Late complications of therapy of Hodgkin's disease: prevention and management

Patients diagnosed with Hodgkin's disease have a high cure rate. However, long-term survivors of the disease are at significantly increased risk for many late complications. The most serious late effects faced by these patients include the development of a second malignancy or cardiovascular disease. Ongoing trials investigating treatment reduction, including using lower radiation dose, smaller radiation field size, and abbreviated chemotherapy, will hopefully help in limiting the treatment-related complications. Continued long-term follow-up of survivors, careful documentation of the broad range of late effects, identification of risk factors, development and evaluation of screening programs, and preventative therapy for specific late complications are important steps in improving the survival and quality of life of patients who have been cured of Hodgkin's disease.     

Strategic plan for pediatric respiratory diseases research: An NHLBI working group report

The Division of Lung Diseases of the National Heart, Lung and Blood Institute (NHLBI) recently held a workshop to identify gaps in our understanding and treatment of childhood lung diseases and to define strategies to enhance translational research in this field. Leading experts with diverse experience in both laboratory and patient‐oriented research reviewed selected areas of pediatric lung diseases, including perinatal programming and epigenetic influences; mechanisms of lung injury, repair, and regeneration; pulmonary vascular disease (PVD); sleep and control of breathing; and the application of novel translational methods to enhance personalized medicine. This report summarizes the proceedings of this workshop and provides recommendations for emphasis on targeted areas for future investigation. The priority areas identified for research in pediatric pulmonary diseases included: (1) epigenetic and environmental influences on lung development that program pediatric lung diseases, (2) injury, regeneration, and repair in the developing lung, (3) PVD in children, (4) development and adaptation of ventilatory responses to postnatal life, (5) nonatopic wheezing: aberrant large airway development or injury? (6) strategies to improve assessment, diagnosis, and treatment of pediatric respiratory diseases, and (7) predictive and personalized medicine for children. Pediatr Pulmonol. 2009; 44:2–13. © 2008 Wiley‐Liss, Inc.     

Hodgkin's disease in homosexual men with generalized lymphadenopathy

The authors present 4 cases of Hodgkin's disease developing in homosexual men with persistent, generalized lymphadenopathy. Laboratory abnormalities associated with the acquired immunodeficiency syndrome (AIDS) and the lymphadenopathy syndrome were present in these patients. In 2 patients, diagnosis of lymphadenopathy syndrome preceded the diagnosis of Hodgkin's disease by 2-3 years; in the other 2, the 2 conditions were noted simultaneously. 2 patients had nodular sclerosing Hodgkin's disease, while the other 2 had mixed cellularity disease. All patients presented with clinical stage III or IV Hodgkin's disease. 2 patients in this group have died: 1 of progressive Hodgkin's disease with evidence of atypical myobacterial infection, and 1 with no evidence of Hodgkin's disease but with AIDS-related infections. The lymphadenopathy syndrome has a presentation similar to that of Hodgkin's disease: lymphadenopathy often accompanied by malaise, fever, night sweats, weight loss, and splenomegaly. When a homosexual man presents with painless adenopathy, with or without constitutional symptoms, the potential diagnosis of Hodgkin's disease or other malignancy should be considered in addition to lymphadenopathy syndrome. Evaluation by lymph node biopsy is advisable. The natural history of Hodgkin's disease in patients at risk for AIDS may be altered to a more aggressive form. Unusual features of Hodgkin's disease observed in this group of patients included presentation with stage IV disease, cutaneous Hodgkin's disease, and bone marrow but no splenic involvement. The effects of the treatment modes used for Hodgkin's disease in homosexual patients should be evaluated for their effect on the risk of AIDS.     

Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors and outcome

The survival of patients with Hodgkin's disease has dramatically improved over the past 30 years because of advances in treatment. However, concern for the risk of long-term complications has resulted in a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. One major consequence of successful treatment of Hodgkin's disease is the development of second malignant neoplasms. We sought to determine the factors most important for development of second tumors in pathologically staged and treated Hodgkin's disease patients followed for long intervals to provide background information for future clinical trials and guidelines for routine patient follow-up. Between April 1969 and December 1988, 794 patients with laparotomy staged (PS) IA-IIIB Hodgkin's disease were treated with radiation therapy (RT) alone or combined radiation therapy and chemotherapy (CT). There were 8,500 person-years of follow-up (average of 10.7 person-years per patient). Age and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed to expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. Seventy-two patients have developed a second malignant neoplasm. Eight patients developed acute leukemia, 10 had non-Hodgkin's lymphoma (NHL), and 53 patients developed solid tumors at a median time of 5 years, 7.25 years, and 12.2 years, respectively, after Hodgkin's disease. One patient developed multiple myeloma 16.5 years after Hodgkin's disease. The relative risk (RR) of developing a second malignancy was 5.6. The absolute excess risk per 10,000 person-years (AR) of developing a second malignancy was 69.6 (7.0% excess risk per person per decade of follow-up). The highest RR occurred for the development of leukemia (RR = 66.2), however because of the low expected risk, the AR was only 9.3. The RR of solid tumors after Hodgkin's disease was lower (4.7); however, the AR was greater (49) than for acute leukemia. Among the solid tumors, breast, gastrointestinal, lung, and soft tissue cancers had the highest absolute excess risks. The risk for developing breast cancer after Hodgkin's disease was greatest in women who were under the age of 25 at treatment. The most significant risk factor for the development of both leukemia and solid tumors was the combined use of radiation therapy and chemotherapy. The RR following RT alone was 4.1 (AR = 51.1); for RT + CT (initially or at relapse) the RR was 9.75 (P < 0.05, nonoverlapping confidence limits, AR = 123.9). Survival following development of a second malignancy was poor in patients with leukemia, gastrointestinal tumors, lung cancer, and sarcoma. Survival from other malignancies including NHL and breast cancer was more encouraging. Second malignant neoplasms are a major cause of late morbidity and mortality following treatment for Hodgkin's disease. The most significant risk factor for the development of second tumors is the extent of treatment for Hodgkin's disease. Recommendations are presented for both prevention and early detection of these tumors.     

Hodgkin's lymphoma

Hodgkin's lymphoma was first described in 1832, but the nature of the pathognomic Reed-Sternberg cell, on which diagnosis of the disease is based, has only been elucidated in the past few years. Radiotherapy has been used to treat localised disease since the 1940s, and in the 1960s, effective combination chemotherapy regimens were introduced for anatomically advanced disease. The past three decades have witnessed continued improvement in outcome to such an extent that Hodgkin's lymphoma is now one of the most curable of all non-cutaneous malignancies. With improved survival and extended follow-up, relevance of treatment-induced late effects has become apparent, and modern therapeutic strategies must fully account for these effects. We review the pathology of Hodgkin's lymphoma, and its clinical presentation, investigation, present management, and natural history, including late effects of treatment.     

International Diabetes Federation: a consensus on Type 2 diabetes prevention.

AIMS: Early intervention and avoidance or delay of progression to Type 2 diabetes is of enormous benefit to patients in terms of increasing life expectancy and quality of life, and potentially in economic terms for society and health-care payers. To address the growing impact of Type 2 diabetes the International Diabetes Federation (IDF) Taskforce on Prevention and Epidemiology convened a consensus workshop in 2006. The primary goal of the workshop and this document was the prevention of Type 2 diabetes in both the developed and developing world. A second aim was to reduce the risk of cardiovascular disease in people who are identified as being at a higher risk of Type 2 diabetes. The IDF plan for prevention of Type 2 diabetes is based on controlling modifiable risk factors and can be divided into two target groups: People at high risk of developing Type 2 diabetes. The entire population. CONCLUSIONS: In planning national measures for the prevention of Type 2 diabetes, both groups should be targeted simultaneously with lifestyle modification the primary goal through a stepwise approach. In addition, it is important that all activities are tailored to the specific local situation. Further information on the prevention of diabetes can be found on the IDF website: http://www.idf.org/prevention.     

