Erythropoietin therapy in cancer patients.

The majority of patients with cancer become anemic during the course of their disease. This anemia appears to be due largely to a blunted erythropoietin (Epo) response and an impaired ability of the bone marrow to respond to endogenous Epo. Both are exacerbated by chemotherapy and radiation therapy. Recombinant human erythropoietin (rhEpo) ameliorates the anemia associated with malignancy. However, we do not yet know whether rhEpo will decrease the need for homologous blood transfusions and improve the quality of life of cancer patients. While rhEpo will greatly alter the treatment of anemia in the 1990s, its precise role in the treatment of oncology patients is still being elucidated.

The effect of glycosylated albumin on platelet aggregation.

BACKGROUND: Albumin has a role in the complicated process of platelet aggregation. Although it is known that quantitative changes in plasma albumin alter platelet aggregation, less is known about the interaction between qualitative changes in plasma albumin and platelets. One common qualitative change in plasma albumin is nonenzymatic glycosylation, which occurs during states of prolonged hyperglycemia. METHODS: Albumin was selectively removed from normal plasma by means of an affinity column. Glycosylated albumin was added to this albumin-poor plasma, and it was used to study platelet aggregation induced by low concentrations of arachidonic acid. Platelet aggregation was determined by light transmittance. RESULTS: As the concentration of glucose in which albumin was incubated was increased, there was progressive augmentation of platelet aggregation. At a plasma glucose of 150 mg/dL, average light transmittance was 9.4%, and at 200 mg/dL, it was 24.6%. These values were significantly different at a p value < .01. At glucose levels of 300 mg/dL and 400 mg/dL, mean light transmittance was 40.6% and 74.4%, respectively, and these values were significantly different with p values of < .01. CONCLUSIONS: Platelet aggregation in response to a relatively low concentration of arachidonic acid is enhanced in the presence of albumin that has been incubated in a medium containing levels of glucose that are higher than would be seen in normal patients but are consistent with those seen in diabetics with less than optimal control. This augmentation of platelet aggregation is statistically significant.

The role of albumin in human physiology and pathophysiology, Part III: Albumin and disease states.

The serum albumin level is one of several clinical parameters of the status of general health. There is a marked correlation between low albumin levels and the incidence of morbidity and mortality in hospitalized patients. Therefore, it is not surprising to find that hypoalbuminemia is a common finding among hospitalized patients. This results from alterations in the catabolic or anabolic rates, losses of albumin, or redistribution between the various fluid compartments of the body. Somewhat less well defined than the role of albumin as a prognostic indicator is its role in compounding pathophysiology. Hypoalbuminemia is known to be associated with delayed wound healing. The hypoalbuminemic state interferes with the normal functioning of the gastrointestinal tract. Qualitative changes in the albumin molecule which occur in renal disease may damage the nephron. Low serum albumin levels may adversely affect the coagulation system. Further investigation into the role of albumin in pathophysiology is warranted.

Use of albumin as a volume expander.

In some hospitals, albumin products account for 10% of the pharmaceutical budget. As much as 60% of these prescriptions are empiric, and from 40 to 70% of albumin that is administered is given for inappropriate reasons. Although the reasons for albumin administration vary, prevention or reversal of hypovolemia is part of the reason in the majority of cases.

Role of albumin in human physiology and pathophysiology.

Albumin is one of the major products of hepatic protein synthesis. Although it is a small molecule, it is an important diagnostic and prognostic determinant, as well as a useful therapeutic agent. A review of the evolution and structure of albumin as well as a description of its colloidal and buffering properties is presented. Synthesis, distribution, and catabolism, the major determinants of serum albumin level, are discussed. Emphasis is given to those mechanisms responsible for the regulation of these processes, including the importance of nutritional status on substrate availability, energy supply, and hormonal modulation.

Risk of symptomatic central venous thrombotic complications in AIDS patients receiving home parenteral nutrition.

BACKGROUND: The acquired immunodeficiency syndrome (AIDS) is frequently complicated by malnutrition that may require parenteral nutritional support. In a non-AIDS population with long-term indwelling central venous catheters, low-dose warfarin therapy has been shown to prevent venous thrombosis. The purpose of this study was to determine the incidence of symptomatic central venous thrombosis in AIDS patients receiving home parenteral nutrition. The incidence of thrombosis on low-dose warfarin was compared with no prophylactic therapy. METHODS: A retrospective review of 47 malnourished AIDS patients started on home parental nutrition was performed. None of the patients had a prior history of venous thrombosis. During this period, 9 of 47 patients were treated with low-dose warfarin therapy. The incidence of clinical and radiologic venous thrombosis was compared in these two groups. RESULTS: Forty-seven patients were treated with parenteral nutrition for 296 patients-months. The rate of central venous thrombosis in patients receiving warfarin (0.016 thromboses per patient-month) was no different from those patients on no prophylactic therapy (0.009 thromboses per patient-month). The most common abnormality in coagulation observed in the entire group during follow-up was thrombocytopenia occurring in 66% of patients. Sixty percent of patients received medications that could interfere with platelet function. CONCLUSIONS: We conclude that routine thrombosis prophylaxis with low-dose warfarin may not be justified in malnourished AIDS patients receiving home parenteral nutrition. Prospective clinical trials are needed to determine the risks and benefits of prophylactic warfarin therapy in this group of patients.

Subcutaneous emphysema: report of a case and review of the literature.

We report the association of subcutaneous emphysema with the use of a suprapubic bladder catheter. Review of the literature has revealed no prior reports of this complication. We have reviewed the literature on causes of tissue emphysema.

