Hemophagocytic lymphohistiocytosis in infancy and childhood.

OBJECTIVE: The current status of hemophagocytic lymphohistiocytosis (HLH) in infants and children has been studied. STUDY DESIGN: Eighty-two cases of pediatric HLH, for which there was no confirmed familial inheritance, were comparatively studied between 36 patients less than 2 years of age and 46 patients more than 2 years of age. RESULTS: In all cases, persistent fever, cytopenia, liver dysfunction, and hepatosplenomegaly were the most frequently noted symptoms. Hyperferritinemia (> 1000 micrograms/L) and elevated blood levels of lactate dehydrogenase (> 1000 IU/L) were observed in 90% and 89.7%, respectively. These figures were considerably higher than for either hypertriglyceridemia (> 2 mmol/L) (50%) or hypofibrinogenemia (< 1.5 gm/L) (57.4%), indicating that increased serum ferritin and lactate dehydrogenase concentrations might be good diagnostic parameters for HLH. These parameters are nonspecific but are of follow-up and prognostic value in these HLH cases. No differences were found in clinical signs and symptoms or other laboratory findings for the two age groups. Immunochemotherapy was administered in the similar regimens to patients in both groups. Of the 82 patients, 13 (15.9%) succumbed to a fatal course within 2 months after diagnosis, and Kaplan-Meir analysis for all cases predicted the overall disease-free patient survival at 4 years from the onset of disease to be 57.2% (95% confidence interval (CI), 45.1% to 69.3%). There was a slightly, but not statistically significant, poorer prognosis for the younger patients: 44.2% (95% CI, 26.0% to 62.4%) survival for the infant group versus 67.2% (95% CI, 51.8% to 82.6%) survival for the older group (p = 0.0569). CONCLUSIONS: Refinement of the treatment is mandatory to improve the outcome of HLH in both infants and older pediatric patients.

Assessment of five-year experience with abdominal organ cluster transplantation.

BACKGROUND: Upper abdominal exenteration (resection of the liver, stomach, spleen, pancreaticoduodenal complex, and part of the colon) for the treatment of otherwise unresectable tumors is one of the more radical operations in oncology. This study was done to analyze retrospectively a five-year experience with exenteration in 57 patients treated with variations of resectional and transplant reconstructive techniques. STUDY DESIGN: Sixty-one transplantations were performed upon 57 patients. Three different organ replacement techniques were used: liver-pancreas-duodenum en bloc (original procedure), liver only (modified procedure), and liver plus pancreatic islets. The diagnoses were cholangiocarcinoma (20 patients), hepatocellular carcinoma (12 patients), endocrine neoplasms (14 patients), sarcoma (six patients), and adenocarcinoma of the pancreas (two patients), colon (two patients), or gallbladder (one patient). Analyses of survival and tumor recurrence were stratified by procedure variations, type and extent of tumor, and immunosuppressive regimen. RESULTS: The three month and one, two, three, and five year actuarial patient survival rates were 82, 56, 38, 33, and 30 percent, respectively. Eighteen (31.5 percent) of the 57 patients are alive after 425 15 (standard deviation) months (range of 17 to 61 months) and 12 patients are tumor free. The actuarial survival rates stratified by transplantation procedure, immunosuppression, and tumor diagnosis and extent showed no statistically significant differences beyond the three different transplantation groups. Endocrine tumors had a better three-year survival rate (64 percent) than sarcoma (44 percent), hepatocellular carcinoma (25 percent), cholangiocarcinoma (20 percent), and the other adenocarcinomas (20 percent). Twenty-three patients (40 percent) died as a result of tumor recurrence. Patients with combined factors of no lymph node involvement, absence of vascular invasion, and metastases to the liver only (11 patients) had the lowest incidence of recurrence (27 compared to 73.5 percent, p = 0.006). CONCLUSIONS: Patients with unresectable endocrine neoplasms, fibrolamellar hepatocellular carcinoma, and selected cholangiocarcinoma confined to the liver can benefit from this radical operative approach. Patients with sarcoma can achieve long survival periods but have a high recurrence rate.

Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathologic risk factors.

