Showing papers on "Transplantation published in 1989"

Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts

Abstract: An important corollary to the recent advances in our understanding of the primary cause of Duchenne muscular dystrophy, is the validation of genuine genetic homologues as animal models of the disease in which potential therapies can be tested. The persistent skeletal muscle necrosis that characterizes human Duchenne muscular dystrophy is also seen in the mdx mouse and is, in both, a consequence of a deficiency of dystrophin, probably within the muscle fibres themselves. As injected muscle precursor cells of one genotype can fuse with host muscle fibres of a different genotype and express the donor genes, we decided to test grafts of normal muscle precursor cells to see if they could induce synthesis of dystrophin in innately dystrophin-deficient mdx muscle fibres. We show that injected normal muscle precursor cells can fuse with pre-existing or regenerating mdx muscle fibres to render many of these fibres dystrophin-positive and so to partially or wholly rescue them from their biochemical defect.

Harvesting Autogenous Iliac Bone Grafts: A Review of Complications and Techniques

Abstract: Autogenous bone grafts from the ilium are frequently harvested for purposes of bone union and/or stability. Although some donor site complications may be unavoidable, awareness of the anatomy and complications may aid in planning the approach and minimizing the risks. Documented donor site complications include pain, nerve and arterial injury, peritoneal perforation, sacroiliac joint instability, and herniation of abdominal contents through defects in the ilium. Strict observation of relevant anatomic considerations will help in avoiding these complications.

Modulation of cardiac autonomic activity during and immediately after exercise.

Abstract: Fluctuations in heart rate above 0.03 Hz reflect autonomic modulation of sinoatrial node activity. To assess the dynamics of autonomic nervous activity during and immediately after exercise, we determined the power spectrum of heart rate and respiratory fluctuations in 43 normal subjects without known cardiac disease, 8 patients with severe congestive heart failure, and 6 patients status-post cardiac transplantation before, during, and after graded-work load exercise on a cycle ergometer. Before exercise, heart rate fluctuations (spectral power) at both high (0.15-0.80 Hz) and low (0.03-0.15 Hz) frequencies were significantly higher in normal subjects than in either heart failure or transplant patients but were not different between the two groups with heart disease. During exercise, heart rate power at all frequencies rapidly and progressively decreased in normal subjects, until at peak exercise it was not different from the other two groups. During recovery, heart rate power increased in normal subjects but remained significantly below base line. The findings demonstrate a marked reduction of autonomic modulation of heart rate in patients with heart failure and after cardiac transplant and support a progressive withdrawal of vagal activity during exercise with a gradual increase during recovery in normal subjects.

Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen.

Abstract: The use of allogeneic bone marrow transplantation as a means of inducing donor-specific tolerance across MHC barriers could provide an immunologically specific conditioning regimen for organ transplantation. However, a major limitation to this approach is the toxicity of whole body irradiation as currently used to abrogate host resistance and permit marrow engraftment. The present study describes methodology for abrogating host resistance and permitting marrow engraftment without lethal irradiation. Our preparative protocol involves administration of anti-CD4 and anti-CD8 mAbs in vivo, 300-rad WBI, 700-rad thymic irradiation, and unmanipulated fully MHC-disparate bone marrow. B10 mice prepared by this regimen developed stable mixed lymphohematopoetic chimerism without any clinical evidence of graft-vs.-host disease. Engraftment was accompanied by induction of specific tolerance to donor skin grafts (B10.D2), while third-party skin grafts (B10.BR) were promptly rejected. Mice treated with the complete regimen without bone marrow transplantation appeared healthy and enjoyed long-term survival. This study therefore demonstrates that stable mixed chimerism with donor-specific tolerance can be induced across an MHC barrier after a nonlethal preparative regimen, without clinical GVHD and without the risk of aplasia.

Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975-1984.

