Pyrogen release in vitro by lymphoid tissues from patients with Hodgkin's disease

The mechanism of fever in patients with Hodgkin''s disease was investigated by examining endogenous pyrogen production by blood, spleen, and lymph node cells incubated in vitro. Blood leucocytes from febrile or afebrile patients with Hodgkin''s disease did not produce pyrogen spontaneously. Spleen cells, however, frequently released pyrogen during initial incubations, unlike spleen cells from patients with non-malignant diseases. Pyrogen production occurred from spleens without observed pathologic infiltrates of Hodgkin''s disease. Lymph nodes involved with Hodgkin''s disease produced pyrogen more frequently than did nodes involved with other diseases. Pyrogen production by tissue cells was prolonged, required protein synthesis, and in some cases was due to mononuclear cells; it did not correlate with fever in the patient. These studies demonstrate spontaneous production of endogenous pyrogen in vitro by lymphoid tissue cells from patients with Hodgkin''s disease.     

A REVIEW OF THE LITERATURE ON THE ETIOLOGY OF HODGKIN'S DISEASE

Extensive research to trace the cause of Hodgkin''s disease to a bacterial or protozoan agent has proven fruitless.Although a viral cause for Hodgkin''s disease has been previously suggested, early explorations along that line have not been confirmed. With the development of newer techniques for the study of viral characteristics certain apparently significant factors in Hodgkin''s disease have been encountered. Most promising has been the consistent demonstration that Seitz-filtered, sterile Hodgkin''s disease lymph node extract can be passed serially in fertile chicken eggs and that the amniotic fluid from these eggs possesses the capacity to interfere with the growth of influenza virus in eggs.     

An autopsy case of malignant lymphogranulomatosis (so-called Hodgkin's disease) inCercopithecus aethiops

A spontaneous case of malygnant lymphogranulomatosis (so-called Hodgkin's disease) inCercopithecus aethiops was histologically diagnosed. The monkey had been imported from Uganda and died about 2 months after its arrival without recognizable clinical signs. Autopsy revealed swelling in the general lymph nodes, spleen, liver, and kidneys. The bone marrow was yellow-brown. The monkey was anemic and hydrothoracic with an increase of ascites. On the microscopic level, the granulomatous and sarcomatous patterns were recognized in each organ with the appearances of Hodgkin's cell and Sternberg-Reed's giant cell. The intranuclear inclusion body was recognized in the lymphoid cell and Hodgkin's cell seen in the spleen.     

Observations on Abnormal Cells in the Peripheral Blood and Spleen in Hodgkin's Disease

The occurrence of abnormal cells in the peripheral blood of patients with Hodgkin''s disease has been described in the literature. In the present investigation several varieties of cells were found, two of which are believed to be typical of the disease. The significance of these cells in the peripheral blood is not yet clear, but there seems to be a correlation between the presence of these characteristic cells in the blood and involvement of the spleen by the disease as determined by microscopical examination. In 11 patients both abnormalities proved to be absent; 13 out of 14 other patients showed both the abnormal cells in the blood and Hodgkin lesions in the spleen.If circulating abnormal cells are indeed an indication of the presence of Hodgkin''s disease in the spleen, involvement of this organ is likely to be due to or to give rise to haematogenous dissemination. The other possibility remains that both the occurrence of abnormal cells in the peripheral blood and splenic involvement are due to a multicentric origin of the disease. It seems most unlikely that the splenic lesions are consistent with localized disease still restricted to the lymphoid system. These findings challenge the validity of the present widely used so-called Rye classification of clinical stages in Hodgkin''s disease.     

