Prevalence and determinants of fatigue in patients with moderate to severe chronic GvHD.

Although fatigue is common after allogeneic hematopoietic cell transplantation, little is known about fatigue in patients with chronic GvHD (cGvHD). The aim of this study was to explore factors associated with fatigue in cGvHD. Data were drawn from a sequentially recruited, cross-sectional study of adults with moderate or severe cGvHD (n=263). Respondents were classified as fatigued or not fatigued based on their response to a single item regarding loss of energy from the Lee cGvHD Symptom Scale. In univariate analysis, factors significantly associated with fatigue included performance status, number of prior cGvHD therapies, cGvHD symptom bother, self-assessed physical and mental health, nutritional status, walk velocity and self-reported physical activity. There were no significant associations between fatigue and disease-related cGvHD variables. Multivariable logistic regression demonstrated that being less active and having pulmonary and/or muscle/joint symptoms were independently associated with fatigue. In conclusion, clinically significant fatigue was prevalent in more than one-third of subjects with cGvHD, and was disabling. Absence of association with measures of cGvHD severity underscores the need to elucidate the pathogenesis of fatigue and its relationship with inflammatory activity. Pulmonary and muscle/joint symptoms and physical inactivity represent potential targets for intervention in clinical studies.

Sleep quality following hematopoietic stem cell transplantation: longitudinal trajectories and biobehavioral correlates.

The present study examined changes in sleep quality following hematopoietic stem cell transplantation (HSCT) and investigated associations with biobehavioral factors. Individuals undergoing HSCT for hematologic malignancies (N=228) completed measures of sleep quality and psychological symptoms pre-transplant and 1, 3, 6 and 12 months post transplant. Circulating inflammatory cytokines (IL-6, TNF-α) were also assessed. Sleep quality was poorest at 1 month post transplant, improving and remaining relatively stable after 3 months post transplant. However, approximately half of participants continued to experience significant sleep disturbance at 6 and 12 months post transplant. Mixed-effects linear regression models indicated that depression and anxiety were associated with poorer sleep quality, while psychological well-being was associated with better sleep. Higher circulating levels of IL-6 were also linked with poorer sleep. Subject-level fixed effects models demonstrated that among individual participants, changes in depression, anxiety and psychological well-being were associated with corresponding changes in sleep after covarying for the effects of time since transplant. Sleep disturbance was most severe when depression and anxiety were greatest and psychological well-being was lowest. Findings indicate that sleep disturbance is a persistent problem during the year following HSCT. Patients experiencing depression or anxiety and those with elevated inflammation may be at particular risk for poor sleep.

A novel preparative regimen for autologous transplant in non-Hodgkin's lymphoma: long-term experience with etoposide and thiotepa.

The purpose of this study was to evaluate the efficacy and toxicity of the preparative regimen of thiotepa and etoposide in patients undergoing autologous transplantation for relapsed non-Hodgkin's lymphoma. The study involved 65 consecutive patients who underwent autologous transplantation using the thiotepa/etoposide regimen for relapsed intermediate-grade NHL at the University of Wisconsin Hospital and Clinics (UWHC) between 1987 and 2001. The regimen consisted of thiotepa 300 mg/m(2)/day and etoposide 700 mg/m(2)/day on days -6, -5, and -4. The median age at the time of transplant was 49 years. A total of 50 patients (76%) had diffuse large-cell lymphoma. A total of 50 (77%) patients had chemosensitive disease, and 15 (23%) were chemoresistant. With a median follow-up of 34 months (range, 3-163), 28 patients (43%) remain in CR and 33 (51%) have developed recurrent or progressive disease. The overall survival and event-free survival at 3 years are 40% (95% CI 26-53%) and 32% (95% CI 20-45%), respectively. There was one death attributed to regimen-related toxicity (RRT). Reversible gastrointestinal toxicity was the major RRT, and there was minimal pulmonary and cardiac toxicity. We conclude that the combination of thiotepa and etoposide is an effective preparative regimen with acceptable RRT.

Tumor load in patients with follicular lymphoma post stem cell transplantation may correlate with clinical course.