Abstract: Using the records linkage system of the Mayo Clinic and of the Rochester Epidemiology Project, which accesses diagnostic data on the entire population of Olmsted County, Minnesota, we identified 45 new cases of idiopathic dilated cardiomyopathy (DCM) and 19 new cases of hypertrophic cardiomyopathy (HCM) among county residents for the years 1975-1984. Overall age- and sex-adjusted incidence rates were 6.0/100,000 and 2.5/100,000 person-years, respectively. The incidence of DCM doubled from 3.9/100,000 in the first 5 years to 7.9/100,000 person-years in the last 5 years of study. The corresponding change for HCM was from 1.4 to 3.6/100,000 person-years. Age- and sex-adjusted prevalence rates as of January 1, 1985, for DCM and HCM were 36.5/100,000 and 19.7/100,000 population, respectively. The prevalence of DCM in persons less than 55 years old was 17.9/100,000, over a third of whom were New York Heart Association functional Class III or IV at diagnosis. These estimates may be of value in determining the potential use of health care resources, particularly cardiac transplantation.

Orthotopic liver transplantation with preservation of the inferior vena cava.

Abstract: Piggyback orthotopic liver transplantation was performed in 24 patients during a period of 4 months. This represented 19% of the liver transplantation at our institution during that time. The piggyback method of liver insertion compared favorably with the standard operation in terms of patient survival, blood loss, incidence of vascular and biliary complications, and rate of retransplantation. The piggyback operation cannot be used in all cases, but when indicated and feasible its advantages are important enough to warrant its inclusion in the armamentarium of the liver transplant surgeon.

Bone transplantation and human immunodeficiency virus. An estimate of risk of acquired immunodeficiency syndrome (AIDS).

Abstract: The possibility of transplanting a bone allograft from a donor infected with human immunodeficiency virus (HIV) is remote, provided there is a combination of rigorous donor selection and exclusion, screening for the HIV antigen and antibody, and histopathologic studies of donor tissues The chance of obtaining a bone allograft from an HIV-infected donor who failed to be excluded by the above techniques is calculated to be one in well over a million, using average estimates On the other hand, if adequate precautions are not taken (for example, by testing only for antibodies to HIV), the risk might be as high as one in 161

Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up

Abstract: By using stereotaxic surgical techniques, ventral mesencephalic tissues from aborted human fetuses of 8 to 10 weeks' gestational age were implanted unilaterally into the striata in two patients with advanced Parkinson's disease. The patients were treated with a cyclosporine, azathioprine, and steroid regimen to minimize the risk for graft rejection. They were examined for 6 months preoperatively and 6 months postoperatively and continued to receive the same doses of antiparkinsonian medication. There were no significant postoperative complications. No major therapeutic effect from the operation was observed. However, in the clinical tests, both patients showed small but significant increases of movement speed for repeated pronation-supination, fist clenching, and foot lifting. The rate of walking also increased in the one patient tested. For both patients, there was an initial worsening postoperatively, followed by improvement vs preoperative performance at 1 to 3 months. Both patients also showed significant improvement in the magnitude of response to a single dose of levodopa (L-dopa), but there was no increase in the duration of drug action. The motor readiness potential increased in both patients postoperatively, primarily over the operated hemisphere. Neurophysiological measurements also showed a more rapid performance of simple and complex arm and hand movements on the side contralateral to transplantation in one patient at 5 months postoperatively. Positron emission tomography demonstrated no increased uptake of 6-L-(18F)-fluorodopa in the transplanted striatum at 5 and 6 months. Taken together, these results suggest that the fetal nigral implants may have provided a modest improvement in motor function, consistent with the presence of small surviving grafts. Although our results support further scientific experimentation with transplantation in Parkinson's disease, widespread clinical trials with this procedure are probably not warranted at this time.

Repair of rabbit articular surfaces with allograft chondrocytes embedded in collagen gel

Abstract: In an attempt to repair articular cartilage, allograft articular chondrocytes embedded in collagen gel, were transplanted into full-thickness defects in rabbit articular cartilage. Twenty-four weeks after the transplantation, the defects were filled with hyaline cartilage, specifically synthesising Type II collagen. These chondrocytes were autoradiographically proven to have originated from the transplanted grafts. Assessed histologically the success rate was about 80%, a marked improvement over the results reported in previous studies on chondrocyte transplantation without collagen gel. By contrast, the defects without chondrocyte transplantation healed with fibrocartilage. Immunological enhancement induced by transplanted allogenic chondrocytes or collagen was not significant at eight weeks after treatment, so far as shown by both direct and indirect blastformation reactions. Thus, allogenic transplantation of isolated chondrocytes embedded in collagen gel appears to be one of the most promising methods for the restoration of articular cartilage.

