Search

BACKGROUND: Pancreatectomy plus celiac axis resection (CAR) is performed in patients with locally advanced pancreatic cancer. The morbidity rates are high, and no survival benefit has been confirmed. It is not known at present whether it is the type of pancreatectomy, or CAR itself, that is the reason for the high complication rates.; METHODS: Observational retrospective multicenter study.; INCLUSION CRITERIA: patient undergoing TP, PD or DP plus CAR for a pancreatic cancer.; RESULTS: Sixty-two patients who had undergone pancreatic cancer surgery (PD,TP or DP) plus CAR were studied. Group 1: 17 patients who underwent PD/TP-CAR (13TP/4PD); group 2: 45 patients who underwent DP-CAR. Groups were mostly homogeneous. Operating time was longer in the PD/TP group, while operative complications did not differ statistically in the two groups. The number of lymph nodes removed was higher in the PD/TP group (26.5 vs 17.3), and this group also had a higher positive node ratio (17.9% vs 7.6%). There were no statistical differences in total or disease-free survival between the two groups.; CONCLUSION: It seems that CAR, and not the type of pancreatectomy, influences morbidity and mortality in this type of surgery. International multicenter studies with larger numbers of patients are now needed to validate the data presented here.

Next-generation three-dimensional modelling software for personalized surgery allows spatially accurate depiction of the hepatic and vasculature anatomy based on the complexity and individual variation in each patient, and could facilitate decision-making about preoperative strategy in perihilar cholangiocarcinoma.

Background: Nab-paclitaxel and gemcitabine have demonstrated a survival benefit over gemcitabine alone in advanced pancreatic cancer (PDA). This study aimed to investigate the clinical, biological, and imaging effects of the regimen in patients with operable PDA. Methods: Patients with operable PDA received two cycles of nab-paclitaxel and gemcitabine before surgical resection. FDG-PET and CA19.9 tumour marker levels were used to measure clinical activity. Effects on tumour stroma were determined by endoscopic ultrasound (EUS) elastography. The collagen content and architecture as well as density of cancer-associated fibroblasts (CAFs) were determined in the resected surgical specimen and compared with a group of untreated and treated with conventional chemoradiation therapy controls. A co-clinical study in a mouse model of PDA was conducted to differentiate between the effects of nab-paclitaxel and gemcitabine. Results: A total of 16 patients were enrolled. Treatment resulted in significant antitumour effects with 50% of patients achieving a >75% decrease in circulating CA19.9 tumour marker and a response by FDG-PET. There was also a significant decrement in tumour stiffness as measured by EUS elastography. Seven of 12 patients who completed treatment and were operated had major pathological regressions. Analysis of residual tumours showed a marked disorganised collagen with a very low density of CAF, which was not observed in the untreated or conventionally treated control groups. The preclinical co-clinical study showed that these effects were specific of nab-paclitaxel and not gemcitabine. Conclusion: These data suggest that nab-paclitaxel and gemcitabine decreases CAF content inducing a marked alteration in cancer stroma that results in tumour softening. This regimen should be studied in patients with operable PDA.

A high throughput screening for anticancer activity of FDA approved drugs identified mycophenolic acid (MPA), an inhibitor of inositol monophosphate dehydrogenase (IMPDH) as an active agent with an antiangiogenesis mode of action. Exposure of pancreatic cancer cell lines to MPA resulted in growth inhibition and reduced the expression of VEGF that was reversed by supplementing the media with guanosine supporting and IMPDH-dependant mechanism. In preclinical in vivo study, MPA showed a moderate inhibition of tumor growth in a panel of 6 human derived pancreatic cancer xenografts but reduced the expression of VEGF. To investigate the effects of MPA in human pancreatic cancer, a total of 12 patients with resectable pancreatic cancer (PDA) received increasing doses of mycophenolate mofetil (MMF) in cohorts of 6 patients each from 5-15 days prior to surgical resection. Treatment was well tolerated with one episode of grade 1 muscle pain, one episode of grade 2 lymphopenia (2 gr/day dose) and one episode of grade 2 elevantion in LFT (all in the 2 gr./day dose). Patients recovered from surgery uneventfully with no increased post-operative complications. Assessment of CD31, VEGF, and TUNEL in resected specimens compared to a non treated control of 6 patients showed no significant variations in any of the study endpoints. In conclusion, this study shows the feasibility of translating a preclinical observation to the clinical setting and to explore a drug mechanism of action in patients. MPA, however, did not show any hints of antiangiogenesis of anticancer clinical activity questioning if this agent should be further developed in PDA.

Resumen El carcinoma de celulas renales con trombo en vena cava inferior es una patologia relativamente rara, que complica la nefrectomia radical. Durante los pasados veinte anos nuestro hospital ha contribuido sustancialmente a la estratificacion quirurgica del carcinoma de celulas renales con extension a la vena cava a traves de diferentes tecnicas. El objetivo de este articulo es describir las diferentes estrategias quirurgicas necesarias y mas apropiadas para el tratamiento de los distintos niveles del trombo tumoral. Consideramos que el diagnostico de la invasion de la vena cava por el tumor y el nivel de extension tumoral estan basados en examenes radiologicos, los cuales son determinantes a la hora del planteamiento quirurgico y exito de la cirugia. Somos partidarios del uso de filtros de vena cava colocados.preoperatoriamente para prevenir el riesgo de tromboembolismos pulmonares durante y despues de la cirugia. El uso de protesis de cava es excepcional, debido a que la obstruccion cronica producida por el trombo tumoral, permitira el desarrollo de una extensa circulacion colateral que actuara como un bypass veno-venoso. Por ultimo, intentamos evitar el uso de bypass veno-venoso o bypass cardiopulmonar con o sin hipotermia y parada cardiocirculatoria, debido a la alta morbimortalidad que conllevan.

