alpha-Interferon and 5-fluorouracil: possible mechanisms of antitumor action

Abstract:

We have treated 17 patients with 5-fluorouracil (5-FU, 300 mg/m2/d by continuous ambulatory infusion for 8 weeks) and interferon alfa-2b (escalating doses to cohorts of three to five patients, given subcutaneously on a daily schedule at 2.0, 3.5, 5.0, and 10.0 x 10(6) IU/m2). The two major toxicities observed were mucositis, which occurred in 10 patients at 2 weeks and required interruption of therapy and 5-FU dose reduction, and chronic fatigue syndrome, which required reduction of the dose of interferon alfa-2b.

Other toxicities seen included elevation in BUN/creatinine, elevation in liver function tests, alopecia, diarrhea, confusion, and myelosuppression. No toxic deaths occurred. Five responses were observed: two complete responses, two partial responses, and one minor response, all in patients with gastrointestinal malignancy; three of the responding patients had previously failed 5-FU-containing regimens.

When we measured 5-FU plasma levels in nine of our patients, they were at or below 1 ng/mL in most patients; however, within 1 hour of administration of interferon alfa-2b, plasma levels rose 16-fold. This elevation of 5-FU levels persisted for at least 24 hours, and could not be accounted for on the basis of altered interleukin-6 levels. When the regimen was tested in eight patients with metastatic renal cell carcinoma as part of a pilot study, three partial responses were observed, and no patient developed disease progression while on treatment. The combination of 5-FU, given by continuous infusion, and interferon alfa-2b, given daily, appears worthy of advancement to phase II trials.

 

Source: Meadows LM, Walther P, Ozer H. alpha-Interferon and 5-fluorouracil: possible mechanisms of antitumor action. Semin Oncol. 1991 Oct;18(5 Suppl 7):71-6. http://www.ncbi.nlm.nih.gov/pubmed/1948133

 

An overview of chronic fatigue syndrome

Abstract:

BACKGROUND: Psychological and immunologic factors both appear to contribute to chronic fatigue syndrome (CFS). By comparing CFS with other disorders in which fatigue is a prominent symptom, the association between fatigue, psychological vulnerability, depression, and immune function may be further defined. Recent data from psychological, neurologic, and immunologic studies that address these issues are reviewed.

METHOD: Articles and abstracts covering CFS and related topics of fatigue, depression, and postinfectious syndromes were identified through MEDLINE and Index Medicus (1980-1990) and by bibliographic review of pertinent review articles.

RESULTS: The 1988 definition of CFS by the Centers for Disease Control encompasses several conditions in which the major characteristic is severe fatigue associated with constitutional symptoms. Several studies have identified immune dysfunction in CFS patients, but the specificity of these findings remains unclear. Most studies have shown that CFS patients, compared with other patients with chronic medical illness, experience more disabling fatigue. Some investigators have found a higher incidence of concurrent and past psychiatric illness in CFS patients compared with other medical patients, thereby suggesting an underlying psychopathology in CFS. However, other studies have not found a higher than expected incidence of past depression in CFS patients and have further shown that many CFS patients have no identifiable psychopathology.

CONCLUSION: CFS appears to be a heterogenous entity. Although there may be a high coincidence of major depression in CFS, a substantial proportion of patients lack any identifiable DSM-III-R psychiatric disorder yet still manifest the syndrome, thereby suggesting it has an autonomous entity. Despite the evolving nature of our current understanding of CFS, a rational diagnostic and therapeutic approach to CFS is possible.

 

Comment in: Pathogenesis of chronic fatigue syndrome. [J Clin Psychiatry. 1992]

 

Source: Krupp LB, Mendelson WB, Friedman R. An overview of chronic fatigue syndrome. J Clin Psychiatry. 1991 Oct;52(10):403-10. http://www.ncbi.nlm.nih.gov/pubmed/1938975

 

Pain syndromes, disability, and chronic disease in childhood

Abstract:

Childhood disability and chronic disease are common, and their prevalence is increasing as children survive with conditions that were previously fatal. It is important that physicians in training learn about disability and handicap, and the functioning of multidisciplinary teams to manage these problems. Chronic ill-health is often very expensive to manage, and some serious and creative thinking about the best way to fund such health care is urgently needed.