Identification of Protein Kinase Inhibitors with a Selective Negative Effect on the Viability of Epstein-Barr Virus Infected B Cell Lines

Epstein-Barr virus (EBV) is a human herpesvirus, which is causally associated with the development of several B lymphocytic malignancies that include Burkitt''s lymphomas, Hodgkin''s disease, AIDS and posttransplant associated lymphomas. The transforming activity of EBV is orchestrated by several latent viral proteins that mimic and modulate cellular growth promoting and antiapoptotic signaling pathways, which involve among others the activity of protein kinases. In an effort to identify small molecule inhibitors of the growth of EBV-transformed B lymphocytes a library of 254 kinase inhibitors was screened. This effort identified two tyrosine kinase inhibitors and two MEK inhibitors that compromised preferentially the viability of EBV-infected human B lymphocytes. Our findings highlight the possible dependence of EBV-infected B lymphocytes on specific kinase-regulated pathways underlining the potential for the development of small molecule-based therapeutics that could target selectively EBV-associated human B lymphocyte malignancies.     

HODGKIN'S DISEASE,a Clinical-Pathological Review of 150 Cases

One hundred and fifty cases of Hodgkin''s disease were analyzed in an effort to detect significant clinical-pathological correlations and to elucidate any possible factors of prognostic or etiological importance.A relatively long survival for patients with Hodgkin''s paragranuloma was not noted in this series. Instead the survival rate among them was closely parallel to that of patients with classical granuloma. Hodgkin''s sarcoma is a more malignant disease with a patient survival rate not more than half that of patients with the granuloma variety. It is not necessarily a disease of older age groups. Great caution must be exercised to avoid including non-Hodgkin''s disease tumors under the heading of Hodgkin''s sarcoma or paragranuloma.The series reported corresponds with many other reported series of Hodgkin''s disease as regards greater incidence in males and longer survival in females. In this series the cases in patients under the age of 15 were all in males. The predominance of initial enlargement of the cervical nodes was again noted in this series, as was the high proportion of negative reaction to tuberculin tests. The incidence of tuberculous lesions in patients who died of Hodgkin''s disease was only slightly greater than in those who died of other lymphoma. Site of origin of the disease apparently affects survival time. There was statistical evidence that gonadal activity might influence the equilibrium of the disease.Lymph node bacteriological cultures were not remarkable. Brucella organisms were absent. Fertile egg passages for detecting possible viral agents revealed increased egg mortality and cutaneous sensitivity reactions to the harvested amniotic fluid.     

Laparoscopy and laparotomy combined with bone marrow biopsy in staging Hodgkin's disease.

The relative merits of laparoscopy with liver and spleen biopsy and staging laparotomy were studied in 91 unselected patients with Hodgkin''s disease. Laparoscopy with liver and spleen biopsy were combined with needle biopsy of the bone marrow and laparotomy was combined with open bone marrow biopsy. In 65 untreated patients six out of seven with liver or marrow disease, or both, were shown to have extranodal lymphomas in these sites by laparoscopy plus needle marrow biopsy. Among 26 patients who had been treated this finding occurred in six out of 10 patients. Spleen biopsies during laparoscopy detected infiltration by lymphoma in 14 out of 37 (38%) patients with diseases spleens. Morbidity was higher after laparotomy than after laparoscopy. Laparoscopy produced abdominal bleeding secondary to splenic biopsy in two patients. All patients with Hodgkin''s disease should be subjected to laparoscopy plus needle marrow biopsy before undergoing laparotomy.     

La forme scléronodulaire de la maladie de Hodgkin: expérience du CHU de Sherbrooke

Scleronodular type of Hodgkin''s disease: experience at the Centre hospitalier universitaire de SherbrookeThe nodular sclerosis type of Hodgkin''s disease appears to be a distinct clinical entity. However, the incidence, the initial localization of the tumour and the survival of the patients are variable. The present study was carried out on a group of 17 patients, all French Canadians living in the province of Quebec, from a total of 31 with Hodgkin''s disease, an incidence of 55%. There were more males (10) than females (7). The mean age of the group was 37 years, but that of the females was lower than that of the males. The mediastinum was involved at the onset in 47% of the patients. The initial staging (according to the classification of Rye) in 76% of the patients was I or II.Four patients showed disease below the diaphragm. The lungs were infiltrated three times, the spleen six times, and the liver five times. The duration of survival of the 17 patients was twice that of the patients with the three other types of the disease.     

Kinetics of indium-III labelled lymphocytes in normal subjects and patients with Hodgkin's disease.

