Patient satisfaction and cost-effectiveness following total pancreatectomy with islet cell transplantation for chronic pancreatitis.

OBJECTIVES: Chronic pancreatitis (CP) results in an extremely poor quality of life and substantially increases health care utilization. Few data exist regarding the cost-effectiveness of surgical treatment for CP. METHODS: This article examined the cost-effectiveness of total pancreatectomy (TP) with islet cell autotransplantation (IAT) for CP. RESULTS: Sixty patients undergoing TP + IAT and 37 patients undergoing TP were identified. Surgery resulted in significant reduction in opiate use, frequency of hospital admissions, and length of stay as well as visual analog scale scores for pain. Total pancreatectomy + IAT resulted in longer survival than TP alone (16.6 vs 12.9 years); 21.6% of patients with TP + IAT were insulin-independent, and those requiring insulin have reduced daily requirements compared with those having TP alone (22 vs 35 IU). The cost of TP + IAT with attendant admission and analgesia costs over the 16-year survival period was £110,445 compared with £101,608 estimated 16-year costs if no TP + IAT was undertaken. CONCLUSIONS: Total pancreatectomy + IAT is effective in improving pain and reducing analgesia. Islet cell transplantation offers the chance of insulin independence and results in lower insulin requirements, as well as conferring a survival advantage when compared with TP alone. Total pancreatectomy + IAT is cost-neutral when compared with nonsurgical or segmental surgical therapy.

Extracorporeal liver perfusion system for artificial liver support across a membrane.

BACKGROUND: An extracorporeal porcine liver perfusion (ECPLP) system circumvents the limitations of hepatocyte based bio-artificial liver, but its clinical application has been limited so far due to the potential risk of transmission of porcine endogenous retroviruses. The aim of this study was to develop an ECPLP model that can provide artificial hepatic support across a semi-permeable membrane, which has the potential to block porcine viruses due to its pore size. MATERIALS AND METHODS: Livers from white landrace pigs were perfused with normothermic oxygenated blood using Medtronic BP560 centrifugal pump (Medtronic, Inc., Minneapolis. MN). This ECPLP system was used to support a "surrogate" patient across the filter Evaclio-EC4A. Function of liver was measured by indocyanine green retention at 15 min (ICGR15). Clearance of galactose, ammonia, and para-aminobenzoic acid infused into the "surrogate" patient circulation was calculated to assess liver support across the membrane. The study was designed as test (n = 15) versus control (n = 5), with control experiments having no liver in the circuit. RESULTS: For the test experiments, we perfused 15 livers with mean hepatic artery pressure of 87 mm Hg and flows of 1.2 L/min. ICGR15 in test experiments was 11%. Ammonia clearance was 945 mg/min/kg, galactose metabolic rate was 111.7 mg/min/Kg, and the hippurate ratio was 91% in the test. In contrast, the control experiments did not show any significant change in the concentration of any of these compounds. CONCLUSION: Our ECPLP model was able to provide hepatic support in an experimental setting across a hollow fiber filter. Further work on an anhepatic animal is needed prior to application in human trials.

Use of the recanalised umbilical vein for islet autotransplantation following total pancreatectomy.

INTRODUCTION: Islet autotransplantation requires access to the portal vein or tributaries. We originally infused islets into the liver via the middle or right colic veins, but since 2005 we have used the recanalised umbilical vein. Here, we describe the technique, the advantages and the early results achieved. MATERIALS AND METHODS: After removal of the pancreas and restoration of the biliary and enteric continuity, the ligamentum teres is transected. The obliterated umbilical vein is identified and recanalised with Bakes dilators giving access to the left portal vein. A Vygon® Nutricath 'S' 11-Fr catheter is inserted and used for the islet infusion. If the ligamentum teres is to be exteriorised for postoperative measurements or subsequent access, it is pulled through a 10-mm laparoscopic port in the epigastrium, sutured to the skin and covered with a dressing. RESULTS: We have used this approach in 17 patients and exteriorised the falciform ligament in 4. There have been no intra- or postoperative complications. CONCLUSIONS: The recanalised umbilical approach is safe and allows for venous sampling and postoperative measurements of the portal pressure. Under local anaesthetic, the umbilical vein can be approached above the umbilicus and exteriorised if repeated transplants are required for allograft patients. and IAP.

Inter-laboratory evaluation of the response of primary human hepatocyte cultures to model CYP inducers - a European Centre for Validation of Alternative Methods (ECVAM) - funded pre-validation study.