The purpose of this study was to evaluate if the tumor load, as determined by a real-time quantitative PCR (RQ-PCR) assay, correlated with the clinical course of follicular lymphoma patients after stem cell transplantation (SCT). Cryopreserved bone marrow and/or peripheral blood samples obtained at different time intervals after SCT from 11 patients (seven allogeneic, T-cell depleted/four autologous) were tested for tumor load, as defined by t(14;18) positive cells/total cells, using RQ-PCR. None of the six patients who remained in remission had samples with a tumor load >0.01% after SCT, although fluctuating tumor loads of 0.01% after SCT (0/6 vs 4/5, P<0.02, Fisher's exact). Our results suggest that RQ-PCR measurable tumor load >0.01% after SCT may correlate with relapsed/progressive disease. Prospective studies with greater numbers of cases are indicated to better determine the critical tumor load that predicts poor outcome after SCT with RQ-PCR.

Adenocarcinoma arising in a transplanted pancreas.

Tumor transmission or de novo tumor development in the transplanted organ is a rare event. Appreciation of the organ-specific risk factors for tumor development and careful inspection of the organ at procurement may reduce but not eliminate this complication. We report the first known combined kidney-pancreas recipient who developed adenocarcinoma in the transplanted pancreas. Molecular typing of the tumor by DNA sequencing supports donor derivation of the tumor. Despite cessation of immunosuppression and reconstitution of the recipient's immune response, the patient died from metastatic pancreatic adenocarcinoma. Comparison is made to the reported outcomes after diagnosis of renal cell carcinoma that appeared early after transplantation

Decreased CD10 expression in grade III and in interfollicular infiltrates of follicular lymphomas.

CD10 expression in various grades and interfollicular infiltrates of follicular lymphoma (FL) has not been well documented. Immunohistochemical staining for CD10 (clone 56C6) was performed on paraffin-embedded tissue from 26 cases of classic FL. Negative or weak expression of CD10 was more frequent in grade III (5/6 [83%]) than in grade I FLs (3/15 [20%]). CD10+ interfollicular infiltrates were present in 16 cases. Six (38%) of 16 cases showed that CD10 expression was strong or moderate in follicular areas but weak or negative in interfollicular infiltrates. Our results suggest that CD10 expression is frequently weak to negative in grade III and in interfollicular infiltrates of FLs. Therefore, lack of CD10 expression on small specimens, such as from needle core biopsy or fine-needle aspiration, does not preclude the possibility of a diagnosis of FL. Furthermore, lack of CD10 expression in diffuse large B-cell lymphoma does not exclude the possibility that the neoplastic lymphocytes are of follicle center cell origin.

Loss of renal function following bone marrow transplantation: an analysis of angiotensin converting enzyme D/I polymorphism and other clinical risk factors.

Chronic renal failure is an acknowledged late complication of BMT. It is related to the intensive chemotherapy, radiation and supporting medications. Polymorphism in the angiotensin converting enzyme (ACE) gene is associated with progression of nephropathy caused by diabetes and IgA nephropathy. We sought to determine whether ACE genotype and other clinical factors were associated with loss of renal function after BMT. We determined the genotype of 106 adult allogeneic BMT recipients, who received a similar preparative regimen, survived 1 year, and had assessment of renal function up to 3 years after BMT. We found that the distribution of genotypes was similar to the general population; 29%, 51%, and 20% for the DD, DI, and II genotypes, respectively. There was no statistical difference in patient survival between the three groups. Among all patients, the average creatinine clearance declined from 124 (95% CI 117, 131) to 89 (95% CI 78, 100) ml/min over the 36 months after BMT. Decline in renal function over time was less for patients with the DD compared to the II genotype (P = 0.040). Renal function in patients with the DD genotype was also better than those with the DI genotype, but this was of borderline statistical significance (P = 0.055). Renal shielding reduced decline in renal function compared to no shielding (P = 0.026). We conclude that the ACE genotype does not seem to influence survival, but the DD genotype may be protective against renal injury after BMT. Furthermore, we confirm that renal shielding during TBI reduces the renal injury after BMT.

Analysis of risk factors for the development of GVHD after T cell-depleted allogeneic BMT: effect of HLA disparity, ABO incompatibility, and method of T-cell depletion.

