"Very early" intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients?

A retrospective cohort multicenter study was conducted to analyze the risk factors for tumor recurrence after liver transplantation (LT) in cirrhotic patients found to have an intrahepatic cholangiocarcinoma (iCCA) on pathology examination. We also aimed to ascertain whether there existed a subgroup of patients with single tumors ≤2 cm ("very early") in which results after LT can be acceptable. Twenty-nine patients comprised the study group, eight of whom had a "very early" iCCA (four of them incidentals). The risk of tumor recurrence was significantly associated with larger tumor size as well as larger tumor volume, microscopic vascular invasion and poor degree of differentiation. None of the patients in the "very early" iCCA subgroup presented tumor recurrence compared to 36.4% of those with single tumors >2 cm or multinodular tumors, p = 0.02. The 1-, 3- and 5-year actuarial survival of those in the "very early" iCCA subgroup was 100%, 73% and 73%, respectively. The present is the first multicenter attempt to ascertain the risk factors for tumor recurrence in cirrhotic patients found to have an iCCA on pathology examination. Cirrhotic patients with iCCA ≤2 cm achieved excellent 5-year survival, and validation of these findings by other groups may change the current exclusion of such patients from transplant programs.

Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study.

OBJECTIVE: To evaluate the outcome of patients with hepatocellular-cholangiocarcinoma (HCC-CC) or intrahepatic cholangiocarcinoma (I-CC) on pathological examination after liver transplantation for HCC. BACKGROUND: Information on the outcome of cirrhotic patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study is limited. METHODS: Multicenter, retrospective, matched cohort 1:2 study. STUDY GROUP: 42 patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study; and control group: 84 patients with a diagnosis of HCC. I-CC subgroup: 27 patients compared with 54 controls; HCC-CC subgroup: 15 patients compared with 30 controls. Patients were also divided according to the preoperative tumor size and number: uninodular tumors 2 cm or smaller and multinodular or uninodular tumors 2 cm or larger. Median follow-up: 51 (range, 3-142) months. RESULTS: The 1-, 3-, and 5-year actuarial survival rate differed between the study and control groups (83%, 70%, and 60% vs 99%, 94%, and 89%, respectively; P < 0.001). Differences were found in 1-, 3-, and 5-year actuarial survival rates between the I-CC subgroup and their controls (78%, 66%, and 51% vs 100%, 98%, and 93%; P < 0.001), but no differences were observed between the HCC-CC subgroup and their controls (93%, 78%, and 78% vs 97%, 86%, and 86%; P = 0.9). Patients with uninodular tumors 2 cm or smaller in the study and control groups had similar 1-, 3-, and 5-year survival rate (92%, 83%, 62% vs 100%, 80%, 80%; P = 0.4). In contrast, patients in the study group with multinodular or uninodular tumors larger than 2 cm had worse 1-, 3-, and 5-year survival rates than their controls (80%, 66%, and 61% vs 99%, 96%, and 90%; P < 0.001). CONCLUSIONS: Patients with HCC-CC have similar survival to patients undergoing a transplant for HCC. Preoperative diagnosis of HCC-CC should not prompt the exclusion of these patients from transplant option.

Model for end-stage liver disease can predict very early outcome after liver transplantation.

Postoperative Model for End-stage Liver Disease (MELD) values have never been assessed to predict very early (<1 week) death after liver transplantation (OLT). We retrospectively reviewed 275 consecutive OLTs performed in 252 recipients reported in a prospective database. We calculated the MELD score (pre-MELD) and consecutive postoperative MELD (post-MELD) scores computed daily during the first postoperative week and on days 15 and 30 after OLT. Post-MELD scores from nonsurviving recipients displayed on a scatterplot of immediate probability of death were adjusted to the best goodness-of-fit curve, and, finally, depicted graphically as a receiver operating characteristic (ROC) curve. Nonsurviving recipients showed higher post-MELD scores: day 1: 23.5 versus 16.6 (P = .05); day 3: 25.1 versus 12.5 (P = .000); day 5: 25.7 versus 11.8 (P = .000); and day 7: 22.1 versus 10.2 (P = .000). Overall comparisons were performed using a time-dependent general linear regression model, revealing higher post-MELD scores for nonsurviving recipients, irrespective of postoperative time (P = .002). The best goodness-of-fit curve was displayed when adjusting to a theoretical exponential regression curve calculated as follows: Probability of dying within the first week (%) = 3.36 x e(0.079 x (post-MELD)) (r = .89; P = .000). The area under the ROC curve was 0.783 (95% confidence interval, 0.630-0.935; P = .001). The model had a positive predictive value of 82.3%, a negative predictive value of 33.1%, and an accuracy of 79.2%. In conclusion, this study corroborated the suggestion that the MELD score may serve as a reliable tool to assess very early death after OLT.

