Clinical Screening of Epipodophyllotoxin VM26 in Malignant Lymphomas and Solid Tumours

Epipodophyllotoxin (VM 26; 4′-demethyl-epipodophyllotoxin-β-D-thenylidene glucoside) has been proved, in clinical screening, to be able to induce apparently complete remissions and pronounced though incomplete regressions in Hodgkin''s disease, reticulosarcoma, and bladder cancer, as well as incomplete regressions in lymphosarcoma. Apparently complete regressions of malignant pleural effusions have been obtained after giving this drug systemically. It has a notable toxic action on the bone marrow.     

Epipodophyllotoxin VP 16213 in Treatment of Acute Leukaemia—Haematosarcoma and Solid Tumours

Epipodophyllotoxin VP 16213 (4-demethyl-epipodophyllotoxin-β-D-ethylidene glucoside), given to 250 patients with various types of malignant disease, induced apparently complete remissions in four out of eight cases of acute monocytoid and acute myelomonocytoid leukaemia but only one complete regression and six incomplete remissions in 21 cases of reticulosarcoma. Incomplete regressions occurred in patients with Hodgkin''s disease, lymphosarcoma, melanoma, and carcinoma of the breast, ovary, testis, bladder, kidney, and thyroid. Seemingly complete regressions of malignant pleural effusion occurred when the drug was given systemically. Toxic side effects interfered with treatment in 40 patients but stopped it in only nine. No signs of toxicity were seen in 114 patients and in 85 the side effects were negligible. VP 16213 represents an advance in the treatment of acute monocytoid leukaemia, which has been up till now insensitive to any drug.     

LYMPHOBLASTOMAS IN CHILDHOOD—Cutaneous Manifestations

The lymphoblastomas occurring in childhood are divided for purposes of discussion into lymphocytoma cutis, mycosis fungoides, lymphosarcoma, Hodgkin''s disease, and leukemia. The cutaneous lesions may be either specific (as a result of the infiltration of the skin with specific cells of the conditions) or toxic (non-specific). With the possible exception of mycosis fungoides, the cutaneous manifestations are not diagnostic. The final diagnosis depends upon microscopic examination of the specific tissue involved and the coordination of the clinical and microscopic findings.     

METHYL-BIS (BETA-CHLOROETHYL) AMINE IN LARGE DOSES IN THE TREATMENT OF NEOPLASTIC DISEASES

Sixty-seven patients with neoplastic diseases were treated with 151 courses of methylbis (beta-chloroethyl)amine hydrochloride (HN₂). Seventy-seven of the courses consisted of single injections of 0.2 to 0.4 mg. per kilogram of body weight, and 35 courses were given as single injections of 0.6 mg. per kilogram of body weight.Twenty-three patients with Hodgkin''s disease were treated. Remissions averaged approximately three months in 13 patients who were in good or fair general physical condition, and 1.5 months in 11 patients who were in poor or moribund condition; one of the 11 did not respond to the therapy.Fifteen patients with lymphosarcoma were treated. Remissions averaged between one and two months in four patients who were in good or fair general physical condition. Of the remaining 11 patients, two showed no response, and the longest remission among the remaining nine was approximately 40 days.Satisfactory remissions of one to three months were obtained in four patients with mycosis fungoides treated with single courses of 0.3 mg. per kilogram of body weight.Serious toxic reactions were observed in six patients, four of whom died. In five of the six instances the reactions consisted of pancytopenia and hemorrhagic diathesis. All these patients were in poor general or hematologic status before therapy.In general, large single doses of HN₂ were neither more nor less effective than the four-to six-day course usually employed with this agent. Combination of the administration of HN₂ with artificial hyperpyrexia, or with concurrent courses of pteroylglutamic conjugates, did not enhance the therapeutic effects of the agent.     

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.     

INFRACLAVICULAR CHEST WALL TUMORS IN HODGKIN'S DISEASE

In six of 91 cases of Hodgkin''s disease observed over a three-year period, a tumor mass filling the infraclavicular hollow was noted. It was on the left side in all instances. Although in four cases it was the only superficial manifestation of Hodgkin''s disease for a long period, in all cases there were ultimately other areas of involvement. The lesion did not occur in any of 81 cases of lymphosarcoma observed concurrently.     

Bleomycin in the Reticuloses

Bleomycin alone was used in the treatment of 54 patients with Hodgkin''s disease in its later stages, 17 with generalized lymphosarcoma, 22 with reticulum cell sarcoma, and 7 with mycosis fungoides. The patients had had radiotherapy and full courses of conventional chemotherapy. Bleomycin was given in doses of 30 mg weekly to an average total dosage of 200 mg, though up to 800 mg could be given because of its marrow-sparing properties. Sixteen (29%) of the patients with Hodgkin''s disease remitted, most of them achieving only a partial remission, and similar results were obtained in the other three reticuloses. Bleomycin would seem to have some beneficial action in the late stages of Hodgkin''s disease, though it is less effective than some drug regimens recently introduced. Nevertheless it may be useful when there is diminished bone marrow reserve. It would be a suitable drug to use in combination therapy of these four reticuloses.     