The distribution in the body and the circulation in the blood of autologous lymphocytes labelled with indium-III were studied in two normal subjects and two patients with Hodgkin''s disease. Four hours after injection radioactivity was identified in the spleen, liver, and bone marrow. Radioactivity, followed by imaging and whole body scanning, began to appear in the lymph nodes four to 18 hours after injection, and some, though not all, lymph node groups in the body could be readily visualised. There were no differences between the normal subjects and the patients with Hodgkin''s disease. The pattern of clearance of radioactivity from the blood was consistent with a normal circulation between blood and lymphoid tissues of the labelled lymphocytes. Since indium-111 stays firmly attached to the cell, it seems an ideal label for studying lymphocyte kinetics, and the use of this technique may have further clinical application.     

Decreased tuftsin concentrations in patients who have undergone splenectomy.

Serum tuftsin concentrations were measured, using a radioimmunoassay developed in Israel, in normal subjects and in patients who had undergone splenectomy. Concentrations in those who had undergone traumatic and elective splenectomy were much lower. The tuftsin concentration in 38 patients with Hodgkin''s disease who had undergone splenectomy during staging laparotomy was not significantly different from the mean concentration in other patients who had had elective splenectomy. In four patients who underwent splenectomy for non-malignant haematological disorders measurements made before and after operation showed that tuftsin concentrations fell significantly in the days after operation. The increased susceptibility to overwhelming infections of patients with Hodgkin''s disease and others who have undergone splenectomy may be related to the low tuftsin concentrations. As pre-splenectomy tuftsin concentrations in patients with Hodgkin''s disease were normal, the practice of performing staging laparotomy and splenectomy in patients with Hodgkin''s disease should perhaps be reconsidered.     

Nasopharyngeal carcinoma and Burkitt's lymphoma in a Canadian family. I. HLA typing,EBV antibodies and serum immunoglobulins.

Two nasopharyngeal carcinomas of the lymphoepithelioma type and two Burkitt''s lymphomas with the characteristic histopathologic features developed in three siblings and one first-degree cousin in a large French-Canadian family. Epstein-Barr virus antibody titres in the two lymphoepithelioma cases but not in the Burkitt''s lymphoma cases were, as expected, greatly elevated. HLA typing of the family members failed to disclose HLA antigens A2 and B Sin-2, which have been associated with lymphoepithelioma in Asia. The occurrence, however, of a plasmacytoma in one other first-degree cousin and low serum IgA values in several siblings and cousins suggests the possibility of a genetically determined predisposing B-cell dysfunction in the development of these tumours.     

Hodgkin's disease and leukemia

Four cases of acute leukemia occurring in patients with Hodgkin''s disease are described. The literature on the association of these two diseases is reviewed. Acute myeloid or undifferentiated leukemias appear to be, at least in part, a complication affecting long-term survivors of Hodgkin''s disease. Reed Sternberg cell leukemia is an unusual form of Hodgkin''s disease and may be associated with a poor prognosis. The cytology and cytochemistry of Reed Sternberg cells are briefly discussed.     

Curative Radiotherapy in Hodgkin's Disease: Significance of Haematogenous Dissemination Established by Examination of Peripheral Blood and Spleen

Studies of peripheral blood leucocyte concentrates in patients with Hodgkin''s disease showed two types of cells believed to be typical for the disease in a number of patients. Involvement of the spleen as diagnosed after splenectomy and histological examination showed a close correlation with the presence of these characteristic cells in the peripheral blood. This is believed to be an argument for haematogenous spread or a multicentric origin of the disease in these cases. The results of attempted curative high-voltage radiotherapy with total node irradiation in 24 patients seem to support this concept. On the basis of the Rye classification of clinical stages the results of radiotherapy are not predictable. Six patients in stage II and seven in stage III were in remission, one in each of stages II and IV, and six in stage III had recurrences of the disease within one year. A division into localized or disseminated forms of the disease based on the investigations of blood and spleen showed all localized cases in remission; of the disseminated cases one reached a remission and all others had recurrences. In three patients the therapy could not be completed. These preliminary treatment results are believed to support the idea of a special role of the spleen in the dissemination of the disease. A new classification of clinical stages in Hodgkin''s disease is proposed.     