Factors affecting survival and tumor recurrence in patients transplanted for hepatocellular carcinoma and coexistent hepatitis C virus.

A better understanding of tumor factors influencing patient and graft survival and recurrence of hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) cirrhosis may be useful to maximize the benefits of liver transplantation (OLT). Sixty-three adults underwent OLT for end-stage liver disease secondary to HCV with concomitant HCC. The outcome measures were patient and graft survival, as well as recurrence-free survival, computed using a stepwise Cox proportional hazards regression analysis. Kaplan-Meier 1-, 3-, and 5-year patient survival rates were 82%, 80%, and 69%, respectively, they were better for incidentally discovered HCC compared with preoperatively diagnosed HCC (P = .04). The overall recurrence-free survival rates were 81%, 76%, and 61% at 1, 3, and 5 years, respectively. Univariate analysis showed that nonincidental HCC (P = .04), pTNM stage (P = .012) and vascular invasion (P = .003) correlated with recipient mortality. Vascular invasion (odds ratio [OR] = 2.12; P = .001) and pTNM (OR = 1.50; P = .008) were independent predictors of overall survival. A combination of tumor vascular invasion with advanced pTNM was associated with a dismal prognosis (log-rank = 21.89; P = .0001). Tumor grading (OR = 1.2; P = .04), pTNM (OR = 3.7; P = .001) and vascular invasion (OR = 1.6; P = .002) were independent predictors of recurrence. In conclusion, advanced pTNM and the presence of vascular invasion are strong predictors of poor survival and tumor recurrence.

Contribution of marginal donors to liver transplantation for hepatitis C virus infection.

The use of marginal liver donors can affect the outcomes of liver transplantation in patients with hepatitis C virus (HCV) infection. There are no firm conclusions about which donor criteria are important for allocation of high-risk grafts to recipients with HCV cirrhosis. We performed 120 consecutive liver transplantations for HCV infection between 1995 and 2005. Marginal donor criteria were considered to be: age >70 years, macrovesicular steatosis >30%, moderate-to-severe liver preservation injury, high inotropic drug dose (dopamine >15 microg/kg/min; epinephrine, norepinephrine, or dobutamine at any doses), peak serum sodium >155 mEq/L, any hypotensive episode <60 mm Hg and >1 hour, cold ischemia time >12 hours, ICU hospitalization >4 days, bilirubin >2 mg/dL, AST and/or ALT >200 UI/dL. Graft survival with donors showing these marginal criteria was compared with optimal donors using Kaplan-Meier analysis and the log-rank test. Independent predictors of survival were computed with the Cox proportional hazards model. Fifty-six grafts (46%) were lost during follow-up irrespective of the Model for End-Stage Liver Disease (MELD) scores of the recipients in each category. Upon univariate analysis, grafts with moderate-to-severe steatosis (P = .012), those with severe liver preservation injury (P = .007) and prolonged cold ischemia time (P = .0001) showed a dismal prognosis at 1, 3, and 5 years. Upon multivariate analysis, fat content (P = .0076; OR = 4.2) and cold ischemia time >12 hours (P = .034; OR = 7.001) were independent predictors of graft survival. Among HCV recipients, marginal liver donors worked similar to those from "good" donors, except for those with fatty livers >30%, especially when combined with a prolonged cold ischemia time.

Treatment of peritoneal carcinomatosis from ovarian cancer. Present, future directions and proposals.

