The Long-Term Benefit of Liver Transplantation for Hepatic Metastases From Neuroendocrine Tumors.

Selection criteria and benefit of liver transplantation for hepatic metastases from neuroendocrine tumors (NETs) remain uncertain. Eighty-eight consecutive patients with metastatic NETs eligible for liver transplantation according to Milan-NET criteria were offered transplant (n = 42) versus nontransplant options (n = 46) depending on list dynamics, patient disposition, and age. Tumor burden between groups did not differ. Transplant patients were younger (40.5 vs. 55.5 years; p < 0.001). Long-term outcomes were compared after matching between groups made on multiple Cox models adjusted for propensity score built on logistic models. Survival benefit was the difference in mean survival between transplant versus nontransplant options. No patients were lost or died without recurrence. Median follow-up was 122 months. The transplant group showed a significant advantage over nontransplant strategies at 5 and 10 years in survival (97.2% and 88.8% vs. 50.9% and 22.4%, respectively; p < 0.001) and time-to-progression (13.1% and 13.1% vs. 83.5% and 89%; p < 0.001). After adjustment for propensity score, survival advantage of the transplant group was significant (hazard ratio = 7.4; 95% confidence interval (CI): 2.4-23.0; p = 0.001). Adjusted transplant-related survival benefit was 6.82 months (95% CI: 1.10-12.54; p = 0.019) and 38.43 months (95% CI: 21.41-55.45; p < 0.001) at 5 and 10 years, respectively. Liver transplantation for metastatic NETs under restrictive criteria provides excellent long-term outcome. Transplant-related survival benefit increases over time and maximizes after 10 years.

Regulation of glucose homeostasis in humans with denervated livers.

The liver plays a major role in regulating glucose metabolism, and since its function is influenced by sympathetic/ parasympathetic innervation, we used liver graft as a model of denervation to study the role of CNS in modulating hepatic glucose metabolism in humans. 22 liver transplant subjects were randomly studied by means of the hyperglycemic/ hyperinsulinemic (study 1), hyperglycemic/isoinsulinemic (study 2), euglycemic/hyperinsulinemic (study 3) as well as insulin-induced hypoglycemic (study 4) clamp, combined with bolus-continuous infusion of [3-3H]glucose and indirect calorimetry to determine the effect of different glycemic/insulinemic levels on endogenous glucose production and on peripheral glucose uptake. In addition, postabsorptive glucose homeostasis was cross-sectionally related to the transplant age (range = 40 d-35 mo) in 4 subgroups of patients 2, 6, 15, and 28 mo after transplantation. 22 subjects with chronic uveitis (CU) undergoing a similar immunosuppressive therapy and 35 normal healthy subjects served as controls. The results showed that successful transplantation was associated with fasting glucose concentration and endogenous glucose production in the lower physiological range within a few weeks after transplantation, and this pattern was maintained throughout the 28-mo follow-up period. Fasting glucose (4. 55+/-0.06 vs. 4.75+/-0.06 mM; P = 0.038) and endogenous glucose production (11.3+/-0.4 vs. 12.9+/-0.5 micromol/[kg.min]; P = 0.029) were lower when compared to CU and normal patients. At different combinations of glycemic/insulinemic levels, liver transplant (LTx) patients showed a comparable inhibition of endogenous glucose production. In contrast, in hypoglycemia, after a temporary fall endogenous glucose production rose to values comparable to those of the basal condition in CU and normal subjects (83+/-5 and 92+/-5% of basal), but it did not in LTx subjects (66+/-7%; P < 0.05 vs. CU and normal subjects). Fasting insulin and C-peptide levels were increased up to 6 mo after transplantation, indicating insulin resistance partially induced by prednisone. In addition, greater C-peptide but similar insulin levels during the hyperglycemic clamp (study 1) suggested an increased hepatic insulin clearance in LTx as compared to normal subjects. Fasting glucagon concentration was higher 6 mo after transplantation and thereafter. During euglycemia/hyperinsulinemia (study 3), the insulin-induced glucagon suppression detectable in CU and normal subjects was lacking in LTx subjects; furthermore, the counterregulatory response during hypoglycemia was blunted. In summary, liver transplant subjects have normal postabsorptive glucose metabolism, and glucose and insulin challenge elicit normal response at both hepatic and peripheral sites. Nevertheless, (a) minimal alteration of endogenous glucose production, (b) increased concentration of insulin and glucagon, and (c) defective counterregulation during hypoglycemia may reflect an alteration of the liver-CNS-islet circuit which is due to denervation of the transplanted graft.