Combination Chemotherapy in Generalized Hodgkin's Disease

Fifty-two patients with generalized Hodgkin''s disease were treated with a combination of mustine hydrochloride, vinblastine, procarbazine, and prednisolone. Complete remissions were obtained initially in six out of seven patients (86%) who had previously received no treatment, in 15 out of 19 (79%) who had had only radiotherapy in the past, and in 9 out of 26 (35%) who had previously been given chemotherapy with or without radiotherapy. Of these 30 patients in whom a complete remission was obtained 22 have been free of any symptoms or signs of disease for periods ranging from 4 to 22 months. The response to treatment was rapid, and toxicity was not a major problem, except in those who had previously been treated with cytotoxic drugs used continuously and not in courses. A comparative trial of radiotherapy and combination therapy in the treatment of Stage III Hodgkin''s disease is strongly recommended.     

Vincristine in the Treatment of Neoplastic Disease

Seventy-eight patients with advanced malignant disease were treated with vincristine, an alkaloid derived from Vinca rosea Linn. Fifty-nine of these survived one month from the beginning of treatment and could be evaluated. Twenty made a good response, with return to activity and more than 75% regression of tumour deposits. Seven made a fair response with resumption of partial activity and at least a 25% regression of tumour deposits. Favourable results were seen in patients with Hodgkin''s disease, reticulum cell sarcoma, lymphosarcoma, carcinoma of the breast, acute leukemia and choriocarcinoma. The duration of remission was usually brief but in five instances exceeded six months. Toxic reactions include a high incidence of alopecia and neurologic complications. The bone marrow depression is constant and predictable.     

NEWER THERAPY FOR LEUKEMIA,POLYCYTHEMIA, AND LYMPHOMA

X-radiation remains the treatment of choice in most cases of leukemia and lymphoma, but new agents are playing an increasing role in therapy. Radioactive phosphorus does not produce radiation sickness and results with it are comparable to those of x-ray therapy in chronic leukemia. Urethane and nitrogen mustard may produce remissions in patients with chronic leukemia who have become resistant to radiation. Triethylene melamine may be administered orally with nitrogen mustard-like effects and is undergoing further trial. Aminopterin, ACTH and cortisone often cause short remissions in acute leukemia. Urethane is the best treatment available for multiple myeloma. Polycythemia vera is well controlled by radioactive phosphorus combined with venesection. Nitrogen mustard is often effective and triethylene melamine shows promise in Hodgkin''s disease. Antianemic substances such as iron and liver extract are of no value in the treatment of anemia caused by leukemia, lymphoma and myeloma.     

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.     

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.     

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.     

Computed tomography of abdomen in staging and clinical management of lymphoma.

During July 1976 to Demember 1977, 150 patients with Hodgkin''s disease and 138 with non-Hodgkin''s lymphoma were examined by computed tomography (CT). In 45 cases 50 repeat examinations were conducted. Concurrent laparotomy and lymphography were performed on 68 and 56 patients respectively. The overall incidence of false-positive CT examinations as confirmed by laparotomy was 7.4%. In 18 patients with non-Hodgkin''s lymphoma in the abdomen there was good correlation between the two techniques. Of the 50 patients with Hodgkin''s disease who underwent laparotomy, 17 had splenic disease and 14 minimally enlarged lymph nodes in 20 areas; CT, however, detected only four diseased spleens and five minimally enlarged lymph nodes. Nevertheless, CT often detected enlarged lymph nodes missed by lymphography and was 23% more efficient than lymphography in detecting unsuspected disease. CT also detected unsuspected disease in patients with relapse of lymphoma. CT may replace other non-invasive investigations of abdominal disease in patients with lymphoma and give a reliable guide to prognosis. It does not, however, eliminate the need for laparotomy in staging Hodgkin''s disease.     

Prednisone in MOPP chemotherapy for Hodgkin's disease.

High remission rates have been produced by MOPP (mustine, vincristine, procarbazine, and prednisone) chemotherapy in patients with advanced Hodgkin''s disease, but the prednisone component has caused adverse effects in patients who have undergone radiotherapy. The remission rates and length of remission were reviewed in 211 patients with Hodgkin''s disease who received chemotherapy either with or without prednisone. In contrast to the findings of a British study, there were no significant differences in remission rates or length of remission between patients who had received prednisone and patients who had not. There were differences between the British prospective study and this retrospective one, but it is difficult to know what accounted for the substantial differences in the findings.     

Nephrotic Syndrome in Chronic Lymphocytic Leukaemia

Two patients with chronic lymphocytic leukaemia and the nephrotic syndrome are described in whom deposits were shown in renal glomerular basement membranes in a pattern suggesting immune-complex glomerulonephritis. This renal lesion has been described in one case of squamous carcinoma of the bronchus, in one case of Burkitt''s lymphoma, and in three cases of Hodgkin''s disease though not previously in chronic lymphocytic leukaemia. Immune-complex glomerulonephritis is, however, a recognized finding in mice infected with leukaemogenic viruses     

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.     

THE CARCINOLYTIC EFFECT OF ACTINOMYCIN C—A Report of Clinical Studies

Actinomycin C was administered to 35 patients with a variety of malignant states. There was no evidence of any toxic reaction.Of 11 patients with Hodgkins disease, four had brief objective remission ranging from two to four months. Individual patients with chronic myelogenous leukemia, multiple myeloma and neuroblastoma had short periods of clinical improvement.The usefulness of actinomycin C appears to be limited. It may best be used in instances of Hodgkin''s disease where pancytopenia prevents the use of other agents.     

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.     

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.