Identification of TPM2 and CNN1 as Novel Prognostic Markers in Functionally Characterized Human Colon Cancer-Associated Stromal Cells.

Stromal infiltration is associated with poor prognosis in human colon cancers. However, the high heterogeneity of human tumor-associated stromal cells (TASCs) hampers a clear identification of specific markers of prognostic relevance. To address these issues, we established short-term cultures of TASCs and matched healthy mucosa-associated stromal cells (MASCs) from human primary colon cancers and, upon characterization of their phenotypic and functional profiles in vitro and in vivo, we identified differentially expressed markers by proteomic analysis and evaluated their prognostic significance. TASCs were characterized by higher proliferation and differentiation potential, and enhanced expression of mesenchymal stem cell markers, as compared to MASCs. TASC triggered epithelial-mesenchymal transition (EMT) in tumor cells in vitro and promoted their metastatic spread in vivo, as assessed in an orthotopic mouse model. Proteomic analysis of matched TASCs and MASCs identified a panel of markers preferentially expressed in TASCs. The expression of genes encoding two of them, calponin 1 (CNN1) and tropomyosin beta chain isoform 2 (TPM2), was significantly associated with poor outcome in independent databases and outperformed the prognostic significance of currently proposed TASC markers. The newly identified markers may improve prognostication of primary colon cancers and identification of patients at risk.

Liver Transplantation for Hepatic Trauma: A Study From the European Liver Transplant Registry.

BACKGROUND: Liver transplantation is the most extreme form of surgical management of patients with hepatic trauma, with very limited literature data supporting its use. The aim of this study was to assess the results of liver transplantation for hepatic trauma. METHODS: This retrospective analysis based on European Liver Transplant Registry comprised data of 73 recipients of liver transplantation for hepatic trauma performed in 37 centers in the period between 1987 and 2013. Mortality and graft loss rates at 90 days were set as primary and secondary outcome measures, respectively. RESULTS: Mortality and graft loss rates at 90 days were 42.5% and 46.6%, respectively. Regarding general variables, cross-clamping without extracorporeal veno-venous bypass was the only independent risk factor for both mortality (P = 0.031) and graft loss (P = 0.034). Regarding more detailed factors, grade of liver trauma exceeding IV increased the risk of mortality (P = 0.005) and graft loss (P = 0.018). Moreover, a tendency above the level of significance was observed for the negative impact of injury severity score (ISS) on mortality (P = 0.071). The optimal cut-off for ISS was 33, with sensitivity of 60.0%, specificity of 80.0%, positive predictive value of 75.0%, and negative predictive value of 66.7%. CONCLUSIONS: Liver transplantation seems to be justified in selected patients with otherwise fatal severe liver injuries, particularly in whom cross-clamping without extracorporeal bypass can be omitted. The ISS cutoff less than 33 may be useful in the selection process.

Improved liver function after portal vein embolization and an elective right hepatectomy.

BACKGROUND: Portal vein embolization (PVE) is used before extensive hepatic resections to increase the volume of the future remnant liver within acceptable safety margins (conventionally >0.6% of the patient's weight). The objective was to determine whether pre-operative PVE impacts on post-operative liver function independently from the increase in liver volume. METHODS: The post-operative liver function of patients who underwent an anatomical right liver resection with (n = 28) and without (n = 53) PVE were retrospectively analysed. Donors of the right liver were also analysed (LD) (n = 17). RESULTS: Patient characteristics were similar, except for age, weight and American Society of Anesthesiologists (ASA) score that were lower in LD. Post-operative factor V and bilirubin levels were, respectively, higher and lower in patients with PVE compared with patients without PVE or LD (P < 0.05). Patients with PVE had an increased blood loss, blood transfusions and sinusoidal obstruction syndrome. The day-3 bilirubin level was 40% lower in the PVE group compared with the no-PVE group after adjustment for body weight, chemotherapy, operating time, Pringle time, blood transfusions, remnant liver volume, pre-operative bilirubin level and pre-operative prothrombin ratio (P = 0.001). CONCLUSIONS: For equivalent volumes, the immediate post-operative hepatic function appears to be better in livers prepared with PVE than in unprepared livers. Future studies should analyse whether the conventional inferior volume limit that allows a safe liver resection may be lowered when a PVE is performed.