Metabolic effects of liver transplantation in cirrhotic patients.

To assess whether liver transplantation (LTx) can correct the metabolic alterations of chronic liver disease, 14 patients (LTx-5) were studied 5+/-1 mo after LTx, 9 patients (LTx-13) 13+/-1 mo after LTx, and 10 patients (LTx-26) 26+/-2 months after LTx. Subjects with chronic uveitis (CU) and healthy volunteers (CON) were also studied. Basal plasma leucine and branched-chain amino acids were reduced in LTx-5, LTx-13, and LTx-26 when compared with CU and CON (P < 0.01). The basal free fatty acids (FFA) were reduced in LTx-26 with respect to CON (P < 0.01). To assess protein metabolism, LTx-5, LTx-13, and LTx-26 were studied with the [1-14C]leucine turnover combined with a 40-mU/m2 per min insulin clamp. To relate changes in FFA metabolism to glucose metabolism, eight LTx-26 were studied with the [1-14C]palmitate and [3-3H]glucose turnovers combined with a two-step (8 and 40 mU/m2 per min) euglycemic insulin clamp. In the postabsorptive state, LTx-5 had lower endogenous leucine flux (ELF) (P < 0.005), lower leucine oxidation (LO) (P < 0.004), and lower non-oxidative leucine disposal (NOLD) (P < 0.03) with respect to CON (primary pool model). At 2 yr (LTx-26) both ELF (P < 0.001 vs. LTx-5) and NOLD (P < 0.01 vs. LTx-5) were normalized, but not LO (P < 0.001 vs. CON) (primary and reciprocal pool models). Suppression of ELF by insulin (delta-reduction) was impaired in LTx-5 and LTx-13 when compared with CU and CON (P < 0.01), but normalized in LTx-26 (P < 0.004 vs. LTx-5 and P = 0.3 vs. CON). The basal FFA turnover rate was decreased in LTx-26 (P < 0.01) and CU (P < 0.02) vs. CON. LTx-26 showed a lower FFA oxidation rate than CON (P < 0.02). Tissue glucose disposal was impaired in LTx-5 (P < 0.005) and LTx-13 (P < 0.03), but not in LTx-26 when compared to CON. LTx-26 had normal basal and insulin-modulated endogenous glucose production. In conclusion, LTx have impaired insulin-stimulated glucose, FFA, and protein metabolism 5 mo after surgery. Follow-up at 26 mo results in (a) normalization of insulin-dependent glucose metabolism, most likely related to the reduction of prednisone dose, and, (b) maintenance of some alterations in leucine and FFA metabolism, probably related to the functional denervation of the graft and to the immunosuppressive treatment.

Metabolic effects of successful intraportal islet transplantation in insulin-dependent diabetes mellitus.

