesis and sex, age, anatomical stage and presence of splenic or hepatic involvement by tumor. Addition of iron to normal human lymphocytes produced little or no change in ferritin synthesis. These data indicate that part of the intracellular ferritin detected in peripheral blood lymphocytes from patients with Hodgkin's disease and from normal individuals resulted from de novo synthesis rather than from uptake and storage of serum ferritin, and suggests that elevated ferritin levels detected in the serum and tumor tissue of Hodgkin's disease patients originate from lymphocytes.     

Atypical CT findings of cervical lymphadenopathy due to Hodgkin''s disease. A case report

We describe a case of Hodgkin's disease with cervical lymphadenopathy which may easily be confused with a granulomatous process both radiologically and pathologically.     

Activation of eosinophils in the airways of lung transplantation patients

Eosinophils are important inflammatory cells involved in liver and renal allograft rejection. The role of these cells is less well defined in lung allograft rejection. Eosinophils may be activated in lung rejection and release cytotoxic eosinophil cationic protein (ECP). Other states of disease in lung transplant recipients, such as cytomegalovirus (CMV) and bacterial infection, may also be associated with activated eosinophils. We postulated that ECP may be detectable and elevated in the airway lavage samples obtained from lung transplant patients and may contribute to disease pathogenesis. METHODS: Fifty BAL samples were collected from 38 lung transplant patients. Their most recent pulmonary function test results within 1 week of collection were noted. The samples were analyzed for the concentration of ECP, WBC count and differential cell count, and total protein level. The results were analyzed to identify the presence of disease or abnormal lung function associated with a positive ECP test. Student's t test was used and a p value of <0.05 was considered significant. RESULTS: We found that ECP levels were elevated in 36% (n=14) of the patients. Those patients with a positive test result were more likely to have acute rejection, CMV disease, or the presence of a cultured pathogen in BAL compared to patients with a negative test result (p<0.01). CONCLUSIONS: The presence of BAL ECP is associated with disease in lung transplant patients. Since ECP is directly cytotoxic, it may contribute to disease pathogenesis.     

The effect of a 50 Hz magnetic field on cognitive function in humans

Accumulation of eosinophils in the lung with concomitant tissue damage are defining histopathologic features of human asthma. Through degranulation and the release of proinflammatory proteins such as major basic protein (MBP), eosinophils may perpetuate this inflammatory response. We investigated the extent of eosinophil degranulation in a murine model of allergic pulmonary inflammation. In this paradigm, the mice develop pulmonary eosinophilia, mucus hypersecretion, tissue damage, and airway edema and hyperreactivity. To evaluate the degree of eosinophil degranulation, we used a polyclonal antibody to murine MBP (mMBP) to perform dot blot analysis of bronchoalveolar lavage (BAL) cells and fluids, and immunohistochemical fluorescent analysis of lung tissue sections. After ovalbumin antigen challenge, we were unable to detect immunoreactive mMBP in the BAL fluids from either nonsensitized or sensitized mice. However, after lysis of the recoverable BAL cells, we were able to detect mMBP by immunoblot analysis, with the levels of immunoreactive mMBP directly related to the number of recoverable eosinophils. We also examined paraffin-embedded, lung tissue sections for patterns of mMBP deposition. Whereas lung sections from allergic mice revealed prominent peribronchial eosinophilia after antigen challenge, tissue sections from nonsensitized animals rarely displayed eosinophils. Despite the presence of numerous eosinophils, no immunohistologic evidence of extracellular mMBP could be found in antigen-challenged allergic mice. Furthermore, rechallenged allergic mice displayed a significant increase in the number of recruited pulmonary eosinophils but all immunoreactive mMBP was still intracellular. We conclude that the recruited pulmonary eosinophils have not substantially degranulated. These results suggest that, in this murine model of allergic inflammation, eosinophil degranulation and release of mMBP does not contribute to the observed pulmonary inflammation and airway hyperreactivity.     

Drosophila MAP kinase kinase suppresses the vulvaless phenotype of lin-3, let-23 and lin-45 mutations in Caenorhabditis elegans

In this study coexpression of cytokeratin and desmin, and occasionally also Ki-1 antigen, was displayed in extrafollicular reticulum cells of reactive lymph nodes. The absence or expression of trace amounts of these proteins in normal lymphoid tissue suggests that activation of T cell regions is correlated with the increased frequency of cytokeratin, desmin and Ki-1 expressing cells, and therefore may be a transient phenomenon. S-100-positive interdigitating reticular cells were found occasionally in extrafollicular T cell region of normal lymph nodes. They were, however, more numerous in reactive lymphatic tissue. In the myasthenic thymuses cells forming Hassall's corpuscles displayed coexpression of cytokeratin, desmin and Ki-1 antigen. Medullary epithelial cells were also cytokeratin-positive and, additionally, Ki-1 antigen was expressed on some cells dispersed in whole thymic tissue. S-100-positive interdigitating reticular cells were especially numerous in the thymic medulla and some of them found inside the Hassall's corpuscles. In Hodgkin's disease deficiency of cytokeratin and desmin in extrafollicular reticulum cells is a constant phenomenon in spite of a classic inflammatory background. However, Ki-1 antigen displayed Reed-Sternberg cells which, similar as some thymic cell elements, appear to originate from stromal perivascular mesenchyme. This fact suggests that Reed-Sternberg cells in Hodgkin's disease are pathologic counterparts of extrafollicular reticulum cells which represent a cellular differentiation defect to produce desmin and cytokeratin but with a possibility of Ki-1 antigen expression. The consequence of this may be the disregulation of immune system and the observed immunologic abnormalities. Further studies are needed to elucidate the role of Epstein-Barr viruses in this process. S-100-positive interdigitating reticular cells were in close contact with Reed-Sternberg cells and they were especially large and with numerous cells processes in the mixed cellularity (MC) subtype. The occurrence of interdigitating reticulum cells with S-100 protein expression, especially numerous in the T cell region activated of peripheral lymphatic tissue, as well as their close contact with Reed-Sternberg cells and with cells forming Hassall's corpuscles suggest their eventual possible role in the function of the immune system.     