Sofosbuvir and ribavirin before liver re-transplantation for graft failure due to recurrent hepatitis C: a case report.

BACKGROUND: Recurrent hepatitis C virus infection after liver transplantation is associated with reduced graft and patient survival. Re-transplantation for graft failure due to recurrent hepatitis C is controversial and not performed in all centers. CASE PRESENTATION: We describe a 54-year-old patient with hepatitis C virus genotype 1b infection and a null response to pegylated interferon-α and ribavirin who developed decompensated graft cirrhosis 6 years after a first liver transplantation. Treatment with sofosbuvir and ribavirin allowed for rapid negativation of serum HCV RNA and was well tolerated despite advanced liver and moderate renal dysfunction. Therapeutic drug monitoring did not reveal any clinically significant drug-drug interactions. Despite virological response, the patient remained severely decompensated and re-transplantation was performed after 46 days of undetectable serum HCV RNA. The patient is doing well 12 months after his second liver transplantation and remains free of hepatitis C virus. CONCLUSIONS: The use of directly acting antivirals may allow for successful liver re-transplantation for recipients who remain decompensated despite virological response and is likely to improve the outcome of liver re-transplantation for end-stage recurrent hepatitis C.

Rectal outcomes after a liver-first treatment of patients with stage IV rectal cancer.

BACKGROUND: The treatment of patients with metastatic rectal cancer remains controversial. We developed a reverse strategy, the liver-first approach, to optimize the chance of a curative resection. The aim of this study was to assess rectal outcomes after reverse treatment of patients with metastatic rectal cancer. METHODS: From May 2000 to November 2013, a total of 34 consecutive selected patients with histology-proven adenocarcinoma of the rectum and liver metastases were prospectively entered into a dedicated computerized database. All patients were treated via our reverse strategy. Rectal and overall survival outcomes were analyzed. RESULTS: Most patients presented with advanced disease (median Fong clinical risk score of 3; range 2-5). One patient failed to complete the whole treatment (3%). Rectal surgery was performed after a median of 3.9 months (range 0.4-17.8 months). A total of 73.3% patients received preoperative radiotherapy. Perioperative mortality and morbidity rates were 0 and 27.3% after rectal surgery. Severe complications were reported in two patients (6.1%): one anastomotic leak and one systemic inflammatory response syndrome. The median hospital stay was 11 days (range 5-23 days). Complete local pathological response was observed in three patients (9.1%). The median number of lymph nodes collected was 14. The R0 rate was 93.9%. There was no positive circumferential margin. After a mean follow-up of 36 months after rectal surgery, 5-year overall survival was 52.5%. Five patients experienced pelvic recurrence. CONCLUSIONS: In our cohort of selected patients with stage IV rectal cancer, the reverse strategy was not only safe and effective, but also oncologically promising, with a low morbidity rate and high long-term survival.

Current status of robotic liver resection: a systematic review.

Robotic surgery is an emerging technique for the management of patients with liver disease, and only a limited number of reports are available. A systematic search of electronic databases (PubMed, Embase and Cochrane), including only case series with more than five patients, identified nine series (with one from our institution), which totaled to 232 patients. Overall, the peri-operative outcomes of the reported patients are similar to those utilizing the laparoscopic and open approaches. Robotic surgery appears to be a valid option for selected hepatic resections in experienced hands. It could represent a bridge toward minimally invasive approaches for confirmed liver surgeons. By contrast, the long-term oncological outcomes remain uncertain and need further studies.

Augmented environments for the targeting of hepatic lesions during image-guided robotic liver surgery.