Research gaps and opportunities in autoimmune hepatitis—Results of the international autoimmune hepatitis group research workshop 2022

Autoimmune hepatitis (AIH) is a rare autoimmune liver disease that is characterised by a chronic inflammatory immune reaction directed against hepatocytes. The disease results in a substantial reduction in quality of life and potentially leads to liver-related complications or death. The International Autoimmune Hepatitis Group (IAIHG) initiated a series of research workshops to uncover the scientific gaps and opportunities in AIH. This review summarises the results of the latest workshop in Maastricht in 2022 and reviews the current challenges in adult AIH, particularly in relation to four important aspects of AIH: diagnostics; new immunomodulatory therapies; clinical trial design; and unmet clinical needs. This review also summarises the progress made since the AIH workshop in 2017. Patients and patient representatives were actively involved in the parallel working groups alongside clinicians and researchers. Despite 40 years of experience with diagnosing and treating AIH, false diagnoses occur and treatment is still based on nonselective immunosuppression. In addition to the need for more specific diagnostic tests, prognostic markers and tailor-based treatments, a major unmet clinical need was identified in areas of care delivery and health-related quality of life.     

Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation.

AIMS: To establish a unified working diagnostic tool for the metabolic syndrome (MetS) that is convenient to use in clinical practice and that can be used world-wide so that data from different countries can be compared. An additional aim was to highlight areas where more research into the MetS is needed. PARTICIPANTS: The International Diabetes Federation (IDF) convened a workshop held 12-14 May 2004 in London, UK. The 21 participants included experts in the fields of diabetes, public health, epidemiology, lipidology, genetics, metabolism, nutrition and cardiology. There were participants from each of the five continents as well as from the World Health Organization (WHO) and the National Cholesterol Education Program-Third Adult Treatment Panel (ATP III). The workshop was sponsored by an educational grant from AstraZeneca Pharmaceuticals. CONSENSUS PROCESS: The consensus statement emerged following detailed discussions at the IDF workshop. After the workshop, a writing group produced a consensus statement which was reviewed and approved by all participants. CONCLUSIONS: The IDF has produced a new set of criteria for use both epidemiologically and in clinical practice world-wide with the aim of identifying people with the MetS to clarify the nature of the syndrome and to focus therapeutic strategies to reduce the long-term risk of cardiovascular disease. Guidance is included on how to compensate for differences in waist circumference and in regional adipose tissue distribution between different populations. The IDF has also produced recommendations for additional criteria that should be included when studying the MetS for research purposes. Finally, the IDF has identified areas where more studies are currently needed; these include research into the aetiology of the syndrome.     

Workshop report: identification of research needs breast cancer etiology

A workshop to evaluate the scientific evidence for the etiologic associations between modifiable lifestyle and environmental risk factors and to identify areas for future research in breast cancer etiology was sponsored jointly by the Canadian Breast Cancer Initiative and the Canadian Breast Cancer Research Initiative in May, 2001. Reviews of the scientific evidence in these topics were commissioned and an expert panel convened to consider the reviews and make recommendations for research. The panel concluded that there was substantial evidence to proceed with additional research in several areas of breast cancer etiology. Particular support for future research for several lifestyle and environmental risk factors including alcohol, diet, physical activity, anthropometric factors, hormonally active agents and occupational exposures was identified. Several emerging hypotheses for breast cancer etiology were also considered and recommendations made in these areas. Specific areas for future consideration included: insulin-like growth factors, pharmaceuticals, viruses, psychosocial factors, and functional polymorphisms. The panel also identified common themes for future research including: studies of exposures across the life cycle; research in populations with unusual exposure levels; consideration of effect modification; development of improved exposure assessment methods and use of intermediate endpoints; separation of disease subtypes by hormone receptor status, stage and tumour markers; and consideration of biological mechanisms in breast cancer etiology.     

