Predicting early recurrence after resection of initially unresectable colorectal liver metastases: the role of baseline and pre-surgery clinical, radiological and molecular factors in a real-life multicentre experience.

BACKGROUND: Advances in surgical techniques and systemic treatments have increased the likelihood of achieving radical surgery and long-term survival in metastatic colorectal cancer (mCRC) patients with initially unresectable colorectal liver metastases (CRLMs). Nonetheless, roughly half of the patients resected after an upfront systemic therapy experience disease relapse within 6 months from surgery, thus leading to the question whether surgery is actually beneficial for these patients. MATERIALS AND METHODS: A real-world dataset of mCRC patients with initially unresectable liver-limited disease treated with conversion chemotherapy followed by radical resection of CRLMs at three high-volume Italian institutions was retrospectively assessed with the aim of investigating the association of baseline and pre-surgical clinical, radiological and molecular factors with the risk of relapse within 6 or 12 months from surgery. RESULTS: Overall, 268 patients were included in the analysis and 207 (77%) experienced recurrence. Ninety-six (46%) of them had disease relapse within 6 months after CRLM resection and in spite of several variables associated with early recurrence at univariate analyses, only primary tumour resection at diagnosis [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.32-0.89, P = 0.02] remained significant in the multivariable model. Among patients with resected primary tumours, pN+ stage was associated with higher risk of disease relapse within 6 months (OR 3.02, 95% CI 1.23-7.41, P = 0.02). One hundred and forty-nine patients (72%) had disease relapse within 12 months after CRLMs resection but none of the analysed variables was independently associated with outcome. CONCLUSIONS: Clinical, radiological and molecular factors assessed before and after conversion chemotherapy do not reliably predict early recurrence after secondary resection of initially unresectable CRLMs. While novel markers are needed to optimize the cost/efficacy balance of surgical procedures, CRLM resection should be offered as soon as metastases become resectable during first-line chemotherapy to all patients eligible for surgery.

Bile detection of squamous cell carcinoma antigen (SCCA) in extrahepatic cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a rare biliary tract tumor with poor prognosis that often is challenging to diagnose and the majority of patients present with advanced stage. Squamous cell carcinoma antigen 1 (SCCA1) overexpression has been found in different tumors associated with poor prognosis and chemoresistance. AIMS: To assess the presence and possible prognostic role of SCCA1/2 isoforms in bile and serum of patients with CCA. METHODS: Forty seven surgical patients (36 with CCA and 11 with benign diseases) were prospectively included in the study. Serum and bile specimens were collected at the time of surgery and free and IgM-complexed SCCA was quantified by ELISA (Xeptagen, srl). RESULTS: Free or IgM linked SCCA was rarely found in serum, while SCCA was detectable in bile samples of patients with CCA, especially in those with extrahepatic form (43% vs 17%, p = 0.008), but not in controls. Despite similar tumor stage, these positive patients presented a trend toward a higher percentage of portal invasion (27% vs 15%) and of tumor recurrence than negative cases (62% vs 40%), although the difference was not statistically significant. CONCLUSION: These preliminary results indicate that bile testing for SCCA is a specific marker of extrahepatic CCA, with potential prognostic value.

The impact of liver resection on survival for locally advanced intrahepatic cholangiocarcinoma tumors: A propensity score analysis.

BACKGROUND: Aim of work was to investigate the prognostic impact of liver resection (LR) on locally advanced Intrahepatic Cholangiocarcinoma (IC) in comparison to alternative palliative chemotherapy (CTx). METHOD: A retrospective cohort study performed utilizing Surveillance, Epidemiology, and End Results (SEER) database to identify Locally advanced IC patients. Based on the American Joint Committee on Cancer (AJCC) Staging System, locally advanced IC was defined as: Stage III and IVa - 7th edition (7th-ed) or stage III - 8th edition (8th-ed). Study population were sub-classified into: LR group and a propensity score (PS) matched CTx group. RESULTS: In 7th-ed module, the median survival for LR group (n = 154) was 35 months, and the 3-year survival rate was 40.8%. In PS matched CTx group (n = 154); the median survival was 14 months and the 3-year survival rate was 5.5% (P = 0.007). Survival rates were superior for LR group over PS matched CTx group in 8th-ed module as well. Worse prognosis has been reported in LR patients above 65 years old (HR 2.618, P = 001) and in multifocal lesions (HR 1.890, P = 0.025). CONCLUSION: Hepatic resection was associated with a favorable impact on prognosis over chemotherapy for IC stage III and IVa of the 7th edition and for stage IIIb of 8th edition of AJCC staging system. Worse outcome has been observed in LR patients >65 years and with multifocal lesions. Randomized control studies are recommended to confirm the role of surgical resection in the management for advanced cases of IC, and to clarify the related prognostic factors.