BACKGROUND: Stereotactic navigation technology can enhance guidance during surgery and enable the precise reproduction of planned surgical strategies. Currently, specific systems (such as the CAS-One system) are available for instrument guidance in open liver surgery. This study aims to evaluate the implementation of such a system for the targeting of hepatic tumors during robotic liver surgery. MATERIAL AND METHODS: Optical tracking references were attached to one of the robotic instruments and to the robotic endoscopic camera. After instrument and video calibration and patient-to-image registration, a virtual model of the tracked instrument and the available three-dimensional images of the liver were displayed directly within the robotic console, superimposed onto the endoscopic video image. An additional superimposed targeting viewer allowed for the visualization of the target tumor, relative to the tip of the instrument, for an assessment of the distance between the tumor and the tool for the realization of safe resection margins. RESULTS: Two cirrhotic patients underwent robotic navigated atypical hepatic resections for hepatocellular carcinoma. The augmented endoscopic view allowed for the definition of an accurate resection margin around the tumor. The overlay of reconstructed three-dimensional models was also used during parenchymal transection for the identification of vascular and biliary structures. Operative times were 240 min in the first case and 300 min in the second. There were no intraoperative complications. CONCLUSIONS: The da Vinci Surgical System provided an excellent platform for image-guided liver surgery with a stable optic and instrumentation. Robotic image guidance might improve the surgeon's orientation during the operation and increase accuracy in tumor resection. Further developments of this technological combination are needed to deal with organ deformation during surgery.

A survival analysis of the liver-first reversed management of advanced simultaneous colorectal liver metastases: a LiverMetSurvey-based study.

BACKGROUND: Liver-first reversed management (RM) for the treatment of patients with simultaneous colorectal liver metastases (CRLM) includes liver-directed chemotherapy, the resection of the CRLM, and the subsequent resection of the primary cancer. Retrospective data have shown that up to 80% of patients can successfully undergo a complete RM, whereas less than 30% of those undergoing classical management (CM) do so. This registry-based study compared the 2 approaches. METHODS: The study was based on the LiverMetSurvey (January 1, 2000 to December 31, 2010) and included patients with 2 or more metastases. All patients had irinotecan and/or oxaliplatin-based chemotherapy before liver surgery. Patients undergoing simultaneous liver and colorectal surgery were excluded. RESULTS: A total of 787 patients were included: 729 in the CM group and 58 in the RM group. Patients in the 2 groups had similar numbers of metastases (4.20 vs 4.80 for RM and CM, P = 0.231) and Fong scores of 3 or more (79% vs 87%, P = 0.164). Rectal cancer, neoadjuvant rectal radiotherapy, and the use of combined irinotecan/oxaliplatin chemotherapy were more frequent in the RM group (P < 0.001), whereas colorectal lymph node involvement was more frequent in the CM group (P < 0.001). Overall survival and disease-free survival were similar in the RM and CM groups (48% vs 46% at 5 years, P = 0.965 and 30% vs 26%, P = 0.992). CONCLUSIONS: Classical and reversed managements of metastatic liver disease in colorectal cancer are associated with similar survival when successfully completed.

Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans.

Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS.

Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis.

AIMS: Because of its efficacy, oxaliplatin (OX) is increasingly used as a chemotherapeutic agent in the treatment of colorectal liver metastases (CRLM). Oxaliplatin-associated liver toxicity has been reported and can affect clinical practice, but studies on its prevalence and a full pathological description are lacking. The aims of this study were to fill this gap by providing, from a pathologist's perspective, a detailed assessment of the spectrum of hepatic lesions associated with OX, to suggest a scoring system to quantify them, and to investigate the protective effect of bevacizumab against OX-associated damage. METHODS AND RESULTS: The spectrum of oxaliplatin-associated liver lesions was investigated in a multi-institutional series of surgically resected CRLM (n = 385). Among 274 patients treated by OX, 54% had moderate/severe sinusoidal obstruction syndrome (SOS). Peliosis, centrilobular perisinusoidal/venular fibrosis and nodular regenerative hyperplasia (NRH) developed in 10.6%, 47% and 24.5%, respectively. The 111 patients treated by surgery alone had no lesions. Hepatic lesions were less severe in patients treated with OX/bevacizumab (n = 70) compared with the group treated by OX alone (n = 204), with an incidence of moderate/severe SOS (31.4% versus 62.2%), peliosis (4.3% versus 14.6%), NRH (11.4% versus 28.9%, respectively) and centrilobular/venular fibrosis (31.4% versus 52%, respectively) (P < 0.001). CONCLUSIONS: Pathologists should be aware of the distinctive lesions associated with OX and of their high prevalence. OX-related lesions are less frequent in patients treated with bevacizumab, suggesting that this drug has a preventive effect. Uniform criteria for diagnosis and grading of OX-associated lesions should help to include histological data in the optimal multidisciplinary management of CRLM.

