Comparison of outcomes following surgical resection, percutaneous ablation or stereotactic body radiation therapy in early-stage, solitary and small (≤3 cm) treatment-naïve hepatocellular carcinoma.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is associated with high local control rates in hepatocellular carcinoma (HCC). This study reports the outcomes of SBRT compared to surgical resection (SR) and percutaneous ablation (PA) for treatment-naïve, solitary HCCs ≤3 cm. METHODS: This was a retrospective study of patients with BCLC stage 0/A HCC with a single ≤3 cm lesion, treated with curative intent between 2016 and 2020. SBRT was used for patients considered unsuitable for SR or PA. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were treatment-related clinical toxicity rates and local control (LC) rates. RESULTS: There were 112 patients included in this study. SBRT was delivered in 36 patients (32.1%), 51 had PA (45.5%) and 25 underwent SR (22.3%). Median follow-up was 23 months (range, 3-60 months) from diagnosis. The 3-year PFS and OS were 67% and 69% following SBRT, 55% and 80% following PA, and 85% and 100% following SR, respectively. Patients in the SR cohort had significantly better 3-year PFS and OS compared to SBRT and PA groups (p = 0.03 and p = 0.04, respectively). There was no significant difference in PFS (p = 0.15) or OS (p = 0.23) between SBRT and PA treated patients. The 3-year LC rate for the entire cohort was 98%. CONCLUSIONS: In patients with treatment-naïve, early-stage solitary HCCs ≤3 cm, SBRT was associated with comparable PFS, OS and LC outcomes to PA. SBRT should be considered as a curative intent therapy to avoid treatment stage migration in this favourable prognostic cohort of patients.

Combined Heart-Lung-Liver Transplantation for Patients With Cystic Fibrosis: The Australian Experience.

BACKGROUND: Combined multivisceral transplantation has emerged as a therapeutic option for a select patient cohort; however, clinical decision-making remains complex and controversial. The aim of this study was to examine patient characteristics, operative complications, and long-term outcomes of all patients who have undergone combined heart-lung-liver transplantation (HLLTx) in Australia. METHODS: In this study, we performed a retrospective analysis of all adult patients who have undergone combined HLLTx in Australia to date. Recipient clinical characteristics, waitlist, and transplant outcomes are described. RESULTS: Eight adult patients have received HLLTx at a single Australian transplant center. Recipients of HLLTx have typically been young (median age, 30.1 years; range, 24-37), underweight (median body mass index, 19.8 kg/m2; range, 16.2-30.4) patients with cystic fibrosis (n = 8, 100%) with severe airflow obstruction (median forced expiratory volume in the first second of expiration, 24% predicted; range, 17%-48%) accompanied by liver cirrhosis confirmed on histopathology (n = 8, 100%). Despite relative preservation of synthetic function and low model for end-stage liver disease scores (median, 8; range, 6-17), all recipients had complications of portal hypertension prior to transplantation, with many patients having suffered life-threatening variceal hemorrhage. In this cohort, HLLTx was associated with overall posttransplant survival of 87.5% at 30 days, 71.4% at 1 year, and 42.9% at 5 years. Listing for combined HLLTx was associated with prolonged waitlist times relative to bilateral sequential single-lung transplantation (median 556 vs 56 days, respectively), however waitlist mortality and/or delisting was comparable between groups. CONCLUSIONS: Taken together, these findings highlight the opportunities and challenges facing combined (heart-) lung and liver transplantation in patients with multiorgan failure.

Duodenal expression of iron transport molecules in untreated haemochromatosis subjects.