BACKGROUND: The selection of patients for resective therapy of hepatic colorectal metastases remains controversial. A number of clinical and pathologic prognostic risk factors have been variably reported to influence survival. METHODS: Between January 1981 and December 1991, 204 patients underwent curative hepatic resection for metastatic colorectal cancer. Fourteen clinical and pathologic determinants previously reported to influence outcome were examined retrospectively. This led to a proposed TNM staging system for metastatic colorectal cancer (mTNM). RESULTS: No operative deaths occurred (death within 1 month). Overall 1-, 3-, and 5-year survivals were 91%, 43%, and 32%, respectively. Gender, Dukes' classification, site of primary colorectal cancer, histologic differentiation, size of metastatic tumor, and intraoperative blood transfusion requirement were not statistically significant prognostic factors (p > 0.05). Age of 60 years or more, interval of 24 months or less between colorectal and hepatic resection, four or more gross tumors, bilobar involvement, positive resection margin, lymph node involvement, and direct invasion to adjacent organs were significant poor prognostic factors (p < 0.05). In the absence of nodal disease or direct invasion, patients with unilobar solitary tumor of any size, or unilobar multiple tumors of 2 cm or smaller (stages I and II) had the highest survival rates of 93% at 1 year, 68% at 3 years, and 61% at 5 years. Unilobar disease with multiple lesions greater than 2 cm (stage III) resulted in 1-, 3-, and 5-year survivals of 98%, 45%, and 28%, respectively. Patients with bilobar involvement (multiple tumors, any size, or a single large metastasis) (stage IVA) had survival rates of 88% at 1 year, 28% at 3 years, and 20% at 5 years (p < 0.00001). Patients with nodal involvement or extrahepatic disease (stage IVB) experienced the poorest outcome with 1-, 3-, and 5-year survivals of 80%, 12%, and 0%, respectively (p < 0.00001). CONCLUSIONS: The proposed mTNM staging system appears to be useful in predicting the outcomes after hepatic resection of metastatic colorectal tumors.

Corrective treatment and anatomic considerations for laparoscopic cholecystectomy injuries.

BACKGROUND: Complete reports of biliary and vascular injuries after laparoscopic cholecystectomy are rare. STUDY DESIGN: Fifteen patients with complex laparoscopic cholecystectomy injuries underwent corrective operations. The injuries consisted of 14 bile duct injuries and one large laceration of a cirrhotic liver. Five of the bile duct injuries were accompanied by inadvertent occlusion of the right hepatic artery, and one was further complicated by portal vein occlusion. One hepatic artery occlusion and one portal vein occlusion were successfully reconstructed. Two patients with arterial occlusion required right hepatic lobectomy. Corrective biliary operations consisted of common hepaticojejunostomy (seven cases), right and left hepaticojejunostomies (one case), right anterior and left hepaticojejunostomies (two cases), right hepaticojejunostomy (one case), right posterior hepaticojejunostomy (one case), and left hepaticojejunostomy after right lobectomy (two cases). RESULTS: Except for a patient with a severe laceration of a cirrhotic liver who died as a result of hepatic failure, the remaining 14 patients are alive and well with normal hepatic function tests at six and 37 months after corrective operations. CONCLUSIONS: A knowledge of anatomy is critical to the prevention of injuries to the hepatobiliary tree and related structures during laparoscopic cholecystectomy.

Early clinical and histologic viability of human liver-small intestinal allografts after implantation.

Our procedure for donor harvesting and preserving intestinal grafts has matured. In 27 consecutive cases, a protocol was established whose essentials consist of (a) selecting hemodynamically stable donors, (b) antibiotic pretreatment of the donor, and (c) short warm ischemic times (< 40 minutes). Assessment of graft quality can be achieved by daily inspection of stomas, inspection for diarrhea > 2.5 1/day in adults or > 300 ml in children, and weekly protocol or clinically directed endoscopic biopsies. Edema and microscopic separation of the mucosal surface and sloughing are routinely found during the first few post-engraftment days, but the crypt cells remain and regenerate a normal mucosa within a week. Recovery of a normal mucosal surface took place in all cases.

The latest advances in liver transplantation at the pittsburgh transplantation institute: evolution of FK506, liver-intestinal transplantation, clinical xenotransplantation, and the induction of graft acceptance.

During the past 30 years orthotopic liver transplantation (OLTx) has become a highly successful form of therapy, and as of this writing it is being performed at more than 100 institutions in the U.S., and a similar number in Europe. This is testimony to the great advances achieved in this field since the 1960s and 1970s, when there were essentially only two places actively engaged in liver transplantation. Essential to its success have been the technical refinements introduced during the last three decades, which have allowed many surgeons around the world to be able to do the procedure safely. Liver transplantation is still considered as one of the most complex operations, and therefore the margin of error is small and attention to technical detail is crucial to a satisfactory outcome. This is magnified in importance since OLTx, unlike kidney, heart, pancreas and intestinal transplantation, lacks a back-up system, such as dialysis, ventricular assist device, insulin or total parenteral nutrition. Thus, the smallest mistake in the surgical management of the patient may prove fatal.