Cytotoxic lymphocytes in infectious mononucleosis.

Seven patients with a clinical diagnosis of infectious mononucleosis (IM) and detectable heterophil antibodies were found to have peripheral blood lymphocytes that were cytotoxic for lymphoid cells containing Epstein-Barr virus from a patient with Burkitt''s lymphoma. The cytotoxic lymphocytes persisted in the peripheral circulation for up to 45 days. Patients who had had IM 1 to 5 years previously lacked such cytotoxic lymphocytes. Patients who had signs and symptoms of IM but no detectable heterophil antibodies lacked cytotoxic lymphocytes. The lymphocytes of one patient with IM showed progressive diminution of cytotoxic ability after prednisone treatment.     

Sensitisation to Hodgkin's disease spleen tissue in patients with malignant lymphoma: follow-up study.

The leucocyte migration responses of patients with malignant lymphoma to an unidentified factor in Hodgkin''s spleen tissue were serially studied and related to clinical progress. Initial sensitisation responses did not correlate with presenting histological or clinical status or with subsequent clinical progress. Enhancement of responses after treatment, however, was associated with good clinical progress. In patients who relapsed, sensitisation to spleen factor diminished, whereas responses were preserved at one year in those in maintained remission. Sensitisation to the splenic factor may be a useful index of response to treatment in patients with malignant lymphoma; diminishing sensitisation may indicate relapse.     

Commentary: assessing the effects of environmental pollution when people know that they have been exposed.

OBJECTIVE: To examine the effectiveness of routine clinic review in detecting relapse after treatment for Hodgkin''s disease. DESIGN: Review of hospital records. SETTING: Regional centre for cancer treatment and research. SUBJECTS: 210 patients with Hodgkin''s disease recruited to a chemotherapy trial protocol between 1984 and the end of 1990 who had achieved a complete or partial remission after treatment. MAIN OUTCOME MEASURES: The number of clinic visits made by patients over the period of observation, the number of relapses occurring during that time, and the route by which relapse was detected. RESULTS: The 210 patients generated 2512 outpatient reviews, and 37 relapses were detected. Thirty relapses (81%) were diagnosed in patients who described symptoms, which in 15 cases had resulted in an earlier appointment being arranged. In only four cases (11%; 95% confidence interval 4% to 25%) was relapse detected as a result of routine physical examination on investigation of a patient who did not have symptoms. CONCLUSIONS: Relapse of Hodgkin''s disease after treatment is usually detected as a result of the investigation of symptoms rather than by routine screening of asymptomatic patients. It is therefore proposed that the frequency of routine follow up visits should be reduced and greater emphasis placed on patient education. This should underline the importance of symptoms and encourage patients to arrange an earlier appointment if these develop.     

Psychological problems associated with diagnosis and treatment of lymphomas. I: Retrospective study.

Patients treated for Hodgkin''s disease and non-Hodgkin''s lymphoma have a better prognosis than other patients with cancer so may have a lower prevalence of psychological and social morbidity. Trained interviewers used standardised methods to assess 90 patients at a mean of 32 months after the diagnosis of Hodgkin''s disease or non-Hodgkin''s lymphoma. Chemotherapy and radiotherapy had commonly caused adverse effects including hair loss, vomiting, nausea, and loss of appetite. Although most patients were free of disease and not receiving treatment at follow up, some still suffered from a lack of energy (31 patients), loss of libido (19), irritability (22), and tiredness (19); 30 patients complained of continued impairment of thinking or disturbance of short term memory. After diagnosis 21 patients had suffered from an anxiety state or depressive illness, or both, while 27 had experienced borderline anxiety or depression, or both. Mood disturbance was positively correlated with adverse effects of treatment, particularly those affecting the gastrointestinal tract. Social adjustment was less affected, but failure to return to work, or a long delay in returning to work, and a persistent lack of interest in leisure activities gave cause for concern. These findings of substantial psychiatric and social morbidity in patients with Hodgkin''s disease and non-Hodgkin''s lymphoma prompted a prospective study of these patients to determine their nature and duration.     