Multivariate analysis was performed to determine the independent factors affecting the risk of acute GVHD (aGVHD) grades II to IV and extensive chronic GVHD (cGVHD) and the rate of survival in 481 recipients of T cell-depleted (TCD) marrow allografts who received transplants at a single center between 1991 and 2000. All patients received grafts partially depleted of CD3+ T cells by complement-mediated lysis using 2 narrow-specificity monoclonal antibodies (MoAbs), T10B9.1A-31 (n = 400) or Muromonab-Orthoclone OKT3 (n = 81). Factors considered in the analysis included patient/donor sex, age, cytomegalovirus (CMV) status, and ABO blood group along with T-cell dose, disease, and disease status, donor relationship, HLA antigen (Ag)mismatch (MM), growth-factor use, anti-thymocyte globulin use, year of transplantation, and the MoAb used for TCD. The results showed an association of HLA with an increased relative risk (RR) of aGVHD for recipients of grafts from relateddonors that were > or =2 Ag MM (n = 73, RR = 2.09, P = .005), matched unrelated (UR) donors (n = 130, RR = 1.98, P = .004), and > or =2 Ag MM UR donors (n = 34, RR = 2.68, P = .003) compared with the baseline matched-sibling group (n = 121). No increased risk of aGVHD was seen for 0 to 1 Ag MM family donors (n = 24) or 1 Ag MM UR donors (n = 99). aGVHD risk was increased with minor, but not major or major-minor, ABO disparity (RR = 2.0, P = .003) compared with that of ABO-identical pairs. We found less effective TCD and resultant higher T-cell dose for recipients of grafts that were T cell depleted using OKT3. However, the use of OKT3 and not the T-cell dose was associated with increased aGVH-D risk (RR of 1.84, P = .001). Increased risk of extensive cGVHD was associated with patient age of >20 years (RR = 2.2, P < .0001) and with CMV status (positive patient/negative donor, RR = 1.9, P = .002). Decreased survival was associated with older age (>20 years), a > or =2 Ag MM related donor, a 1 or > or =2 Ag MM UR donor, risk group, and a CMV-positive patient/-negative donor pair. There was no difference in survival for 0 to 1 Ag MM related or matched UR donors compared with the baseline group. These data indicate that there are quantitative as well as potential qualitative differences in outcome depending on the TCD method. Expected and unexpected risk factors for GVHD and survival were associated with partial TCD. Our data support the consideration of ABO match in donor selection, the preferential selection of CMV-positive donors for CMV-positive recipients, and the acceptance of 1 but not > or =2 Ag HLA MM donors.

Heme and the endothelium. Effects of nitric oxide on catalytic iron and heme degradation by heme oxygenase.

We studied the effects of nitric oxide (NO) on the control of excess cellular heme and release of catalytically active iron. Endothelial cells (ECs) exposed to hemin followed by a NO donor have a ferritin content that is 16% that of cells exposed to hemin alone. Hemin-treated ECs experience a 3.5-fold rise in non-heme, catalytic iron 2 h later, but a hemin rechallenge 20 h later results in only a 24% increase. The addition of a NO donor after the first hemin exposure prevents this adaptive response, presumably due to effects on ferritin synthesis. NO donors were found to reduce iron release from hemin, while hemin accumulated in cells. A NO donor, in a dose-dependent fashion, inhibited heme oxygenase activity, measured by bilirubin production. Using low temperature EPR spectroscopy, heme oxygenase inhibition correlated with nitrosylation of free heme in microsomes. Nitrosylation of cellular heme prevented iron release, for while there was heme oxygenase-dependent release of iron in cells incubated with hemin for 24 h, the addition of a NO donor blocked iron release. This indicates that NO readily nitrosylates intracellular free heme and prevents its degradation by heme oxygenase. Nitrosylation of heme was found to reduce sensitization of cells to oxidative injury.

T cell-depleted allogeneic bone marrow transplantation for high-risk non-Hodgkin's lymphoma: clinical and molecular follow-up.