The hepatitis C virus (HCV) is an RNA virus that replicates with a high rate of mutation, especially in the hypervariable region 1 (HVR-1). Continuous viral mutations lead to a mixed and changing populations of mutants, called quasispecies. The nature of the HCV quasispecies may have implications for viral persistence and pathogenies. Studies with liver transplant patients suggest a relationship between the degree of immunosuppression and the complexity of the quasispecies. This study evaluated whether immunosuppressive therapy modifies the evolution of HCV quasispecies among liver transplant recipients compared with immunocompetent HCV patients. Two groups were studied: 11 patients who underwent OLT for HCV-related cirrhosis and 10 control group patients. Two serum samples from each patient were obtained to analyze the HCV HVR1 region by RT-PCR. SSCP analysis failed to show statistically significant differences in the number of quasispecies at basal and final time points or at pretransplant versus posttransplant (7.3+/-2 vs 6.7+/-3 in control patients, respectively, and 4.4+/-2 vs 4.1+/-1 in transplanted patients, respectively). No significant difference was observed between missing or new variants in the control (2.8+/-2 vs 2.3+/-2, respectively) or transplanted group (2.5+/-2 vs 2.2+/-1, respectively). Upon sequence analysis, the genetic complexity was significantly lower among samples after OLT in transplanted patients (0.057+/-0.04 [pretransplant] vs 0.035+/-0.02 [posttransplant]; P=.048). However, no significant differences were found among control patients in basal versus final samples (0.04+/-0.03 vs 0.066+/-0.04, respectively). Our findings seem to demonstrate that viral quasispecies diversity is lower among patients receiving a liver transplant.

Sir, In response to Boeck et al We read with interest the comments made by Boeck et al (2014) about our study. We appreciate their attention to the units used to report CA19.9 levels, which indeed should have been U ml−1 and not U dl−1 as stated. We certainly agree that a high level of CA19.9 at diagnosis may be an indication of advanced disease and that this should be considered in the selection criteria in preoperative studies. Indeed in our study, with small sample size, one patient with very high CA19.9 level who actually progressed during chemotherapy skewed that average level of CA19.9. This patient was not operated and therefore does not affect the tissue results. As Boeck et al mention, levels of CA19.9 should be either a selection criteria or a stratification factor in outcome-oriented preoperative studies that should also include better imaging methods to determine responses and histological, rather than cytological, diagnosis. In our study, however, as the goals were to determine the effects of Nab-paclitaxel in tumour tissue, this criterion was not part of the eligibility criteria. We agree, however, that future controlled studies to confirm our observations should exclude patients with elevated CA19.9 and plan to do so. In clinical practice, however, one of the goals of preoperative treatment is to identify patients with more advanced or resistant disease who can be spared from surgery, as surgery would not be beneficial for those patients. Thus, for patients with resectable or borderline resectable disease by CT scan and high (>180 U ml−1) CA19.9, we usually administer chemotherapy upfront and explore surgically those patients who do not progress after two cycles of treatment provided laparoscopic assessment of peritoneal disease is negative as well. In response to Ramirez et al We read with great interest the comments made by Ramirez et al (2014) in which they highlight the importance of tumour stroma in pancreatic cancer (PDAC) and the role of ‘pancreatic stellate cells' in the development of tumour stroma. The current data, while with still some inconsistencies, show that in preclinical models of PDAC, the combination of gemcitabine and Nab-paclitaxel (PTX) increases the delivery of gemcitabine to the tumour. Mechanistically, this has been explained by a decrease in the expression of the gemcitabine catabolism enzyme cytidine deaminase and hence increasing the intracellular retention time of the active gemcitabine metabolites or by elimination of the PDAC stroma (Von Hoff et al, 2011; Frese et al, 2012). In the only clinical study available so far, we have shown that Nab-PTX markedly alters the PDAC stroma and decreases the number of CAF (Alvarez et al, 2013). The precise mechanisms underlying these observations remain obscure. Selective binding of albumin-coated Nab-PTX to SPARC-positive cells or uptake of nutrient-rich drug by cancer cells by pynocitosis have been proposed and are the subject of specific studies. The role of SPARC has been studied in the MPACT randomised clinical trial and we hope to have these results available in the near future (Von Hoff et al, 2013). As these authors propose, the effects of Nab-PTX on cancer stroma could be a consequence of the direct elimination of cancer cells and interruption of the cancer cell–stroma interactions. Certainly, additional preclinical and translational clinical studies are needed to determine the precise mechanism of action of this, otherwise, clinically effective regimen.

Narcolepsy is a disabling sleep disorder that is characterised by excessive daytime sleepiness and abnormal manifestations in REM (rapid eye movement) sleep that include, among other symptoms, cataplexy (the sudden loss of muscle tone triggered by strong emotions). Studies on the prevalence of narcolepsy-cataplexy in Europe and the United States have yielded a figure of 0.013-0.067% in the general population. Although its prevalence is low, it is probably under-diagnosed for a number of different reasons, the most important perhaps being the difficulties involved in its diagnosis.Because its diagnosis is essentially clinical, complementary tests can often be very helpful. Today, it is one of the most extensively studied sleep disorders at the molecular level. Human narcolepsy is associated with diminished hypocretin/orexin concentrations, unlike the case of canine narcolepsy, where mutations in the Hcrt receptor have been found. The treatment of narcolepsy must be tailored to meet the needs of each patient after an individual analysis of his or her symptoms. Daytime sleepiness can be controlled by drugs that stimulate the central nervous system, the most common being methylphenidate and modafinil. Cataplexy is usually treated with tricyclic antidepressants and selective serotonin reuptake inhibitors. The appearance of new drugs like sodium oxybate sheds a ray of light on the dark horizon of patients with narcolepsy-cataplexy syndrome.Early identification of excessive daytime sleepiness by primary care physicians and specialists is essential for a better management and follow-up of these patients.