Historical review and present status of free fat graft autotransplantation in plastic and reconstructive surgery.

Abstract: Free fat graft autotransplantation for soft-tissue replacement has been a neglected subject in recent years. In a review of the literature, investigations of the various uses of free fat autotransplantation in animals and humans provide an understanding of the problems associated with the use of fat as a free graft. Results of free fat autotransplantation were found to be quite unpredictable, with wide variations in the resulting bulk of the graft. Microscopic studies of this behavior led to controversy as to whether the graft ultimately was made of surviving graft adipocytes (cell survival theory) or host adipocytes (host replacement theory). Studies revealed a "fibroblast-like" mesenchymal cell within adipose tissue that was believed to be an immature adipocyte precursor or preadipocyte. Further characterization of the preadipocyte and its complete differentiation was accomplished using tissue-culture techniques. These investigations provide evidence of the dynamic nature of adipose tissue that strongly supports the cell survival theory and gives explanation to the unpredictable behavior of free fat autografts. Many conditions treated by plastic surgeons require soft-tissue augmentation. Autogenous adipose tissue is the most appropriate and natural replacement material. With new culturing techniques, preadipocytes in a single cell suspension may provide an injectable soft-tissue replacement. This subject appears ripe for investigation.

A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts

Abstract: Cytomegalovirus is a major viral pathogen in patients who undergo renal transplantation, and cytomegalovirus disease is difficult to treat. We therefore conducted a randomized, placebo-controlled, double-blind trial of acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts from cadavers. Acyclovir was given orally in doses of 800 to 3200 mg per day, according to the patients' estimated level of renal function. Patients took the first dose of either acyclovir or placebo six hours before transplantation and continued to take the assigned medication for 12 weeks. Of 118 patients enrolled in the study, 104 completed at least 30 days on the study medication and were included in our analysis of the results. During the first year after transplantation, 4 of 53 patients (7.5 percent) in the acyclovir group had symptomatic cytomegalovirus disease, as compared with 15 of 51 (29 percent) in the placebo group (P = 0.002). There was a single case of cytomegalovirus pneumonia in the acyclovir group, as compared with nine in the placebo group. The greatest prophylactic benefit of acyclovir was observed among seronegative patients who had received a kidney from a seropositive donor; only one of six such patients in the acyclovir group had cytomegalovirus disease, as compared with all seven in the placebo group. Acyclovir decreased the incidence of documented cytomegalovirus infection (with or without symptomatic disease) to 36 percent from 61 percent among the patients who received the placebo (P = 0.011). Among the patients who received acyclovir, the rates of recovery of virus from the blood and urine were significantly reduced, but the rate of viral shedding from the pharynx was not significantly different from that in the placebo group. There were no differences between the groups in the frequency of adverse events or in the rate of survival of either grafts or patients. We conclude that the oral administration of acyclovir, beginning before the transplantation of a renal allograft from a cadaver, reduces the rate of cytomegalovirus infection and disease without affecting the survival rate of either grafts or patients.

Liver transplantation (1).