The aim of the current work was to harmonise protocols between three laboratories by performing independent isolations and cultures of human hepatocytes and to assess their responses to prototypical cytochrome P450 (CYP) enzyme inducers, beta-naphthoflavone (BNF), rifampicin (RIF) or phenobarbital (PB). The magnitudes of the induction responses were CYP and donor-dependent but there was a good reproducibility between laboratories. CYP1A2 activity was evident in all cultures treated with BNF but not RIF or PB. Likewise, CYP3A4/5 activity was induced to the same extent by RIF and PB, while BNF did not affect this CYP in any of the cultures tested. All three compounds caused a concentration-dependent increase in CYP2B6 in cultures from 2 of the 3 laboratories and the response to PB was at least twice that of the other two inducers. In conclusion, the harmonised protocols used to study the response of primary cultures of human hepatocytes to prototypical inducers are transferable, reproducible within a given laboratory and between laboratories. The results obtained will support setting up a definitive validation study of the harmonised protocols.

Total pancreatectomy with islet autotransplantation: an overview.

Pain control is one of the most challenging aspects in the management of chronic pancreatitis. Total pancreatectomy can successfully relieve the intractable abdominal pain in these patients but will inevitably result in insulin-dependent diabetes. Islet autotransplantation aims to preserve, as far as possible, the insulin secretory function of the islet cell mass thereby reducing (or even removing) the requirement for exogenous insulin administration after a total pancreactomy. Despite the relatively small number of centres able to perform these procedures, there are important technical variations in the details of their approaches. The aim of this review is to provide details of the current surgical practice for total pancreatectomy combined with islet autotransplantation, and outline the potential advantages and disadvantages of the variations adopted in each centre.

Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function.

UNLABELLED: Total pancreatectomy is considered the final resort in the treatment of chronic pancreatitis; however, here we show that simultaneous islet autotransplantation can abrogate the onset of diabetes. METHODS: : In Leicester, 46 patients have now undergone total pancreatectomy with immediate islet auto transplant, and they have received a median of 2246 islet equivalent (IEQ)/kg body weight (range, 405-20,385 IEQ/kg body weight). RESULTS: : Twelve patients have shown periods of insulin independence, for a median of 16.5 months (range, 2-63 months), and 5 remain insulin independent. Over the 10 years of follow-up, there has been a notable increase in insulin requirement per kilogram per day, and percentage of glycosylated hemoglobin levels have increased significantly (r = 0.66, P = 0.01). However, 100% of patients tested were C-peptide positive at their most recent assessment, and high fasting and stimulated C-peptide values recorded at 10 years after transplantation, 1.44 (range, 1.09-1.8 ng/mL) and 2.86 ng/mL (range, 1.19-4.53 ng/mL), respectively, suggest significant graft function in the long term. In addition, median serum creatinine has increased very little after the operation (71 nmol/L [range, 49-125 nmol/L] atpreoperation vs 76.5 nmol/L [range 72-81 nmol/L] at year 10), suggesting no diabetic nephropathy. CONCLUSIONS: : Although there is a notable decline in islet function after islet auto transplant, there is still evidence of significant long-term insulin secretion and possible protection against diabetic complications.

Differential effects of curcumin on cryopreserved versus fresh primary human hepatocytes.

Curcumin (CUR) is a major component of a dietary spice derived from the roots of Curcuma longa. It has strong antioxidant activities and hepatoprotective properties. Primary human hepatocytes are clinically used in transplantation or in bioartificial liver devices for the treatment of patients with liver failure. Fresh and cryopreserved hepatocytes are also used in vitro for the study of drugs in pharmacotoxicology. We aimed to assess whether CUR could improve human liver cell viability and prevent oxidative damage responsible for large cell loss during cell preparation. Our study showed beneficial effects of CUR (25 microM) on freshly isolated human hepatocytes, increasing significantly metabolic activity of viable attached cells when seeded with CUR for 24 h. However CUR added during the cell isolation process did not have any significant impact on cell isolation outcomes or on cryopreservation outcomes. Conversely, CUR added during the thawing of frozen cells had a negative effect on the cell attachment capacity of hepatocytes that were cryopreserved in the presence or absence of CUR. In conclusion, although having positive effects on viability and challenge of oxidative stress on cultured human hepatocytes, CUR had no beneficial effect on cell isolation or cryopreservation outcomes.

Ultrasound changes within the liver after total pancreatectomy and intrahepatic islet cell autotransplantation.

