Orthotopic liver transplantation for hepatocellular carcinoma: a thirteen-year single-center experience.

BACKGROUND: When restrictive selection criteria are applied orthotopic liver transplantation (OLT) is the most efficient option for the treatment of hepatocellular carcinoma (HCC) in terms of survival and recurrence rate. Nevertheless, tumor recurrence may occur in 3.5%-21% of recipients, with a consequent negative impact on prognosis. The aim of this study was to analyze the long-term survival and tumor recurrence rate among a cohort of liver transplant recipients with HCC. METHODS: During the period 1994-2007, 130 HCC patients, including 111 males with a mean overall age of 57.8 +/- 7.1 years (range, 38-70), underwent cadaveric donor-OLT. The etiology of liver disease was alcoholic cirrhosis in 66 patients (50.8%) and viral infection in 52 patients (40%). Baseline alpha fetoprotein values were 53.4 +/- 280.9 ng/mL (range, 1-2593). Median interval between inclusion date and transplantation was 179.5 days. RESULTS: After a median follow-up of 40.8 months, 93 recipients (71.5%) were alive. Tumor recurrence was detected in 11 patients (8.5%). Neoplasm recurrence sites were as follows: liver graft (45.4%), bone (36.4%), lymphoadenopathies (27.3%), adrenal glands (27.3%), and lung (27.3%). Overall survival rates at 1, 3, 5, and 10 years were 85.1%, 78.3%, 70.1%, and 57%, respectively. After examination of the explanted liver, Milan criteria were surpassed in 32 recipients (24.6%). Nevertheless, no differences in survival were observed according to fulfilment or not of Milan criteria (log-rank test, P > .05). Hepatitis C virus (HCV) infection, female gender, and tumor recurrence were associated with a worse survival rate (log-rank test, < .05). CONCLUSIONS: OLT is an effective option for the treatment of HCC with good long-term survival and low recurrence rates. In this series, survival was not affected by findings of poor prognostic factors in the explanted liver.

Absceso subfrénico con extensión pleural y subcutánea como complicación de un cálculo vertido al peritoneo durante la colecistectomía laparoscópica: implicaciones terapéuticas / Subfrenic abscess with pleural and subcutaneous involvement as complication of peritoneal gallstone dropped during laparoscopic cholecystectomy: therapeutic implications

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Intra-abdominal adhesions after open and laparoscopic cholecystectomy: an experimental model.

PURPOSE: To evaluate the incidence of intra-abdominal adherences after open and laparoscopic cholecystectomy, on the basis of an experimental study in pigs. MATERIALS AND METHODS: A total of 40 female pigs, mean weight 25 kg, underwent open cholecystectomy by right subcostal laparotomy (group A, n = 22) or laparoscopic cholecystectomy using a Storz laparoscope (group B, n = 18). After surgery, the abdominal wall was closed with polydioxanone suture and staples (group A) or with staples only (group B). One month later, the pigs underwent medial laparotomy to assess whether intra-abdominal adherences had developed. Incidences were compared between groups by the chi-square test with Yates correction. RESULTS: Five pigs in group A and one pig in group B died within 24 hours of surgery, leaving 17 pigs in each group. Mean operative time was similar for both groups (24.7 minutes in group A, 25.3 minutes in group B). In group A, 16 pigs (94%) developed intra-abdominal adherences, in all cases multiple; in group B, only 9 pigs (53%) developed adherences, and in 8 of these pigs only a single adherence was present (P < 0.03). CONCLUSIONS: The results of this study indicate that the incidence of intra-abdominal adherences is statistical lower after laparoscopic cholecystectomy than after open cholecystectomy.

Doppler ultrasonography for the assessment of tumor necrosis after percutaneous ethanol injection prior to liver transplantation as adjuvant therapy of hepatocellular carcinoma.