Liver autotransplantation for the treatment of unresectable hepatic metastasis: an uncommon indication-a case report.

Ex situ ex vivo liver surgery represents a method to expand the surgical indications to treat otherwise unresectable liver tumors. We report the case of a 38-year old woman with hepatic metastasis from a pancreatoblastoma that was judged to be unresectable due to the involvement of the three hepatic veins. To treat the primary tumor, she underwent a pancreaticoduodenectomy, adjuvant chemotherapy, and thermal ablation of a liver metastasis. After appropriate preoperative study and with the permission of the ethics committee, she underwent ex situ ex vivo liver resection. The hepatectomy was performed by removing the whole liver en bloc with the retrohepatic vena cava. The inferior vena cava was reconstructed by interposition of a prosthetic graft. The ex situ ex vivo hepatic resection, a left hepatic lobectomy included the lesion in segments 1-5-7-8. The two hepatic veins were reconstructed using patches of saphenous vein. The organ was preserved continuously for 6 hours using hypothermic perfusion with 4°C Celsior solution. The liver was then reimplanted performing an anastomosis between the reconstructed hepatic veins and the caval prostheses. The patient was discharged at postoperative day 22 and is currently disease-free at 8 months after surgery and 44 months after the initial diagnosis. Ex situ, ex vivo liver surgery offers an additional option for patients with both primary and secondary liver tumors considered to be unresectable using traditional surgical approaches.

Subnormothermic machine perfusion for non-heart-beating donor liver grafts preservation in a Swine model: a new strategy to increase the donor pool?

We previously reported that subnormothermic machine perfusion (sMP; 20°C) is able to improve the preservation of livers obtained from non-heart-beating donors (NHBDs) in rats. We have compared sMP and standard cold storage (CS) to preserve pig livers after 60 minutes of cardiac arrest. In the sMP group livers were perfused for 6 hours with Celsior at 20°C. In the CS group they were stored in Celsior at 4°C for 6 hours as usual. To simulate liver transplantation, both sMP- and CS-preserved livers were reperfused using a mechanical continuous perfusion system with autologus blood for 2 hours at 37°C. At 120 min after reperfusion aspartate aminotransferase levels in sMP versus CS were 499 ± 198 versus 7648 ± 2806 U/L (P < .01); lactate dehydrogenase 1685 ± 418 versus 12998 ± 3039 U/L (P < .01); and lactic acid 4.78 ± 3.02 versus 10.46 ± 1.79 mmol/L (P < .01) respectively. The sMP group showed better histopathologic results with significantly less hepatic damage. This study confirmed that sMP was able to resuscitate liver grafts from large NHBD animals.

Liver transplantation for massive hepatomegaly due to polycystic liver disease: an extreme case.

BACKGROUND: Polycystic liver disease (PLD) is due to a genetic disorder and frequently coexists with polycystic kidney disease (PKD). If the cysts produce symptomatology owing to their number and size, many palliative treatments are available. When none of the liver parenchyma is spared, or kidney insufficiency is marked, the only potentially curable treatment is liver transplantation (LT). CASE REPORT: A 49-year old woman, diagnosed with PLD and PKD, was listed in January 2008 for combined LT and kidney transplantation (KT). A compatible organ became available 8 months later. Despite preserved liver function, the patient's clinical condition was poor; she experienced dyspnea, advanced anorexia, abdominal pain, and severe ascites. At LT, which took 9 hours and was performed using the classic technique, the liver was hard, massive in size (15.5 kg), and not dissociable from the vena cava. The postoperative course was complicated by many septic episodes, the last one being fatal for the patient at 4 months after transplantation. DISCUSSION: LT for PLD in many series shows a high mortality rate. The Model for End-Stage Liver Disease (MELD) score does not stage patients properly, because liver function is usually preserved. The liver can achieve a massive size causing many symptoms, especially malnutrition and ascites; in this setting LT is the only possible treatment. Patients with a low MELD score undergo LT with severe malnutrition that predisposes them to greater susceptibility to sepsis. To identify predictor factors, beyond MELD criteria that relate to the increased liver volume before development of late symptoms is essential to expeditiously treat patients with the poorest prognosis to improve their outcomes.