The intraportal injection of human pancreatic islets has been indicated as a possible alternative to the pancreas transplant in insulin-dependent diabetic patients. Aim of the present work was to study the effect of intraportal injection of purified human islets on: (a) the basal hepatic glucose production; (b) the whole body glucose homeostasis and insulin action; and (c) the regulation of insulin secretion in insulin-dependent diabetes mellitus patients bearing a kidney transplant. 15 recipients of purified islets from cadaver donors (intraportal injection) were studied by means of the infusion of labeled glucose to quantify the hepatic glucose production. Islet transplanted patients were subdivided in two groups based on graft function and underwent: (a) a 120-min euglycemic insulin infusion (1 mU/kg/min) to assess insulin action; (b) a 120-min glucose infusion (+75 mg/di) to study the pattern of insulin secretion. Seven patients with chronic uveitis on the same immunosuppressive therapy as grafted patients, twelve healthy volunteers, and seven insulin-dependent diabetic patients with combined pancreas and kidney transplantation were also studied as control groups. Islet transplanted patients have: (a) a higher basal hepatic glucose production (HGP: 5.1 +/- 1.4 mg/kg/ min; P < 0.05 with respect to all other groups) if without graft function, and a normal HGP (2.4 +/- 0.2 mg/kg/min) with a functioning graft; (b) a defective tissue glucose disposal (3.9 +/- 0.5 mg/kg/min in patients without islet function and 5.3 +/- 0.4 mg/kg/min in patients with islet function) with respect to normals (P < 0.01 for both comparisons); (c) a blunted first phase insulin peak and a similar second phase secretion with respect to controls. In conclusion, in spite of the persistence of an abnormal pattern of insulin secretion, successful intraportal islet graft normalizes the basal HGP and improves total tissue glucose disposal in insulin-dependent diabetes mellitus.

Triggering of antitumor activity through melanoma-specific transduction of a constitutively active tumor necrosis factor (TNF) R1 chimeric receptor in the absence of TNF-alpha.

Tumor necrosis factor-alpha (TNF-alpha) has been intensively studied because of the specific toxicity of this cytokine toward cells that undergo malignant transformation. However, its proinflammatory and immunoregulatory properties always represented a drawback to the TNF-alpha administration in cancer therapy. In this study, we describe an adenovirus-based strategy in which the tumoricidal activity of TNF-alpha can be selectively triggered to eradicate tumors without administering TNF-alpha. This strategy might allow us to prevent TNF-alpha effects on normal tissues and, therefore, to bypass its systemic toxic effects. We inserted the constitutively active version of the Mr 55,000 TNF receptor, which was shown previously (F. Bazzoni et al., Proc. Natl. Acad. Sci. USA, 92: 5376-5380, 1995) to be capable of killing cells upon expression in the absence of its ligand, into a replication-deficient adenovirus, and under the control of a melanoma-specific promoter/enhancer element. We show that, upon infection, the recombinant gene reaches high level of expression in melanoma cell lines and triggers apoptosis by activating the caspase cascade. Expression and function of this receptor is restricted to melanoma cell lines, because morphology, viability, and proliferation of other cell types exposed to the recombinant adenovirus infection are not affected. We show for the first time that a TNF-like apoptotic response can be triggered in the absence of TNF-alpha and can be selectively confined to specific cellular targets. Killing activity and tissue specificity of the recombinant TNF receptor adenovirus, together with the advantage of triggering a TNF-like antitumor activity in the absence of TNF-alpha itself, are ideal features for a vector that might be the choice for gene therapy aimed to eradicate malignant cells.

Immunocytochemical detection and characterization of intrahepatic human pancreatic islets after combined liver-islet allotransplantation.

The unique availability of an explanted liver-islet allograft, removed for primary nonfunction of the liver, led us to evaluate distribution and phenotype of exocrine and endocrine components of the pancreatic graft. Immunocytochemistry was used to map patterns of gene products for islet hormones, proprotein processing enzymes, panneuroendocrine markers, and pancreatic exocrine markers. When compared with age-matched control pancreases, insulin-, glucagon-, somatostatin-, and pancreatic polypeptide-producing cells were similarly represented and distributed within the grafted islet. We also demonstrate that the intrahepatic transplanted islets retained the enzyme machinery able to process the hormone precursors into bioactive fragments. In the clinical setting, this resulted in an immediate functioning of the graft and insulin-independence of the patient one month after transplantation. The purity in islets, as assessed by immunocytochemistry with antibodies to tissue constituents of endocrine and exocrine lineages, was around 40%. Despite the massive intraportal presence of pancreatic acinar tissue, no signs or symptoms attributable to ectopic hypersecretion of exocrine enzymes occurred. In fact, when tested with antibodies to such enzymes, low levels of immunoreactivity were observed in the grafted acinar cells.

Increased retinol binding protein in the sera of patients with severe ischemic damage of the liver after transplantation.