Abstract: Advances in the management of both chronic and acute hepatic disease have been made possible and even mandated by the development of liver transplantation. The clinical use of transplantation has proceeded at a rapid pace since a Consensus Development Conference of the National Institutes of Health concluded in June 1983 that liver transplantation had become a service and not simply an experimental procedure.1 The liver can be transplanted as an extra (auxiliary) organ at an ectopic site, or in the orthotopic location after the removal of the host liver (Fig. 1). This article will focus primarily on the orthotopic procedure. However, there has been renewed interest in the auxiliary operation, which will be discussed separately. Figure 1 Orthotopic Liver Transplantation Candidacy for Transplantation The conceptual appeal of liver transplantation is so great that the procedure may come to mind as a last resort for virtually every patient with lethal hepatic disease. The selection of appropriate recipients from such a large pool requires strict individual assessment. A 1982 estimate of the annual need for liver transplantation was 15 per million population,2 but the current need is undoubtedly higher because there are now fewer restrictions on candidacy. Between 4000 and 50,000 liver transplantations a year may be needed in the United States. The supply of organs will increasingly influence the criteria for candidacy and limit the use of the procedure. Discussions about rationing transplantation services for this reason are nonetheless premature, because the balance between need and supply has not been determined. In the United States, the yearly rate of liver transplantation has reached approximately 1600; it averaged 147 a month between July and December 1988 (Vaughn W, United Network of Organ Sharing: personal communication). The annual rate in Europe approaches this figure. Policies on organ donation will have to be reexamined if substantial growth is to occur. Many potential liver donors are probably rejected unjustifiably. The arbitrary upper age limit observed by most programs3 cannot be justified, because senescence largely spares the liver.4 Atherosclerosis of the hepatic arteries is not usually found beyond the origin of the celiac axis.4 Our own limited experience with livers from donors over 50 years old has been encouraging. Potential donors of all ages are often excluded because of poor arterial-blood gas levels, their need for inotropic or vasopressor drugs, minor abnormalities of liver function, or diseases such as diabetes mellitus.3 The results with livers from such donors in both the United States5 and Europe6 have been as good as those with healthier donors. The use of better techniques of preservation,7-9 which allow the safe storage of liver grafts for a day instead of the previous six or eight hours, should reduce organ wastage, since with this extra time, countrywide and worldwide networks of organ sharing can be created. If there is an adequate organ supply and a way to finance transplantation, the medical issues of candidacy are relatively clear. In a patient with nonmalignant end-stage liver disease that will not recur in the hepatic graft, there is little debate about the rationale for transplantation. Transplantation is more debatable if the recurrence of a non-neoplastic disease is predictable. The most controversial indication for liver transplantation is for the treatment of hepatic cancers. However, none of these applications should be arbitrarily excluded from future trials. Non-neoplastic Liver Diseases By 1982 liver transplantation had been used to treat more than 20 benign diseases.2 Since then, the list has become so long10-15 that it is increasingly reported in broad categories, such as cholestatic or parenchymal disease16 (Table 1). It is therefore easy to lose sight of the fact that more than 60 distinct diseases have been treated with liver transplantation, including 16 in the broad category of inborn errors of metabolism and 14 in the category of cholestatic disease. Table 1 Native Liver Disease in 400 Pediatric and 858 Adult Recipients of Liver Transplants at the University of Pittsburgh, 1981–1988 In adults, the most common diagnoses have been chronic active hepatitis, cryptogenic cirrhosis, primary biliary cirrhosis, alcoholic cirrhosis, and inborn errors of metabolism. Half or more of the pediatric recipients have had biliary atresia, with inborn metabolic errors a distant second.10-13 A number of diseases in which transplantation might have been precluded or strongly discouraged 5 or 10 years ago are no longer absolute contraindications for the procedure, and some are not even questionable. A prime example is alcoholic cirrhosis. With multidisciplinary care for substance abuse in properly selected cases, the results of transplantation for Laennac's cirrhosis are as good as those for other diseases.17 Somewhat more controversial is transplantation in patients with cirrhosis due to hepatitis B virus, because the recurrence of viral infection cannot be reliably prevented. However, many such patients have benefited from transplantation, and it is therefore difficult to make the carrier state an absolute contraindication. An even more difficult issue is whether patients with antibodies to the human immunodeficiency virus (HIV) should be excluded from candidacy. Shortly after screening tests for this disease became widely available in the spring of 1985, HIV infections were reported in kidney, heart, and liver recipients. At our institution, HIV antibodies were found in the stored serum of 18 of 1043 kidney, heart, or liver recipients (1.7 percent) treated between 1981 and 1986.18 The incidence of HIV in the liver recipients was 2.6 percent, and in one third the antibodies predated transplantation. Seroconversion after transplantation — through infection from blood-component therapy or (uncommonly) from the donor's liver — made up the other two thirds.18 The rate of seroconversion at our institution and others has remained unchanged, despite the use of screening assays for HIV antibodies beginning in March 1985.18,19 The patients infected with HIV have been available for study since their transplantation. We have followed 10 children who were six months to 16 years old at the time of transplantation for 1½ to 6 years, with only one late death from a complication related to the acquired immunodeficiency syndrome (AIDS). Among 16 adults, the AIDS-related mortality has been 37 percent. Many patients can thus have prolonged benefit from liver transplantation in spite of positive tests for HIV. How this fact has been used in decision making varies with the transplantation center. The most commonly accepted policy in the United States is to screen all recipients for HIV, but not to exclude transplantation solely because of a positive test. The screening of potential donors is obligatory at all centers. Tests that identify both HIV antigens and antibodies may make the screening of recipients as well as donors more foolproof than it is now. In addition to disease states that at one time would have ruled out liver transplantation, inflexible age proscriptions have been dropped. An upper age limit was eliminated when it was demonstrated that recipients over 50 have a 5-year survival after transplantation, similar to that of younger adults.20 At the other extreme, liver transplantation in very small infants and even newborns has become common, although the results are better with older children.21 Extensive thromboses of the portal, mesenteric, or splenic veins, which previously made transplantation difficult or impossible, have been eliminated in many cases through the use of vein grafts. The vein grafts are connected to the superior mesenteric vein and brought through the transverse mesocolon anterior to the pancreas into the liver hilum for anastomosis to the portal vein of the new liver.22,23 The routine use of imaging techniques to measure the size of the liver and determine the state of the host vessels helps to identify these cases in advance, and appropriate plans can be made. Scarring from multiple upper-abdominal operations, once considered a contraindication by many transplantation teams, is no longer an overriding deterrent in major centers. Earlier splenectomy or portal–systemic shunts cause the greatest concern. Since any of these operations can alter the portal vein, it is no surprise that the majority of complications of portal-vein reconstruction during transplantation have been in patients with earlier shunt operations.24 Mesocaval and distal splenorenal shunts have been least harmful, since they do not involve dissection of the portal hilum. The shunt must be closed at the time of transplantation for optimal vascularization of the graft. Should shunting operations ever be recommended to treat variceal hemorrhage, given that these procedures can jeopardize the success of the ultimate step, liver transplantation? Probably only rarely, since endoscopic sclerosis of the varices is an effective alternative. In some patients with grade A (good-risk) cirrhosis according to Child's system, a distal splenorenal anastomosis may be the best way to relieve portal hypertension. However, it is important to emphasize that a liver transplantation itself decompresses portal hypertension throughout the capillary bed of the healthy new liver. Among patients with variceal bleeding who were too sick to be considered for any operation other than transplantation, the five-year survival after their livers were replaced was far superior to that reported in series of patients at generally better risk who underwent shunting operations.25 The obvious limitations of the shunt in treating variceal bleeding have greatly reduced the frequency of portal diversions in Western countries.

