Biomedical subjects
R Calne
Publications and source records attributed to R Calne.
Impact of immunosuppressants on host tissues and tolerance.
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Criteria and assessment of immunosuppressive agents.
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Liver transplantation for hepatocarcinoma.
A total of 592 patients underwent orthotopic liver transplantation in the Cambridge/King's College Hospital series (January 1980 to May 1991). A total of 89 (15%) patients had either primary or secondary hepatobiliary malignancies. Of these, 66 were hepatocellular carcinoma (HCC) and 13 were cholangiocarcinoma. Of the HCC, 21 were cirrhotics and 45 were noncirrhotics. Eleven patients (12.6%) out of the total 89 died within 1 month without any evidence of recurrent tumor. The most common cause of death was due to postoperative hemorrhage. Of the patients with HCC, 21 (37.5%) had a recurrence of the original tumor and died of the malignancy from 2 months to 5 years after operation. At the time of writing, 18 patients are still alive and the overall 5-year survival rate was 18.6%. The 5-year survival recurrence in patients with HCC was 37.7% in cirrhotic livers. Some patients have been cured of primary malignancy of the liver. Our longest survivor has now survived for 17 years since undergoing transplantation. In 13 patients with cholangiocarcinoma, 6 (46.2%) died due to tumor recurrence and the 5-year survival rate was 23.8%. The indications for liver transplantation are therefore now rapidly expanding. Although the rate of recurrence is high and a long-term cure is rare, HCC remains an appropriate indication for liver transplantation.
Hepatic arterial variations and liver-related diseases of 100 consecutive donors.
We prospectively studied anatomical variations and diseases of the liver in 100 consecutive donor operations during a period of 1 year. The "normal" arterial anatomy with a single hepatic artery (HA) from the celiac trunk was seen in 76% of all cases. Seven of twelve different major variations of the HA may be considered as "rare", one of which cannot be found in the earlier literature. During harvesting, 6% of the livers were discarded, 3% on the basis of infection and 1% because of a polycystic disease. Two cases were rejected as the liver was found to be severely hypoperfused or hypoxic in an otherwise stable donor. Severe steatosis was macroscopically and histologically diagnosed in 3% of the cases, and in three donors a benign tumour was found in the liver or in the gall bladder. Two primarily nonfunctioning livers in the present series of 94 recipient operations were retrieved from this group of severely steatotic livers. As the donor liver was totally "normal" in only 2 out of 3 of the cases, the present study underlines the importance of searching for extremely variable anomalies of the HA and for liver-related diseases during organ harvesting.
The role of HLA typing in clinical kidney transplants: 30 years later.
In summary, the importance of the MHC to the fate of allografts is undoubted. The practical application of this in terms of sending organs long distances with prolonged ischemia time and uncertainty as to the surgical state of the organs leaves an element of doubt as to where the line should be drawn; perhaps the new data from Los Angeles will enable most organs to be used in a localized population catchment area.
Transplantation of abdominal organs in children.
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Protective effects of therapy with a protease and xanthine oxidase inhibitor in short form pancreatic biliary obstruction and ischemia in rats.
The current study was done to evaluate the effects of short term (60 minutes) pancreatic biliary duct obstruction (PBDO) with intraductal hypertension (IDH) stimulated by secretin (0.2 clinical unit per kilogram per hour) and caerulein (0.2 microgram per kilogram per hour) plus 30 minutes of temporary pancreatic ischemia (ISCH) produced by ligation of celiac and superior mesenteric artery on the exocrine pancreas and protective effects of a new potent protease inhibitor, ONO3307 in combination with xanthine oxidase inhibitor, allopurinol, in this multifactor related model of acute pancreatitis in rats. Twelve hours after PBDO with IDH plus ISCH, we observed hyperamylasemia (23 +/- 3 units per milliliter) (p < 0.01); moderate pancreatic histologic changes; pancreatic edema (water content--81 +/- 2 percent) (p < 0.02), as well as the impaired amylase (2,889 +/- 328 units per kilogram per hour) (p < 0.01) and cathepsin B output (7 +/- 3 units per kilogram per hour) (p < 0.01) into the pancreatic juice of rats stimulated by caerulein (control group--serum amylase levels, 6 +/- 1 units per milliliter; pancreatic water content, 74 +/- 1 percent. Furthermore, PBDO with IDH plus ISCH caused the redistribution of lysosomal enzyme from lysosomal fraction (12 kilo times gravity pellet; 40 +/- 3 percent; p < 0.01) to zymogen fraction (1.3 kilo times gravity pellet; 38 +/- 3 percent; p < 0.01) (control group--12 kilo times gravity pellet, 59 +/- 2 percent; 1.3 kilo times gravity pellet, 24 +/- 2 percent) and the impaired pancreatic adenylate energy metabolism (0.79 +/- 0.02, p < 0.02) (control group--energy charge equals 0.88 +/- 0.01). Only PBDO with IDH caused no significant changes. Although only ONO3307 or allopurinol therapy showed the partial significant protective effects against pancreatic injuries, improving serum amylase levels, the administration of ONO3307 in combination therapy with allopurinol showed almost complete protective effects against the pancreatic injuries induced by PBDO with IDH plus ISCH (serum amylase levels, 9 +/- 2 units per milliliter; pancreatic water content, 76 +/- 2 percent; amylase and cathepsin B output, 7,127 +/- 946 and 18 +/- 3 units per kilogram per hour; 1.3 kilo times gravity pellet, 28 +/- 2 percent; 12 kilo times gravity pellet, 54 +/- 2 percent, and energy charge equals 0.85 +/- 0.02).(ABSTRACT TRUNCATED AT 400 WORDS)
Influence of human leukocyte antigen matching on liver allograft survival and rejection: "the dualistic effect".
To date only one published large series of human leukocyte antigen matching and liver allograft survival exists, and considerable confusion has arisen about the advantage or disadvantage of human leukocyte antigen matching. In the present study we have reinvestigated the relationship between human leukocyte antigen mismatch and graft survival in 466 first liver allografts, seeking to clarify the relationship between human leukocyte antigen and both acute rejection and the vanishing bile duct syndrome. In view of current criticism regarding the accuracy of serological tissue typing for human leukocyte antigen-DR, we have used both classic serology and restriction fragment length polymorphism analysis to ensure the accurate assignment of recipient DR types. In addition, we have used polymerase chain reaction amplification and allele-specific and sequence-specific oligonucleotide probes to retest the hypothesis that human leukocyte antigen class II matching may increase susceptibility to the vanishing bile duct syndrome. One-year graft survival was significantly lower in patients with zero or two human leukocyte antigen-A mismatches (52% and 63%, respectively) than in those with one human leukocyte antigen--A mismatch (69%) (p = 0.016 and p = 0.018). A similar effect of B mismatching was observed, with a 1-yr graft survival of 73% for those with one compared with 60% for those with two human leukocyte antigen-B mismatches. In contrast no correlation was found between DR mismatch and graft survival. Human leukocyte antigen class I matching appears to influence graft survival largely through the occurrence of acute rejection and the development of the vanishing bile duct syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
Successful treatment of a primary endodermal sinus tumor of the liver.
A 27-year-old woman had a large hepatic tumor and a markedly increased serum alpha-fetoprotein (AFP) level. A diagnosis of endodermal sinus tumor was made after a needle biopsy was performed on the liver. Clinical and radiologic examinations did not show an alternative primary site. Treatment with cisplatin, etoposide, and bleomycin was started, but, after three cycles, was changed to cisplatin, vincristine, methotrexate, bleomycin, dactinomycin, cyclophosphamide, and etoposide because the serum AFP level was decreasing too slowly. After additional chemotherapy was given, the patient was well but had an increased AFP level and a large residual mass in the liver. A right hemihepatectomy was performed, but no viable tumor was present. The patient is alive and disease-free 5 years later. Thus, AFP levels may be misleading in the presence of large necrotic tumors. The authors stress the need to make a diagnosis of these rare tumors early because aggressive treatment with combination chemotherapy may result in cure.
Citation of original research.
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Effect of hypothermia on pancreatic acinar cells in rats.