Background There is growing evidence in rheumatoid arthritis (RA) that ultrasound assessments (UA) have a better predictive value for X-ray progression than clinical assessments Objectives To analyze the association between UA with a reduced 12-joint ultrasound (US) power Doppler (PD) examination and X-ray progression at 12 months Methods Patients were included with available X-ray examination in a multicenter, observational, prospective cohort of RA patients with moderate disease activity (3.2≤DAS28≤5.1), conducted under conditions of routine daily practice (ECO-DAIStudy) 12-joint PDUS assessments were performed at baseline, 6 and 12 months. Synovitis grey scale (SGS) and PD counts were obtained, and each joint was semi-quantitatively assessed (0 – 3) to obtain SGS and PD scores. X-ray examinations were performed at baseline and at 12 months. An independent, blinded observer read paired films in chronological order and scored them according to Sharp-van der Heijde method. X-ray progression was defined as an increase >1 point and non-progression as ≤0. In order to increase contrast, patients with doubtful X-ray progression (>0 - ≤1) were excluded from association analyses of X-ray progression and US findings. Several cutoffs for SGS and PD were tested, and sensitivity (Se) and specificity (Sp) were computed when a significant association was found Results The sample consisted of 129 patients, including 107 women (82.9%), with median (IQR) age of 56.0 (44.0-66.0) yrs, median time from diagnosis of 5.0 (3.0-11.5) yrs, and rheumatoid factor positivity in 82 patients (63.6%). At baseline, 6 and 12 months, the median (IQR) values of SGS counts were 5.0 (4.0-8.0), 5.0 (2.0-7.0) and 4.0 (2.0-6.0); SGS scores were 8.0 (5.0-11.0), 5.0 (3.0-8.0) and 5.0 (2.0-7.8); PD counts were 4.0 (2.0-6.0), 2.0 (1.0-4.0) and 2.0 (1.0-3.0); and PD scores were 6.0 (2.0-9.0), 3.0 (1.0-6.0) and 2.0 (1.0-5.0), respectively 3.5±3.9 (Friedman test; p Conclusions Power Doppler joint counts or cumulative scores greater than 0.5 or 1.5 in a 12-joint PDUS assessment are significantly associated with X-ray progression. Cutoff of 1.5 performed slightly better for PD-scores than for PD-counts. Grey scale synovitis counts or scores were not significantly associated with X-ray progression Acknowledgements The authors wish to thank Jesus Garrido for providing medical writing and editing services in the development of this abstract. The financial support for these services was provided by AbbVie. Disclosure of Interest E. de Miguel Grant/research support from: AbbVie, E. de Vicente Grant/research support from: AbbVie, F. Diaz Alcazar Grant/research support from: AbbVie, J. de la Iglesia Grant/research support from: AbbVie, M. Garcia Vivar Grant/research support from: AbbVie, J. Ivorra Grant/research support from: AbbVie, J. Rivas Employee of: AbbVie

Background Clinical remission is the treatment target for patients with rheumatoid arthritis (RA). However, different definitions have been proposed. Still, damage and/or subclinical inflammation (eg, positive Doppler signal) may persist despite apparent clinical remission Objectives To examine the validity of different definitions of remission and Doppler ultrasound using X-Ray progression as the gold standard Methods Data were obtained from an observational, prospective, multicenter study in RA patients with moderate disease activity (3.2≤DAS28(CRP)≤5.1) who started anti-TNF therapy, conducted under conditions of daily practice. At recruitment and at months 6 and 12, patients were scheduled for a clinical examination, laboratory data collection and reduced 12-joints Power Doppler (PD) ultrasound examination of the wrist, 2nd and 3rd MCP, elbow, knee, and ankle bilateral joints. Synovitis grey scale and PD counts were obtained, and each joint was semi-quantitatively assessed (0 – 3) to obtain grey scale synovitis and PD scores. DAS28 (ESR/CRP), SDAI, CDAI, and ACR/EULAR remission criteria were collected. At baseline and month 12, radiographs of hands and feet were obtained and assessed by an independent observer in pairwise, chronological order and scored according to Sharp-van der Heijde method. X-Ray progression was defined as an increase >1 point and non-progression as ≤0. Patients with doubtful X-ray progression (progression =1), were excluded from independent tests of X-ray progression and US findings Results The sample consisted of 129 patients, 107 women (82.9%), with median (IQR) age of 56.0 (44.0-66.0) years, median time from diagnosis of 5.0 (3.0-11.5) years, and positive rheumatoid factor in 82 patients (63.6%). At 12 months, Sharp-van der Heijde9s score median increase was 3.0 (0.0-6.5) points, with 36 patients not progressing and 79 with progression (14 patients with doubtful X-ray progression). Remission rates at 6 and 12 months according to different clinical criteria were: CDAI, 10.5% and 15.9%, SDAI, 12.3% and 15.7%; ACR/EULAR, 12.6% and 14.2%, DAS28ESR, 21.1% and 33.9%; DAS28CRP, 45.9% and 56.7%, respectively. Disease activity at any study time by any composite index (DAS28ESR, DAS28CRP, SDAI, CDAI and ACR/EULAR) was not significantly associated with X-Ray progression. PD score ≥1 at baseline and persistence of PD score ≥1 at 6 months were associated with X-Ray progression: OR=5.067 (IC95%: 1.162 – 21.576; p=0.017), and OR=7.474 (IC95%: 2.644 – 21.123; p Conclusions A short 12 joints PD US score shows better predictive validity for structural damage progression in RA than composite indices of disease activity. PD signal, but not clinical disease activity, can predict X-ray progression at 6 and 12 months. Probably in the near future Ultrasound may need to be considered as a component of RA remission criteria. Acknowledgements The authors wish to thank Jesus Garrido for providing medical writing and editing services in the development of this abstract and poster. The financial support for these services was provided by AbbVie. Disclosure of Interest E. de Miguel Grant/research support from: AbbVie, E. de Vicente Grant/research support from: AbbVie, F. Diaz Alcazar Grant/research support from: AbbVie, J. de la Iglesia Grant/research support from: AbbVie, M. L. Garcia Vivar Grant/research support from: AbbVie, J. Uson Jaeger Grant/research support from: AbbVie, J. Ivorra Grant/research support from: AbbVie, J. Rivas Employee of: AbbVie