Left ventricular myocardial structure in aortic valve disease before, intermediate, and late after aortic valve replacement.

Abstract: Left ventricular biplane cineangiography, micromanometry, and endomyocardial biopsies were performed in 27 patients with aortic stenosis (AS) and in 17 patients with aortic insufficiency (AI). Twenty-three patients with AS and 15 with AI were restudied at an intermediate time (18 months after successful valve replacement), and nine patients with AS and six with AI were restudied late (70 and 62 months after surgery). Biopsy samples were evaluated for muscle fiber diameter, percent interstitial fibrosis, and volume fraction of myofibrils. In control biopsy samples obtained from five donor hearts at transplantation, these morphometric variables averaged 21.2 microns, 7.0%, and 57.2%, respectively. After surgery, mass determined by cineangiography decreased from 186 to 115 and 94 g/m2 in patients with AS and from 201 to 131 and 93 g/m2 in patients with AI. At the three studies, muscle fiber diameter was 30.9, 28.0, and 28.7 microns in patients with AS and was 31.4, 27.6, and 26.4 microns in patients with AI. Percent interstitial fibrosis was 18.2, 25.8, and 13.7% in patients with AS and was 20.4, 23.7, and 19.2% in patients with AI. Left ventricular fibrous content decreased from 34.2 to 29.8 and to 12.7 g/m2 in patients with AS and from 42.1 to 28.9 and to 18.9 g/m2 in patients with AI. Volume fraction of myofibrils was 57.7, 56.8, and 49.0% in patients with AS and was 56.8, 56.6 and 48.8% in patients with AI. Thus, the decrease of muscle mass determined by cineangiography at the intermediate time after valve replacement is mediated by regression of myocardial cellular hypertrophy in patients with AS and AI and in addition by a decrease of fibrous content in patients with AI. Late after surgery, left ventricular fibrous content also decreases in patients with AS. This late decrease associated with minor changes of end-diastolic volume may be important for improvement of increased diastolic myocardial stiffness. Even 6-7 years after valve replacement, incomplete regression of structural abnormalities of left ventricular hypertrophy still exists compared with the normal myocardium. The residually increased relative interstitial fibrosis and the small late postoperative decrease of volume fraction of myofibrils, associated with a prosthesis-related slight left ventricular pressure increase, are at the origin of a persistent systolic overload at the myofibrillar level.