OBJECTIVE: To study retinol binding protein variation in the serum of patients who have undergone liver transplantation. METHODS: Retinol binding protein was retrospectively determined by the immunonephelometric method on serum from 14 patients who had undergone orthotopic liver transplantation 2 weeks after the surgery and then once a month during the first year posttransplantation. The patients were divided into two groups on the basis of early (first 10 days) postoperative graft function: group I, 6 patients with severe ischemic damage; and II 8 patients with moderate-severe liver dysfunction. RESULTS: The men retinol binding protein level at one year of follow-up was persistently higher in group I than in group II (83.1 +/- 33.4 vs 44.6 +/- 20.7 mg/L, p < 0.001). Interestingly, retinol binding protein levels remained higher in patients of group I event when the other biochemical parameter of liver function returned to normal. The increase in retinol binding protein serum levels was independent of variation in other parameters of liver and kidney function, but was correlated with an increase in transthyretin and retinol levels. CONCLUSION: Our results show a close relationship between a permanent high retinol binding protein level and severe graft injury after liver transplantation. However, the mechanism underlying the increase remains to be defined.

How long is a 6 cm margin of resection in the stomach?

In order to assess whether the gastric wall undergoes some change in length during gastrectomy operation for cancer, we measured the variation in length of the anterior gastric wall in 25 patients. The first measurement was made at the beginning of laparotomy by placing two stitches on the anterior gastric wall and registering the distance between them. A second and a third measurement were recorded when the stomach was fully isolated just before its transection and subsequently on the anatomic table. The results indicate that the usual recommendations made by pathologists to maintain a 6 cm margin of tissue clearance proximally to the cephalic edge of the tumour, can be safely followed by the surgeons who can correctly assess, during operation, the distance between tumour and the desirable line of transection since no misleading reduction in size of the resected specimen takes place.

Psychosocial adaptation after liver transplantation with particular reference to recipients aware of their cancer.

This study investigated the Psychosocial adjustment in 40 patients who received orthotopic liver transplantation (OLT) for several endstage liver diseases. Twenty patients were grafted because they suffered from liver Cancer as well as cirrhosis. Particular attention was paid to evaluating whether cancer could affect recipients' coping with transplant. Each patient underwent a semi-structured interview to obtain information on their psychosocial life, relationship with the donor, organ acceptance and life expectancy. Interview was performed I year after transplantation. A psychodiagnostic evaluation was also performed using a Minnesota Multiphasic Personality Inventory (MMPI) and a Human Figure Test. Psychosocial adaptation in everyday life following liver transplantation seemed good in most of the patients, whatever the indication for transplantation might be. It can he seen that by replacing the diseased organ a high percentage of oncological patients overcame their fear of cancer.

Central venous catheter sepsis: prognosis and treatment.

The purpose of this study was to evaluate the prognosis of patients with central venous catheter (CVC) sepsis, with particular reference to two therapeutic procedures, 1) CVC exchange over a guide wire and 2) removal of the catheter An evaluation was made of the clinical records of 22 cancer patients receiving total parenteral nutrition because of severe malnutrition and of 27 CVC-related septic episodes defined as growth of the same microorganism on the CVC and in peripheral blood. Bacteriological findings included Candidae n = 17, S albus n = 4, E Cloacae n = 4, Enterococcus n = 1 and P aeruginosa n = 1. In 22 cases the CVC was exchanged and in five cases it was removed on the clinical suspicion of CVC-related sepsis. Nineteen of the 22 patients had their blood culture rendered negative with CVC exchange and in three of the other five patients it was resolved bacteriologically after removal of the CVC. There was no clear effect of the CVC sepsis on the final outcome of the patients' illness. In fact, seven patients eventually died because of reasons apparently unrelated to the CVC sepsis-which had bacteriologically and clinically resolved-and seven patients recovered and were discharged in good condition despite the initial failure of CVC manipulation. The conclusion reached was that death should not occur as a result of CVC sepsis, provided this is properly identified and adequately treated. Since CVC change allows earlier recognition of the complication and effective treatment, it may be considered the therapy of choice in the management of suspected CVC sepsis.