Renal cell carcinoma with inferior vena cava thrombus is relatively uncommon and complicates radical nefrectomy. During the past twenty years our hospital have substantially contributed to the surgical stratification of renal cell carcinoma with extension into inferior vena cava through different techniques. The reason for this article is to discuss the mote efficient and appropiate surgical technique for this pathology. We believe that the diagnosis of vena caval invasion and level of tumoral extension is based on radiological examinations and it is crucial for the success of the surgery. We consider that the use of vena caval filter applied preoperatively could prevent the risk of thromboembolism during and after the surgery. The use of prosthetic grafts is unusual, because the long standing obstruction caused by the tumor thrombus will develope extensive collateral circulation which works as a natural veno-venous bypass. Finally, we try to avoid the use of veno-venous and cardiopulmonar bypass with or without complete hypothermic circulatory arrest due to the high association with adverse outcomes and mortality.

Background: Preemptive therapy required highly predictive tests for CMV disease. CMV antigenemia assay (pp65 Ag) has been commonly used for rapid diagnosis of CMV infection. Amplification methods for early detection of CMV DNA are under analysis. Objectives: To compare two diagnostic methods for CMV infection and disease in this population: quantitative PCR (qPCR) performed in two different samples, plasma and leukocytes (PMNs) and using a commercial diagnostic test (COBAS Amplicor Monitor Test) versus pp65 Ag. Study design: Prospective study conducted in liver transplant recipients from February 2000 to February 2001. Results: Analyses were performed on 164 samples collected weekly during early post-trasplant period from 33 patients. Agreements higher than 78% were observed between the three assays. Optimal qPCR cut-off values were calculated using ROC curves for two specific antigenemia values. For antigenemia ≥10 positive cells, the optimal cut-off value for qPCR in plasma was 1330 copies/ml, with a sensitivity (S) of 58% and a specificity (E) of 98% and the optimal cut-off value for qPCR-cells was 713 copies/5 × 106 cells (S:91.7% and E:86%). Using a threshold of antigenemia ≥20 positive cells, the optimal cut-off values were 1330 copies/ml for qPCR-plasma (S 87%; E 98%) and 4755 copies/5 × 106 cells for qPCR-cells (S 87.5%; E 98%). Prediction values for the three assays were calculated in patients with CMV disease (9 pts; 27%). Considering the assays in a qualitative way, the most sensitive was CMV PCR in cells (S: 100%, E: 54%, PPV: 40%; NPV: 100%). Using specific cut-off values for disease detection the sensitivity, specificity, PPV and NPV for antigenemia ≥10 positive cells were: 89%; 83%; 67%; 95%, respectively. For qPCR-cells ≥713 copies/5 × 106 cells: 100%; 54%; 33% and 100% and for plasma-qPCR ≥ 1330 copies/ml: 78%, 77%, 47%, 89% respectively. Conclusions: Optimal cut-off for viral load performed in plasma and cells can be obtained for the breakpoint antigenemia value recommended for initiating preemptive therapy with high specificities and sensitivities. Diagnostic assays like CMV pp65 Ag and quantitative PCR for CMV have similar efficiency and could be recommended as methods of choice for diagnosis and monitoring of active CMV infection after transplantation.

To analyze the outcome of children with intestinal failure (IF) included as candidates for intestinal transplantation (IT). Patients, Eight out of 23 children with IF assessed since July 1997 met criteria for IT and were included on the waiting list. The causes of IT were Short Bowel Syndrome (SBS) in 6 and Microvillus Inclusion Disease (MID) in 2. The indication of IT were end stage liver disease (ESLD) in 5 (related to total parenteral nutrition administration, TPN), progressive hepatic fibrosis in 2 and loss of venous access in 1. The patients with ESLD were included for combined liver-small bowel transplantation (LSBT) and the remaining for isolated intestinal transplantation (IIT).Two children died waiting for LSBT, 4 patients are on the waiting list, 2 for LSBT and 2 for IIT (length of stay: 4-11 months). Two children were transplanted, one with IIT in a 2.5 years old boy with MID, and one with LSBT in a 22 months girl with SBS and ESLD. Both patients recovered intestinal function after transplantation and are a live (follow-up of 19 and 10 months respectively). The LSBT's patient is under treatment for postransplant lymphoproliferative disease (PTLD).The lack of suitable donors for the small children candidate to IT explains the long period of stay on the waiting list and the high pretransplant mortality. Two strategies are possible; early referral of children with IF to a transplant center and surgical techniques like ex vivi-hepatic reductions of the LSB graft.