The use of allogeneic BMT in patients with relapsed non-Hodgkin lymphoma (NHL) offers the advantage of tumor-free bone marrow and possibly a 'graft-versus-lymphoma effect' which may decrease the risk of recurrence. However, allogeneic BMT also poses an increased risk of death due to graft-versus-host disease (GVHD) which can be ameliorated by T cell depletion. We performed a retrospective review of 37 patients who underwent T cell-depleted allogeneic BMT for aggressive and indolent NHL between 1988 and 1996. Polymerase chain reaction (PCR) was used to identify indolent NHL patients with the BCL2/IgH translocation which served as a marker of residual disease. Sixteen of 37 patients (44%) are alive and progression-free with a median follow-up of 4.4 years (range 1-10.3). The incidence of grade 2-4 acute GVHD was 36% and extensive chronic GVHD developed in 12%. Patients with aggressive NHL have an overall PFS of 33% (12-54%); those with chemotherapy-resistant and sensitive disease have PFS of 17% (0-47%), and 40% (15-65%) respectively at 5 years. Patients with indolent histologies have overall PFS of 62% (37-86%); those with chemotherapy-resistant and sensitive disease have PFS of 55% (25-85%) and 80% (45-100%) respectively at 5 years. Eight patients with indolent disease had a BCL2/IgH translocation detectable by PCR. Five of these eight patients remain alive and progression free at a median of 6.5 years after BMT (range 2.1-7.4 years), four of whom remain PCR positive from 1.7 to 2.9 years after transplantation. We conclude that T cell-depleted allogeneic BMT poses a low risk for death due to GVHD, and should be considered for patients with relapsed and refractory indolent NHL.

Desferrioxamine enhances the effects of gamma radiation on clonogenic survival and the formation of chromosomal aberrations in endothelial cells.

Vascular injury and endothelial damage contribute to the efficacy and complications of radiotherapy. Iron chelation protects against iron-catalyzed oxidative injury, but it also inhibits DNA synthesis in proliferating cells and can cause apoptosis. We examined the prevailing effects of iron chelation on the survival of gamma-irradiated human umbilical vein endothelial cells by treating monolayers, primarily in the G1/G0 phase of the cell cycle, with the iron chelator desferrioxamine for 24 h prior to gamma irradiation. Desferrioxamine treatment alone diminished plating efficiency by inducing apoptosis and delaying proliferation; this effect disappeared by 48 h. Desferrioxamine treatment reduced clonogenic survival after exposure to 2.5 Gy gamma radiation, but neither iron loading with hemin nor treatment with another iron chelator, 2,2-dipyridyl, which is a potent inhibitor of ribonucleotide reductase, had an effect on survival after irradiation. Clonogenic survival and chromosomal aberrations were measured in parallel in endothelial cells treated with desferrioxamine after increasing doses of gamma radiation. In a linear-quadratic model of survival, desferrioxamine treatment did not change the occurrence of directly lethal lesions, but it significantly increased sublethal injury. Desferrioxamine was not clastogenic alone, but it increased the frequency of formation of chromosomal rings and of excess acentric fragments after gamma irradiation.

Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene for remission induction. HGTRI 0103.

This study will evaluate the safety and efficacy of allogenic donor lymphocyte infusions in patients who have relapsed hematologic malignancies after allogeneic bone marrow transplantation (BMT). Donor lymphocyte transfusions have resulted in the cure of some patients with relapsed leukemia or lymphoproliferative disorder after allogeneic BMT, but has been complicated by the development of graft versus host disease (GvHD). We hypothesize that a retroviral vector containing the Herpes simplex thymidine kinase (HStk) gene will allow for retention of the anti-leukemia response of transfused donor lymphocytes while allowing for the adverse effects of GVHD to be mitigated. Patients with relapsed hematologic malignancies after allogeneic BMT will be infused with ex vivo gene modified donor lymphocytes. The Herpes Simplex thymidine kinase (HStk) gene will be transduced into the cells ex vivo using LTKOSN. 1 vector supernate. Insertion of the HStk gene into lymphocytes confers a sensitivity to the anti-herpes drug ganciclovir (GCV). This selective destruction of donor lymphocytes in situ will be used to abrogate the effect of graft versus host disease, if it develops.

Effect of T cell subset dose on outcome of T cell-depleted bone marrow transplantation.