Peritoneal carcinomatosis, considered years ago as a final stage of unresectable cancer, can now be managed with curative intention by means of a radical cytoreductive surgical procedure with associated peritonectomy and intraperitoneal chemotherapy, as described by Sugarbaker. Malignant neoplasms such as mesothelioma and pseudomyxoma peritonei, ovarian and colon cancer nowadays are experiencing some new therapeutical approaches. Higher survival rates can be reached in ovarian cancer, which is commonly diagnosed in the presence of peritoneal carcinomatosis, using an optimal cytoreductive radical surgery with intraperitoneal chemotherapy. An actualised review of the treatment of advanced ovarian cancer and a proposal of a national multicentre protocol for the treatment of peritoneal carcinomatosis from ovarian cancer has been performed by a group of Spanish surgeons and oncologists dedicated to a therapeutical approach to this pathology.

Management of peritoneal surface malignancy with cytoreductive surgery and perioperative intraperitoneal chemotherapy.

AIMS: A new treatment strategy combining maximal cytoreductive surgery for treatment of macroscopic disease and maximal perioperative intraperitoneal chemotherapy for residual microscopic disease, suggests that in a selected group of patients benefit is possible. The purpose of this study was to report our experience with this combined treatment and to identify the principal prognostic factors. METHODS: The study included 266 patients from 9 institutions operated on between July 1990 and July 2004. The median age was 55 years. RESULTS: The mortality rate was 7.8% and the morbidity rate 37.5%. The overall median survival was 13.7 months. Positive independent prognostic factors by multivariate analysis were gender, perioperative intraperitoneal chemotherapy and treatment by the second-look procedure. CONCLUSIONS: The therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in a selected group of patients with an acceptable morbidity and mortality.

Adjuvant chemotherapy for prevention of recurrence of invasive hepatocellular carcinoma after orthotopic liver transplantation.

UNLABELLED: Orthotopic liver transplantation (OLT) is the best treatment for nonresectable hepatocellular carcinoma (HCC), but tumor recurrence reduces long-term and medium-term survival. The effectiveness of adjuvant chemotherapy to prevent tumor recurrence has not been fully established. METHODS: Three hundred eighty-seven consecutive patients, including 43 with HCC superimposed on liver cirrhosis, underwent OLT. Twelve patients with one or more prognostic criteria for HCC recurrence were entered into a prospective prophylaxis protocol with monthly cycles of cisplatin (60 mg/m(2)) and adriamycin (30 mg/m(2)), beginning the fourth week post-OLT for a maximum of seven sessions. RESULTS: The 5-year survival of the non-HCC patients was 65.7% and that of the HCC patients was 60.46% (P = NS). Chemotherapy was reasonably well tolerated, but the 9 patients with hepatitis C- or B-associated cirrhosis showed viral and histological recurrence of the primary disease. A high proportion of patients (7 of 12) developed tumor recurrence during the first year after OLT. Six of these patients died, all but one due to HCC relapse. Five patients remain healthy and tumor free at 58 to 130 months. Post-OLT adjuvant chemotherapy does not avoid tumor recurrence and its fatal consequences but may contribute to prolonged tumor-free survival among a significant proportion of patients with high-risk HCC. However, the uncertain implications on viral recurrence and the lack of control groups do not allow post-OLT chemotherapy to be recommended outside controlled clinical trials, which are clearly warranted.

Treatment of refractory cholestatic pruritus with molecular adsorbent recirculating system (MARS).

UNLABELLED: Pruritus is a common complication of cholestatic liver diseases or liver graft dysfunction. Current medical therapies lack efficacy. The molecular adsorbent recirculating system (MARS) represents an interesting therapeutic option. Our objective was to report our experience in the management of four patients with intractable pruritus with MARS. PATIENTS AND METHODS: The MARS treatment cycle included three consecutive treatments, each of 8 hours duration. The four patients with intractable pruritus who were treated had primary biliary cirrhosis/autoimmune hepatitis overlap syndrome (n = 1), ductopenic allograft rejection (n = 2), or posttransplant cholestatic HCV recurrence (n = 1). Intensity of pruritus was documented 24 hours before as well as 24 hours, 7 and 30 days after MARS therapy, and at the end of follow-up. We measured complete blood cell counts, glucose, BUN, creatinine, sodium, potassium, AST, ALT, GGT, alkaline phosphatase, bilirubin, prothrombin activity, and activated partial thromboplastin time. RESULTS: MARS therapy was well tolerated. Patient 1 experienced temporal relief of pruritus, but needed another MARS cycle because of relapse. Patient 2 experienced partial and temporary relief of pruritus, was listed for retransplantation, and received a liver graft 2 months later. Patient 3 showed a dramatic reduction in the degree of pruritus with MARS. Pruritus in patient 4 decreased promptly with MARS therapy and conversion of immunosuppression to tacrolimus, thereby avoiding retransplantation. CONCLUSION: MARS therapy is a promising, safe therapeutic option to treat refractory pruritus caused by cholestatic liver disorders.