Antiviral prophylaxis with lamivudine appears to reduce hepatitis B virus (HBV) infection after liver transplantation, although recurrence of infection occurs in at least 20% of the patients because of the development of drug resistance. Treatment for HBV reinfection with lamivudine pretransplantation and posttransplantation together with hepatitis B immunoglobulin could abolish recurrence of HBV infections following liver transplantation. We report the experience at our center in which lamivudine has been used in combination with low doses of immunoglobulin. Lamivudine (100 mg/d) was administered to liver transplant candidates for at least 4 weeks before transplantation and was continued posttransplantation indefinitely. Immunoglobulin was administered intramuscularly (10,000 IU at time of liver transplantation; 1,000 IU for 1 week; 1,000 IU weekly the first month; and 1,000 IU monthly thereafter). Lamivudine and low-dose immunoglobulin administration prevents posttransplantation recurrence of hepatitis B with 100% efficiency; it is well tolerated and is less cost-effective than high-dose immunoglobulin regimens.

Palliative treatment for nondisseminated unresectable peripheral cholangiocarcinoma (PCC) carries a 0% 5-year survival rate. The role of orthotopic liver transplantation (OLT) in these patients is controversial because the survival rate is lower than with other indications for transplantation and the lack of available donor organs. The aim of this paper was to review the Spanish experience in OLT for PCC to identify prognostic factors for survival.We retrospectively reviewed 23 patients undergoing OLT in Spain for PCC over a period of 13 years.The actuarial survival rates were 77%, 65%, and 42% at 1, 3, and 5 years, respectively. The main cause of death was tumor recurrence (35%). Prognotic factors for an adverse outcome were pTNM classification (P.05) in the univariate analysis and perineural invasion (P.05) and stages III or IVA (P.05) in the multivariate analysis.OLT for nondisseminated irresectable PCC displays higher survival rates at 3 and 5 years than palliative treatments, especially for tumors in the initial stages, which means that more information is needed to help better select PCC patients for transplantation.

Liver transplantation for chronic HBV-induced cirrhosis is associated with a high rate of recurrence and poor long-term survival. Prolonged and combined prophylaxis with hepatitis B immunoglobulin (HBIg) and lamivudine has been demonstrated to prevent HBV recurrence, but its lifelong administration is highly expensive. An alternative strategy may be the use of an HBV vaccine after liver transplantation. Herein we report the results of administration of a reinforced recombinant HBV vaccine to liver transplant recipients. Twelve patients transplanted for HBV-related liver disease and treated with HBIg for at least 24 months were administered HBV vaccine (40 μg administered intramuscularly and repeated 1 and 2 months thereafter) 2 months after beginning the last HBIg dose. The response rate to HBV vaccination was 75% (9/12 patients). Serum titers of anti-HBs were considered to be protective when they reached levels >10 IU/L. Responding patients were followed for a median of 43 ± 22.5 months; during this period none of the responders showed evidence of HBV recurrence. These results suggest that vaccine administration after liver transplant may avoid HBV recurrence allowing HBIg withdrawal. However, future studies are necessary to define an optimal schedule.

Aim The aim of this study was to analyze the results of living donor in a pediatric liver transplantation program. Patients Twenty-six living donor liver transplantations were performed in children from 0.5 to 14.8 years of age. The main indication was biliary atresia (72%) followed by tumors (2 hepatoblastomas and 1 hepatocarcinoma). Left lateral segments were used in 23 (1 transformed into a monosegment), 1 left lobe was used in 1, and right lobes were used in 2. Arterial reconstruction employed saphenous venous grafts in the first 3 cases and end-to-end anastomoses with a microsurgical technique in the following 22 cases. Results There has been no major morbidity in the donors, with a median hospitalization of 6 days. Four grafts have been lost; 2 in the first 3 cases. In only 1 case, the graft loss was related to the procedure saphenous venous graft thrombosis). Early biliary complications were frequent (23%). Six month, 1 year, and 5 year graft and patient survival rates were 91%, 85%, and 85% and 100%, 96%, and 96%, respectively. Conclusions Living donor liver transplantation is an excellent option for transplantation in children.

Minimal hepatic encephalopathy is often present in patients with chronic liver disease. The aim of this work was to determine changes in the dynamics of sleep electroencephalogram (EEG) in cirrhotic patients without overt encephalopathy. Twenty such cirrhotic subjects included in the protocol of hepatic transplantation of our hospital were studied and compared with 20 age-matched healthy volunteers. Spectral analysis of all-night EEG was estimated by computing the fast-Fourier transform in 2-second epochs, and averaging every 60 seconds. Artifacts were off-line suppressed, sleep stages (stage 2, stage 3-4 and REM) were determined, and the EEG mean dominant frequency (MDF) was calculated in each of these stages. Results show that in cirrhotic patients, nocturnal MDF evolution discloses a clear alteration of the ultradian EEG frequency oscillations present in controls. Also, the mean value of MDF in REM episodes was larger in cirrhotics than the corresponding value in controls.1) sleep EEG evidences the existence of minimal hepatic encephalopathy; 2) the spectral analysis of EEG in minimal hepatic encephalopathy showed that the changes of MDF during sleep are an early marker of cerebral dysfunction in cirrhotic patients.