Liver segments: an anatomical rationale for explaining inconsistencies with Couinaud's eight-segment concept.

BACKGROUND AND PURPOSE: An increasing number of surgical and radiological observations call Couinaud's concept of eight liver segments into question and such inconsistencies are commonly explained with anatomical variations. This paper was intended to demonstrate that, beyond variability, another anatomical principle may allow to understand supposedly differing concepts on liver segmentation. MATERIALS AND METHODS: The study was performed on 25 portal vein casts scanned by helical CT. The branches of the right and left portal vein and their corresponding territories were determined both anatomically and mathematically (MEVIS LiverAnalyzer, MEVISLab). RESULTS: The number of branches coming-off the right and left portal vein was never 8, but many more (mean number 20, range 9-44). Different combinations of these branches and their respective territories, carried out in this study, yielded larger entities and supposedly contradictory subdivisions (including Couinaud's eight segments), without calling upon anatomical variability. CONCLUSIONS: We suggest the human liver to be considered as corresponding to 1 portal venous territory at the level of the portal vein, to 2 territories at the level of the right and left branch of the portal vein, and to 20 at the level of the rami of the right and left branch. This "1-2-20-concept" is a rationale for reconciling apparent discrepancies with the eight-segment concept. On a pragmatic level, in cases in which imaging or surgical observations do not fit with Couinaud's scheme, we propose clinicians not to autonomically conclude to the presence of an anatomical variation, but to become aware of the presence of an average of 20 (and not 8) second-order portal venous territories within the human liver.

Improved long-term outcome of surgery for advanced colorectal liver metastases: reasons and implications for management on the basis of a severity score.

BACKGROUND: The outcome of liver resection for colorectal liver metastases (CRLM) appears to be improving despite the fact that surgery is offered to patients with more-severe disease. To quantify this assumption and to understand its causes we analyzed a series of patients on the basis of a standardized severity score and changes in management occurring over the years. METHODS: Patients' characteristics, operative data, chemotherapies and follow-up were recorded. CRLM severity was quantified according to Fong's clinical risk score (CRS), modified to take into account the presence of bilateral liver metastases. Three periods were analyzed, in which different indications, surgical strategies and uses of chemotherapy were applied: 1984-1992, 1993-1998, and 1999-2005. RESULTS: Between January 1984 and December 2005, 210 liver resections were performed in 180 patients (1984-1992, 43 patients; 1993-1998, 42 patients; 1999-2005, 95 patients). CRLM severity increased throughout the time periods, as did the use of neoadjuvant chemotherapies, repeat resections, and multistep procedures. While the disease-free survival did not improve over time, the 1-, 3- and 5-year overall survival rate increased from 85%, 30%, and 23% in the first period, to 88%, 60%, and 34% in the second period, and to 94%, 69%, and 46% in the third period. CONCLUSIONS: Analysis according to the CRS showed that despite the fact that patients had more severe disease, the overall survival improved over the years, mainly thanks to more aggressive treatment of recurrent disease. Management of advanced CRLM should, from the start, take into account the likelihood of secondary procedures.

'Liver first' approach in the treatment of colorectal cancer with synchronous liver metastases.