INTRODUCTION: Percutaneous ethanol injection (PEI) is considered to be a curative treatment for hepatocellular carcinoma (HCC). The imaging technique of choice for the assessment of local response after PEI has not been well defined, but helical computerized tomography (hCT) has been recommended. The aim of this study was to assess the accuracy of Doppler ultrasonography (US) for evaluation of tumor necrosis after PEI. PATIENTS AND METHODS: Twenty-one patients with single HCC listed for liver transplantation underwent multisession US-guided PEI. Liver Doppler US was done at the 4th week after PEI. Complete response was defined as the absence of any intratumoral Doppler signal. The liver was analyzed in transplant recipients during the follow-up. Complete pathological response was defined as necrosis > or = 90% of total tumor volume. Histological and sonographic findings were compared. RESULTS: Twelve patients underwent transplantation (9 men, mean age 60 +/- 5.2 years). Nine of these (75%) showed a complete ultrasonographic response. In the explanted liver, complete necrosis was present in 6 nodules, and incomplete necrosis was seen in the remaining 6 cases. In comparison with histology, Doppler US showed values of sensitivity, specificity, positive predictive values, and negative predictive values of 50%, 100%, 100%, and 60%, respectively. Overall accuracy was 75%. CONCLUSIONS: In our series, Doppler US showed low sensitivity but high specificity in the assessment of HCC necrosis after PEI. The ultrasonographic finding of complete response requires hCT for confirmation, but the presence in Doppler US of neoplastic viable tissue is enough to indicate a further cycle of PEI.

Safety of percutaneous ethanol injection as neoadjuvant therapy for hepatocellular carcinoma in waiting list liver transplant candidates.

UNLABELLED: Orthotopic liver transplantation (OLT) as therapy of hepatocellular carcinoma (HCC) improves the survival of a selected group of patients. Unfortunately, the progressive increase in waiting time for OLT may allow tumor progression. Percutaneous ethanol injection (PEI) has been proposed as neoadjuvant therapy for HCC in patients awaiting OLT, but its safety has not been defined. PATIENTS AND METHODS: During a 60-month period, 34 patients (27 men, overall mean age of 58.5 years, range 41-67) with HCC, were listed for OLT. Ultrasonography-guided PEI was delivered into 39 nodules at 117 sessions on an inpatient basis. Written informed consent was obtained from all patients before PEI. Doppler-ultrasonography was done before PEI, immediately after, and 4 weeks later. Noninvasive monitoring of arterial pressure, cardiac rate, and temperature was performed during the procedure and during a 24-hour period after each session. Pain was considered significant if analgesia was required or discontinuation of PEI necessary. Fever was defined as a temperature > or =37.5 degrees C after PEI. RESULTS: Minor complications included pain in 45 sessions (38.5%), fever in 17 (14.5%), arterial hypertension in 14 (12%), hypotension in 7 (7%), and vomiting in 2 (1.7%). The major complications were segmental liver infarction (n = 3), portal branch venous thrombosis (n = 2), ascites (n = 2), and one case each of subcapsular hematoma, duodenal ulcer, pneumonia, hepatic encephalopathy, and hepatic artery thrombosis. In all cases, clinical outcomes were favorable with conservative treatment. No evidence of tumor seeding in the needle track was reported and no PEI-related mortality observed. CONCLUSIONS: PEI is a safe neoadjuvant therapy for HCC on waiting list liver transplant candidates. In our series, pain and self-limited fever were the most frequent complications. Clinically significant severe complications were uncommon, and nonconservative treatments were not required.

Prospective interventional study to evaluate the efficacy and safety of liposomal amphotericin B as prophylaxis of fungal infections in high-risk liver transplant recipients.

