Derek Manas

Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.

BACKGROUND & AIMS Hepatocellular cancer (HCC) commonly complicates chronic liver disease and increases in incidence have been reported despite falling prevalences of viral hepatitis. METHODS Following the introduction of centralised specialist teams to manage patients with cancer in England, we characterised the demographics of patients with HCC referred to the Newcastle-upon-Tyne Hospitals NHS Foundation Trust between 2000 and 2010. Regional HCC mortality data was from Public Health England. RESULTS HCC related mortality in the region rose 1.8 fold in 10 years, from 2.0 to 3.7 per 100,000. 632 cases were reviewed centrally, with 2-3 fold increases in referrals of patients with associated hepatitis C, alcoholic liver disease or no chronic liver disease and a >10 fold increase in HCC associated with non-alcoholic fatty liver disease (NAFLD). By 2010 NAFLD accounted for 41/118 (34.8%) cases. Irrespective of associated etiologies, metabolic risk factors were present in 78/118 (66.1%) cases in 2010, associated with regional increases in obesity and diabetes. Median overall survival was just 10.7 months. Although patients with NAFLD associated HCC were older (71.3 yr vs. 67.1 yr; p<0.001) and their cancers less often detected by surveillance, their survival was similar to other etiologies. This was attributed to significantly higher incidental presentation (38.2%) and lower prevalence of cirrhosis (77.2%). CONCLUSIONS HCC related mortality is increasing, with typical patients being elderly with metabolic risk factors. The prognosis for most of the cases is poor, but older patients with co-morbidities can do well, managed, within a specialist multidisciplinary team if their cancer is detected pre-symptomatically.

Submaximal cardiopulmonary exercise testing predicts complications and hospital length of stay in patients undergoing major elective surgery.

Objective:To investigate the null hypothesis that an objective, noninvasive technique of measuring cardiorespiratory reserve, does not improve the preoperative assessment of patient risk of postoperative complications, when compared with a standard questionnaire-based assessment of functional capacity. Summary Background Data:Postoperative complications may be increased in patients with reduced cardiorespiratory function. Activity questionnaires are subjective, whereas cardiopulmonary exercise testing (CPET) provides an objective definition of cardiorespiratory reserve. The use of preoperative CPET to predict postoperative complications is not fully defined. Method:CPET and an algorithm-based activity assessment (Veterans Activity Questionnaire Index [VASI]) were performed on consecutive patients (n = 171) with low subjective functional capacity (metabolic equivalent score [METS] < 7), being assessed for major surgery. A morbidity survey determined postoperative day 7 complications. Logistic regression defined independent predictors of complication group. Receiver-operating curve (ROC) analysis defined the predictive value of CPET to outcome. P < 0.05 value demonstrated significance. Results:Objective cardiorespiratory reserve did not differ between operated (n = 116) and nonoperated patients (n = 55). Median complication rate on postoperative day 7 was 1. Patients with >1 complication had an increase in hospital LOS compared to the group with ≤1 complication (26 vs. 10 days; P < 0.001). Anaerobic threshold (AT) was higher in the group with ≤1 complication (11.9 vs. 9.1 mL/kg/min; P = 0.001) and demonstrated high accuracy (AUC = 0.85), sensitivity (88%), and specificity (79%), at an optimum AT of 10.1 mL/kg/min (defined by the furthest left point on the ROC curve). AT, VASI, and surgical reintervention were independent predictors of complication group. Preoperative AT significantly improved outcome prediction when compared with the use of VASI alone. Conclusion:An objective measure of cardiorespiratory reserve was an independent predictor of a major surgical group with increased postoperative complications and hospital LOS. AT measurement significantly improved outcome prediction compared with an algorithm-based activity assessment.