Diminished anticoagulant and fibrinolytic activity following liver transplantation.

This study analyzed the coagulation changes in twenty patients after orthotopic liver transplantation. The procoagulant, anticoagulant, and fibrinolytic systems were studied during the first two postoperative weeks. Within the first postoperative day all extrinsic and intrinsic pathway factors became normal except factors IX, VII, and X, which recovered within the next 24 hr. Of interest are the changes in factor VIII, which reached a high concentration with an increase in its antigenic fraction during the study. However, coagulation inhibitors showed a different pattern. In fact, antithrombin III (AT-III) and protein C (PC) needed from 7 to 14 days to reach normal values. Total protein S (TPS) and free protein S (FPS) did not recover until day 7, whereas heparin cofactor II (HC-II) remained at subnormal levels throughout the study. Thrombin-antithrombin III complex (TAT) values were strikingly elevated in the immediate postoperative period. Fibrinolysis parameters showed plasminogen (PL) levels in the normal range until day 4. Antiplasmin (AP) followed a curve parallel to that of plasminogen but its levels were higher during this observation period. Similarly the initial elevation in plasminogen activator inhibitor 1 endothelial type (PAI-1) levels remained high until days 4 and 7. In summary, it can be concluded that during the postoperative phase after OLT a hypercoagulable state is developed as a result of diminished anticoagulant and fibrinolytic activity. This coagulation might be a nontechnical factor contributing to the thrombotic vascular complications of some liver recipients.

Importance of surveillance mycobacterial cultures after liver transplantation.

The routine use of isoniazid prophylaxis after liver transplantation is a controversial issue because the benefits must be weighed against the risk of hepatotoxicity. We decided not to institute isoniazid prophylaxis but to study the efficacy of a surveillance mycobacterial program. One hundred patients were included in the protocol. Sputum and urine samples were processed before transplantation and on days 15, 30, 60, 90, 12, 150, and 180 for acid-fast stain and culture. One case of tuberculosis was promptly identified and successfully treated. Cases of tuberculosis with negative surveillance cultures were not identified. Our approach indicates that surveillance mycobacterial cultures can permit rapid identification of tuberculosis after liver transplantation and it is an alternative for groups who questioned isoniazid prophylaxis.

[The results of duodenopancreatectomy in periampullar pathology]. / Resultados de la duodenopancreatectomía cefálica en patología periampular.

OBJECTIVE: To examine mortality and morbidity rates after pancreaticoduodenectomy in 69 consecutive patients with periampullar disease operated on between 1985 and 1993 at the Reina Sofía Hospital, Córdoba, Spain. PATIENTS: Fifty five patients (79.7%) had malignant neoplasm whereas 14 (20.3%) had benign disease. In 58 patients a Whipple procedure was performed; pancreaticoduodenectomy with preservation of the pylorus (Traverso-Longmire) was performed in the remaining 11 patients. RESULTS: Eighteen patients (26%) had postoperative complications; peritoneal bleeding (1); biliary fistula (3); pancreatic fistula (4); digestive fistula (2); and pancreatitis (2). Two patients with pancreatic and duodenal carcinoma died. Thirteen patients were readmitted: 3 bleeding episodes in anastomotic ulcer; 3 hepaticojejunostomy obstruction; and the remaining 6 patients with tumor recurrence. CONCLUSIONS: In our experience duodenopancreatectomy was a safe procedure in periampullar disease, with an acceptable morbidity and mortality rates.