Muscle transplantation between young and old rats: age of host determines recovery

Abstract: As compared with age-matched controls, extensor digitorum longus (EDL) muscles autografted in young rats regenerated significantly greater mass (1.8 times) and developed greater maximum contractile force (2.6 times) than EDL muscles autografted in old rats. A cross-age transplantation study showed that the mass and maximum force of old muscles grafted into young hosts were not significantly different from those of young muscles grafted into the same young hosts. Conversely, young muscle grafted into old hosts regenerated no better than old muscles grafted into the same old hosts. We conclude 1) that chronological age alone is not a factor that limits the intrinsic ability of a muscle to regenerate and 2) that the poor regeneration of muscles in old animals is a function of the environment for regeneration provided by the old host.

Homologous meniscus transplantation. Experimental and clinical results.

Abstract: The increase in severe ligament injuries of the knee has led to consideration of the need for meniscal transplantation in reconstructive operations for chronic rotational instability. Transplantation of the medial meniscus was carried out in two groups of 15 sheep. In one group lyophilised, γ-sterilised allogenic menisci were transplanted and these underwent a complete remodelling in 48 weeks. In the other group, deep frozen allogenic menisci were used and these remained fully functional without remodelling. We then carried out meniscal transplantation in 22 patients who were followed-up for a mean of 14 months. Arthroscopy was possible in two-thirds of the cases at an average of 8 months after operation. Both types of transplanted menisci, lyophilised and deep frozen, decreased in size, as small as a regenerated meniscus in some cases. In general the deep frozen menisci showed better results.

Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia.

Abstract: To determine the incidence of secondary cancers after bone marrow transplantation, we reviewed the records of all patients at our center who received allogeneic, syngeneic, or autologous transplants for leukemia (n = 1926) or aplastic anemia (n = 320). Thirty-five patients were given a diagnosis of secondary cancer between 1.5 months and 13.9 years (median, 1.0 year) after transplantation. Sixteen patients had non-Hodgkin's lymphomas, 6 had leukemias, and 13 had solid tumors (including 3 each with glioblastoma, melanoma, and squamous-cell carcinoma). There were 1.2 secondary cancers per 100 exposure-years during the first year after transplantation (95 percent confidence interval, 0.7 to 2.0). The rate declined to 0.4 (95 percent confidence interval, 0.2 to 0.7) after one year. The age-adjusted incidence of secondary cancer was 6.69 times higher than that of primary cancer in the general population. In a multivariate model, the predictors (and relative risks) of any type of secondary cancer were acute graft-versus-host disease treated with either antithymocyte globulin (relative risk, 4.2) or an anti-CD3 monoclonal antibody (13.6) and total-body irradiation (3.9). Two additional factors were associated with secondary non-Hodgkin's lymphomas: T-lymphocyte depletion of donor marrow (12.4) and HLA mismatch (3.8). We conclude that recipients of bone marrow transplantation have a low but significant risk of a secondary cancer, particularly non-Hodgkin's lymphoma.

Automated islet isolation from human pancreas.

Abstract: An automated method for the isolation of human pancreatic islets is described. The procedure meets the following requirements: 1) minimal traumatic action on the islets, 2) continuous digestion in which the islets that are progressively liberated can be saved from further enzymatic action, 3) minimal human intervention in the digestion process, and 4) high yield and purity of the isolated islets. After purification of Ficoll gradients, an average of 2279 islets/g pancreas was obtained, with an average purity of 79% islets. The average volume and average insulin content of the final islet preparation were 348 mm3 and 93.4 U, respectively. The islets were morphologically intact with a normal degree of beta-cell granulation, responded to glucose stimulation with a fivefold increase of insulin secretion over basal levels, and produced normoglycemia after transplantation into diabetic mice. The procedure is being used in the second phase of clinical trials of islet transplantation in patients with insulin-dependent diabetes mellitus.