Aim: There is a need to develop biomarkers to predict the outcome of patients with metastatic colorectal cancer (CRC) treated with chemotherapy (Ch) plus Bevacizumab (B). It has been reported that during exposure to B there is a switch in the plasma levels of angiogenesis growth factors and related cytokines called angiogenic switch (AS). It is not known if changes in these circulating factors affect the response of patients with CRC to Ch + B. The aim of this study is to determine the influence of AS in the PFS in pts with metastatic CRC treated with Ch + B. Methods: Treatment naive, ECOG 0-1, metastatic CRC pts were eligible. Patients received induction treatment with XELOX-B or XELIRI-B at standard doses x 6 cycles followed by maintenance treatment with B plus Capecitabine until progression. Angiogenic related cytokines (HGF, PIGF, MCP-3, MM-9, Eotaxin, bFGF and IL-18) were prospectively analyzed at baseline and at the time of each CT evaluation (every eight weeks). AS + was defined by A) doubling of PIGF compared to baseline or B) PIGF elevation with a simultaneous elevation of any two of bFGF, HGF, MCP-3, IL-18 or MMP-9 compared to baseline. Results: Of 62 patients enrolled, 24 (36.7%) have progressed. Median PFS is 15.6 (95% CI: 8.3 to 16.4) months for the entire population. Twenty-five pts (40.3%) were AS + , out of which 23 were detected at first on-study evaluation (week 8). 18 were classified as AS+ based on both criteria, 4 based on criteria A) and 3 based on criteria B). One year (95% CI) PFS for AS+ pts was 82.6% (53.0% to 94.4%) versus 32.9% (13.9% to 53.5%) for AS- pts (p Conclusions: There is a statistically significant improved PFS amongst metastatic CRC AS+ pts treated with first line Ch + B combination compared with AS–pts. Disclosure: All authors have declared no conflicts of interest.

We present the first case of intestinal transplant (IT) performed in Spacin.28 months old boy with secretory diarrhea since the first month of life, diagnosed of microvillous inclusion disease (MID). He is on total parenteral nutrition (TPN) and had suffered of multiple episodes of catheter related sepsis with lost of standard venous access. An isolated small bowel transplant from a cadaveric donor was performed at the age of 3 years. The native ileocaecal valve and colon were not removed.Enteral feeding was started in the 2nd. week after the IT. On the 25th day he was off TPN. Since the 77th day, he eats regular foods by mouth. At the 6th month post IT the ileostomy was closed. Among the complications, he suffered a rotavirus infection on the 38th post IT day and an episode of mild rejection responsive to methil-prednisolone bolus.The IT is a therapeutic option that can be already offered with possibilities of success in our country. Although the colonic enterocytes express MVD, the recipient ileocaecal valve and colon can be preserved.

Liver granulomatosis is an occasional finding in posttransplant liver biopsies. Its diagnosis is made more difficult by the variety of conditions that can lead to it. In the nontransplant setting, the association of liver granulomatosis and hepatitis C virus (HCV) infection has occasionally been described.We describe the case of a patient with a liver transplantation for an HCV-associated cirrhosis who developed an alteration of liver tests. Granulomatosis was detected on the liver biopsy.Other causes of granulomatosis were satisfactorily excluded. The development of the lesions coincided with a viral flare-up.We think that HCV can be listed among the possible causes of liver granulomas in the posttransplant setting and that it must be considered in the differential diagnosis of this condition.

The cases of four liver transplant recipients who developed invasive candidiasis (2 cholangitis, 1 perihepatic abscess, 1 candidemia) due to azole-resistant, Candida glabrata are reported. Three patients were receiving azolic compounds (2 itraconazole, 1 fluconazole) when the infection was diagnosed. All four patients received fluconazole as intestinal decontamination during the first three weeks post transplantation. The infections occurred two months after transplantation in all patients, and in one patient Candida infection was the direct cause of death. Infection of the biliary tree was the origin of candidiasis in three patients; the fourth patient developed neutropenic-related candidemia. Fluconazole MICs exceeded 16 micrograms/ml in all cases; itraconazole MICs were 16, 2, 1, and 2 micrograms/ml, respectively. The potential role of Candida species other than albicans in these patients after administration of azole agents is discussed.

There is a rare cause of chronic intestinal pseudo-obstruction (CIPO) characterised by a lymphocytic infiltrate in the muscle of the intestine, which is called idiopathic lymphocytic leiomyositis. Few cases have been reported and prognosis is very poor. We present a case with a comparatively benign evolution, showing good response to immunosuppressive therapy. The patient was a healthy 16 year old female who presented with a crisis of postprandial bloating followed by diarrhoea and vomiting. During the following months she lost 10 kg in weight and any attempt at oral feeding resulted in severe abdominal distension and vomiting. Therefore, total parenteral nutrition was finally prescribed. Plain abdominal film and small bowel follow through indicated huge dilatation of the small intestine with air fluid levels. Gastroscopy and colonoscopy were normal, as were mucosal biopsies. Human immunodeficiency virus, hepatitis …

