Autologous peripheral blood stem cell transplantation for malignant lymphoma

Autologous peripheral blood stem cell transplantation (PBSCT) for patients with malignant lymphoma has been extensively performed in Japan for several years. Some of the disease states of lymphoma are considered to be a good candidate for auto-PBSCT application. Sensitive relapsers in non Hodgkin's lymphoma should be treated with a combination of salvage therapy and high dose chemo(radio)-therapy with stem cell support, and up-front PBSCT is recommended for poor risk aggressive lymphoma. The clinical results and indications for auto-PBSCT including other types of lymphoma such as lymphoblastic lymphoma, mantle cell lymphoma, low-grade lymphoma and Hodgkin's disease will be reviewed in this paper.     

Nodular lymphocyte predominance Hodgkin's disease. A distinct clinicopathological entity

This article reviews the evidence that the nodular form of lymphocyte predominance Hodgkin's disease ("nodular paragranuloma") should be recognised as a distinct clinico-pathological entity. The disease is characterised histologically by very large primary lymphoid follicles, containing polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The "L and H" or "popcorn" cells scattered within the nodules show clear differences from classical Reed-Sternberg cells, both in their cytological appearance and in their marker profile, being frequently negative for CD15 and for the EBV genome, but often positive for B cell antigens, CD45 (leucocyte common antigen), CDw75 (LN1), epithelial membrane antigen (EMA) and J chain. These findings suggest that L and H cells may be Ig-synthesising monoclonal B cells. Nodular lymphocyte predominance Hodgkin's disease pursues a much more indolent courses that classical Hodgkin's disease, and long term survival is common. It has other distinctive clinical features, e.g. a unimodal age distribution, a predilection to involve single lymph nodes, and a very low incidence of thymic involvement. There is a tendency for diffuse large cell non-Hodgkin's lymphoma, usually of B cell type, to develop during the course of the disease. This type of Hodgkin's disease thus has many features that distinguish it from the nodular sclerosis and mixed cellularity varieties, and it is hoped that future studies will gather more information on its clinical behavior and on the nature of the putative neoplastic cells, as well as exploring different protocols for its treatment.     

Hodgkin's disease: impact on childbearing

Although Hodgkin's disease is considered one of the "curable" cancers, the high cure rates associated with this disease are not accomplished without risk of potentially severe, immediate, and late side effects. Because the predominant histologic subtype of Hodgkin's disease found in the United States generally affects the 15- to 25-year-old age group, the disease, its treatment, and the side effects of treatment will affect many women of childbearing age. The treatment and its effects on the patient and offspring, including posttreatment fertility, are key issues for perinatal nurses.     

Maintenance therapy with interferon alfa 2b in Hodgkin's disease

We performed a randomized clinical trial to assess the efficacy and toxicity of interferon alfa 2b (IFN) as maintenance therapy in patients with advanced Hodgkin's disease in complete remission (CR) after conventional chemotherapy. One hundred and thirty-five patients (stage IIIB-IV B) were initially treated with EBVD (epirubicin, bleomycin, vinblastine, dacarbazine). IF CR was achieved they were randomly assigned to receive either maintenance therapy with IFN 5.0 MU three times a week for one year or no further treatment (control group). Clinical and laboratory characteristics at diagnosis were quite similar in both groups. After a median follow-up of 74.3 months (range 49 to 108), 61 out of 68 patients (91%; 95% confidence interval (CI): 76% to 97%) remain in first complete remission in the IFN-treated group compared to 38 out of 67 (58%; 95% CI: 49% to 71%) in the control group (p<.01). Overall survival was also better in the IFN treated group: 62 patients (92%; 95% CI: 82% to 97%) are alive free of disease at 7-years compared to 40 patients (67%, 95%: 55% to 76%) in the control group (p<.01). Toxicity secondary to IFN administration was mild and no dose modification was necessary during treatment. All patients received the planned dose of IFN. This was not an intent-to treat analysis. IFN administration as maintenance therapy was appears to be the only cause of improvement in outcome in these patients. We feel that IFN should be considered as maintenance therapy in patients with advanced Hodgkin's disease because this treatment improves the final outcome without the excessive toxicities of more aggressive therapeutic approaches such as bone marrow transplantation during first CR. We hope that IFN will be considered in future randomized clinical trials in order to define it's role in the treatment of Hodgkin's disease.     