INTRODUCTION: Invasive fungal infections are a life-threatening complication in transplant recipients. The prevalence of fungal infection after orthotopic liver transplantation (OLT) is 5% to 42%. The most common isolated pathogens are Candida and Aspergillus species. High-risk liver transplant recipients are more susceptible to the development of invasive fungal infections, with prevalence >40% and mortality rates of 78% to 100%. The strategy for fungal prophylaxis in this population has not been defined. PATIENTS AND METHODS: Among 100 consecutive OLT followed for 28 months, 21 recipients (15 men, overall mean age of 48.5 years, range 23-65 years) were considered to be high risk for the development of fungal infections when they presented at least one of the following criteria: acute liver failure, assisted ventilation >7 days, retransplantation, relaparotomy, antibiotic therapy >14 days, transfusion requirements >20 red blood cells units, and/or biliary leakage. This group received intravenous liposomal amphotericin B (1 mg/kg/d for 7-10 days). RESULTS: One-year survival in the high-risk group was 80%. Prevalence of invasive fungal infection was 9.5%. No Candida infection was observed. Two patients developed Aspergillus infection: an abdominal aspergillosis treated with percutaneous drainage and liposomal amphotericin B (5 mg/kg/d) showed a favorable clinical outcome. The other patient who developed brain aspergillosis died 25 days after OLT. Adverse events related to the drug were hypokalemia (n = 2), back pain (n = 3), and renal dysfunction (n = 2). None of these events required withdrawal of the prophylaxis regimen. CONCLUSION: In our series, prophylaxis with liposomal amphotericin B in high-risk liver graft recipients showed a low rate of severe fungal infections. More studies are needed in order to determine the highest risk population and the best drug dosage.

[Ureteral implantation in peritoneum. Exceptional complication in renal transplantation]. / Implantación ureteral en peritoneo. Una complicación excepcional en el trasplante renal.

Because of the extraperitoneal location, generally used for renal grafting, intraperitoneal urine leaks are a rare complication after transplantation. We report a patient on peritoneal dialysis who developed ascites, abdominal pain, anuria and shock suddenly after renal transplantation. The patient was immediately taken back to the operating room. An abnormal implantation of ureter into the peritoneum overlying the bladder when carrying out an unstented parallel incision extravesical ureterone-ocystostomy was identified. After correcting ureter implantation the patient had immediate diuresis, renal function rapidly improved, with no further complications. Contributing causes were poor exposure, thickened peritoneum secondary to recurrent peritonitis, and the presence of residual peritoneal dialysis fluid.

Implantación ureteral en peritoneo. Una complicación excepcional en el trasplante renal / Ureteral implantation into periotoneum. An unusual complication of kidney transplantation

En el trasplante renal la fuga de orina intraperitoneal es una complicación rara, debido a la implantación habitual en retroperitoneo. Informamos del caso de un paciente en diálisis peritoneal que inmediatamente al trasplante presenta ascitis, dolor abdominal, anuria y shock. Con rapidez es llevado de nuevo a quirófano. Se identificó una implantación del uréter en peritoneo y no en vejiga, en el curso de una ureteroneocistostomía extravesical no tutorizada. Después de corregir la implantación ureteral el paciente recuperó la diuresis, mejoró rápidamente su función renal, sin más complicaciones. Fueron factores contribuyentes la limitada exposición, el engrosamiento peritoneal secundario a peritonitis recurrente y la presencia de fluido de diálisis peritoneal residual (AU)

Wound erysipelas following appendectomy caused by group B beta-hemolytic Streptococcus (Streptococcus agalactiae).