The role of liver transplantation in hepatobiliary malignancy. A retrospective analysis of 95 patients with particular regard to tumor stage and recurrence

Abstract: The role of hepatic transplantation in patients with nonresectable liver or bile duct cancer remains a controversial issue. An analysis of 95 consecutive cases was undertaken to evaluate retrospectively the pathological tumor stage--in accordance with the TNM system--and outcome after transplantation. Included were patients with the following diagnoses: hepatocellular carcinoma (n = 52), cholangiocellular carcinoma (n = 10), hepatoblastoma (n = 2), hemangiosarcoma (n = 2), bile duct carcinoma (n = 20), and liver metastases from different primary tumors (n = 9). The overall actuarial survival rate at 5 years was 20.4%. Median survival improved significantly within the last 4 years as compared to the preceding era (18.06 vs. 4.0 months). Currently 27 patients are alive, with the longest follow-up more than 12 years. The incidences of residual or recurrent tumor were 27 and 28, respectively. Particularly in patients who underwent transplantation for hepatocellular or bile duct carcinoma without extra-hepatic tumor spread, the results were significantly better; median survival time achieved for these two groups were 120 (p less than 0.01) and 35 months (p less than 0.05). Prolonged survival without tumor recurrence was not seen in patients with cholangiocellular carcinoma or liver metastases. These results demonstrate clearly that liver transplantation for hepatobiliary malignancy is still justified on the premises of careful patient selection by adequate tumor staging.

Embryonic Origins and Assembly of Blood Vessels

Abstract: Embryonic blood vessels develop in two ways: angiogenesis, which is growth by budding, branching, and elongation of existing vessels, and in situ formation of endothelial vesicles that coalesce with elongating vessels. It is assumed that the former is more prevalent, with the latter restricted to vessels that form near the endoderm:mesoderm interface. Neither the relative contributions of each of these processes in the formation of specific blood vessels nor the origins of precursors (angioblasts) of these intraembryonic endothelial populations are known. Antibodies that recognize quail endothelial cells can be used to follow the movements and differentiation of endothelial cell precursors after the transplantation of putative precursor populations from quail into chick embryos. Using this method, it has been shown that all intraembryonic mesodermal tissues, except the prechordal plate, contain angiogenic precursors. After transplantation some angioblasts move in all directions away from the site of implantation, invading surrounding mesenchyme and contributing to the formation of arteries, veins, and capillaries in a wide area. Although it is clear that these invasive angioblasts, which behave unlike any other embryonic mesenchymal cell type, are found throughout the embryo, it is not known whether they represent a unique endothelial cell type in mature blood vessels. Irrespective of their original location in the donor embryo, transplanted angioblasts will form vascular channels that are appropriate for the tissues surrounding their site of implantation. These results indicate that the control over vascular assembly resides within the connective-tissue-forming mesenchyme of the embryo.

Graft-versus-Host Disease as Adoptive Immunotherapy in Patients with Advanced Hematologic Neoplasms

Abstract: The occurrence of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation for leukemia is thought to decrease the probability of recurrence. To study this effect (called adoptive immunotherapy) we modified the prophylaxis of GVHD in patients with advanced hematologic neoplasms (mostly leukemia) who received bone marrow transplants. Patients under 30 years of age were randomly assigned to one of three regimens of post-transplantation immunosuppression: Group I (n = 44) received a standard course of methotrexate for 102 days after transplantation, Group II (n = 40) received an abbreviated (11-day) course of methotrexate, and Group III (n = 25) received the standard course of methotrexate plus viable buffy-coat cells from the marrow donors. All 109 patients received cyclophosphamide (60 mg per kilogram of body weight on each of two days), total-body irradiation (2.25 Gy daily for seven days), and unmodified marrow from HLA-identical sibling donors. The frequency of GVHD of Grades II through IV was 25 percent in Group I, 59 percent in Group II, and 82 percent in Group III (P = 0.0001). The incidence of chronic GVHD, however, did not differ significantly among the groups (33, 51, and 44 percent, respectively), nor did the five-year probability of recurrence of disease (38, 45, and 33 percent, respectively). However, mortality from causes other than cancer was 34 percent in Group I, 45 percent in Group II, and 64 percent in Group III (I vs. III, P = 0.024); the deaths were due primarily to infections complicating the course of GVHD. With a median follow-up of 5.1 years (range, 3.9 to 7.4), disease-free survival was 41 percent in Group I, 30 percent in Group II, and 24 percent in Group III (the differences were not statistically significant). We conclude that abbreviating methotrexate prophylaxis or infusing donor buffy-coat cells increased the incidence of acute GVHD and related mortality without altering the incidence of chronic GVHD or the recurrence of malignant disease.