Pilot, multicenter and prospective trials with an anti-CEA antibody.

In this paper we summarize the investigations performed by our group utilizing an anti-CEA monoclonal antibody (F023C5) labelled with different radionuclides in humans. Since 1983 radioimmunoscintigraphy (RIS) was performed on 51 patients with 64 localizations of colo-rectal carcinoma (pilot study). A multicenter clinical trial in a large number of patients (509 pts of which 284 with gastrointestinal cancer) was subsequently carried out in collaboration with ten nuclear medicine centres. High sensitivity and specificity values were obtained by these studies and many unsuspected lesions were recorded. In order to better define the clinical role of RIS, a prospective study was performed on 59 patients with suspected local relapses of colo-rectal cancer. A comparative evaluation of RIS, CT scan, US and MRI was done. RIS and MRI had the highest accuracy (86%) followed by CT scan (68%) and US (54%).

A new approach to the diagnosis of central venous catheter sepsis.

One hundred forty-four cancer patients harboring a central venous catheter (CVC) were prospectively investigated to assess the relationship between hub culture, clinical assessment of sepsis before removal, and CVC sepsis. In 22 patients, the CVC was removed because of clinical assessment of catheter sepsis expressed by the staff prior to the removal. For each CVC removal, peripheral blood (qualitative method), hub, and CVC tip (quantitative method) cultures were performed. Clinical sepsis (disappearance of fever after CVC removal) was observed in 13 patients, microbiologic "sepsis" (identification of the same microorganisms on the CVC tip and in the peripheral blood) in seven patients, and clinical and/or microbiologic sepsis in 16 patients. Staphylococcus epidermidis was the microorganism most frequently identified. Hub culture was negative in 48% and positive for a low number and a high number of colonies in 35% and 17%, respectively. The predictive value of hub culture was 96% when testing negative and 8% and 37% (p = 3 x 10(-3)) when testing positive for a low and a high number of colonies, respectively. Predictive values of clinical assessment were 55% if positive and 97% if negative. Combining hub cultures and clinical assessment, the risk of sepsis varied from 2% with both evaluations negative to 89% in the case of positive clinical assessment associated with positive high-count hub. Inasmuch as the CVCs used have a disposable hub, it is possible to have an accurate diagnosis of CVC sepsis without removing the CVC.

Does portal nutrition benefit liver protein synthesis?

There are only a few experimental investigations on the feasibility and potential advantages of intraportal nutrition in animals and only two uncontrolled studies in humans. The purpose of this study was to compare some metabolic variables in patients who received portal or systemic nutrition after elective surgery for colorectal cancer. Twenty patients were randomized to receive postoperatively for a week a hypocaloric, "protein sparing" standard infusion via the portal (catheter in the gastroepiploic vein) (10 patients) or systemic (10 patients) route. We evaluated the basal concentrations of some visceral and acute-phase proteins and their variations in the first postoperative week and the nitrogen balance. Statistical analysis was performed by the two-tailed Student t test. There was no difference in the daily changes of the visceral and acute-phase proteins after surgery in the two groups of patients, but in the portal group there was a significantly better recovery of the level of total protein, albumin, and cholinesterase at the end of the portal infusion vs the systemic group (p < or = .005, .03, and .02, respectively). In regard to the nitrogen balance, although there was no difference in the overall balance between portal and systemic nutrition, if we separate the acute phase of the injury from the later one we do not see any significant difference in the first period but we do see a highly significant advantage for the portal group during the last 2 days (p < or = .0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Post-absorptive and insulin-mediated muscle protein metabolism in liver-transplanted patients.