BACKGROUND AND AIMS: In HFE associated hereditary haemochromatosis, the duodenal enterocyte behaves as if iron deficient and previous reports have shown increased duodenal expression of divalent metal transporter 1 (DMT1) and iron regulated gene 1 (Ireg1) in affected subjects. In those studies, many patients had undergone venesection, which is a potent stimulus of iron absorption. Our study investigated duodenal expression of DMT1 (IRE and non-IRE), Ireg1, hephaestin, and duodenal cytochrome-b (Dyctb) in untreated C282Y homozygous haemochromatosis patients, iron deficient patients, and iron replete subjects. METHODS: Total RNA was extracted from duodenal biopsies and expression of the iron transport genes was assessed by ribonuclease protection assay. RESULTS: Expression of DMT1 (IRE) and Ireg1 was increased 3-5-fold in iron deficient subjects compared with iron replete subjects. Duodenal expression of DMT1 (IRE) and Ireg1 was similar in haemochromatosis patients and iron replete subjects but in haemochromatosis patients with elevated serum ferritin concentrations, both DMT1 (IRE) and Ireg1 expression were inappropriately increased relative to serum ferritin concentration. Hephaestin and Dcytb levels were not upregulated in haemochromatosis. DMT1 (IRE) and Ireg1 levels showed significant inverse correlations with serum ferritin concentration in each group of patients. CONCLUSIONS: These findings are consistent with DMT1 (IRE) and Ireg1 playing primary roles in the adaptive response to iron deficiency. Untreated haemochromatosis patients showed inappropriate increases in DMT1 (IRE) and Ireg1 expression for a given level of serum ferritin concentration, although the actual level of expression of these iron transport genes was not significantly different from that of normal subjects.

Labor epidurals improve outcomes for babies of mothers at high risk for unscheduled cesarean section.

CONTEXT: Epidural placement for labor in the general population of laboring women is associated with increased incidence of operative deliveries, prolongation of labor, and may be associated with an increased cesarean section rate. The risks and benefits associated with epidural placement for labor in the subpopulation of mothers at high risk for cesarean section have not been studied. OBJECTIVE: To determine if a population of mothers and babies at high risk for cesarean section will have improved outcomes with labor epidural placement. DESIGN: A decision and cost analysis examining epidural placement for labor on a population of women who are at high risk for unscheduled cesarean section and may benefit from scheduled cesarean section as determined by threshold analysis was performed. Outcomes and probabilities were determined through analysis of the Department of Defense's 1996 National Quality Management Program (NQMP) Birth Product Line data set containing more than 7000 deliveries. Outcomes were defined using variables comprised of all documented conditions that occurred during the peripartum and neonatal hospitalizations. The 1997 NQMP data set was used to validate the results. SETTING: Military Treatment Facilities throughout the United States and abroad and civilian facilities in the United States providing care to military dependents. PATIENT POPULATION: Active duty and dependent pregnant women and babies. RESULTS: About 8% of mothers in this patient population were found to be at high risk for cesarean section. The decision and cost analyses showed that babies of the high risk mothers who received epidurals for labor had better clinical outcomes (p<0.05) and the procedure was cost neutral (p=0.23). The procedure did not increase the frequency of cesarean section, and there was no effect on maternal outcomes scores. These results were confirmed by the validation study. CONCLUSIONS: There is a sizable subpopulation of women at high risk for cesarean section whose babies may have better outcomes with epidural placement with no sacrifice in maternal outcomes or costs.

Increased hepatic iron and cirrhosis: no evidence for an adverse effect on patient outcome following liver transplantation.

It has been suggested that preexisting severe hepatic iron overload may adversely affect outcome after liver transplantation. The pathogenesis of iron overload in cirrhosis in the absence of hemochromatosis gene (HFE) mutations is poorly understood. The relationships between liver disease severity and etiology, degree of hepatic iron overload, and post-liver transplantation outcome were studied in 282 consecutive adult patients with cirrhosis. Thirty-seven percent of patients had stainable hepatic iron. Increased hepatic iron concentration was significantly associated with more severe liver disease (P<.001), male sex (P = .05), the presence of spur cell anemia (P<.0001), and hepatocellular liver disease (P<.0001). The HFE mutations were uncommon in patients with increased hepatic iron stores. Increased hepatic iron concentration was not associated with greater utilization of resources or a lower survival after liver transplantation. Child-Pugh score at the time of liver transplantation was the only independent variable affecting patient survival (P = .0008). In summary, our data suggest that the severity of the liver disease rather than hepatic iron concentration is the most important determinant of outcome after liver transplantation and that, in general, increasing hepatic iron concentration in cirrhosis is a surrogate marker of the severity of the underlying liver disease.

Confirmation of the role of the Mayo Risk Score as a predictor of resource utilization after orthotopic liver transplantation for primary biliary cirrhosis.