This study was designed to evaluate the effects of direct pancreatic surface cooling on the exocrine pancreas. We measured the changes in serum amylase levels, pancreatic water, amylase and cathepsin B as a lysosomal enzyme, content, histological changes of acinar cells, and the subcellular distribution of cathepsin B after 1-2- and 3-hours of direct pancreatic cooling in rats. In addition, we evaluated the in-vivo amylase and cathepsin B output stimulated by caerulein, in-vitro lysosomal and mitochondrial fragility as well as the pancreatic adenylate energy metabolism. 2-hours cooling showed slight yet significant changes, but 3-hours cooling caused most significant changes including hyperamylasemia, increased pancreatic amylase content and very mild histological changes. Furthermore, 3-hours cooling caused a remarkable redistribution of cathepsin B activity from the lysosomal fraction to the heavier zymogen fraction, and colocalization of the lysosomal enzyme with the digestive enzyme, the impaired amylase and cathepsin B output into pancreatic juice stimulated by caerulein as well as the accelerated fragility of lysosomes and mitochondria, and impaired pancreatic adenylate energy metabolism. These results indicate the impaired exocrine pancreatic functions induced by direct pancreatic cooling injury induced by cooling as shown in the other models of experimental pancreatitis. Moreover, this cooling model of pancreatitis seems to be useful in understanding the early events in the pathogenesis of acute pancreatitis, and we must take these "cold" injuries of exocrine pancreas into considerations, particularly in the pancreas transplantation and in other major abdominal surgeries where the pancreas is exposed to cooling.
Effects of acute pancreatitis on hepatic secretion of lysosomal enzymes into bile and hepatic lysosomal fragility: protective effects of a new synthetic protease inhibitor, ONO 3307.
To evaluate the effects of acute pancreatitis on hepatic function and hepatic cellular and subcellular organellar fragility, we studied 1) the hepatic secretion of lysosomal enzymes (beta-glucuronidase, beta-galactosidase, and N-acetyl-beta-glucosaminidase) into bile in the isolated perfused rat liver model; 2) the aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and lysosomal enzyme levels in the effluent in an isolated liver model; 3) hepatic lysosomal fragility in an in vitro incubation study; and 4) protective effects of a new low molecular weight synthetic protease inhibitor, ONO 3307, against hepatic injury in doses of 2 and 5 mg/kg.h in acute pancreatitis induced by a supramaximal dose of cerulein in rats. Decreased hepatic secretion of lysosomal enzymes into bile and accelerated hepatic lysosomal fragility were observed in acute pancreatitis induced by cerulein. ONO 3307 showed a significant protective effect against this hepatic injury in acute pancreatitis, the dose of 5 mg/kg.h showing a more potent effect than the dose of 2 mg/kg.h. These results suggest that the impaired hepatic function, including depressed hepatic secretion of lysosomal enzymes, seems to be closely related to accelerated hepatic fragility and that some unknown protease, which is present in pancreatitis and is susceptible to inhibition by ONO 3307, plays a crucial pathologic role in the development of this liver injury during acute pancreatitis.
Has effective immunosuppression eliminated the need for transplant immunology?
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Immunosuppression for organ grafting.
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Cadaveric renal transplantation in elderly recipients: is it worthwhile?
The aim of this study is to analyse whether or not old age alone significantly affects the outcome of patient and graft survival in cadaveric renal transplantation, and thus whether it should be a selection criterion for induction into transplant programmes, given the current shortfall in donor organs in the United Kingdom. Data is presented on all 307 solitary cadaveric renal allografts performed at Addenbrooke's Hospital, Cambridge between January 1983 and December 1987. Patients are divided into those aged less than 60 years (n = 243) and those aged 60 years and over (n = 45) at the time of transplantation. There is no significant difference in graft survival between the two groups (60.3% and 62.2%) at 18-60 months (mean 42 months) post-transplantation. Patient survival in the two groups is significantly different (83% and 64.4%, P less than 0.01) at the same point. Causes of graft loss, death, and end-stage renal failure are analysed. It is suggested that patients aged 60 years and over may require less immunosuppression but that graft loss from rejection in this group has a high associated mortality. We conclude that cadaveric renal transplantation in the elderly should only be undertaken after careful selection, paying particular attention to evidence of cardiovascular disease and full counselling of the risk of death with these patients.
Orthotopic liver transplantation at Addenbrooke's Hospital Cambridge 1968 to 1991.
Liver grafting is now established as the optimal treatment for patients with end-stage parenchymal liver disease. Twenty-three years of experience at a single center is presented. The 1-year actuarial patient survival rate for all cases transplanted in Cambridge has now risen from 10% in 1968 to 1970 to 80% in 1990 to 1991. Increasing numbers of patients are being referred for transplantation with an ever-increasing range of indications being developed. Many inborn errors of metabolism can now be cured by liver grafting. There is still, however, considerable scope for improvement in many areas of patient treatment from operative and postoperative care to long-term immunosuppressive management. Much remains to be done to minimize early sepsis- and rejection-related deaths and late immunosuppression-related morbidity.