BACKGROUND: Case description of a patient who developed erysipelas of the surgical wound following appendectomy for acute appendicitis, and literature review of invasive group B streptococcal infections. METHODS: A 65-year-old man with perforated appendicitis underwent urgent appendectomy and drainage. Antibiotic prophylaxis with tobramycin (100 mg) and metronidazole (500 mg) was administered. At surgery, a phlegmon was identified with free perforation of the appendix and purulent peritoneal fluid. Appendectomy, irrigation with 0.9% NaCl solution, and drainage with a Silastic closed-suction drain was performed. A literature search in all languages was performed using MEDLINE, using the search terms surgical site infection, wound infection, group B streptococcus, Streptococcus agalactiae, necrotizing fasciitis, and postoperative infection. RESULTS: Erysipelas of the surgical wound developed on the fourth postoperative day. Intravenous penicillin and amoxicillin/clavulanic acid were administered empirically. Culture of the wound drainage identified Streptococcus agalactiae and a few colonies of Escherichia coli. The broad-spectrum antibiotic was discontinued, and a 10-day course of penicillin was completed. CONCLUSIONS: Erysipelas of the surgical wound is unusual, and infection with group B streptococci is rare compared with infection by group A streptococci. Streptococcus agalactiae is recognized to be increasingly virulent, with an increasing predilection for bacteremic infections in healthy hosts. Although Streptococcus agalactiae remains highly susceptible to antimicrobial agents effective against gram-positive cocci, the changing epidemiology and potentially invasive nature of these infections should have clinicians alert to the possibility of infection caused by group B streptococci.

Revised genomic structure of the human MAGP1 gene and identification of alternate transcripts in human and mouse tissues.

The human MAGP1 (or MFAP2) and mouse Magp1 genes code for the microfibril-associated glycoprotein-1 (MAGP-1), an extracellular matrix protein of microfibrillar structures. We report a revised 5' genomic structure including the use of a single transcription start site that gives rise to a 32-bp 5' exon spanning a segment of the previously described exon B. No evidence of heterogeneous 5' ends from the use of alternative promoters was found in human tissues and cell lines. We located the genetic marker D1S170 to a position 3 kb downstream of the polyadenylation site. Large-scale comparison of the human and mouse genes revealed conservation of sequence outside the coding exons. Although the 5' flanking regions were found to be divergent certain cis-elements for transcription factors are conserved, including Sp1, AP-2, AP-4, NF-kappaB, and c-ETS motifs. We identified a total of five splice variants in addition to the canonical MAGP1A/Magp1A form. These transcripts are species-specific and are generated by different processing mechanisms. The alternate forms MAGP1A', MAGP1B, and MAGP1C are expressed in human tissues; and the two variants Magp1A" and Magp1D were found only in mouse. The alternatively spliced forms show restricted patterns of expression relative to the canonical isoform.

Intensive care during prolonged anhepatic state after total hepatectomy and porto-caval shunt (two-stage procedure) in surgical complications of liver transplantation.

BACKGROUND/AIMS: Recently, total hepatectomy and temporary porto-caval shunt has been indicated in surgical complications of liver transplantation. Four cases of liver transplantation which presented liver hemorrhage at the time of implant, and a 5th case with surgical trauma of hepatic hilum are presented. METHODOLOGY: The graft was removed and a porto-caval shunt was performed in all patients. Retransplantation was possible in all recipients, after an anhepatic period of 16-24 hours. RESULTS: Early persistent ionic hypocalcemia and late olyguric renal failure were the most constant and prominent complications during the anhepatic period. Two patients died of renal failure and respiratory distress syndrome at 6 and 28 days, respectively, after liver transplantation. The other 3 patients are alive and without complications at 48, 33 and 11 months of follow-up. CONCLUSIONS: Total hepatectomy with a temporary porto-caval shunt and later retransplantation must be considered as a useful procedure for surgical complications of liver transplantation which may not be treated using other techniques. Special attention should be paid to preserve renal function in the anhepatic state in order to improve survival in similar cases of two-stage liver transplantation.

[Technical solution in kidney retransplantation in a patient with femoro-femoral bypass]. / Solución técnica en el retrasplante renal de un paciente portador de un by-pass femoro-femoral.

Over the last decade kidney transplantation has become a common therapeutic procedure for patients with end-stage renal diseases. Between 1988 and 1998 donors rate per million population has dramatically increased in our environment, thus providing us with more chances to offer kidney transplantation to a larger number of patients. The technico-surgical difficulties that have to be faced however, are increasingly frequent and require a search for new approaches and innovative changes to the usual surgical techniques for our patient's benefit.