Primary nonfunction of hepatic allografts with preexisting fatty infiltration.

Abstract: One of the unresolved problems in liver transplantation is how to determine accurately the cause of the primary nonfunction that is seen in about 10% of hepatic grafts (1, 2). It is often assumed that ischemic injury has occurred when the new liver does not function. Acute immunologic injury comparable to the humorally mediated hyperacute rejection of kidneys probably occurs rarely, if at all (3), but an indolent version of hyperacute hepatic rejection that is not clearly associated with demonstrable preformed antibodies can cause hemorrhagic necrosis within 1 or 2 days (4). The other most common etiology of primary nonfunction probably is intraoperative injury of the transplant when a flawed operation is performed by the recipient team (1). Preexisting acute or chronic hepatic disease in the recipient will undoubtedly aggravate any of the foregoing factors, or may itself preclude success. Although hepatic injury may occur as part of the trauma that has led to brain death or may be an iatrogenic complication of the care that is provided, this may be difficult to prove even with biopsies of the homograft. Makowka et al. (5) have reported a surprising lack of correlation between so-called good- and bad-risk donor parameters and the clinical outcome of the recipient. We report here 2 examples of acute fatty infiltration of livers that had been procured from seemingly good donors who had been in good health until 1 and 2 ½ days previously. The grafts that were full of fat never functioned and were replaced immediately in 1 case and 3 days later in the other. This report suggests how to identify and avoid this lethal situation.

Induction of classical transplantation tolerance in the adult.

Abstract: Transplantation tolerance across histoincompatibilities in multiple non-H-2 minors (B10.BR into CBA/Ca) and "minor" plus H-2D (B10.A into CBA/Ca) antigens has been achieved successfully by combined adult bone marrow transplantation and treatment with CD4 and CD8 mAbs. The tolerant state was confirmed by permanent acceptance of donor strain skin grafts, and in vitro unresponsiveness to donor cells. Tolerance was associated with partial donor chimerism to various degrees. Tolerance to minor transplantation antigens induced in this manner was restricted to recipient-type MHC. The possibility was raised that tolerance resulted, at least in part, from clonal anergy rather than deletion.

Detection of focal hepatic masses: prospective evaluation with CT, delayed CT, CT during arterial portography, and MR imaging.

Abstract: The sensitivities of contrast medium-enhanced computed tomography (CT), delayed CT (DCT), CT during arterial portography (CTAP), and magnetic resonance (MR) imaging for detecting focal liver lesions were prospectively evaluated in eight patients who subsequently underwent hepatic lobectomy or transplantation. Pathologic evaluation of the resected liver specimens demonstrated 37 lesions. The sensitivities were 81% (30 of 37 lesions) for CTAP, 57% (21 of 37 lesions) for MR imaging, 52% (12 of 23 lesions) for DCT, and 38% (14 of 37 lesions) for contrast-enhanced CT. The difference between the sensitivity of CTAP and the sensitivities of the other imaging tests was statistically significant (P less than .004). Of the lesions smaller than 1 cm in diameter, CTAP depicted 61% (11 of 18 lesions), MR imaging 17% (three of 18 lesions), CT 0% (zero of 18 lesions), and DCT 0% (zero of nine lesions). It is concluded that for preoperative detection of focal hepatic masses, CTAP is the most accurate technique available to most radiologists. Patients with primary or secondary hepatic neoplasms who are being considered for hepatic resection should undergo CTAP as part of their preoperative examination.