The aim of this study was to analyze the donor risk factors associated with second orthotopic liver transplantation (reOLT) and graft loss after OLT within 1 month. A total of 649 OLTs performed in 11 centers in Spain during the period from 1992 to 1993 were analyzed retrospectively. Eleven donor and recipient variables were studied. Biochemical evolution of the OLT, biliary and arterial complications, patient status (alive, retransplanted, or dead), and follow-up were also recorded. Bivariate study demonstrated that extended preservation (12 hr) was associated with increased biliary complications (P = 0.02), and lower prothrombin time (P = 0.04). In a logistic model regression for biliary complications, ischemia12 hr was an independent risk factor (odds ratio = 2.2, 95% confidence interval [CI] = 1.1-4.3). The multivariate Cox proportional model of potential risk factors showed that only urgent reOLT (relative risk [RR] = 2.7, 95% CI = 1.4-5.4) was independently associated with higher 30-day mortality. Donor plasma sodium155 mmol/L (RR = 1.4, 95% CI = 1.0-2.2) and incompatible ABO graft (RR = 3.2, 95% CI = 1.3-7.9) were independently associated with increased rate of reOLT before 30 days. Donor plasma sodium155 mmol/L (RR = 2, 95% CI = 1.1-3.6) and incompatible graft (RR = 3.3, 95% CI = 1.4-8.2) were independently associated with graft loss (death or reOLT) before 1 month. We conclude that cold ischemia should be kept less than 12 hr in order to avoid biliary complications. Donors over 60 years old or with plasma sodium155 should be carefully evaluated before OLT.

Aim Analyze the results of a paediatric intestinal transplantation (IT) program in Spain. Patients During an 5-year period, 18 children were included as candidates for IT. The causes for intestinal failure (IF) were short bowel syndrome (n = 13), motility disorders (n = 3), and congenital epithelial disorders (n = 2). Nine children were admitted for a combined liver-small bowel transplant (LSBT), seven for an isolated intestinal transplantation (IIT) and two for a multivisceral transplantation (MVT). In three of the candidates for IIT the indication had to be changed to LSBT because of progression of the liver damage. Results Eight candidates are on the waiting list: four for LSBT, two for IIT, and two for MVT. Four children died before transplantation. All were children under 1 year and candidates for LSBT. One child died during an attempted MVT. Five children underwent transplantation. Grafts were IIT in two and LSBT in three. Of these children, two are on a normal diet (respective follow-up times: 40 and 18 months), two died, both with functioning liver and intestinal grafts (hemorrage after liver biopsy and lymphoproliferative disease), and one developed an untreatable rejection that lead to loss of the intestinal graft; currently, she is on the waiting list for LSBT. Conclusions The morbidity and mortality of IT are high, but it is the only possible treatment for children in IF who cannot be adequately managed with parenteral nutrition. A severe problem is the the scarcity of suitable donors for the very low weight children who are candidates for LSBT.

Introduction. Palliative treatment for nondisseminated irresectable hilar cholangiocarcinoma (HCC) carries a 0% 5-year survival rate. The role of orthotopic liver transplantation (OLT) in these patients is controversial because the survival rate is lower than that for other indications for transplantation and the lack of available donor organs. The aim of this paper was to review the Spanish experience in OLT for HCC and identify prognostic factors for survival. Methods. We retrospectively reviewed 36 patients undergoing OLT for HCC over 13 years. Results. The actuarial survival rate at 1, 3, and 5 years was 82%, 53%, and 30%, respectively. The main cause of death was tumor recurrence (53%). In the univariate analysis, the factors for a poor prognosis were vascular invasion (P .001) namely 0% survival at 3 years when present versus 63% and 35% at 3 and 5 years, respectively, when it was not; and stages III to IVA (P .05), namely 15% survival at 5 years versus 47% for stages I to II. Lymph node and perineural invasion also reduce survival. In the multivariate analysis, the factors for poor prognosis included vascular invasion (P .01) and stages III to IVA (P .01). Conclusions. OLT for nondisseminated irresectable HCC has higher survival rates at 3 and 5 years than palliative treatments, especially with initial stage tumors, which means that more information is needed to better select cholangiocarcinoma patients for transplantation.

The hepatitis C virus (HCV) is an RNA virus that replicates with a high rate of mutation, especially in the hypervariable region 1 (HVR-1). Continuous viral mutations lead to a mixed and changing populations of mutants, called quasispecies. The nature of the HCV quasispecies may have implications for viral persistence and pathogenies. Studies with liver transplant patients suggest a relationship between the degree of immunosuppression and the complexity of the quasispecies. This study evaluated whether immunosuppressive therapy modifies the evolution of HCV quasispecies among liver transplant recipients compared with immunocompetent HCV patients. Two groups were studied: 11 patients who underwent OLT for HCV-related cirrhosis and 10 control group patients. Two serum samples from each patient were obtained to analyze the HCV HVR1 region by RT-PCR. SSCP analysis failed to show statistically significant differences in the number of quasispecies at basal and final time points or at pretransplant versus posttransplant (7.3 2 vs 6.7 3 in control patients, respectively, and 4.4 2 vs 4.1 1 in transplanted patients, respectively). No significant difference was observed between missing or new variants in the control (2.8 2 vs 2.3 2, respectively) or transplanted group (2.5 2 vs 2.2 1, respectively). Upon sequence analysis, the genetic complexity was significantly lower among samples after OLT in transplanted patients (0.057 0.04 [pretransplant] vs 0.035 0.02 [posttransplant]; P .048). However, no significant differences were found among control patients in basal versus final samples (0.04 0.03 vs 0.066 0.04, respectively). Our findings seem to demonstrate that viral quasispecies diversity is lower among patients receiving a liver transplant. HEPATITIS C VIRUS (HCV) is a major causative agent for chronic liver disease leading to orthotopic liver transplantation (OLT). After OLT, HCV recurrence occurs in most patients. HCV has been characterized as a positive-sense, single-stranded RNA virus like many other RNA viruses, the HCV genome shows high mutation frequencies. The resulting genetic diversity, especially in the hypervariable region (HVR-1) of the envelope gene (E2), makes HCV exist as a viral quasispecies, which are defined as a complex population of different (but closely related) HCV genomes with sequences differing by only a few nucleotides that circulate simultaneously in each individual patient. The evolution of the quasispecies seems to have important implications for escape from immune surveillance. If this is the case, viral persistence in HCV infection may be related to the emergence of variants in the quasispecies. Studies with liver transplant patients suggest a relationship between the degree of immunosuppression and the complexity of the quasispecies. In the present study we evaluated whether immunosuppressive therapy could modify the evolution of HCV quasispecies among liver transplant recipients when compared with immunocompetent HCV patients. Our findings seem to demonstrate that viral quasispecies diversity is lower among patients receiving a liver transplant. From the Departments of Gastroenterology (J.M.G., S.D.C.T., G.M.G., M.G.G., J.M.V.-G., P.M., R.B.M.), Department of General Surgery (E.D.V.L.), and Department of Infectious Diseases (J.F.A.), Hospital Ramon y Cajal, Madrid, Spain. Address reprint request to R. Barcena Marugan, MD, Department of Gastroenterology, Hospital Ramon y Cajal, Ctra, Colmenar Km 9.1, 28034 Madrid, Spain. E-mail: rbarcena@