The continuing evolution of mechanical ventricular assistance

A great number of patients suffer and die of the sequelae of acute and chronic heart failure each year. Although advances in medical and surgical therapy have benefited many of these patients, most have disease that is refractory to any definitive therapy. For these patients cardiac transplantation is the only remaining hope. Unfortunately, because of the increasing demand for donor organs in the face of a fixed and limited supply, this option is available to only a small percentage of these patients. Even in patients accepted for transplantation, a significant waiting list mortality has been observed. A variety of VADs have been developed since the first successful case of mechanical cardiac assistance more than 30 years ago. These devices differ in basic mechanical function, method of insertion, and degree of implantability and thus have different indications and potential applications. Whereas the intraaortic balloon pump and centrifugal pumps are effective short-term support modalities, extracorporeal and implantable pulsatile devices have been used successfully for long-term support of patients with reversible and nonreversible cardiac failure. Although these pumps have most commonly been used as bridges to transplantation, increasing clinical experience has supported the notion of long-term mechanical assistance as a definitive therapy for patients with end-stage heart disease. Although complications, particularly infection and thromboembolism, pose significant challenges and long-term device reliability remains to be fully determined, available implantable devices appear to be capable of providing effective long-term support. As data are obtained from currently ongoing trials comparing VAD support with medical therapy for end-stage heart failure, ethical and economic issues will assume increasing importance.     

Evans syndrome after autologous bone marrow transplant for recurrent Hodgkin's disease

The association of immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) with Hodgkin's disease has been known for many years. Autoimmune cytopenia has also been described in patients that have undergone allogeneic or autologous bone marrow transplantation. We report a rare case of Evans syndrome in a patient 3 years after autologous bone marrow transplantation for recurrent Hodgkin's disease.     

Single-species infections of Echinostoma caproni cercariae in pulmonate snails and concurrent infections of E. caproni and Echinostoma trivolvis cercariae in Biomphalaria glabrata

Secondary malignancies (lymphomas, leukemias, and solid tumors) occurring after bone marrow transplantation are now more frequently reported, as the patients surviving the early phase of the graft and remaining free of their original disease are more numerous. Besides early Epstein-Barr virus-associated B-cell lymphoproliferative diseases, which are the most common type and most often of donor origin, few late-occurring lymphomas have been described that might represent a distinct entity. We report here a case of Hodgkin's disease developing 8 years after allogeneic bone marrow transplantation for chronic myelogeneous leukemia. Only two Hodgkin's diseases after allogeneic bone marrow transplantation have been reported in the literature so far. The case we report is of interest because of its donor origin and its association with Epstein-Barr virus infection.     

What's new in transplant immunology: problems and prospects

In the past 40 years, transplantation has moved from an experimental form of therapy used almost exclusively for renal failure to an accepted treatment for end-stage kidney disease, heart disease, liver disease, lung disease, and diabetes mellitus. Tissue transplantation for conditions from thermal injury to Parkinson disease is being investigated. The primary barrier in transplantation medicine is the immunologic reaction of the recipient to donor organs and tissues. Currently available drugs permit excellent short-term graft survival but have not led to reliable long-term survival. Recent advances in the understanding of this immune response have suggested new approaches to induction of immunologic tolerance and reduction of late graft losses. Because of the excellent short-term success of current agents, integration of these new approaches into clinical trials is challenging and raises important questions about the design of such trials.     

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).     

Update on immunotherapy for recurrent pregnancy loss

Results of recent, randomized, placebo-controlled clinical trials have raised questions about the efficacy of immunotherapy for recurrent spontaneous abortion (RSA). Most of the clinical trials have shown a 70% successful pregnancy rate with immunotherapy. The controversy comes from variations in success rates in the control populations, which have ranged from 29% to 76%. Explanations for these variations includes small sample sizes and heterogeneity by the populations studied as well as cointervention by the placebo. A meta-analysis has been proposed to investigate these explanations. Because the trials have largely used husband's leukocytes for immunization, alternative forms of immunotherapy have been sought. Two treatments that have been proposed but have not completed testing a randomized, placebo-controlled trials are intravenous immunoglobulin (IVIG) and immunization with seminal plasma. A safe and efficacious method is needed to treat recurrent spontaneous abortion; it is hoped that results of proposed studies will answer this controversy.     