Resource utilization is an important consideration when patients are selected for orthotopic liver transplantation (OLT). The Mayo Risk Score has been proposed to help predict optimum time for OLT. We assessed the relation between Mayo risk score, Child-Pugh score, and resource utilization and outcome after OLT for primary biliary cirrhosis. The mean Mayo risk score was greater in patients who died than in the survivors (8.6 +/- 1.4 v 7.1 +/- 1.8; P <.05). There was a positive correlation between Mayo risk score and the 4 resource variables studied (intraoperative blood requirements, time ventilated, and duration of intensive care unit and hospital stays). Patients with a Mayo risk score greater than 7.8 used almost twice the resources of patients with a risk score less than 7.8. A positive correlation also existed between Child-Pugh score and duration of hospital stay. The mean Child-Pugh score in patients who died was greater than that in survivors (10.7 +/- 2.0 v 8.5 +/- 2.8, P =.03). This study confirms that Mayo Risk score is an important predictor of resource utilization and outcome after OLT.

Hepatocyte growth factor/scatter factor-induced intracellular signalling.

Hepatocyte growth factor (HGF) identical to scatter factor (SF) is a glycoprotein involved in the development of a number of cellular phenotypes, including proliferation, mitogenesis, formation of branching tubules and, in the case of tumour cells, invasion and metastasis. This fascinating cytokine transduces its activities via its receptor encoded by the c-met oncogene, coupled to a number of transducers integrating the HGF/SF signal to the cytosol and the nucleus. The downstream transducers coupled to HGF/MET, most of which participate in overlapping pathways, determine the development of the cell's phenotype, which in most cell types is dual.

The C282Y mutation in the haemochromatosis gene (HFE) and hepatitis C virus infection are independent cofactors for porphyria cutanea tarda in Australian patients.

BACKGROUND/AIM: Whether mutations in the putative haemochromatosis gene (HFE) and hepatitis C virus act independently to precipitate porphyria cutanea tarda is unknown. The aim of the study was to investigate the relationship between mutations in HFE, hepatitis C and porphyria cutanea tarda. METHODS: The frequencies of the C282Y and H63D mutations in HFE were determined in 27 patients with porphyria cutanea tarda and compared with the reported control frequencies. In addition, the presence of hepatitis C virus infection was identified and related to the patients' HFE status. RESULTS: The C282Y mutation was found in 44.4% of patients compared with the control frequency of 12% (p<0.001). Three patients were homozygous for the C282Y mutation, two of whom did not meet current clinical diagnostic criteria for expressed haemochromatosis. The proportion of patients with the H63D mutation did not differ from the reported control frequency. The mean transferrin saturation and serum ferritin concentration were similar in porphyria cutanea tarda patients who were homozygous normal and heterozygous for the C282Y mutation, but greater in both groups than previously reported in healthy controls. Seven (25.9%) patients were anti-HCV IgG positive. None of these patients carried the C282Y mutation. Porphyria cutanea tarda patients heterozygous for the C282Y mutation and patients with anti-HCV antibodies had elevated transferrin saturations and serum ferritin concentrations. CONCLUSIONS: The raised frequency of the C282Y mutation in porphyria cutanea tarda indicates that this mutation is likely to be a predisposing factor. However, abnormalities of iron indices also exist in porphyria cutanea tarda patients without mutations in HFE. Hepatitis C virus infection is likely to be another common precipitating factor for porphyria cutanea tarda which acts independently of the C282Y mutation.

Measurement of the fractional uptake of macromolecules by the renal vascular bed compared to other vascular beds.