[Long-term results of the surgical treatment of chronic pancreatitis]. / Resultados a distancia en el tratamiento quirúrgico de la pancreatitis crónica.

We analized the long-term results after surgical treatment in 41 patients with chronic pancreatitis. Twenty one of them underwent resection: 19 pancreaticoduodenectomy (11 Whipple procedure and 8 Traverso Longmire); total pancreatectomy (1) and near-total pancreatectomy (1). In the remaining 20 patients a drainage procedure was carried out: Puestow-Duval (5); Partington (7); double derivation: pancreatic and biliar (5); triple derivation: pancreatic, biliar, gastric (2) and Nardi procedure+quisteduodenostomy in one patient. The following were evaluated: persistent pain; chronic alcoholism; nutrition status; exocrine function (syntomatic steatorrea, use of pancreatic enzyme preparation and fecal determination of glucide, protids and lipids) and endocrine function (glucose and insulin levels and glucose oral test). Surgery failed to relieve pain in 15.6% of the patients; failures were associated chronic alcoholism (p < 0.05); 18 patients (44%) required oral pancreatic enzymes. There weren't significant differences between resection and drainage procedures regarding the exocrine function. However, endocrine function was significantly worse (p < 0.05) after pancreaticoduodenectomy than after drainages procedures. Among the late, the endocrine function was better after Partington operation than after the Puestow-Duval.

[The palliative treatment of pancreatic cancer: percutaneous drainage versus surgical diversion]. / Tratamiento paliativo del cáncer de páncreas: drenaje percutáneo versus derivación quirúrgica.

In a retrospective study, the outcome of 56 patients with unresectable carcinoma of the exocrine pancreas undergoing two palliative operations (bypass surgery vs percutaneous transhepatic biliary drainage with endoprosthesis) for the management of biliary obstruction was evaluated. Morbidity and mortality were similar in the two groups. Postop hospital stay was 8 days for the intubated, and 15 days for operated patients (p less than 0.01). Although the symptom-free period was similar in both groups, intubated patients had a shorter period of poor-quality life.

[Prognostic factors in severe acute pancreatitis. Univariate and multivariate study]. / Factores pronósticos en la pancreatitis aguda severa. Estudio univariante y multivariante.

OBJECTIVES: The aim of this study was to analyze the prediction of mortality in patients with severe acute pancreatitis. PATIENTS AND METHODS: In a retrospective study 43 patients with severe acute pancreatitis were included. All patients required ICU admittance and surgical treatment. We evaluated severity according to Ranson's criteria, APACHE II score, CT scan classification (Hill), intraoperative findings (Vankemmel's classification) and number of organs failure. We performed a univariant and multivariant statistic study with lineal discriminant analysis. RESULTS: The overall mortality was 46.5%. Ranson's score and APACHE II did not correlate with mortality. Hill's classification did not reach significance either. However, only the Vankemmel's classification and the number of organs failure had statistic value (p < 0.01). After lineal discriminant analysis, the association of more than 4 Ranson's criteria, APACHE II up to 9 points, grades IV and V in Hill's classification and 4 organs failure had a predictive value for mortality. CONCLUSIONS: In our limited experience the Vankemmel's classification and the number of organs failure had a predictive value for mortality in patients with acute pancreatitis. The association of more than 4 Ranson's criteria. APACHE II up to 8 points, grades IV-V in Hill's classification and 4 organs failure disclosed poor prognosis.

[Self-expanding metallic endoprostheses in the palliative treatment of biliary obstructions in nonresectable carcinoma of the head of the pancreas]. / Endoprótesis metálicas autoexpansivas en el tratamiento paliativo de la ictericia obstructiva en el carcinoma de cabeza de páncreas irresecable.