Cyclosporine Withdrawal from a Mycophenolate Mofetil–Containing Immunosuppressive Regimen: Results of a Five-Year, Prospective, Randomized Study

Maintenance immunosuppression with cyclosporine (CsA) is associated with nephrotoxicity, hyperlipidemia, and hypertension. This long-term study (core study + 4 yr of follow-up) investigated the long-term efficacy and safety of CsA withdrawal from a mycophenolate mofetil (MMF)-based regimen. Seventy-seven patients were maintained on CsA, MMF, and steroids (CsA-MMF group), and 74 were given a CsA-free regimen of MMF and steroids (MMF group). Serum creatinine and creatinine clearance were measured at 6-month intervals. Patient and graft survival, acute rejection episodes, malignancies, BP, and lipid profile were also recorded. At 5 yr, patient and graft survival was 93 and 88%, respectively, for the MMF group and 95 and 92%, respectively, for the CsA-MMF group. During follow-up, seven MMF patients experienced acute rejection episodes compared with one CsA-MMF patient (P = 0.0283). Nine grafts were lost to chronic rejection in the MMF group versus three in the CsA-MMF group. No demographic or immunologic characteristics were associated with acute or chronic rejection in the MMF group, but the doses of both MMF and steroids decreased significantly between 1 and 5 yr. The MMF group showed a trend toward improved creatinine clearance (67.4 versus 61.7 ml/min; P = 0.0500). Withdrawal of CsA from an MMF-containing immunosuppressive regimen resulted in an increased risk for acute rejection episodes and graft loss as a result of rejection throughout the 5-yr study period. The creatinine clearance-confirmed improvement in renal function observed at year 1 was maintained at 5 yr BP and cholesterol levels were well controlled in both groups.

Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen in stable kidney transplant recipients: a randomized, controlled study.

Background. Long-term maintenance immunosuppression with cyclosporine (CsA) is associated with chronic transplant nephropathy and adverse effects on blood pressure and lipid profile. Several nonrandomized studies suggest that CsA might safely be withdrawn from immunosuppressive regimens containing mycophenolate mofetil (MMF; CellCept). Methods. A randomized, controlled study with 187 patients enrolled from 21 centers was conducted to compare CsA withdrawal with ongoing CsA therapy in stable renal transplant recipients receiving a triple-drug immunosuppressive regimen of MMF (2 g/day), CsA (Neoral), and corticosteroids. The primary endpoint was creatinine clearance at 6 months after complete withdrawal. Results. In the intent-to-treat population, CsA withdrawal was associated with lower total cholesterol and low-density lipoprotein cholesterol (−0.3 mmol/L, P =0.02; −0.4 mmol/L, P =0.015). There was a trend toward improved creatinine clearance (4.5 mL/min, P =0.16) and serum creatinine (−1 vs. +4 &mgr;mol/L, P =0.34). In the per-protocol population, which excluded patients with acute rejections, the improvements in creatinine clearance and serum creatinine were statistically significant (7.5 mL/min, P =0.02; −11 vs. +4 &mgr;mol/L, P =0.0003). Reversible acute rejections, the majority of which were mild, occurred in nine CsA withdrawal versus two CsA continuation patients (10.6% vs. 2.4% of each group, P =0.03), with no graft loss. Conclusion. Withdrawal of CsA from an MMF-containing triple-drug immunosuppressive regimen improves renal function and lipid profile at the cost of a modest increase in acute rejections, without graft loss.

Mycophenolate mofetil monotherapy in liver transplantation

Chronic renal failure is a major cause of morbidity and mortality after orthotopic liver transplantation. We did a randomised controlled trial of mycophenolate mofetil monotherapy in liver transplant patients who developed renal failure associated with calcineurin-inhibitor (ciclosporin or tacrolimus) immunosuppressive therapy. Although renal failure improved when the calcineurin-inhibitor dose was reduced and ultimately stopped, the trial was stopped when three of five patients on monotherapy developed organ rejection requiring a second transplantation.

The trouble with kidneys derived from the non heart-beating donor: a single center 10-year experience.