A new liver autotransplantation technique using subnormothermic machine perfusion for organ preservation in a porcine model.

BACKGROUND: Hepatic resection is the gold standard of therapy for primary and secondary liver tumors, but few patients are eligible for this procedure because of the extent of their neoplasms. Improvements in surgical experience of liver transplantation (OLT), hepatic resection and preservation with sub-normothermic machine perfusion (MP) have prompted the development of a new model of large animal autotransplantation. METHODS: Landrace pigs were used in this experiment. After intubation, hepatectomy was performed according to the classic technique. The intrahepatic caval vein was replaced with a homologous tract of porcine thoracic aorta. The liver was perfused with hypothermic Celsior solution followed by MP at 20 °C with oxygenated Krebs solution. An hepatectomy was performed during the period of preservation, which lasted 120 minutes, then the liver was reimplanted into the same animal in a 90° counterclockwise rotated position. The anastomoses were performed in the classic sequence. Samples of intravascular fluid, blood and liver biopsies were obtained at the end of the period of preservation in MP and again at 1 and 3 hours after liver reperfusion to evaluate graft function and microscopic damage. RESULTS: All animals survived the procedure. The peak of aspartate aminotransferase was recorded 60 minutes after reperfusion and the peak of alanine aminotransferase and lactate dehydrogenase after 180 minutes. Histopathologic examination under the light microscope identified no necrosis or congestion. Intraoperative echo-color Doppler documented good patency of the anastomosis and normal venous drainage. CONCLUSION: This system made it possible to perform hepatic resections and vascular reconstructions ex situ while preserving the organ with mechanical perfusion (ex vivo, ex situ surgery). Improving surgical techniques regarding autotransplantation and our understanding of ischemia-reperfusion damage may enable the development of interesting scenarios for aggressive surgical treatment or radiochemotherapy options to treat primary and secondary liver tumors unsuitable for conventional in situ surgery.

Neoadjuvant therapy protocol and liver transplantation in combination with pancreatoduodenectomy for the treatment of hilar cholangiocarcinoma occurring in a case of primary sclerosing cholangitis: case report with a more than 8-year disease-free survival.

Cholangiocarcinoma has historically represented a major contraindication to liver transplantation at many centers because of its high recurrence rate and low disease-free survival rate, even after radical surgery. Novel neoadjuvant therapy protocols combined with demolitive surgery and liver transplantation seem to achieve successful results in terms of overall and disease-free survivals. Surgery frequently seems to be unsatisfactory only for patients also suffering from chronic cirrhosis or end-stage liver disease. We have reported a case of hilar cholangiocarcinoma occurring in a case of primary sclerosing cholangitis treated with neoadjuvant radiochemotherapy and endoscopic brachytherapy, followed by liver transplantation combined with pancreatoduodenectomy, who has survived free of disease for >8 years.

Prospective validation of a new priority allocation model for liver transplant candidates: an interim analysis.

BACKGROUND: The system that controls the waiting list (WL) and organ allocation for liver transplantation (OLT) seeks to achieve 3 main goals: objectivity, low dropout risks and good post-OLT results. We sought to prospectively validate a priority allocation model that is believed to achieve objectivity without penalizing dropout risk and post-OLT results. METHODS: We evaluated a study group of 272 patients enrolled in 2006-2007. WL candidates were divided into 2 categories: cirrhotic patients classified according to Model for End-Stage Liver Disease (MELD) score (MELD list and patients with hepatocellular carcinoma (HCC) organized according to a specific score (non-MELD list). The allocation algorithm for donor-recipient match assigned an optimal graft to the first MELD candidate with a MELD score of >or=20; a suboptimal graft, to the first non-MELD patient. A respective control group of 327 patients transplanted from 2003-2006 was characterized by a unique WL with a free allocation policy. We performed an interim analysis of this prospectively controlled study. RESULTS: Although the study group showed a lower percentage of OLT (P < .05) than the control group (37% vs 45%), it selected patients for OLT based on a higher MELD score (P < .05), thus obtaining similar dropout, post-OLT survivals, and intention-to-treat (ITT) survival probabilities as the controls. Among MELD patients, we observed a significantly reduced dropout and better ITT survival profiles than those of the control group (P = .02), whereas the similar results were delivered among non-MELD patients (P > .05). Among patients with a MELD score of >or=20, the prevalences of suboptimal grafts (0% vs 48%) and of early graft losses (0% vs 21%) were lower in the study than in the control group (P < .05). CONCLUSIONS: We prospectively validated a priority allocation model based on objective criteria that achieved high ITT survival rates.