Use of composite endpoints in thrombolysis trials of acute myocardial infarction

Although preventing early mortality following acute myocardial infarction (MI) is the most important goal of thrombolytic therapy, insistence on its use as the only or principal endpoint in trials of acute MI will limit the number of new thrombolytic-antithrombotic regimens that can be tested, and thus may inhibit future progress of this important area of cardiovascular therapeutics. Trials of thrombolytic therapy over the past decade, as discussed in this article, have demonstrated that: (1) thrombolytic therapy improves both mortality and intermediate endpoints, and (2) intermediate nonfatal endpoints are strongly linked to long-term mortality. Taken together, these facts provide strong evidence that intermediate nonfatal events can be used as valid endpoints in future trials of thrombolytic therapy. The unsatisfactory outcome composite endpoint, which incorporates mortality and important intermediate endpoints, will make it possible to compare innovative new regimens in much smaller trials. Ultimately, both of these approaches (i.e., megatrials using a mortality endpoint and smaller trials utilizing a composite unsatisfactory outcome endpoint) can be used in a complementary fashion. A new regimen could first be tested using the unsatisfactory outcome endpoint; if it showed particular promise, it could then become a candidate for testing in a megatrial. Conversely, if it did not prove better than standard regimens, futile research in tens of thousands of patients might be prevented. Thus, the use of composite endpoints will expand the number of new thrombolytic-antithrombotic regimens that can be tested and, it is hoped, accelerate progress in the treatment of acute MI.     

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.     

Clinical trials and projected future of liver xenotransplantation

The trial and error of the pioneering xenotransplant trials over the past three decades has defined the limitation of the species used. Success was tantalizingly close with the chimpanzee, baboon, and other primates. The use of more disparate species has been frustrated by the xenoantibody barrier. Future attempts at clinical xenotransplantation will be hampered by the consideration of the species of animals and the nature of the organs to be transplanted. On one hand, primate donors have the advantage of genetic similarity (and therefore potential compatibility) and less risk of immunologic loss. On the other hand, pig donors are more easily raised, are not sentient animals, and may be less likely to harbor transmissible disease. It is recognized that the success of xenotransplantation may very with different organs. Because it is relatively resistant to antibody-mediated rejection, the liver is the organ for which there is the greatest chance of long-term success. Consideration of using xenotransplants on a temporary basis, or as a "bridge" to permanent human transplantation, may allow clinical trials utilizing hearts or kidney xenografts. Issues on metabolic compatibility and infection risks cannot be accurately determined until routine success in clinical xenotransplantation occurs. Based on a limited experience, the conventional approaches to allotransplantation are unlikely to be successful in xenotransplantation. The avoidance of immediate xenograft destruction by hyperacute rejection, achieved using transgenic animals bearing human complement regulatory proteins or modulating the antigenic target on the donor organ, is the first step to successful xenotransplantation. The ability to achieve tolerance by establishing a state of bone marrow chimerism is the key to overcoming the long-term immunologic insults and avoiding the necessarily high doses of nonspecific immunosuppression that would otherwise be required and associated with a high risk of infections complications. Xenotransplantation faces criticism that is strongly reminiscent of that leveled against human-to-human transplantation during the late 1960s and early 1970s. Yet with persistence, the field of human-to-human transplantation has proved highly successful. This success was the result of a stepwise increase in our understanding of the biology of rejection, improvements in drug management, and experience. It is possible that xenotransplantation may not be universally successful until further technologic advances occur; yet cautions exploration of xenotransplantation appears warranted to identify those areas that require further study.     

Improved survival of Hodgkin's patients in south-east Netherlands since 1972

In the past 30 years, staging and treatment of Hodgkin's disease have changed dramatically, and prolonged remission can now be induced in the majority of patients. Our purpose was to assess improvement in long-term survival, previously reported for specific patient groups, among unselected patients diagnosed and treated between 1972 and 1993 in general hospitals in South-East Netherlands. Data on all 345 Hodgkin's patients were derived from the population-based Eindhoven Cancer Registry; histopathology and clinical records were reviewed. Follow-up was attained up to 1994. Relative survival rates, i.e. the ratio of observed to expected rates, were 80% after 5, 70% after 10 and 67% after 15 years. Independent prognostic factors for lower overall survival were (in decreasing order of significance): advanced age, histology (lymphocyte depletion), advanced stage and earlier period of diagnosis. Distribution of age and stage did not change over the study period, but there was a modest increase in the incidence of the nodular sclerosis histological subtype. Crude 5-year survival rates improved from 60% in the period 1972-1976 to 81% in the period of 1987-1992 (P < 0.005). The largest improvement occurred in the 1970s and was most prominent among those aged over 50 years. As previously reported, cured Hodgkin's patients exhibit a higher mortality rate, which can be explained by treatment-related long-term complications such as second malignancies and cardiovascular diseases. The relatively high survival rates compared to other population-based studies may be attributable to the existence of a regional network within the framework of a comprehensive cancer centre. Better staging, new combinations of chemotherapy, improved radiation technology, advances in supportive care as well as more frequent intensive treatment of the elderly could explain the improvement in prognosis.     