Solución técnica en el retrasplante renal de un paciente portador de un by-pass femoro-femoral / Technical solution in the kidney retransplant of a patient with a femoro-femoral by-pass

El trasplante renal se ha convertido en la última década en una forma de tratamiento habitual para los pacientes con enfermedades renales terminales. Entre 1988 y 1998 la tasa de donantes por millón de habitantes ha aumentado espectacularmente en nuestro medio, ello implica que cada vez es posible ofrecer un trasplante renal a un número mayor de pacientes, de modo que las dificultades técnico-quirúrgicas con las que debemos enfrentarnos son cada vez más frecuentes, siendo preciso buscar e incorporar nuevos enfoques y modificaciones imaginativas de la técnica quirúrgica en beneficio de nuestros pacientes. (AU)

Developmental expression of latent transforming growth factor beta binding protein 2 and its requirement early in mouse development.

Latent transforming growth factor beta (TGF-beta) binding protein 2 (LTBP-2) is an integral component of elastin-containing microfibrils. We studied the expression of LTBP-2 in the developing mouse and rat by in situ hybridization, using tropoelastin expression as a marker of tissues participating in elastic fiber formation. LTBP-2 colocalized with tropoelastin within the perichondrium, lung, dermis, large arterial vessels, epicardium, pericardium, and heart valves at various stages of rodent embryonic development. Both LTBP-2 and tropoelastin expression were seen throughout the lung parenchyma and within the cortex of the spleen in the young adult mouse. In the testes, LTBP-2 expression was seen within lumenal cells of the epididymis in the absence of tropoelastin. Collectively, these results imply that LTBP-2 plays a structural role within elastic fibers in most cases. To investigate its importance in development, mice with a targeted disruption of the Ltbp2 gene were generated. Ltbp2(-/-) mice die between embryonic day 3.5 (E3.5) and E6.5. LTBP-2 expression was not detected by in situ hybridization in E6.5 embryos but was detected in E3.5 blastocysts by reverse transcription-PCR. These results are not consistent with the phenotypes of TGF-beta knockout mice or mice with knockouts of other elastic fiber proteins, implying that LTBP-2 performs a yet undiscovered function in early development, perhaps in implantation.

Organization of the mouse microfibril-associated glycoprotein-2 (MAGP-2) gene.

A 1.4-kb EST clone encoding mouse microfibril-associated glycoprotein-2 (MAGP-2), identified by its similarity with the reported human cDNA, was used to screen a mouse 129 genomic bacterial artificial chromosome (BAC) library. The mouse gene contains 10 exons spanning 16 kb, located on the distal region of Chromosome (Chr) 6. The exons range in size from 24 to 963 bp, with the ATG located in exon 2. The tenth and largest exon contains 817 bp of 3' untranslated sequence, including a B2 repetitive element. Northern analysis demonstrates abundant expression of MAGP-2 mRNA in skeletal muscle, lung, and heart. Sequence analysis of additional cDNA clones suggests that the two mRNA forms of MAGP-2 in the mouse arise from alternative polyadenylation site usage. The promoter does not contain an obvious TATA box, and the sequence surrounding the start site does not conform to the consensus for an initiator promoter element. Additionally, the mouse promoter contains 22 copies of a CT dinucleotide repeat sequence located approximately 155 bp 5' to exon 1. MAGP-2 gene and compared it with that of the human gene (Hatzinikolas and Gibson 1998). While the mouse and human MAGP-2 proteins are similar in sequence, the promoters for the two genes share little in common. The presence of two mRNA species for MAGP-2 in the mouse raised the possibility that more than one isoform of the protein might be synthesized. We have characterized both mRNA species and determined that they do not code for different variants of the protein.

Prothymosin alpha.