A Comparison of Nitrogen Mustard and Vinblastine Sulfate in the Treatment of Patients with Hodgkin's Disease

In a crossover study the effectiveness of intermittent maintenance doses of nitrogen mustard was compared to that of vinblastine sulfate in the treatment of 61 patients with advanced Hodgkin''s disease. Forty-five of the patients had had previous radiation therapy. Nine of 29 patients who received nitrogen mustard as the first drug had a complete response and five had a partial response. The comparative results in 32 patients receiving vinblastine sulfate first were nine complete responses and 13 partial responses. The median duration of the complete responses to each drug was 43 weeks. The partial responses were of shorter duration. When the second drug was given in adequate doses, almost as many patients responded with a similar median duration of response.It is concluded that nitrogen mustard and vinblastine sulfate are equally effective single agents in the treatment of patients with advanced Hodgkin''s disease and that patient preference would favour vinblastine sulfate because of its negligible side effects.     

Risk of second primary cancers after Hodgkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation.

OBJECTIVE--To analyse the risk of second primary cancers during long term follow up of patients with Hodgkin''s disease. DESIGN--Cohort study. SETTING--The British National Lymphoma Investigation (a collaborative group of over 60 participating centres in Britain treating lymphomas). PATIENTS--2846 patients first treated for Hodgkin''s disease during 1970-87, for whom follow up was complete in 99.8%. MAIN OUTCOME MEASURES--Second primary cancers; uniform pathology reviews confirmed the diagnosis of Hodgkin''s disease and of second primary non-Hodgkin''s lymphomas. RESULTS--113 second primary cancers occurred. Relative risk of cancer other than Hodgkin''s disease was 2.7 (95% confidence interval 2.3 to 3.3) compared with the general population, with significant risk of leukaemia (16.0(9.1 to 26.0)); non-Hodgkin''s lymphoma (16.8(9.8 to 26.9)); and cancers of the colon (3.2 (1.4 to 6.2)), lung (3.8 (2.6 to 5.4)), bone (15.1 (1.8 to 54.7)), and thyroid (9.4 (1.1 to 33.9)). Absolute excess risk associated with treatment was greater for solid tumours than for leukaemia and lymphomas. Relative risk of leukaemia increased soon after treatment, reaching a peak after five to nine years. It was increased substantially after chemotherapy (27.9 (12.7 to 52.9)), combined treatment with radiotherapy and chemotherapy (21.5 (7.9 to 46.8)), and relative to number of courses of chemotherapy but was not significantly increased after radiotherapy (2.5 (0.1 to 14.1)). Relative risk of non-Hodgkin''s lymphoma increased in the first five years after treatment and remained high but showed no clear relation with type or extent of treatment. Relative risk of solid tumours was less raised initially but increased throughout follow up and for lung cancer 10 years or more after entry was 8.3 (4.0 to 15.3). The risk of solid tumours increased after treatments including radiotherapy and after chemotherapy alone. The risk after chemotherapy increased significantly with time since first treatment. CONCLUSION--The risk of solid cancer, not of leukaemia, is the major long term hazard of treatment for Hodgkin''s disease, and this seemed to apply after chemotherapy as well as after radiotherapy. These risks of second cancers are important in choice of treatment and in follow up of patients, but they are small compared with the great improvements in survival which have been brought about by modern therapeutic methods for Hodgkin''s disease.     

Double immunoenzymatic staining for the simultaneous detection of Epstein-Barr virus induced antigens

Summary A double indirect immunoenzymatic staining was developed for the simultaneous visualization of Epstein-Barr virus-induced early antigens and virus capsid antigens in P3HR1 lymphoblastoid cell line.The double immunocytochemical staining was performed with a four-stage and a two-stage procedure employing human sera and monoclonal antibodies against Epstein-Barr virus-induced antigens, followed by the addition of specific alkaline phosphatase and peroxidase labeled antisera.The selection of substrates yielding reaction products of contrasting colours enabled the observer to distinguish cells expressing Epstein-Barr virus capsid antigens (blue) from cells expressing Epstein-Barr virus early antigens (brown).