Oxygen tension alters the effects of cytokines on the megakaryocyte, erythrocyte, and granulocyte lineages

Whereas patients with multiple myeloma continue to relapse after autologous transplantation and are unlikely to be cured, the probability of progression is less after allogeneic transplantation and a proportion of patients may be cured. This is attributable to an immunologically mediated graft-versus-myeloma (GVM) effect which is akin to the well-known graft-versus-leukemia effect. The available clinical and experimental evidence strongly support the existence of GVM, but it is not known whether GVM is separable from graft-versus-host disease (GVHD) in practice. The best way to exploit GVM reactions is unclear, and the morbidity and mortality associated with GVHD undermine long-term survival. There is usually a time lag of a few weeks between immune intervention and disease response. There is a propensity for extramedullary disease recurrence in patients whose marrow disease is controlled with immunologic manipulation. Exploration of GVM outside conventional allogeneic transplantation or after autologous transplantation is necessary to increase the number of patients likely to benefit from this phenomenon and to make it safer. This article reviews the currently available literature on the subject.     

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.     

Mechanical circulatory support in heart failure]

Heart transplantation is an established therapy for end-stage cardiac disease. The number of organ donors is limited, and the mortality on the waiting list is increasing. To give these patients a chance to survive their waiting time, chronic mechanical circulatory support, especially left ventricular assist devices have been clinically established. The results with this therapy are encouraging. Because of these results trials using these devices as an alternative for cardiac transplantation are initiated. Due to the further development and miniaturization of such devices this indication will become more important. The most interesting patients are the one, in which devices could be explanted after chronic support, because their myocard has recovered. If we can find a way to identify such patients a new form of therapy for end-stage heart disease could be established.     

Increased mortality after successful treatment for Hodgkin's disease

PURPOSE: To determine the impact of treatment toxicity on long-term survival in pediatric Hodgkin's disease. PATIENTS AND METHODS: We studied late events in 387 patients treated for pediatric Hodgkin's disease on four consecutive clinical trials at St Jude Children's Research Hospital from 1968 to 1990. Relative risks, actuarial risks, and absolute excess risks for cause-specific deaths were calculated. RESULTS: As of April 1997, 316 (82%) of patients were alive, with a median follow-up of 15.1 (range, 2.9 to 28.6) years. In this cohort, which represented 5,623 person-years of follow-up, 71 fatal events resulted from Hodgkin's disease (n=36), second malignancies (n=14), infections (n=7), accidents (n=7), cardiac disease (n=6), and asphyxiation (n=1). The 5-year estimated event-free survival (EFS) for the entire cohort was 79.6%+/-2.1 %, which declined to 63.1%+/-4.4% by 20 years. Cumulative incidences of cause-specific deaths at 25 years were 9.8%+/-1.6% for Hodgkin's disease, 8.1%+/-2.6% for second malignancy, 4.0%+/-1.8% for cardiac disease, 3.9%+/-1.5% for infection, and 2.1%+/-0.8% for accidents. Standardized incidence ratios showed excess risk for all second malignancies (12; 95% confidence interval [CI], 8 to 17), acute myeloid leukemia (81; 95% CI, 16 to 237), solid tumors (11; 95% CI, 7 to 16), and breast cancer (33; 95% CI, 12 to 72). Standardized mortality ratios also showed excess mortality from cardiac disease (22; 95% CI, 8 to 48) and infection (18; 95% CI, 7 to 38). CONCLUSION: Compared with age- and sex-matched control populations, survivors of pediatric Hodgkin's disease who were treated before 1990 face an increased risk of early mortality related to second cancers, cardiac disease, and infection.     

Bone marrow transplantation for non-Hodgkin's lymphoma: a review

High dose chemotherapy and stem-cell rescue (bone marrow transplantation) is used increasingly in the treatment of malignant disorder. Numerous trials have demonstrated the effectiveness of bone marrow transplantation in the treatment of non-Hodgkin's lymphoma. However, there are many unanswered questions as to the role of high-dose therapy in certain subtypes of lymphoma, the timing of transplant, and even the type of transplant to perform. An attempt will be made to clarify many of these unanswered questions. The utilization of high-dose therapy for non-Hodgkin's lymphoma is recommended for most patients who have relapsed after initial therapy. Transplantation in first remission is not recommended routinely. Allogeneic bone marrow transplantation should by reserved for individuals with poorly responding disease or in individuals with bone marrow involvement. The precise roles of purging and transplantation of individuals with low grade lymphoma are being investigated.