OBJECTIVE: Intrahepatic infusion is the most common method of islet autotransplantation. Structural and functional changes within the liver may result from a number of factors, including embolization of the terminal branches of the portal vein, the effects of high insulin concentration on surrounding hepatocytes or responses to the death of admixed exocrine tissue. Awareness of the potential changes in the appearance of the liver on ultrasonography (USS), together with an assessment of liver function, is important in the postoperative surveillance of these patients. METHODS: We retrospectively reviewed 83 patients who underwent total pancreatectomy between 1993 and 2006. Thirty-three patients had total pancreatectomy alone (control group) and 50 patients underwent total pancreatectomy and islet autotransplantation (islet group). The islets were infused into the left lobe of the liver through the middle colic or recannalated umbilical vein. All patients underwent USS as part of their hepaticojejunostomy surveillance (initially every 6 months and then yearly). RESULTS: "Echogenic nodularity" of the liver was observed in 25% of the islet group of patients and in none of the control group patients (P=0.03). These USS changes occurred from 6 to 12 months after islet autotransplantation and were not associated with any significant loss of liver function or increase in insulin requirements. The islet group had significantly less insulin requirement compared with the control group (P<0.01). CONCLUSION: Echogenicity with a nodular appearance is a common ultrasonographic finding in the liver after intrahepatic islet autotransplantation. These changes do not seem to adversely affect liver function or insulin requirement. Appreciating these changes is important to avoid misinterpretation or over-interpretation of postoperative USS images.

Effects of progestins of human proliferative endometrium: an in vitro model of potential clinical relevance.

Endometrium biopsy is a useful indicator of endometrium proliferation and is clinically relevant to diagnose cell proliferation and to evaluate response to progestin treatment and to monitor hormone replacement therapy. The aim of our study was to investigate the in vitro effects of progesterone and synthetic progestins on endometrium explants with a particular focus on estradiol receptor (ER) and progesterone receptor (PR) expression which reflects through cell secretion the hormone treatment efficiency. Most widely used progestagens belonging to three distinctive groups were investigated, i.e, medroxyprogesterone acetate (MPA), norethindrone acetate (NOR) and nomegestrol acetate (TX) which are respectively pregnane, 19-nortestosterone and norpregnane derivatives. We used organ culture from human proliferative endometrium, in which tissue integrity, particularly gland/stroma relationships are preserved. Progestins induce epithelial cell secretion and most effects were observed at the highest concentration tested (10(-7) M) and by TX and MPA on homogeneous and on heterogeneous (including also secretory glands) proliferative endometrium respectively. In these conditions, ER as well as PR expression were decreased on both glandular and stromal cells. In contrast, progesterone at 10(-7) M significantly decreased only PR, in glands and in stroma of homogeneous proliferative endometrium, and just in stroma of heterogeneous endometrium. NOR exhibited less effects. At lower concentrations (10(-8) M, 10(-9) M), significantly less effects were observed by synthetic progestins on proliferative endometrium. The experiments show that the different types of progestins do not exhibit in vitro similar effects. Since progestins variably act on proliferative endometrium, the exposure of endometrium explants to progestins may be a useful tool to predict clinical response to hormone therapy (individual "hormonogram") and to monitor endometrium proliferation.

[Effects of progestins on human endometrium in vitro]. / Effets des progestatifs sur l'endomètre humain in vitro.

In order to obtain a better evaluation of the epithelial proliferation of the human endometrium, we developed an "in vitro" model to quantify the effects of hormonal treatments, as an "hormonogram". We particularly aimed to evaluate the effects of steroids used in the replacement hormone therapy during menopausis in the view of predicting and preventing the development of precancerous lesions of the endometrium. This study has evaluated the effects of different progestins currently used in hormone therapy, progesterone, medroxy-progesterone acetate (MPA), nomegestrol acetate (TX), norethindrone acetate (NOR) on human proliferative endometrium explant culture, using two means: prostaglandin F2 alpha (PGF2 alpha) output in medium culture, and immunoexpression of estradiol receptor (ER), progesterone receptor (PR) and proliferative antigen Ki67 in tissue. After culture, quantitative studies on ER or PR immunoexpression could be assessed by image analysis procedure in contrast to Ki67 immunoexpression too weak low in non tumorous endometrium to be quantified. PGF2 alpha output, was decreased by progesterone, TX and MPA in both proliferative endometrium subtypes. With regards to receptor immunoexpression, progesterone only decreased PR expression in proliferative endometrium. PR immunoexpression in stromal cells was decreased by all progestins in homogeneous proliferative endometrium explants. TX decreased PR and ER expression in glands and stroma of homogeneous proliferative endometrium. MPA exhibited similar effects but only on heterogeneous proliferative endometrium. In brief, our results show that in vitro progestative treatment on endometrium reduced PGF2 alpha output and decreased PR and/or ER immunoexpression, although the in vitro effects of each progestin were not similar and varied with the endometrium subtype (proliferative homogeneous or heterogeneous). This study opens new fields of research particularly to investigate the endometrial proliferative activity using explant culture.