Cirrhotic patients after liver transplantation show a near-normal glucose homeostasis when in stable condition. In contrast, the basal and insulin-mediated whole-body protein metabolism remain altered several years after the graft. To examine whether the persisting defect of protein metabolism was due to the muscle, 7 non-diabetic liver-transplanted patients in stable condition were studied by means of the catheterization of the brachial artery and the deep forearm vein (to measure the balance across the forearm) and the infusion of labelled leucine and phenylalanine associated with indirect calorimetry. Whole-body proteolysis (as determined by endogenous leucine flux, ELF), protein synthesis (from non-oxidative leucine disposal, NOLD) and leucine oxidation (LO) were reduced in comparison to previously obtained values in a normal population. Insulin infusion (while maintaining euglycemia) induced a not significant variation of forearm phenylalanine Ra (24.4-->16.5 micromol/100 ml forearm min(-1); proteolysis) and Rd (18.5-->19.7; protein synthesis). In contrast, the whole-body insulin-dependent inhibitions of ELF (31.5-->21.8 micromol/m(2) min) and NOLD (27.3-->18.4) were impaired with respect to a normal population. On the basis of the present results, we conclude that skeletal muscle is not responsible for the alterations of leucine metabolism persisting after liver transplantation. By exclusion, this points to the liver as the major determinant of the leucine metabolism defect.

Morbidity and mortality after surgical resection of liver tumors. Analysis of 229 cases.

Two hundred and twenty-nine resections of hepatic tumors were performed over the past 10 years. The intraoperative death rate, 30-day operative mortality and major complication rate were 1.3%, 8.3% and 20%, respectively. Both morbidity and mortality were significantly related to the type of surgery and to the extent of the resection to contiguous organs and/or structures. Cirrhotic patients (40% in hepatocellular carcinoma) had a higher mortality rate (19%). Intraoperative blood loss was related to the extent of the resection and was significantly higher in patients with major complications and/or death. The main problem was postoperative liver failure in cirrhotic patients, which is difficult to predict and to treat.

Catheter sepsis from infusate contamination.

Ten patients harboring an indwelling CVC with contamination of the infusate are described. Six patients developed sepsis, which was resolved in all patients except one who died from misdiagnosed septic shock. The majority of microorganisms responsible for the infusate contamination were opportunistic pathogens and in five cases were S. epidermidis. There was no apparent correlation between contamination rate of the infusate and subsequent sepsis of the patients. Reasons for the high prevalence of Staphylococcus epidermidis include ubiquitous diffusion of this microorganism, marked affinity for prosthetic devices, especially by the slime-producing strains, and increased susceptibility of debilitated cancer patients to infection. Recognition that the possibility exists for infusate contamination during compounding should alert all members of the Nutritional Support Team to use aseptic technique when preparing and handling the intravenous solutions. Infusate-related sepsis is a potentially lethal but preventable event.

Bone lesion in a patient with transplanted liver for a metastatic carcinoid. The role of somatostatin receptor scintigraphy.

A patient who had previously undergone ileal resection and liver transplantation for a gastroenteropancreatic (GEP) tumor was evaluated with somatostatin receptor scintigraphy (SRS) using 111In-DTPA-D-Phe1-pentetreotide. Eighteen months after surgery, during follow-up procedures, conventional imaging techniques (ultrasound, computed tomography, magnetic resonance imaging) only showed a relapse in the gastropancreatic lymph nodes, while SRS demonstrated skeletal spread. This case report emphasizes the clinical impact of SRS on the management of patients affected by neuroendocrine gastroenteropancreatic tumors.

Inflammatory pseudotumor of the liver: report of two cases.

Inflammatory pseudotumor of the liver is a very rare lesion. Herein we describe two cases of this entity which occurred in two women aged 22 and 49 years, respectively. Both cases were considered to be clinically malignant and only the histopathologic examination revealed the non-neoplastic nature of the disease. Ultrastructural and immunohistochemical studies further supported the evidence of a reactive disease.

[The surgical treatment of hepatocarcinoma]. / Il trattamento chirurgico dell'epatocarcinoma.

At the National Cancer Institute of Milan, 118 patients underwent surgical resection and 35 had liver transplants for HCC (hepatocarcinoma). Postoperative mortality was 14% and 17% after resection and transplantation respectively. The five-year survival was 35% for resected patients and 83% at 30 months for transplanted patients. Analysis of the literature shows that patients receiving a liver transplant for HCC stage I-II survive longer than those resected at the same stage.