Regulatory elements of the erythropoietin gene.

Because the human hepatoma cell line Hep3B produces erythropoietin (Epo) in a regulated fashion, it can be used to investigate the cis-acting regulatory elements of the Epo gene. Comparison of primate and mouse sequences shows strong homology not only in the coding sequence but also within the 5' flanking region, the first intron, and the 3' flanking region. These portions of the Epo gene were inserted 5' and 3' to a reporter gene, human growth hormone (GH). 5A is a 1,192-base pair (bp) HindIII-Xbal fragment that extends from 378 bp 5' to the cap site through the first intron. To obviate the problem of false initiation of translation from the Epo ATG start codon, this site was changed to TAG by site-directed mutagenesis. 3A is a 255-bp Accl-BglII fragment that extends 67 bp upstream from the Epo termination codon and covers most of the 3' noncoding region of homology. The plasmid DNAs were transfected by electroporation into Hep3B cells with RSVCAT as an internal standard to correct for transfection efficiency. One aliquot of cells was exposed to 50 mumol/L CoCl2 or to 1% O2. At the end of the incubations, GH and Epo were measured in the cell media and the cell pellet was assayed for CAT. Production of GH was stimulated 1.7-fold by cobalt or hypoxia. Furthermore, addition of 3A to the GH gene, irrespective of orientation, stimulated GH production 2.6-fold with CoCl2 and 2.3-fold with hypoxia. Stable cell lines were produced by cotransfection of the above constructions, along with the selectable marker pSV-Neo. In two clones, exposure to hypoxia resulted in much more marked (16-fold) induction of GH. Stimulus of both GH and Epo production by hypoxia was partially abrogated by carbon monoxide. These results demonstrate the presence of promoter and enhancer elements within the human Epo gene that are appropriately responsive to hypoxia and cobalt.

Pseudo-Cushing's syndrome in human immunodeficiency virus-infected patients.

To our knowledge, an association between human immunodeficiency virus infection and pseudo-Cushing's syndrome has not previously been described. We describe four HIV-infected patients with pseudo-Cushing's syndrome, characterized by striking dorsocervical and submandibular fat accumulation and central obesity. In each case, cortisol levels were either normal or suppressed adequately with administration of dexamethasone, excluding the diagnosis of true Cushing's syndrome. Immune function and weight improved significantly preceding the development of pseudo-Cushing's syndrome. Three of the four patients were taking a common protease inhibitor at the onset of symptoms, and the fourth reported the exacerbation of his symptoms with the addition of a protease inhibitor. The observed characteristic pattern of fat deposition may be attributable to a specific effect of new antiretroviral therapies or may relate to recovery independent of medication usage. Distinguishing between pseudo-Cushing's syndrome and true Cushing's syndrome is critical for preventing the unnecessary and potentially harmful treatment of such patients. Further research into the mechanisms of this novel phenomenon is needed.

Immunotoxin combined with chemotherapy for patients with AIDS-related non-Hodgkin's lymphoma.

BACKGROUND: The objective of this study was to develop and test a combined therapeutic approach for patients with AIDS-related lymphoma (ARL), employing agents with independent mechanisms of action and nonoverlapping toxicity. This study was designed to test the feasibility and tolerance of combining low dose chemotherapy with infusional immunotoxin in the treatment of ARL patients. METHODS: Previously untreated patients received low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, and vincristine (m-BACOD) on a 21- to 28-day schedule. Patients who did not have progressive disease by Cycle 3 received anti-B4-blocked ricin (anti-B4bR), a murine monoclonal antibody linked to modified ricin, 20 microg/kg/day for 7 days administered by continuous infusion on an outpatient basis. A repeat cycle of anti-B4-bR was administered during Cycle 4 of chemotherapy based on tolerance. Patients received two cycles of chemotherapy beyond complete remission up to eight cycles. Study endpoints were toxicity, development of human antimurine antibody (HAMA) and human antiricin (HARA), tumor response, and survival. RESULTS: Twenty-six of 44 patients received the immunotoxin therapy. Anti-B4-bR infusion was associated with transaminase elevation (Grade 3) in 14 of 26 patients (58%), and flulike symptoms were common. HAMA or HARA was observed in 8 patients (31%). The overall response rate was 57% (13 complete responses and 12 partial responses). The median survival for all patients was 8.9 months. CONCLUSIONS: This study demonstrates the safety and feasibility of using chemotherapy and immunotoxin therapies in combination and supports their further evaluation to improve the outcomes of patients with ARL.

Parasitic sinusitis and otitis in patients infected with human immunodeficiency virus: report of five cases and review.

We describe five cases of parasitic sinusitis and otitis in patients infected with human immunodeficiency virus (HIV) and review 14 reported cases. The pathogens identified in our group of patients included agents such as Microsporidium, Cryptosporidium, and Acanthamoeba species. The clinical features common to these patients included a long history of HIV seropositivity associated with advanced immunosuppression and multiple opportunistic infections as well as long-standing local symptoms refractory to multiple courses of antibacterial agents. Symptoms often included fever and chills in addition to local tenderness and discharge. Invasive diagnostic procedures were necessary to obtain the final diagnosis and to initiate appropriate therapy. Although most patients responded at least partially to specific therapy, relapses and recurrences were frequent in patients who did not receive long-term suppressive therapy. The general outcome for HIV-infected patients with parasitic sinusitis and otitis was poor; however, deaths were generally associated with other complications of the underlying HIV infection.