BACKGROUND The demand for renal transplantation has increasingly outstripped the supply of donor organs especially over the past 10 years. Although related and unrelated live donation is being promoted as one option for increasing the donor pool, it is unlikely that this will in itself be able to bridge the gap. Non-heart beating donors (NHBD) can provide an alternative supply of organs, which should substantially increase the donor pool. METHODS In Newcastle, NHBD kidneys have been used for transplantation for a period of 10 years. In the early period (1988-1993) excellent results were obtained (90.5% success); however, these donors were controlled NHBD, Maastricht category III. In the second phase (1994-1998) increasing numbers of donors were obtained from the Accident and Emergency Department unit. These were failed resuscitation for cardiac arrest (category II). The rates of success in this period were poor (45.5% success) and the program was halted. The third phase of the program used machine perfusion of the kidneys and glutathione S transferase enzyme analysis to assess viability. RESULTS Using such approaches renal transplants from largely category II donors produced a success rate of 92.3% which was significantly better than the phase II period of the program (P=0.023, Fisher two-tail test). CONCLUSION Machine perfusion and viability assessment of NHB kidneys in phase III of the program has increased our donor pool as well as improved the graft survival. This is particularly relevant for the use of the category II NHB donor where the incidence of primary nonfunction was high, illustrated by phase II where machine perfusion/viability assessment was not used.

Angiotensin II Activates IκB Kinase Phosphorylation of RelA at Ser536 to Promote Myofibroblast Survival and Liver Fibrosis

BACKGROUND & AIMS The transcription factor nuclear factor-kappaB (NF)-kappaB promotes survival of hepatic myofibroblasts and fibrogenesis through poorly defined mechanisms. We investigated the activities of angiotensin II and I kappaB kinase (IKK) in regulation of NF-kappaB activity and the role of these proteins in liver fibrosis in rodents and humans. METHODS Phosphorylation of the NF-kappaB subunit RelA at serine 536 (P-Ser(536)-RelA) was detected by immunoblot and immunohistochemical analyses. P-Ser(536)-RelA function was assessed using vectors that expressed mutant forms of RelA, cell-permeable blocking peptides, and assays for RelA nuclear transport and apoptosis. Levels of P-Ser(536)-RelA were compared with degree of fibrosis in liver sections from chronically injured rats and patients with hepatitis C virus-mediated fibrosis who had been treated with the AT1 antagonist losartan. RESULTS Constitutive P-Ser(536)-RelA is a feature of human hepatic myofibroblasts, both in vitro and in situ in diseased livers. Autocrine angiotensin II stimulated IKK-mediated phosphorylation of RelA at Ser(536), which was required for nuclear transport and transcriptional activity of NF-kappaB. Inhibition of angiotensin II, the angiotensin II receptor type 1 (AT1), or IKK blocked Ser(536) phosphorylation and stimulated myofibroblast apoptosis. Treatment of fibrotic rodent liver with the angiotensin converting enzyme (ACE) inhibitor captopril or the IKK inhibitor sulphasalazine resulted in loss of P-Ser(536)-RelA-positive myofibroblasts and fibrosis regression. In human liver samples, increased numbers of P-Ser(536)-RelA-positive cells were associated with fibrosis that regressed following exposure to losartan. CONCLUSIONS An autocrine pathway that includes angiotensin II, IKK, and P-Ser(536)-RelA regulates myofibroblast survival and can be targeted to stimulate therapeutic regression of liver fibrosis.

AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease

BackgroundThe incidence and mortality of hepatocellular cancer (HCC) complicating alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD) is rising in western societies. Despite knowing the at risk populations for HCC development, the lack of sensitive and specific means of surveillance hampers disease detection at curable stages. The most widely used serum HCC marker is alpha-fetoprotein (AFP), while PIVKA-II, glypican-3 (GP3) and Squamous Cell Carcinoma Antigen -1 (SCCA-1) have been proposed as new biomarkers. Assessment of these HCC biomarkers has largely been performed in patients with viral hepatitis. We conducted a cross sectional study assessing the value of these serum proteins, as well a novel candidate biomarker -follistatin – in patients with HCC arising on a background of ALD or NAFLD.MethodsPre-treatment serum samples from 50 patients with HCC arising on a background of ALD (n = 31) or NAFLD (n = 19) were assessed by specific ELISA assay for PIVKAII, Glypican-3, SCCA-1 and Follistatin. Results were compared and contrasted with a control patient group with biopsy proven steatohepatitis-related cirrhosis (n = 41). The diagnostic accuracy of each of the candidate biomarkers was evaluated using receiver operating characteristic (ROC) curve analysis, reporting the area under the curve (AUC) and its 95% confidence interval (CI). Performance was compared to that of the established biomarker, AFP.ResultsSerum levels of all proteins were assessed by specific ELISA assays. GP3, SCCA-1 and follistatin had no HCC surveillance benefit in these patients. AFP and PIVKAII were superior to the other markers, particularly in combination.ConclusionWe conclude that while novel means of surveillance are urgently required, the combination of AFP and PIVKAII for HCC is an improvement on AFP alone in ALD/NAFLD patients. Furthermore, our data in this homogenous subset of patients- particularly that confirming no role for SCCA-1 – suggests that the choice of optimal biomarkers for HCC surveillance may be determined by the aetiology of underlying chronic liver disease.