Pediatric rheumatologists are involved with the care of many children with chronic and recurrent musculoskeletal pain; however, they have not perhaps focused enough research effort on the investigation of pain and its management. Whether reflex neurovascular dystrophy, fibromyalgia, and chronic fatigue syndrome are part of a disease continuum is unclear, but it seems probable that psychosocial problems are often important contributing factors in all three conditions.

Immunoglobulin subclass deficiencies are being increasingly delineated, occurring in chronic fatigue syndrome as well as many other disease states. Their clinical relevance still remains, for the most part, uncertain. Short stature occurs in many chronic illnesses, and the role of growth hormone treatment in these conditions is beginning to be investigated.

 

Source: Malleson PN. Pain syndromes, disability, and chronic disease in childhood. Curr Opin Rheumatol. 1991 Oct;3(5):860-6. http://www.ncbi.nlm.nih.gov/pubmed/1836344

 

Psychiatric management of PVFS

Abstract:

Psychiatric management of PVFS (considered as a subtype of CFS) is a pragmatic approach to a disorder for which strictly biomedical treatments have so far had little to offer. Psychiatric assessment embraces a comprehensive (biopsychosocial) approach, and distinguishes factors that perpetuate the condition from those that may have precipitated it. Treatments are targeted at perpetuating factors.

Few controlled treatment trials have been reported in patients selected specifically as meeting criteria for CFS. There is evidence available, however, that suggests useful management strategies. An uncontrolled study of treatment of CFS with combined antidepressant drug and psychological treatment has produced promising results. In addition there is useful evidence arising from the study and treatment of the individual symptoms of CFS, occurring both in isolation as part of other syndromes.

The results of controlled trials of antidepressant drugs, and of psychological and rehabilitative treatment are awaited. It is already possible to offer provisional guidelines for treatment.

 

Source: Sharpe M. Psychiatric management of PVFS. Br Med Bull. 1991 Oct;47(4):989-1005. http://www.ncbi.nlm.nih.gov/pubmed/1794095

 

Postviral fatigue syndrome and psychiatry

Abstract:

The postviral fatigue syndrome overlaps with psychiatry at a number of points. First, there is the influence that some psychological states have on physiological processes, such as immunity. Second, psychological symptoms, particularly depression but also anxiety, are a major feature of the syndrome. Third, difficulties in the doctor-patient relationship are common.

Each of these three areas are discussed in detail. Special attention is given to the possible mechanisms underlying the occurrence of psychological symptoms, which are sufficient to make a psychiatric diagnosis in at least two thirds of cases.

It is concluded that the bulk of the scientific evidence points to psychiatric disturbances being primary but that this does not account for the syndrome in its entirety and other mechanisms probably operate as well. Much of the conflict between doctor and patient arises from misconceptions about the nature and cause of psychological disturbances.

 

Source: David AS. Postviral fatigue syndrome and psychiatry. Br Med Bull. 1991 Oct;47(4):966-88. http://www.ncbi.nlm.nih.gov/pubmed/1794094

 

Post-viral fatigue syndrome. Epidemiology: lessons from the past

Abstract:

This chapter outlines the recorded epidemiological history of PVFS (including the early epidemics of myalgic encephalomyelitis) and the development of the concept, including the realisation that endemic cases also occur.

Cases of PVFS are still not recorded by the Surveillance Centre for Communicable Diseases, so it is very difficult to detect and monitor any outbreak in the community, since each GP may only have two or three such patients and would, therefore, not be aware of an epidemic in the community as a whole if it occurred.

Epidemiological issues raised by the early epidemics, including the delineation of the syndrome, the question of bias, the role of hysteria and the role of depression; the issue of symptom distribution, and its implications for aetiology; and a multiaxial framework for understanding the association with psychological symptoms are discussed. The value of a future multidisciplinary research programme designed to disentangle direct and predisposing causes of PVFS is emphasised.