Moderne Pharmakotherapie des Morbus Hodgkin

High cure rates have been achieved in the treatment for patients with Hodgkin's disease in the past 30 years. Depending on stage at diagnosis and further risk factors up to 95% of patients with Hodgkin's disease can be cured with first-line treatment. Modern therapeutic strategies aim at both reducing therapy-induced late toxicities while maintaining effective tumor control. Patients with early stage Hodgkin's disease are now treated with a short course of chemotherapy for control of occult disease and involved field (IF) irradiation. For patients with early unfavourable stages, effectiveness of treatment shall be optimised by introducing the escalated BEACOPP schedule which has been established in the treatment of advanced stages. Questions to be answered in the treatment of advanced stages concern the optimal number of cycles of an effective chemotherapy regimen and the necessity of additional radiation therapy. The role of erythropoetin and PET-imaging is currently being evaluated in ongoing trials. In the future, new therapeutic approaches with biological agents will be of interest.     

Increased risk of second cancers in managing Hodgkin's disease: the 20-year Leiden experience

Summary Between January 1969 and December 1988, 482 patients were treated for Hodgkin's disease at the Leiden University Hospital. All cases were routinely recorded in the Hospital Information System, which has an active annual follow-up. Of all patients, 57% remained relapse free. According to the kinds of treatment they received, the following major categories were established: radiotherapy only (28.2%), chemotherapy only (20.1%), only initial combination of radiotherapy and chemotherapy (34.2%), all other combinations of radio- and chemotherapy (15.4%), or not registered (2.1%). Twenty-seven second cancers were observed; six leukemias, five non-Hodgkin lymphomas, and 16 solid tumors. Of all solid tumors only nine occurred in relapse-free patients. The overall relative risk of second cancers increased with the duration of follow-up. Using general population incidence rates to calculate expected numbers, the risk for developing leukemia, non-Hodgkin lymphoma, and solid tumors was increased 36-fold, 31-fold, and 2.4-fold, respectively. The cumulative risk of developing a second cancer 10 years after diagnosis of Hodgkin's disease was 7% for both the radiotherapy-only and the initial combination of radio- and chemotherapy group. It was 16% and 17% for the chemotherapy-only and the other combinations of radio- and chemotherapy group, respectively. Multivariate analysis (using the Cox regression model) show an increased risk of second cancers (RR=0.7) when a relapse of Hodgkin's disease resulting in increasing cumulative therapy occurred. Age at diagnosis of Hodgkin's disease was an important determinant for the risk of non-Hodgkin lymphoma and solid tumors. Cumulative chemotherapy intensity was an important factor in increasing leukemic risk in a dose-response fashion. Apart from this, the stage of Hodgkin's disease, although closely related to the kind of therapy, seemed to have an independent effect on leukemic risk.     

Prevention of common neurodegenerative disorders in the elderly

Since population aging has become a worldwide phenomenon, the burden of the age-related neurodegenerative diseases is expected to increase dramatically in both developed and developing nations. Alzheimer's disease is the most common neurodegenerative disorder among old people. Prevention may represent an ideal solution to the challenge posed by this condition. Recent epidemiological studies have revealed a number of risk and protective factors that could influence occurrence of dementia including Alzheimer type dementia. We propose that an active and stimulating lifestyle in late life as well as an optimal control of vascular and other chronic diseases both at middle age and late life can be two possible intervention strategies to prevent or postpone the onset of dementia, and perhaps other neurodegenerative disorders such as Parkinson's disease.     

Maternal and perinatal factors associated with hospitalised infectious mononucleosis in children,adolescents and young adults: record linkage study

Background  

There is current interest in the role of perinatal factors in the aetiology of diseases that occur later in life. Infectious mononucleosis (IM) can follow late primary infection with Epstein-Barr virus (EBV), and has been shown to increase the risk of multiple sclerosis and Hodgkin's disease. Little is known about maternal or perinatal factors associated with IM or its sequelae.     