A review of epidemiologic studies of triazine herbicides and cancer

We evaluated epidemiologic evidence pertaining to the human carcinogenic potential of triazine herbicides in general and of atrazine, the most common triazine. Cancers for which data are available included non-Hodgkin's lymphoma, Hodgkin's disease, leukemia, multiple myeloma, soft tissue sarcoma, colon cancer, and ovarian cancer. The investigations had methodologic limitations, including lack of in-depth exposure measurements and small numbers of subjects with heavy exposure and/or with many years since starting exposure, possibly required for the induction of cancer. The relation between triazines and non-Hodgkin's lymphoma has been assessed in four independent population-based case-control studies, reporting odds ratios ranging from 1.2 to 2.5. However, chance and/or confounding by other agricultural exposures may have produced these weak statistical associations. Furthermore, a pooled analysis of three of the case-control studies and the combined analysis of two retrospective follow-up studies did not demonstrate the types of dose-response or induction time patterns that would be expected if triazines were causal factors. The epidemiologic data pertaining to Hodgkin's disease, leukemia, multiple myeloma, soft tissue sarcoma, colon cancer, and ovarian cancer were inadequate for determining whether associations with atrazine or triazines exist in humans. For each of these cancers, only one or two studies evaluating the relationship were available, and the results of the studies typically were imprecise.     

The roles of adhesion molecules, cytokines and chemokines in allergic inflammation

Recently, adhesion molecules, as well as eosinophils, have been found to play an important role in the inflammatory processes in allergic disease. We demonstrated here as below. Characteristics of adhesion molecules expression on eosinophils in asthma, namely, high-intensity expression of adhesion molecules. Induction of adhesion molecule expression by PAF and RANTES and in addition induction by the supernatant of mononuclear cells from mite-allergic asthmatic patients stimulated with mite-allergen as well as with a combination of the recombinant IL-3, GM-CSF and IL-5. Elevated soluble ICAM-1 in bronchial asthma. Moreover, the presence of a large variety of membrane receptors and the identification of cytotoxic molecules (mainly granule basic proteins) have indicated that eosinophils should be considered as effector cells. We therefore investigated the possible release of granule proteins in response to signaling from ICAM-1 and its ligands. The concentrations of eosinophil cationic protein and eosinophil-derived neurotoxin in supernatants of eosinophils were significantly greater (p < 0.05) in the presence of recombinant soluble ICAM-1 than without it. These results suggest that signaling from ICAM-1 and its ligands might induce eosinophil activation and might be involved in degranulation of eosinophil granule proteins. In addition, reactive oxygen species generated by eosinophils have also been considered capable of causing airway injury at the inflamed focus. We examined the effect of recombinant soluble ICAM-1 and its ligands on eosinophil-induced radical oxygen products. Recombinant soluble ICAM-1 augmented eosinophil oxidative metabolism. It was concluded that signaling via adhesion molecules might play an important role in the pathogenesis of allergic inflammation through activation of eosinophils, such as through an increase in oxidative metabolism or degranulation of eosinophil granule proteins.     

Fibrin deposits in Hodgkin's disease

Fibrin deposits were observed in the involved lymph nodes and/or spleens of 15 patients with Hodgkin's disease by specific immunofluorescence and by electron microscopy. Two basic patterns of fibrin deposition were observed: 1) intercellular deposits, chiefly associated with nonneoplastic-appearing lymphoid cells and 2) deposits associated with the collagen fibers of young connective tissue. In addition, coarse fibrin deposits were observed in areas of necrosis, presumably a non-specific finding. Fibronectin was also observed in intercellular areas, but staining was less intense than for fibrin. Fibrin deposits were also observed in 3 of 6 cases of non-Hodgkin's lymphoma, indicating that the finding is not an exclusive feature of Hodgkin's disease. The pathogenesis and possible significance of fibrin deposition in Hodgkin's disease are related to earlier observations of activation of the coagulation system on neoplasia and cell-mediated immunity and to the possible role of fibrin, fibronectin, and their breakdown products in angiogenesis and fibroplasia.     

Deficient major histocompatibility complex class II antigen presentation in a subset of Hodgkin's disease tumor cells

Hodgkin's disease is a common malignancy of the lymphoid system. Although the scarce Hodgkin and Reed-Sternberg (HRS) tumor cells in involved tissue synthesize major histocompatibility complex (MHC) class II and costimulatory molecules such as CD40 or CD86, it is unclear whether these tumor cells are operational antigen-presenting cells (APC). We developed an immunofluorescence-based assay to determine the number of MHC class II molecules present on the surface of single living HRS cells. We found that in fresh Hodgkin's disease lymph node biopsies, a subset of HRS cells express a substantial number of surface MHC class II molecules that are occupied by MHC class II-associated invariant chain peptides (CLIP), indicating deficient loading of MHC class II molecules with antigenic peptides. Cultured Hodgkin's disease-derived (HD) cell lines, however, were found to express few MHC class II molecules carrying CLIP peptides on the cell surface and were shown to generate sodium dodecyl sulphate (SDS)-stable MHC class II alphabeta dimers. In addition to showing deficient MHC class II antigen presentation in a subset of HRS cells, our results show that the widely used HD-cell lines are not ideal in vitro models for the disease. The disruption of MHC class II-restricted antigen presentation in HRS cells could represent a key mechanism by which these tumor cells escape immune surveillance.