The genomic landscape of response to EGFR blockade in colorectal cancer.

Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.

Cooperative Role of Thrombopoietin and Vascular Endothelial Growth Factor-A in the Progression of Liver Cirrhosis to Hepatocellular Carcinoma.

Primary thrombopoietic mediator thrombopoietin (THPO) is mainly produced by the liver; it may act as a growth factor for hepatic progenitors. Principal angiogenesis inducer vascular endothelial growth factor-A (VEGF-A) is critical for the complex vascular network within the liver architecture. As a cross-regulatory loop between THPO and VEGF-A has been demonstrated in the hematopoietic system, the two growth factors were hypothesized to cooperatively contribute to the progression from liver cirrhosis (LC) to hepatocellular carcinoma (HCC). The mRNA and protein expression levels of THPO, VEGF-A, and their receptors were examined, compared, and correlated in paired cancerous and LC tissues from 26 cirrhosis-related HCC patients, using qRT-PCR and immunohistochemistry. THPO and VEGF-A were alternatively silenced by small interfering RNA (siRNA) in human liver cancer cell lines Huh7 and HepG2. THPO and VEGF-A expressions significantly increased in tumor versus LC tissues. HCC and paired LC cells expressed similar levels of THPO receptor (R), whereas vascular endothelial growth factor receptor (VEGFR) -1 and VEGFR-2 levels were higher in HCC than in corresponding LC tissue samples. A significant linear correlation emerged between THPO and VEGF-A transcripts in HCC and, at the protein level, THPO and THPOR were significantly correlated with VEGF-A in tumor tissues. Both HCC and LC expressed similar levels of gene and protein hypoxia inducible factor (HIF)-1α. Positive cross-regulation occurred with the alternative administration of siRNAs targeting THPO and those targeting VEGF-A in hypoxic liver cancer cell lines. These results suggest THPO and VEGF-A might act as interdependently regulated autocrine and/or paracrine systems for cellular growth in HCC. This might be clinically interesting, since new classes of THPOR agonistic/antagonistic drugs may provide novel therapeutic options to correct the frequent hemostatic abnormality seen in HCC patients.

Liver Transplantation for Hepatocellular Carcinoma in the Era of Immune Checkpoint Inhibitors.

Hepatocellular carcinoma (HCC) remains the leading oncological indication for liver transplantation (LT), with evolving and broadened inclusion criteria. Immune checkpoint inhibitors (ICIs) gained a central role in systemic HCC treatment and showed potential in the peri-transplant setting as downstaging/bridging therapy before LT or as a treatment for HCC recurrence following LT. However, the antagonistic mechanisms of action between ICIs and immunosuppressive drugs pose significant challenges, particularly regarding the risk of acute rejection (AR). This review analyzes the main signaling pathways targeted by ICI therapies and summarizes current studies on ICI therapy before and after LT. The literature on this topic is limited and highly heterogeneous, precluding definitive evidence-based conclusions. The use of ICIs before LT appears promising, provided that a sufficient wash-out period is implemented. In contrast, the results of post-LT ICI therapy do not support its wide clinical application due to high AR rates and overall poor response to treatment. In the future, modern graft preservation techniques might support the selection of good ICI responders, but data from high-level studies are urgently needed.

The value of a combined radiological-surgical approach in allowing curative resection of a locally advanced type IIIa Klatskin tumor.

We report the case of a 53-year-old patient subjected to percutaneous embolization of right and middle hepatic veins to induce liver segments 2-3 hypertrophy before extended right hepatic resection for a locally advanced type IIIa perihilar cholangiocarcinoma. Hepatic vein embolization (HVE) was performed 3 weeks after surgical recanalization of left portal vein (severely narrowed at its origin due to tumor infiltration) interposing an internal jugular vein graft between main and distal left portal vein. Nine days after HVE, future liver remnant volume increased from 395 to 501 cc, i.e. 25.1% of standardized total liver volume, allowing to perform a radical right hepatic trisectionectomy plus caudatectomy. He was discharged home on postoperative day 15th after an uneventful postoperative course, with no sign of posthepatectomy liver failure.

Post-surgical recurrence of hepatocellular carcinoma along resection margin treated by percutaneous US-guided ablation.