Prothymosin alpha (ProT alpha) is a highly acidic protein widely distributed in mammalian cells. Since its discovery in 1984, the biological role of this protein has been controversial. Initially, ProT alpha was considered a thymic factor with a hormonal-like role in the maturation of T-lymphocytes. However, molecular and cellular analyses led to conclude that ProT alpha is a nuclear protein required in proliferation events while failing to show a clear immunological effect. The involvement of ProT alpha in changes in the compaction state of chromatin has been recently elucidated with the demonstration that this protein induces the unfolding of chromatin fibres in a process that seems to be mediated by the interaction of ProT alpha with histone H1. This finding opens up new perspectives in the study of the dynamics of the genetic material in mammalian cells. Furthermore, the relationship between ProT alpha and apoptosis as well as with proliferation makes this protein an attractive target in the search for modulators of cell death and tumour growth.

Signaling pathway by which TGF-beta1 increases expression of latent TGF-beta binding protein-2 at the transcriptional level.

The cytokine transforming growth factor-beta has multiple effects on a wide variety of cell types. These effects include modulation of growth and regulation of gene transcription. In the present work, we demonstrate that TGF-beta1 increases transcription of the latent transforming growth factor-beta binding protein-2 ( LTBP-2) gene in cultured human fetal lung fibroblasts leading to a significant increase in LTBP-2 mRNA steady state level. The stability of LTBP-2 mRNA was not appreciably altered. A corresponding increase in production of LTBP-2 protein accompanied the increase in mRNA. Through the use of specific inhibitors, we demonstrate that a member of the Ras super family and a protein kinase C, probably of the atypical (non-diacylglycerol, non-Ca++ dependent) class are likely to be components in the signaling pathway. However, phospholipases, G proteins and extracellular-signal regulated kinases do not appear to be involved. These results combined with previous findings on elastin regulation by TGF-beta1 (Kucich et al. (1997). Am. J. Respir. Cell Mol. Biol., 17: 10-16) demonstrate that TGF-beta1 can coordinately increase the steady state levels of mRNAs encoding components of the elastic fiber, but through diverse mechanisms. In contrast to LTBP-2, increased elastin expression is achieved by message stabilization. Furthermore, the TGF-beta1 signaling pathways differ and while the pathway leading to increased LTBP-2 transcription shares components with those modulating transcription of other genes, it is unlikely to be precisely congruent with any other previously described one.

The mouse tumor necrosis factor receptor 2 gene: genomic structure and characterization of the two transcripts.

The mouse TNFR2 gene has been cloned, sequenced, and characterized as a gene spanning >44 kb of the genome. By alignment of five genomic clones we have established that TNFR2 consists of 10 exons and 9 introns with exons ranging in size from 35 bp to 2.6 kb and introns ranging from 322 bp to >16 kb. All splice acceptor and donor sites conform to the canonical AG/GT rule. The translation initiation and termination sites are located in exon 1 and 10, respectively. Although TNFR2 lacks a canonical TATA box, the gene is transcribed from a unique start site located 70 bp upstream of the ATG initiation codon that conforms to the consensus Inr motif. Several cis-elements for transcription factors were identified in the 5' flanking region, including NF-1, Sp-1, AP2, gamma-IRE, and NF-kappaBeta motifs. Functional analysis indicates that the region -705/-412 contains a negative cis-acting element and that the minimal promoter contains motifs that confer LPS inducibility. Two mouse TNFR2 mRNAs of 3.2 and 4.1 kb are detected by Northern blot analysis, but until now their origin has not been explained. No evidence of alternative splicing of the coding exons was found. However, hybridization studies and amplification of cDNA ends suggest the use of a noncanonical polyadenylation signal in the untranslated region of exon 10. A comparative analysis of the 3' untranslated regions of the human and mouse TNFR2 genes shows highly divergent 3' ends. The possibility of an ancestral mouse TNFR2 mRNA similar to the short transcript is discussed.