Introduccion. La narcolepsia es un trastorno del sueno incapacitante que se caracteriza por una somnolencia diurna excesiva y manifestaciones anormales del sueno REM (rapid-eye-movements) que incluye, entre otros sintomas, la cataplejia (perdida brusca del tono muscular desencadenada por emociones fuertes). Los estudios de prevalencia para la narcolepsia-cataplejia en Europa y Estados Unidos la situan en un 0,013-0,067% de la poblacion general. Si bien su prevalencia es baja, probablemente este infradiagnosticada por diferentes causas, destacando quiza la dificultad en su diagnostico. Desarrollo. Al ser su diagnostico fundamentalmente clinico, las pruebas complementarias en muchos casos pueden ser de gran ayuda. Hoy en dia es uno de los trastornos del sueno molecularmente mas estudiados. La narcolepsia humana se asocia con una disminucion de las concentraciones de hipocretina/orexina, a diferencia de la narcolepsia canina, en la que se han encontrado mutaciones en el receptor Hcrt. El tratamiento de la narcolepsia debe ser individualizado, analizando a cada paciente y sus sintomas de forma aislada. La somnolencia diurna se controla con estimulantes del sistema nervioso central: basicamente metilfedinato y modafinilo. La cataplejia suele tratarse con antidepresivos triciclicos e inhibidores selectivos de la recaptacion de la serotonina. Con la llegada de nuevos farmacos como el oxibato sodico se aporta un rayo de luz en el oscuro horizonte del paciente narcoleptico-cataplejico. Conclusion. Resulta crucial la identificacion precoz de una somnolencia diurna excesiva por medicos de atencion primaria y especialistas para un mejor manejo y seguimiento de estos pacientes.

The Liver Transplant Program was begun at "La Paz" Children's Hospital on January 1986 after a long period of experimental activities. This was the first experience in the Madrid Community. From January 1986 to June 1989 we made 32 orthotopic liver transplants in 25 patients, seven received a second graft and one them received a liver segment because the donor had a large liver. 114 patients were evaluated but only 84 were considered candidates for liver transplantation. The different diseases of the transplants were: biliary atresia (9), Alagille syndrome (4), deficit alpha 1-antitrypsin (3), autoimmune hepatitis (2), neonatal hepatitis (1), Byler disease (1), Wolman disease (1). absent bile ducts (1), Wilson disease (1). Surgical technique was the same that has been described by Starzl using Eurocollins and lactate Ringer. In the 100% we made multiorgan procurement, liver and kidneys, 7% with heart and two heart-lung with hypothermia. In one occasion the donor operation was done out of the country (RFA--Düsseldorf). We never used by-pass during anhepatic phase. Arterial reconstruction was done by end-to-end anastomosis and in five patients we used aortic graft. Our arterial thrombosis rate was 18%. In one patient the portal vein was atrophic and we used a femoral graft between superior mesenteric vein and donor portal vein. For biliary reconstruction we used Roux-en-Y with intraluminal stent in 18 cases and choledocho-choledochus anastomosis in seven cases. Four patients had biliary complications: two biliary fistulas secondary to arterial thrombosis, biliary stenosis and bowel perforation by the intraluminal stent.(ABSTRACT TRUNCATED AT 250 WORDS)

Background, Liver granulomatosis is an occasional finding in posttransplant liver biopsies. Its diagnosis is made more difficult by the variety of conditions that can lead to it. In the nontransplant setting, the association of liver granulomatosis and hepatitis C virus (HCV) infection has occasionally been described. Methods. We describe the case of a patient with a liver transplantation for an HCV-associated cirrhosis who developed an alteration of liver tests. Granulomatosis was detected on the liver biopsy. Results. Other causes of granulomatosis were satisfactorily excluded. The development of the lesions coincided with a viral flare-up. Conclusion. We think that HCV can be listed among the possible causes of liver granulomas in the posttransplant setting and that it must be considered in the differential diagnosis of this condition.