BACKGROUND: The aim of this study was to evaluate the safety and efficacy of percutaneous ablation for hepatocellular carcinoma (HCC) hepatic recurrence along surgical resection margins to achieve complete cure or bridge for additional treatment. No current recommendations exist for these lesions. METHODS: Retrospective review of post-surgical recurrent HCC located along surgical margins treated by percutaneous ultrasound-guided ablation from 2006-2014. Ablation was performed by radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI), selected for recurrence in proximity to extrahepatic organs. RESULTS: In total, nine patients (49-82 y, mean 73.8±8.3) were treated for 13 recurrent HCC nodules (9-35 mm, mean 21.5±8.1) located along resection margins by RFA (11 nodules) and PEI (2 nodules). Mean time between surgery and percutaneous ablation was 64 months (range 10-149). At a mean follow-up of 17 months (±9), complete ablation was achieved in 9 nodules (69.2%, 8 after RF, 1 after PEI) and partial ablation was achieved in 4 nodules (3 after RFA, 1 after PEI). Complications were limited to minor abdominal pain in 2 patients requiring medical therapy (15.3%). Of the 4 partially ablated nodules, subsequent therapy achieved complete response in 3 nodules (1 patient with TACE, 1 patient with stereotactic radiotherapy, and one with liver transplantation), while the last nodule progressed despite subsequent TACE. CONCLUSIONS: HCC recurrence along the surgical margin can be safely and effectively treated by percutaneous therapy, despite the misconception of the surgical margin as a hostile location. Percutaneous treatment may bridge the patient for additional therapy.

[Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHCC): a double cancer in the non-cirrhotic liver]. / Carcinoma epatocellulare (HCC) e colangiocarcinoma intraepatico (IHCC): doppio tumore su fegato non cirrotico. Presentazione di un caso.

The authors report a case of a large tumour, located in the right hepatic lateral segments, (size: 15 cm), consisting of a hepatocellular carcinoma (size: 10 cm) and an intrahepatic cholangiocarcinoma (size: 5 cm). The mass was detected by ultrasonography during an examination for abdominal pain in an 80-year-old female. After tumour biopsy and histological examination, hepatic resection was performed. The postoperative course was uneventful and the patient was discharged 6 days after surgery. The rarity of this double cancer is stressed.

Liver transplantation for "mass-forming" sclerosing cholangitis after laparoscopic cholecystectomy.

INTRODUCTION: Chronic biliary obstruction consequence of a bile duct injury may require liver transplantation (LT) in case of secondary biliary cirrhosis, intractable pruritus or reiterate episodes of cholangitis. "Mass-forming" sclerosing cholangitis leading to secondary portal vein thrombosis and pre-sinusoidal portal hypertension has not been reported so far. PRESENTATION OF CASE: We present the case of a patient who underwent laparoscopic cholecystectomy for Mirizzi syndrome. The persistent bile duct obstruction due to a residual gallstone fragment was treated by a prolonged biliary stenting. Following repeated bouts of cholangitis, a fibrous centrohepatic scar developed, conglobating and obstructing the main branches of the portal vein and of the biliary tree. The patient developed secondary portal vein thrombosis and portal hypertension. After an extensive diagnostic work-up, including surgical exploration to rule out malignancy, the case was successfully managed by liver transplantation. DISCUSSION: Mass-forming sclerosis of the bile duct and biliary bifurcation may develop as a consequence of chronic biliary obstruction and prolonged stenting. Secondary portal vein thrombosis and pre-sinusoidal portal hypertension represents an unusual complication, mimicking Klatskin tumor. CONCLUSION: A timely and proper management of post-cholecystectomy complications is of mainstay importance. Early referral to a specialized hepato-biliary center is strongly advised.

Liver transplantation for symptomatic centrohepatic biliary cystadenoma.

Biliary cystadenoma is a rare benign cystic tumor of the liver. The mainstay of treatment is complete resection, either by enucleation or by formal hepatectomy, since incomplete removal entails not only constant recurrence but also the risk of malignant transformation to cystadenocarcinoma. A case of symptomatic centrohepatic biliary cystadenoma involving the main vasculobiliary structures of the liver is reported. After an unsuccessful attempt at resection resulting in an intrahepatic biliary injury, relief of jaundice and radical excision were achieved by total hepatectomy and liver transplantation. The patient is now alive and well 4 years after transplant, disease-free, with normal liver and renal function while receiving everolimus monotherapy. This is the first report of liver transplantation performed for the treatment of this tumor. With the case on the background, diagnostic aspects and available therapeutic strategies for biliary cystadenoma are reviewed and discussed.