T cell depletion using the murine monoclonal antibody (moAb) T10B9 is unique in that the T cell receptor (TCR)gamma delta bearing subset is relatively spared compared to the TCR alpha beta + subset. We evaluated the probabilities of engraftment, acute and chronic graft-versus-host disease (GVHD), relapse, and survival in 273 recipients of marrow T cell depleted using T10B9. Sixty-two patients received marrow from an HLA-identical sibling, 54 patients received partially matched related donor marrow and 157 patients received unrelated donor marrow. Limiting dilution analysis (LDA) was used to estimate total clonable T cell dose in all patients and a modified LDA using moAb-coated immunomagnetic beads was used to estimate TCR alpha beta +, CD4+, and CD8+ T cells in a subset of patients. TCR gamma delta + cell dose was estimated by flow cytometry. Cox proportional hazards regression models were used to assess the impact of T cell subset dose/kg of body weight on outcome. We found a significant association of TCR gamma delta + T cell dose (P = 0.004), but not TCR alpha beta + T cell dose or total clonable T cell dose, with the probability of engraftment. TCR alpha beta +, CD4+, CD8+ and total clonable T cell dose were significantly associated (P < 0.001) with the risks of grade 2-4 acute GVHD in recipients of marrow from related donors but not in recipients of marrow from unrelated donors. Neither total clonable T cell dose nor any T cell subset dose was found to be significantly associated with chronic GVHD, relapse or survival. The results confirm preclinical studies showing TCR gamma delta + T cells promote engraftment. TCR gamma delta + T cells are not associated with an increased risk of acute GVHD while TCR alpha beta T cells are associated with acute GVHD but not engraftment in recipients of marrow grafts T cell depleted using T10B9. These findings support the hypothesis that T cell subsets differentially contribute to alloengraftment and GVHD.

Nitric oxide donors modulate ferritin and protect endothelium from oxidative injury.

Ferritin protects endothelial cells from the damaging effects of iron-catalyzed oxidative injury. Regulation of ferritin occurs through the formation of an iron-sulfur cluster within a cytoplasmic protein, the iron regulatory protein (IRP) that controls ferritin mRNA translation. Nitric oxide has been shown to inhibit iron-sulfur proteins and is present at vascular sites of inflammation; therefore, we undertook a study to examine the influence of nitric oxide on changes in endothelial cell ferritin content in response to iron exposure, and the subsequent effects on susceptibility to oxidative injury. Iron-loaded endothelial cells (EC) exposed to nitric oxide donors synthesize markedly less ferritin. Treatment of EC with a nitric oxide donor increases IRP affinity for ferritin mRNA concomitant with a loss of cytoplasmic aconitase activity in iron-laden EC. Iron-treated EC exposed to NO donors were resistant to oxidative injury despite their low ferritin content when examined 1 h after the treatment period. In contrast, 24 h later, these same cells become sensitive to oxidants, whereas iron-treated EC that are ferritin-rich continue to be resistant. In conclusion, NO inhibits the increase of EC ferritin after exposure to iron but provides short-term protection against oxidants; ferritin, in turn, provides durable cytoprotection by inactivating reactive iron.

Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro.

Low density lipoprotein (LDL), if it becomes oxidized, develops several unique properties including the capacity to provoke endothelial cytotoxicity via metal-catalyzed free radical-mediated mechanisms. As were previously have shown that iron-catalyzed oxidant injury to endothelial cells can be attenuated by the addition of exogenous iron chelators such as the lazaroids and deferoxamine, we have examined whether the endogenous iron chelator, ferritin, might provide protection from oxidized LDL. LDL oxidized by iron-containing hemin and H2O2 is toxic to endothelial cells in a time- and dose-dependent fashion. Endothelial cell ferritin content is increased by pretreatment of cells with iron compounds or by the direct addition of exogenous apoferritin; ferritin-loaded cells are markedly resistant to the toxicity caused by oxidized LDL. Iron inactivation by ferritin depends on its ferroxidase activity. When a recombinant human ferritin heavy chain mutant, 222, which is devoid of ferroxidase activity, is added to endothelial cells, unlike the excellent protection afforded by the wild-type recombinant heavy chain, endothelial cells are not protected from oxidized LDL. To assess the in vivo relevance of our observation, we examined human coronary arteries of cardiac explants taken from patients with end-stage atherosclerosis. Large amounts of immunoreactive ferritin are focally detected in atherosclerotic lesions, specifically in the myofibroblasts, macrophages, and endothelium without a notable increase in Prussian blue-detectable iron. These findings suggest that ferritin may modulate vascular cell injury in vivo.

Endothelial cell heme oxygenase and ferritin induction in rat lung by hemoglobin in vivo.