Prognostic evaluation of the donor risk index among a prospective cohort of Italian patients undergoing liver transplantation.

BACKGROUND/AIM: The definition of an extended criteria donor for orthotopic liver transplantation (OLT) remains controversial. The donor risk index (DRI) has become the main tool to define the marginality of hepatic grafts in the United States. The aim of this study was to prospectively evaluate the prognostic ability of DRI among a cohort of Italian patients undergoing OLT. METHODS: From December 2006 to March 2008, we prospectively calculated DRI in all consecutive cadaveric grafts. Recipient inclusion criteria were: adult patients with chronic liver disease enlisted for primary OLT. The primary end point was the incidence of primary graft dysfunction (PDF), namely, aspartate aminotransferase (AST) >2000 U/mL and prothrombin time <40% on postoperative days 2-7. RESULTS: We enrolled 74 donor-recipient pairs fulfilling the inclusion criteria. Donor characteristics included DRI 1.7 (range, 0.9-3.0); age 57 years (range, 18-81); ultrasound signs of steatosis in 22 donors (30%); and ischemia time was 536 minutes (range, 290-690). Recipient characteristics are: age 55 years (range, 27-68); hepatocellular carcinoma in 36 subjects (49%); MELD was 16 (range, 7-39); and Child-Pugh score was 8 (range, 6-14). In terms of the primary end points, the DRI did not provide a significant PDF predictor (P = .84). Among all evaluated donor and recipient variables, the following were related to the incidence of graft PDF: donor age (P = .07), ultrasound signs of steatosis (P = .02), donor AST (P = .05), cell saver infusion (P = .07), and warm (P = .04) and cold ischemia (P = .07) times. CONCLUSION: The preliminary data of this study showed a poor correlation between DRI and PDF incidence after OLT.

Progression of hepatocellular carcinoma before liver transplantation: dropout or liver transplantation?

BACKGROUND: Tumor progression before liver transplantation (OLT) is the main cause of dropout from the waiting list (WL) of patients with hepatocellular carcinoma (HCC). The aim of this study was to show a correlation between adopted dropout criteria and dropout/intention-to-treat survival rates of WL HCC patients. METHODS: The study period was 2000 to 2007. The dropout criteria were macroscopic vascular invasion, metastases, or a poorly differentiated tumor. Adult patients with benign chronic liver disease enlisted for primary OLT in the same period represented the control group. RESULTS: Dropout probability of study (n = 128) versus control group (n = 377) subjects was similar: namely, 12% at 1 year in both groups (P = NS). Intention-to-treat survival curve of the HCC group overlapped that of the benign group (5-year survival rates were 73% and 71%, respectively; P = NS). At the time of listing, 103 study group patients were within the Milan criteria (MC): among these patients, 29 (28%) showed tumor progression beyond MC before OLT. Simulating the dropout of these 29 patients at the time of diagnosis of tumor progression, we compared the dropout probability of the 103 patients within MC with that of the control group. As a result, the 1- and 2-year dropout rates became 37% and 53%, respectively, in the study group, which were significantly higher than those in the controls (P < .01). CONCLUSION: HCC patients on the WL showed a significantly greater dropout rate than subjects with benign cirrhosis when too restrictive radiologic dropout criteria were used. The adoption of criteria more related to biological aggressiveness of a tumor decreased the dropout risk for HCC patients without impairing their intention-to-treat survival rates.

Alcohol abuse and de novo tumors in liver transplantation.

INTRODUCTION: Organ transplant recipients show an increased incidence of cancer ranging from 4% to 16% owing to several causes: immunosuppression, viral infection, individual predisposition, and so on. MATERIALS AND METHODS: We retrospectively reviewed the records of 43/683 (6.3%) recipients of 734 liver transplants performed from November 1991 to November 2008 who experienced a de novo neoplasm. CONCLUSION: Alcohol abuse significantly increased the rate of all de novo neoplasms and particularly pharyngogastroesophageal cancers among population of liver transplant recipients. Minimization of immunosuppressive therapy is necessary to reduce the risk of a de novo neoplasm. Strict posttransplant follow-up is required to identify early gastroenteric tumors.