Cardiovascular disease: cause of morbidity and mortality in adult survivors of childhood cancers

Although important advances have been made in curing childhood cancer in the last several decades, long-term survivors face considerable morbidity and mortality because of late effects from their initial anticancer therapy. By 30 years after treatment, the cumulative mortality from treatment-related medical illness actually exceeds that of mortality from cancer recurrence. Cardiovascular disease, in particular, is a leading threat to the well-being of adult survivors of childhood cancers. Unfortunately, the mechanisms of these late cardiac effects are understudied and poorly understood. This article reviews cardiotoxicity associated with 2 major anticancer regimens used in treating childhood cancer patients: anthracycline treatment and radiation therapy. The known pathophysiology and clinical cardiac risk factors that further predispose these patients to late-onset cardiac events are discussed. Basic and translational research is urgently needed to clarify pathophysiologic mechanisms of late cardiac effects and to develop therapies to improve both long-term survival and quality of life of adults cured of pediatric cancers.     

Late relapse among patients treated for Hodgkin's disease

Of 1360 consecutive patients with Hodgkin's disease treated at Stanford University, 1312 patients (96%) had complete remission, but 424 patients had a relapse. Fifty-five patients had relapses 36 months or more after completion of therapy. The actuarial risk of relapse in patients disease-free 3 years after therapy was 12.9%. The occurrence of late relapse was significantly related to stage I disease and nodular sclerosis histologic subtype. Late relapse was detected in 88% of patients by history, physical findings, or chest radiographs. Most patients with stage III and IV disease had late relapses in previously irradiated nodes or extranodally, but patients with stage I and II disease had late relapses primarily in unirradiated nodes. Disease-free survival after salvage therapy for late relapse was similar to that seen after treatment of earlier relapse. Prolonged surveillance of patients for late relapse is necessary after treatment of patients with Hodgkin's disease.     

Clinical, biologic, and histologic features of late relapses in diffuse large cell lymphoma.

After completing chemotherapy and achieving a complete remission (CR), patients with diffuse intermediate-grade lymphoma and immunoblastic lymphoma are usually considered cured if they are able to maintain that remission continuously for 24 months. Recently, we observed a number of patients with these disorders who relapsed after a continuous CR of greater than or equal to 30 months from the beginning of therapy or 24 months from completing chemotherapy. This finding led us to examine 503 consecutive cases to determine the risk of late relapse and their clinical and biologic features. We found that the overall risk of late relapse of those who attained CR was 6.8%, but several features at presentation were associated with a high risk: (1) the presence of a divergent histology; (2) a sclerosing large cell lymphoma; (3) a diagnosis based on an extranodal site with no nodal tissue available for examination. When none of these features were present, the risk of late relapse was minimal (only 3%). When any of these features was present, the risk was 14%. Most striking was the 43% late relapse rate of patients with divergent histology. All but one of the eight B-cell tumors studied at relapse showed kappa light chain restriction. Five of these eight has a low S phase at the time of relapse, suggesting chemotherapeutic selection of a clone of cells with a low proliferative potential that could have given rise to the late relapse. Nucleic acid flow cytometry and immunophenotypic studies on three tumors at initial diagnosis and after relapse failed to support the hypothesis of a second de novo lymphoma and were consistent with a true recurrence of the original tumor. The results of salvage chemotherapy in this group of late relapses showed a high CR rate (57%) but no evidence of a trend for cure in the time to treatment failure curve. In contrast to the experience with Hodgkin's disease, retreatment with the same or a similar regimen used for the original induction was not associated with durable response. Clinicians should be aware of the potential for a late relapse in cases with divergent histology and the need for new treatment strategies for such cases.     

Managing Overweight and Obesity in Adults to Reduce Cardiovascular Disease Risk

Daily lifestyle practices and habits profoundly affect the likelihood of developing cardiovascular disease (CVD). Abundant research and multiple recent consensus documents support the role of regular physical activity, not smoking cigarettes, maintaining a healthy body weight, controlling cholesterol levels, and controlling blood pressure to lower the risk of CVD. These strategies also play important roles in avoiding ever developing risk factors. Despite overwhelming knowledge in this area, adherence to lifestyle strategies remains suboptimal. Challenges remain in helping the public to act upon the current knowledge in this area. Recent guidelines for managing cholesterol and blood pressure provide new guidance in these areas. Controversy, however, exists related to specific recommendations in both of these areas. Similar strategies that are applied to adults for improving lifestyle habits and practices to lower CVD risk also apply to children and adolescents. A clear consensus exists that lifestyle strategies play a critical role in preventing, managing, and reducing cardiovascular disease and its risk factors.     