Iron-derived reactive oxygen species play an important role in the pathogenesis of various vascular disorders including vasculitis, atherosclerosis, and capillary leak syndromes such as the adult respiratory distress syndrome (ARDS). We have suggested that acute incorporation of the heme moiety of hemoglobin released from red blood cells into endothelium could provide catalytically active iron to the vasculature. Adaptation to chronic heme stress involves the induction of heme oxygenase and ferritin; the latter provides cytoprotection against free radicals in vitro. The present studies examine the bioavailability of heme, derived from hemoglobin, to induce heme oxygenase and ferritin in rat lungs in vivo. Intravenous injection of methemoglobin, but not oxyhemoglobin, increases total lung heme oxygenase mRNA approximately fivefold after 16 h. Accompanying this mRNA induction, expression of total lung heme oxygenase enzyme activity is also markedly enhanced. In situ hybridization for heme oxygenase reveals mRNA accumulation in the lung microvascular endothelium, implying incorporation of heme into endothelial cells. Similarly, methemoglobin significantly increases the ferritin protein content of rat lungs and in parallel, ferritin light-chain mRNA increases approximately 1.6-fold, whereas heavy-chain mRNA is upregulated by approximately 1.9-fold. Immunoreactive ferritin is present in lung microvascular endothelium after methemoglobin treatment, suggesting incorporation of heme iron into pulmonary vasculature. Subcutaneous injection of Sn-protoporphyrin IX, a competitive inhibitor of heme oxygenase, does not affect methemoglobin-induced ferritin synthesis in lungs. We speculate that methemoglobin, which might be generated by activated leukocytes in ARDS associated with disseminated interavascular coagulation, can provide heme iron to lung microvascular endothelium to induce heme oxygenase and ferritin.

Herpes simplex virus decreases endothelial cell plasminogen activator inhibitor.

Herpes simplex virus (HSV) infection is histopathologically associated with vascular injury, fibrinoid necrosis and inflammatory cell infiltrates. We have previously shown in vitro that HSV infection of human umbilical vein endothelial cells (HUVEC) promotes a procoagulant phenotype manifest by the induction of tissue factor, the loss of thrombomodulin, and an increase in platelet adhesion. In these studies we examined the effects of HSV infection on HUVEC plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA). HSV infection caused the loss of PAI-1 in the extracellular matrix (ECM) and that released into the supernatant of HUVEC. Both activity and antigen levels of the Serpin inhibitor are diminished as a result of HSV infection. The loss of inhibitor is not secondary to diminished vitronectin (Vn), the primary binding protein of PAI-1 in the ECM, but appears to be secondary to decreased synthesis at the RNA level. Tissue plasminogen activator (t-PA) synthesis is also decreased in endothelial HSV infection. PAI-1 loss may further promote a procoagulant phenotype in HSV infection in vivo.

Hemolytic uremic syndrome following bone marrow transplantation.

Bone marrow transplant (BMT) is increasingly being offered as therapy for certain hematologic and other advanced malignancies. We present one representative patient in detail and summarize data from a series of 10 patients who received a BMT and, as a late complication, developed a hemolytic uremic syndrome (HUS). All patients presented with the triad of microangiopathic hemolytic anemia, renal insufficiency and thrombocytopenia from 30 to 875 days after BMT, and despite aggressive supportive management, plasma exchange, IgG administration and/or ex vivo staphylococcal protein A column plasma treatment, eight of 10 patients died from complications related to HUS between 11 to 139 days after diagnosis. In contrast to other reports of HUS after BMT, the present series of patients is heterogeneous with respect to underlying diagnosis, type of BMT (allogeneic or autologous), pretransplant conditioning regimen, presence of graft-versus-host disease, and use of cyclosporin. Additionally, nine of 10 patients were in clinical remission at the time of diagnosis of HUS, and six of 10 patients had achieved a complete recovery following BMT. The cause of HUS in this series of patients is probably multifactorial and related to the intensive pretransplant conditioning regimen.

What is the value of the computer for the physician?

Computer technology is advancing at an increasingly rapid rate. Although the computer's former role in the health care field was primarily limited to the financial and marketing departments of health care facilities, the computer is moving beyond the managerial departments and into the realm of the practicing physician. Much of this change in the use of computers in this field is due to the pressures of cost containment, DRG requirements, the availability of microcomputers, and the desire for improved health care. In the areas of clinical care, medical research, and medical education, the computer is rapidly becoming an indispensable tool through its technological adaptation. The computer is an obvious adjunct to the problem of improving cost efficiency without compromising the efforts toward better health care.