 

Source: Jenkins R. Post-viral fatigue syndrome. Epidemiology: lessons from the past. Br Med Bull. 1991 Oct;47(4):952-65. http://www.ncbi.nlm.nih.gov/pubmed/1794093

 

Post-viral fatigue syndrome. Epidemiology: a critical review

Abstract:

Numerous reports in medical journals, lay magazines, and newspapers bear witness to the level of interest in the postviral fatigue syndrome and the heated controversy about the true nature of this condition. For many, it represents a ‘rag bag’ diagnosis into which unsolved diagnostic problems are discarded. Others are in no doubt that there is a discrete syndrome, probably with a specific causation.

The real answer almost certainly lies somewhere in between, but the truth can only be established through epidemiological studies designed to answer key questions. Does it exist at all, and, if so, how frequently does it occur? Who is most likely to get it and what is its cause? What is the nature of its implied association with viral infections and what is the role of other frequently postulated factors, such as psychiatric morbidity? What is its natural history and is there any evidence that any of the treatment/management regimes on offer can effectively lead to symptomatic relief or improve prognosis?

In this chapter, we consider the evidence on these key questions, identify some of the deficiencies in our current knowledge and highlight the kind of research which is still required.

 

Source: Wallace PG. Post-viral fatigue syndrome. Epidemiology: a critical review. Br Med Bull. 1991 Oct;47(4):942-51. http://www.ncbi.nlm.nih.gov/pubmed/1794092

 

History of postviral fatigue syndrome

Abstract:

In writing a history of any illness there is always a dilemma whether to attempt the story of the condition ‘itself’, the medical attempts to define its nature, or to glimpse it via our changing reactions. The easiest is a straightforward account of the attempts of scientists to solve a problem–the classic medical detective story. However, this is often more fiction than fact.

Medicine rarely moves smoothly from ignorance to knowledge, but often in a more circular fashion. A historical approach is thus not solely a record of who did what, but also contributes to our understanding of the problems under scrutiny in this issue. Terminology is never easy in this subject, but the following conventions will be used: The terms neurasthenia and ME will be used in their actual context (as authors themselves used them), without defining either. Post-infectious fatigue syndrome (PIFS) will cover similar conditions when related to infective episodes. All will be used in a neutral fashion, to refer to changing realities as understood by doctors and historians.

This chapter attempts both chronological description and social analysis. The justification for this approach is clear in the case of neurasthenia, since ‘as so little was known of its pathological basis physicians’ statements regarding the disease were composed more of social and cultural elements than of scientific knowledge. Although much has changed, a contemporary account still reveals as much about cultural attitudes as the advance of science.

 

Source: Wessely S. History of postviral fatigue syndrome. Br Med Bull. 1991 Oct;47(4):919-41. http://www.ncbi.nlm.nih.gov/pubmed/1794091

 

Psychiatric perspectives: an overview

Abstract:

This chapter reviews the evidence concerning the importance of psychological and social factors in the aetiology and pathogenesis of chronic fatigue syndrome. The diagnosis is often offered to doctors by patients; and we consider attribution, stigma, collusion between doctor and patient, and abnormal illness behaviour in this context. We then give a brief description of a model for common mental disorders, and show how chronic fatigue syndrome relates to this model. It emerges that there are special vulnerability factors in these patients’ personalities before the viral illness, but the disorder is seen as being released by the viral illness. By the time the disorder becomes established the original causal nexus is seen as no longer so important, and the disorder can be seen as a form of abnormal illness behaviour maintained by special factors. The implications for treatment are then considered.

 

Source: Woods TO, Goldberg DP. Psychiatric perspectives: an overview. r Med Bull. 1991 Oct;47(4):908-18. http://www.ncbi.nlm.nih.gov/pubmed/1794090

 

Treatment of chronic fatigue syndrome

Abstract:

Chronic Fatigue Syndrome is a disorder which is characterised by profound fatigue together with a variety of other subjective clinical features which persist over a prolonged period of time. The aetiology remains at present uncertain and therefore rational therapeutic strategies are difficult to plan. This paper reviews currently used forms of treatment aimed at correcting the possible pathophysiological mechanisms and discusses the problems associated with the management of this condition.

 

Source: McBride SJ, McCluskey DR. Treatment of chronic fatigue syndrome. Br Med Bull. 1991 Oct;47(4):895-907. http://www.ncbi.nlm.nih.gov/pubmed/1794089