Health-related quality of life among men with HIV infection: effects of social support, coping, and depression

In a prospective cohort study, baseline data were collected on 226 males with HIV infection attending three infectious disease clinics in a southern state. As a result of advances in HIV treatment, understanding the association between psychosocial factors and health-related quality of life has become an important area of study. The purpose of this study was to assess the total effects of social support and coping as well as the direct and indirect effects of these factors through depression on health-related quality of life. Subjects were interviewed and answered the following standardized questionnaires: The HIV Cost and Services Utilization Study tool, Coping with HIV Questionnaire, Social Support Appraisals Scale, and Centers for Epidemiological Studies Depression instrument. Path models with strictly ordered relationships were fitted to study the effects of the psychosocial variables on each quality of life subscale. We found that coping and social support had total effects on some, but not all dimensions of health-related quality of life, whereas depression was associated with all dimensions of health-related quality of life. Furthermore, the effects of both social support and coping were mainly through the intermediate variable, depression. In the era of highly active antiretroviral therapy (HAART), when quality of life issues are of paramount importance, strategies to improve social support, coping, and particularly, depressive symptoms are strongly encouraged.     

Body mass index in midlife and late‐life as a risk factor for dementia: a meta‐analysis of prospective studies

The relationship between body mass index (BMI) (in midlife and late‐life) and dementia was investigated in meta‐analyses of 16 articles reporting on 15 prospective studies. Follow‐ups ranged from 3.2 to 36.0 years. Meta‐analyses were conducted on samples including 25 624 participants evaluated for Alzheimer's disease (AD), 15 435 participants evaluated for vascular dementia (VaD) and 30 470 followed for any type of dementia (Any Dementia). Low BMI in midlife was associated with 1.96 [95% confidence interval (CI): 1.32, 2.92] times the risk of developing AD. The pooled relative risks for AD, VaD and Any Dementia for overweight BMI in midlife compared with normal BMI were 1.35 (95% CI:1.19, 1.54), 1.33 (95% CI: 1.02, 1.75) and 1.26 (95% CI: 1.10, 1.44), respectively. The pooled relative risks of AD and Any Dementia for obese BMI in midlife compared to normal BMI were 2.04 (95% CI: 1.59, 2.62) and 1.64 (95% CI: 1.34, 2.00), respectively. Continuous BMI in late‐life was not associated with dementia. Small numbers of studies included in pooled analyses reduce generalizability of findings, and emphasize the need for publication of additional findings. We conclude that underweight, overweight and obesity in midlife increase dementia risk. Further research evaluating late‐life BMI and dementia is required.     

Critical micronutrients in pregnancy, lactation, and infancy: considerations on vitamin D, folic acid, and iron, and priorities for future research

The Early Nutrition Academy and the European Commission-funded EURRECA Network of Excellence jointly sponsored a scientific workshop on critical micronutrients in pregnancy, lactation, and infancy. Current knowledge and unresolved questions on the supply of vitamin D, folic acid, and iron for pregnant women, lactating women, and infants, and their health effects were discussed. The question was addressed of whether, and under which circumstances, supplementation with these micronutrients in addition to usual dietary intakes is advisable. The workshop participants concluded that public health strategies for improving supplementation with these micronutrients in pregnancy, lactation, and infancy are required. Further research priorities should focus on adequately powered human intervention trials to obtain a stronger evidence base for the amounts of vitamin D, folic acid, and iron that have optimal effects on health. The conclusions of the workshop should help to inform the scientific community as well as public health policy strategies.