Genetic and expression analysis of MET, MACC1, and HGF in metastatic colorectal cancer: response to met inhibition in patient xenografts and pathologic correlations.

PURPOSE: We determined the gene copy numbers for MET, for its transcriptional activator MACC1 and for its ligand hepatocyte growth factor (HGF) in liver metastases from colorectal carcinoma (mCRC). We correlated copy numbers with mRNA levels and explored whether gain and/or overexpression of MET and MACC1 predict response to anti-Met therapies. Finally, we assessed whether their genomic or transcriptional deregulation correlates with pathologic and molecular parameters of aggressive disease. EXPERIMENTAL DESIGN: One hundred three mCRCs were analyzed. Copy numbers and mRNA were determined by quantitative PCR (qPCR). Thirty nine samples were implanted and expanded in NOD (nonobese diabetic)/SCID (severe combined immunodeficient) mice to generate cohorts that were treated with the Met inhibitor JNJ-38877605. In silico analysis of MACC1 targets relied on genome-wide mapping of promoter regions and on expression data from two CRC datasets. RESULTS: No focal, high-grade amplifications of MET, MACC1, or HGF were detected. Chromosome 7 polysomy and gain of the p-arm were observed in 21% and 8% of cases, respectively, and significantly correlated with higher expression of both Met and MACC1. Met inhibition in patient-derived xenografts did not modify tumor growth. Copy number gain and overexpression of MACC1 correlated with unfavorable pathologic features better than overexpression of Met. Bioinformatic analysis of putative MACC1 targets identified elements besides Met, whose overexpression cosegregated with aggressive forms of colorectal cancer. CONCLUSIONS: Experiments in patient-derived xenografts suggest that mCRCs do not rely on Met genomic gain and/or overexpression for growth. On the basis of pathologic correlations and bioinformatic analysis, MACC1 could contribute to CRC progression through mechanisms other than or additional to Met transcriptional upregulation.

Intraoperative placement of transparietohepatic biliary drainage in remedial hepaticojejunostomy: technique and clinical experience.

Remedial biliary surgery most often entails a Roux-en-Y hepaticojejunostomy. Sometimes the duct wall at the porta hepatis has been so damaged by inflammatory changes that the postoperative external drainage of bile away from a biliodigestive suture at risk of dehiscence is advisable. A technique of intraoperative placement of transparietohepatic biliary drainage was devised. The maneuver implies retrograde cannulation of a major intrahepatic duct with a vascular irrigation needle that is pushed to create the transhepatic path. Of 220 remedial hepaticojejunostomies performed in 211 patients (including 151 liver transplant recipients), the technique was applied in 49 (22%) of the most difficult cases in which the preoperative radiologic approach to the biliary tree had failed, was unsafe, or was unfeasible. The only major complication was a parenchymal tear needing perihepatic packing when the maneuver was performed too early after liver transplantation. Postoperative biliary fistula occurred in 2 patients (4%) and access to the biliary tract for percutaneous bilioplasty was provided in the short-term follow-up evaluation of 14 patients (29%).

Severe course of primary hyperoxaluria and renal failure after domino hepatic transplantation.

We report herein a domino orthotopic liver transplantation (LT), from a 38-year-old woman undergoing liver-kidney transplantation (LKT) for primary hyperoxaluria type I (PH1) to a recipient with cirrhosis and hepatocellular carcinoma. Delayed onset of PH1 and renal failure and 10% residual alanine-glyoxylate aminotransferase (AGT) activity in domino liver justified its use for domino procedure. The clinical course after LKT was similar to that described in other series, including ours. Renal function started promptly and maintained despite sustained hyperoxaluria from dissolution of oxalotic deposits. Conversely, the domino recipient manifested severe hyperoxaluria and developed nephrolithiasis and renal insufficiency with rapid progression over 2 months. A new LT resulted in slow decrease of oxaluria and improvement of renal function. Therefore, PH1 behaved quite differently in these two patients, leading us to conclude that domino LT using livers from PH1 patients should be considered very carefully, only as a bridge to definitive LT in recipients with critical clinical conditions.