Liver transplantation for Alagille's syndrome.

Twenty-three children with Alagille's syndrome and end-stage liver disease underwent liver transplantation with cyclosporine and low-dose steroid immunosuppression. Two to 9 years (mean, 4.4 years) after surgery, 13 (57%) of the children were still alive, with normal liver function. Three of the fatalities were due to cardiovascular failure secondary to associated cardiopulmonary disease. Mortality was higher among patients who had more severe cardiac disease and patients who had previously undergone a Kasai procedure. Although it has a higher than average risk, liver transplantation can be efficacious in patients with Alagille's syndrome and end-stage liver disease.

Hepatic resection versus transplantation for hepatocellular carcinoma.

During the 10-year period (1980 to 1989), 76 patients with hepatocellular carcinoma (HCC) were treated by subtotal hepatic resection (HX) and 105 patients by orthotopic liver transplantation (TX) under cyclosporine-steroid therapy. Overall 1- to 5-year survival rates of the HX group were 71.1%, 55.0%, 47.2%, 37.2%, and 32.9%, respectively, and those of the TX group were 65.7%, 49.0%, 39.2%, 35.6%, and 35.6%, respectively. The survival rates after HX and after TX correlated well with pTNM stages and were similar in each stage between the two groups. However, when HCC was associated with cirrhosis of the liver, the survival rates after TX were significantly better than those after HX at each stage of pTNM classification. The tumor-recurrence rate was high both after HX (50%) and TX (43%), particularly in advanced stages of pTNM classification (60% or more). Twelve patients after HX and 13 patients after TX lived more than 5 years during this 10-year period. Fibrolamellar HCC and early stages of HCC were highly represented among the long-term survivors. Further improvement in survival rates depends on nonsurgical anti-cancer therapy before and/or after surgical removal of HCC.

Initial studies with FK506 in renal transplantation.

FK506 is a novel immunosuppressive agent which is approximately 100 times as potent as cyclosporine in vitro. In this initial trial, 65 renal transplant patients of high complexity received primary FK506 immunosuppression. Overall, graft and patient survival rates are 80% and 98.5%, respectively. A major advantage of FK506 is its potency with relatively few side effects, which has permitted elimination of steroids in 31 (60%) of these patients. Because of these encouraging results, a randomized trial comparing the therapeutic efficacy and toxicity of FK506 and cyclosporine is currently underway at our institution.

Long survival in rats after multivisceral versus isolated small-bowel allotransplantation under FK 506.

Abdominal multivisceral allotransplantation (MVTX) from Brown Norway donor rats to Lewis recipient rats was performed under a 14-day course of low (0.32 mg/kg) or high-dose (0.64 mg/kg) intramuscular FK 506 to which weekly further injections were added in some of the high-dose animals. With all three regimens, long survival was frequently achieved with good intestinal adsorption and weight gain, but histopathologic evidence of intestinal rejection existed in the most lightly treated animals. The liver, stomach, and pancreas had only minor abnormalities. Rejection of isolated intestinal grafts was more difficult to control based on histopathologic criteria, and satisfactory results were obtained only with the most aggressive treatment protocol, suggesting that the liver in the MVTX had provided an advantage to the companion organs of the graft, of which the intestine was most vulnerable. Histopathologically, the lymphoid elements of the intestine, including the Peyer's patches, appeared to be the most immunogenic component of the intestine. Epithelium near lymphoid areas was secondarily involved with villous atrophy, cryptitis, and abscess formation. Beginning within 12 days in successful MVTX experiments, the lymphoreticular components of the graft intestine, including the Peyer's patches, lamina propria, and mesenteric nodes, were shown with anti-Ia monoclonal antibodies to be repopulated with recipient cells. This finding in grafts that appeared to be permanently accepted was surprising and contrary to expectations from the literature on intestinal allotransplantation.

One hundred ten consecutive primary orthotopic liver transplants under FK 506 in adults.

An account is given of the 6- to 12-month survival, and causes of failure in 110 consecutive patients who underwent primary liver transplantation under treatment from the outset with FK 506 and steroids. The patient survival is 92.7%, and the first graft survival is 87.3%. At a very high frequency, the patients achieved good graft function, and they had a relatively low morbidity that was partially ascribable to minimal use and early discontinuance (in 60% of cases) of steroids. Renal dysfunction and other adverse findings were largely confined to patients with poor initial graft function and consequent apparent alteration of the kinetics of FK 506 elimination, causing functional overdosage. Results compare very favorably with our past record using conventional immunosuppression, and support the belief that FK 506 is a superior immunosuppressive agent which is suitable for chronic administration.

The question of FK 506 nephrotoxicity after liver transplantation.