OBJECTIVE: A study of immediate and long-term results with the self-expandable metallic stent (Wallstent), in the treatment of biliary obstruction in 25 patients with non resectable carcinoma of the head of the pancreas was carried out. Stent placement was successful in all patients. RESULTS: Complication rate was 4% (n = 1); one patient had venous bleeding after percutaneous catheter placement. There was no procedure related mortality (30-day mortality); hospital stay was 6, 7 days (2-12). Average survival was 6 months (+/- 2.97). Average patency of the initial stent lasted 5 months (+/- 2.01); comfort index was 83%. Five patients required re-admission. Late complications were cholangitis in 2 and stent occlusion in 4. Disimpaction in one patient and placement of additional stent (PAL-MAZ) in the remaining 3 patients were performed. One patient required surgical treatment; hepaticojejunostomy was performed. Elapse time between prostheses placement and stent occlusion was 3.4 months (2-4.5). CONCLUSIONS: We conclude that metallic stent placement has low morbidity without mortality and provide good quality of live. The most frequent late complication was prostheses obstruction.

[Hepatic confluence tumors: results and quality of life according to the type of treatment]. / Tumores de la confluencia hepática: resultados y calidad de vida según el tipo de tratamiento.

We analyzed survival rate and quality of life according to the treatment modality in 52 patients with hilar tumors. Six of them underwent resection (11.5%); 4 without hepatectomy, one left hepatectomy and one trisegmentectomy. The remaining 46 patients were treated by: radiologic external-internal drainage (12), placement of percutaneous endoprostheses (14), surgical intubation (18), and cholangioanastomoses to segment III in 2. Prognostic factors (PITT and A.P.A.C.H.E. II), survival time and quality of life were analyzed. Survival and comfort index were significantly better (p < 0.001) in the resection group than in the palliation one. Among palliative procedures percutaneous endoprostheses and surgical intubation offered better quality of life (p < 0.001) than radiologic external-internal drainage. We conclude that resection improves survival and offers better quality of life than palliative procedures. Our results suggest that resection during laparotomy should be attempted in order to improve results in the treatment of hepatic confluence tumors.

[Hemodynamic changes in hepatic transplant in pigs anesthetized with isoflurane]. / Alteraciones hemodinámicas en el trasplante de hígado en cerdos anestesiados con isofluorano.

An anesthetic model with isofluorane is reported, with the hemodynamic abnormalities induced in 10 pigs of Landrace breed undergoing orthotopic hepatic transplant with centrifugal pump. ECG, arterial blood pressure, central venous pressure, pulmonary artery pressure and rectal temperature were monitored in all the animals. Hemodynamic parameters were measured in four periods: a) baseline; b) preanhepatic phase; c) anhepatic phase, and d) after revascularization. After a period of hemodynamic stability in preanhepatic phase, there was a reduction in cardiac output (p less than 0.01) and stroke volume (p less than 0.05) and an increase in heart rate, which were maintained during the rest of the operation. Central venous pressure, pulmonary capillary pressure and mean arterial pressure remained constant. Throughout the process there was a progressive increase in systemic vascular resistances, particularly pulmonary vascular resistance which, together with mean pulmonary arterial pressure, showed a significant increase in the last phase. During the bypass period there was a significant reduction of temperature. It was concluded that satisfactory results in experimental liver transplant are achieved with isofluorane and venous bypass with centrifugal pump.

Donation after cardiac death: where, when, and how?

The continuing shortage of donors has led to the increasing use of marginal grafts. Surgical techniques such as split, domino, and living donations have not been able to decrease waiting list mortality. Donation after cardiac death (DCD) was the only source of grafts prior to the establishment of brain death criteria in 1968. Thereafter, donation after brain death emerged as the leading source of grafts. The context in which irreversible cessation of circulatory and respiratory functions happens was the cornerstone to definite the four categories of DCD by the First International Workshop on DCD held in Maastricht in 1995. Controlled (CDCD) and uncontrolled (UDCD) categories now account for 10%-20% of the donor pool in several countries. Despite initial high rates of primary nonfunction and ischemic-type biliary lesions, refinements in protocols and surgical techniques have led to excellent 1- and 3-year graft survivals of 80% and 70%, respectively with PNF and ITBL rates below 3%. The institution of UDCD and CDCD depends on legal considerations of presumed consent and withdrawal of maneuvers, respectively. The potential for DCD programs is huge; it may be the only real, effective way to increase the grafts pool, both in adult and pediatric populations. Recent advances in perfusion machines will surely optimize this donor pool and allow new therapies for graft resuscitation.