Long-term renal function in kidneys from non-heart-beating donors: A single-center experience

BACKGROUND Cadaveric kidneys from brain-stem-dead donors continue to be limited because the number of donors has reached a plateau. Wide recruitment of non-heart-beating donors (NHBD) could significantly increase the donor pool. NHBD renal transplants are underused because of the concern of poor quality graft function from such donors. In response to this perception, we reviewed 46 NHBD renal transplants performed in our center since 1998. METHODS All NHBD kidneys were machine-perfused using the Newcastle continuous-hypothermic pulsatile preservation system before transplantation. A control heart-beating-donor (HBD) group was taken as the next consecutive HBD renal transplant to the NHBD transplant. The outcome and quality of function of the groups of renal transplants were analyzed for short-term and long-term performance. RESULTS The renal transplant patients were matched for donor and recipient factors. Survival rates for allografts and patients were similar for 1 to 3 years. There was an increased incidence of delayed graft function in the NHBD renal transplants in the perioperative period. The creatinine clearance was 22.8+/-2.3 mL/minute for NHBD patients and 44.4+/-2.9 mL/minute for HBD patients at the time of discharge from hospital. This difference equalized after 3 months and the creatinine clearance for NHBD was 44.2+/-2.4 mL/minute and for HBD 49.2+/-3.4 mL/minute. CONCLUSIONS Our results for NHBD renal transplants confirm that such grafts suffer primary warm ischemic injury, shown by the increased incidence of acute tubular necrosis and consequent delayed graft function. This produced poor renal function at the time of hospital discharge. After 3 months, the renal function of NHBD cases improved to the level seen in HBD patients.

Cardiorespiratory Fitness Predicts Mortality and Hospital Length of Stay After Major Elective Surgery in Older People

Objective:This study aimed to define the relationship between cardiorespiratory fitness and age in the context of postsurgery mortality and morbidity in older people. Background:Postsurgery mortality and morbidity increase with age. Cardiorespiratory fitness also declines with age, and the independent and linked associations between cardiorespiratory fitness and age on postsurgical mortality and morbidity remain to be determined. Methods:An unselected consecutive group of 389 adults with a mean age of 66 years (range 26–86 years) underwent cardiorespiratory exercise testing before major hepatobiliary surgery at a single center. Mortality and critical care unit and hospital lengths of stay were collected from patient records. Primary outcomes were in-hospital all-cause mortality after surgery and hospital and critical care lengths of stay. Results:Anaerobic threshold was the most significant independent predictor for postoperative mortality (P = 0.003; &bgr; = −0.657 and odds ratio = 0.52) in 18 of 389 (4.6%) patients who died during their in-hospital stay. Age was not a significant predictor in this model. Older people with normal cardiorespiratory fitness spent the same number of days in the hospital or critical care unit as younger people with similar cardiorespiratory fitness (13 vs 12; P = 0.08 and 1 vs 1; P = 0.103). Patients older than 75 years with low cardiorespiratory fitness spent a median of 11 days longer in hospital (23 vs 12; P < 0.0001) and 2 days longer in critical care (2.9 vs 0.9; P < 0.0001) when compared with patients with adequate cardiorespiratory fitness. Conclusions:Cardiorespiratory fitness is an independent predictor of mortality and length of hospital stay and provides significantly more accurate prognostic information than age alone. Clinicians should consider both the prognostic value of cardiorespiratory testing and techniques to preserve cardiorespiratory function before elective surgery in older people.