Formal studies have not been published on the nephrotoxicity of FK 506 when the drug was used from the outset. This kind of information was sought in 101 recipients of primary livers, 24 hearts, and 3 double lungs or heart-lung. Perioperative renal dysfunction was commonly seen, which appeared to be related to FK 506 doses and plasma levels, particularly when the drug was given IV. This was reversible. Late renal function has been generally satisfactory in all three cohorts of patients, and the incidence of hypertension has been low. The therapeutic index of FK 506 is a good one, as revealed by these observations in patients whose most notable achievement was a low mortality.

Selected topics on FK 506, with special references to rescue of extrahepatic whole organ grafts, transplantation of "forbidden organs," side effects, mechanisms, and practical pharmacokinetics.

FK 506 is a superior immunosuppressive agent that should improve the grafting of organs that already are part of our every day transplant practices, as well as those which are presently impractical. Immune intervention for serious autoimmune diseases also should be a more attractive option with this drug. Lessons are still being learned about dosage and what determines safe dose schedules. At a basic level, the study of FK 506 and its comparison to CyA may have shed light on mechanisms and characteristics of the whole class of so-called macrolide immunosuppresants and their cytosolic binding sites.

Rejection of multivisceral allografts in rats: a sequential analysis with comparison to isolated orthotopic small-bowel and liver grafts.

Multivisceral isografts and allografts were transplanted to Lewis rats, and the histopathologic changes were studied in the liver, intestine, and other constituent organs. Rats receiving isografts had indefinite survival with maintenance of weight. With multivisceral allografts (from Brown-Norway donors), the intestinal component was rejected more severely than the companion liver and with about the same severity as when intestinal transplantation was performed alone. Intestinal rejection in either circumstance was a lethal event, causing death in 10 to 12 days. The earliest (by day 4) and most intense cellular rejection was in the Peyer's patches and mesenteric lymph nodes. This was associated with or followed by cryptitis, epithelial cell necrosis, focal abscess formation, mural necrosis, and eventual perforation. Liver allografts transplanted alone or as part of multivisceral grafts also had histopathologic evidence of rejection, but this was self-limiting and spontaneously reversible when the liver was transplanted alone. Thus the Achille's heel of multivisceral grafts is the intestinal component that is not protected by the presence of the liver in the organ complex. Better immunosuppression should permit successful experimental and clinical transplantation of such grafts.

The hepatotropic influence of cyclosporine.

The effect of cyclosporine on liver regeneration has been investigated in 25 dogs that underwent an end-to-side portacaval shunt (Eck fistula) followed by 4 days continuous infusion of the drug into the left branch of the portal vein. Three different cyclosporine infusion rates were used: 0.06, 0.6, and 4.0 mg/kg/day. Control animals received the intravenous vehicle of cyclosporine at the same rate as the treated animals; a second control group received insulin, 0.42 units/kg/day. Hepatocyte 3H-thymidine-labeled mitoses (index of hyperplasia) and hepatocyte volume (index of hypertrophy) were studied in the left (infused) and right (control) lobes in each animal. Cyclosporine vehicle had no measurable effect on hepatocytes that suffered typical atrophy and moderate increase in mitotic index after the Eck fistula. Cyclosporine infusion stimulated cell renewal significantly and restored hepatocyte size in the infused lobes with a dose-response relation. Similar positive effects were observed in the right (nonperfused) lobes, although they were less than those in the left (infused) lobes. This was because of an unmistakable spillover of cyclosporine from the infused lobes, especially in the large-dose group. No sign of hepatotoxicity was detected at any cyclosporine infusion rate. Cyclosporine has a remarkable hepatotropic effect that may be helpful in the context of liver transplantation.

Liver transplantation in the treatment of primary liver cancer.

One hundred and fifteen patients underwent orthotopic liver transplantation (OLT) for primary liver malignancy. Overall survivals of these patients were significantly lower than those of patients with non-malignant diseases (5-year survival rates 37% and 65%, respectively). Hepatocellular carcinoma (HCC) was the most common malignancy among our patients (n = 80). Fibrolamellar HCC (n = 9) was associated with better survival than non-fibrolamellar HCC (N = 71) among the lesions greater than or equal to 5 cm in diameter. More frequent recurrence was noted in patients with large tumors (greater than or equal to 5 cm), multiple tumors, and gross vascular involvement. A significant lower survival rate was observed in patients with bile duct cancer (n = 19) than in those with HCC or epithelioid hemangioendothelioma (n = 8). Careful patient selection and effective adjuvant anti-cancer therapy are needed to improve the results of OLT for primary liver malignancy.