Macromolecules resembling soluble immune complexes can be made from heat-aggregated human gamma globulin (AHGG). In 15 rats, we studied vascular trapping of 125I-labeled AHGG (AHGG)-125I) given by constant I.V. infusion over 1 hour while tissue blood flow was marked by intermittant aortic arch injections of 85Sr-labeled microspheres. Red cells labeled with 51Cr (RBC-51Cr) were also infused so that when the tissues were removed at the end of the experiment, the vascular volume of each tissue specimen could be balculated to correct issue 125I for AHGG-125I which was not trapped but simply in transit in the bascular space at the time the tissue was removed. These data permitted us to calculate the fractional uptake of AHGG-125I (FM) for a given tissue in comparison to any other tissue. We chose to compared the FM of each tissue to the FM of renal cortex. This comparison was expressed as a ratio termed the FM ratio for the given tissue. The following tissues had FM ratios significantly greater than 1.00 (i.e., per unit blood flow, these tissues trapped AHGG-125I more avidly than renal cortex): liver, spleen, skin, stomach, fat, testes, and large bowel. The respective ratios were 381 +/- 74, 15.7 +/- 4.0, 11.8 +/- 4.0, 7.47 +/- 1.95, 6.24 +/- 1.0 +/-, 3.03 +/- 0.67, 2.86 +/- 0.72 (all p less than 0.025). The FM ratio for adrenal, heart, thymus, and diaphragm were not significantly different from 1.00. The FM ratio of lung and brain were significantly less than 1.00: 0.014 +/- 0.008 and 0.14 +/- 0.065, respectively (p less than 0.001 for both). In 13 experiments, glomeruli was 23.8 +/- 3.5 per cent as assessed by recovery of the microspheres contained in renal cortex. Compared to whole renal cortex, the isolated glomeruli contained only minor amounts of AHGG-125I. We conclude that tissues vary widely with respect to their ability to trap macromolecules. When uptake is viewed in terms of the amount of complex trapped per unit delivery rate, many organs trap AHGG-125I for more avidly than renal cortex. Furthermore, under the present experimental conditions, glomeruli are not the major intrarenal site of macromolecule uptake.

Effect of renal decapsulation on renal function.

Marked increases in renal volume commonly occur in acute tubular necrosis and acute transplant rejection. Based on studies in the dog, we have previously suggested that the renal swelling observed in states of acute renal injury may be due principally to an increase in compliance of the kidney. The present study was undertaken in an effort to assess whether compliance-mediated increases in renal volume might affect renal function. In 15 dogs we compared the function of a decapsulated kidney (DK) to that of the contralateral intact kidney (IK); in 12 dogs we compared the function of a partially decapsulated kidney (PDK) to that of the contralateral IK. We compared the function of DK or PDK to IK, first under control conditions (ureteral pressure (UP) equals 0 mmHg), then at increased intrarenal pressure (UP equals 30 mmHg for both kidneys plus iv saline loading), and then during a recovery period (UP of both kidneys restored to 0 mmHg). The rationale is that probably DK is more compliant than IK; thus at increased intrarenal pressure DK volume should increase more than IK volume. Under control conditions DK and IK function were normal and equal; however, during increased intrarenal pressure, glomerular filtration rate (GFR) was about 20% less and Na and H20 excretion were about 30% less in DK than in IK. When intrarenal pressure was restored toward control by lowering UP to 0 mmHg, DK and IK function were once again equal. Similar but less marked changes occurred in the experiments comparing PDK and IK function. The impairment of renal function in DK vs. IK at increased intrarenal pressure was not explained by renal blood flow distribution, backdiffusion of glomerular filtrate, or by surface losses of fluid from DK. We suggest that impairment of renal function in DK vs. IK during increased intrarenal pressure is in some way related to the greater expansion of DK (21.0 +/- 0.02%) vs. IK (9.7 +/- 0.03%) at increased intrarenal pressure.

Whole kidney volume/pressure relationships.

We measured changes in kidney volume and intrarenal pressure produced by step-wise, steady state increases and decreases in ureteral pressure (UP). The purpose of such maneuvers, termed exercises, was to examine the relationship between changes in kidney volume and the changes in intrarenal pressure responsible for those in kidney volume. Changes in kidney volume were assessed from directly measured changes in kidney weight. Changes in the intrarenal pressure distending the renal capsule (renal subcapsular pressure [RSCP]) were measured by a strain guage diaphragm-type microtransducer placed between cortex and capsule. We measured these whole kidney volume/pressure events before and after saline loading and examined their relationship to changes in renal function following saline loading. We found that after four "exercises", the kidney became more complaint, i.e., occupied a larger volume at any given UP or RSCP, and that the compliance of the kidney was further increased following saline loading. However, about one hour after saline loading, RSCP returned to or below pre-saline loading levels and renal volume returned to pre-saline loading levels; nevertheless, the natriuresis persisted. Thus, an increase in renal volume is not necessary to sustain increased sodium and water excretion in post-saline loading. Finally, we found evidence that the renal capsule provides the major force opposing expansion of outer cortex when intrarenal pressure is increased.