BACKGROUND: In patients with synchronous colorectal liver metastases, an approach reversing the traditional therapeutic order - i.e. starting with chemotherapy first, doing the liver surgery second, and performing the colorectal surgery last - is theoretically appealing as it avoids the risk of metastatic progression during treatment of the primary tumor. The present series updates on a previously reported pilot experience. PATIENTS AND METHODS: 35 patients with advanced synchronous colorectal metastases and nonobstructive colorectal tumors were treated with the reversed approach. Data were collected in a prospective database. RESULTS: The median number of metastases was 6, the median size of the largest metastasis was 6 cm. Five patients could not complete the program (one death from sepsis during chemotherapy, 3 cases of progressive disease under treatment, and one case of vanishing liver metastases). The remaining 30 patients responded and underwent R0 liver resections with no major complications. One patient needed a Hartmann's procedure for obstruction after a first-step hepatectomy, and 1 patient had a rectal anastomotic leak. Median survival was 44 months. Overall survival rates of the 30 patients who completed the program at 1, 2, 3, 4 and 5 years were 100, 89, 60, 44 and 31%. CONCLUSIONS: The reverse approach appeared feasible and safe, with operability and survival rates better than expected for patients with similar severity. Potential problems, in particular regrowth of vanishing metastases and primary tumors, chemotherapy-associated liver damage, and large bowel obstruction, can be minimized by careful multidisciplinary selection, planning and execution.

Fascia: a pragmatic overview for surgeons.

The term "fascia" is a very frequently used notion, particularly in an anatomical, surgical, and radiological context. A closer look at the underlying concepts, however, reveals that the denomination is all but a consistent one. It is this use of one and the same term for very different entities that is one of the sources for controversial opinions on fascial structures and their applications in surgical practice. This article summarizes and illustrates examples of structures called fasciae. Considering the impossibility to give a simple, universal definition, we conclude that a precise description and iconographic documentation of the structure under consideration remain mandatory. They should replace the presumably unequivocal, but in fact often nebulous, notion "fascia" in surgical, radiological, and anatomical articles.

Liver transplantation for Budd-Chiari syndrome: A European study on 248 patients from 51 centres.

BACKGROUND/AIMS: The results of liver transplantation for Budd-Chiari syndrome (BCS) are poorly known and the role and timing of the procedure are still controversial. The aim of this study was to investigate the results of transplantation for BCS, focusing on overall outcome, on prognostic factors and on the impact of the underlying disease. METHODS: An enquiry on 248 patients representing 84% of the patients transplanted for BCS in the European Liver Transplantation Registry between 1988 and 1999. RESULTS: Of the 248 patients, 70.4% were female and 29.6% male. The mean age was 35.7 years. The overall actuarial survival was 76% at 1 year, 71% at 5 years and 68% at 10 years. 77% of deaths occurred in the first 3 months: 47% were due to infection and multiple organ failure, and 18% to graft failure or hepatic artery thrombosis. Late mortality (>1 year) occurred in nine patients, due to BCS recurrence in four of them. The only pre-transplant predictors of mortality on multivariate analysis (Cox) were impaired renal function and a history of a shunt. CONCLUSIONS: Liver transplantation for BCS is an effective treatment, irrespective of the underlying cause, and should be considered before renal failure occurs.

Impairment of renal function after islet transplant alone or islet-after-kidney transplantation using a sirolimus/tacrolimus-based immunosuppressive regimen.

The immunosuppressive (IS) regimen based on sirolimus/low-dose tacrolimus is considered a major determinant of success of the Edmonton protocol. This regimen is generally considered safe or even protective for the kidney. Herein, we analyzed the impact of the sirolimus/low-dose tacrolimus combination on kidney function. The medical charts of islet transplant recipients with at least 6 months follow up were reviewed. There were five islet-after-kidney and five islet transplantation alone patients. Serum creatinin, albuminuria, metabolic control markers and graft function were analyzed. Impairment of kidney function was observed in six of 10 patients. Neither metabolic markers nor IS drugs levels were significantly associated with the decrease of kidney function. Although a specific etiology was not identified, some subsets of patients presented a higher risk for decline of kidney function. Low creatinin clearance, albuminuria and long-established kidney graft were associated with poorer outcome.