Transarterial chemoembolization followed by moderately hypofractionated radiotherapy in hepatocellular carcinoma: Long-term results of RTF3 regimen.

PURPOSE: In early-stage hepatocellular carcinoma (HCC) patients merely fit for surgery, transarterial chemoembolization (TACE) achieve low long-term disease control. We evaluated the efficacy and safety of its combination with moderately hypofractionated radiotherapy (hRT) using RTF3 regimen. MATERIAL AND METHODS: Between 2006 and 2016, 61 consecutive patients treated in our single expert center for a Barcelona Clinic Liver Cancer (BCLC) A HCC by TACE followed by hRT 3Gy/fraction were retrospectively included. RESULTS: Sixty of the 61 included presented Child-Pugh A cirrhosis (A5, n=41, 67.2%; A6: n=19, 31.1%). Fourteen patients (22.9%) were already treated for a HCC, mainly by radiofrequency (n=12). All patient received a TACE followed by 3Gy per fraction hRT. Mean radiation dose was 54Gy (range: 48-60). After a median follow-up of 118 months, median time-to-progression, progression-free survival (PFS) and overall survival (OS) was 21.3, 18.1, and 31.5 months, respectively. In univariate analysis, PFS was related to dose > 54Gy (HR: 2, P=0.036), and OS was correlated to Child-Pugh A6 or B7 (HR: 1.93, P=0.03) and overall hRT time (HR: 1.06, P=0.015). At progression, orthotopic liver transplantation was performed in 8 patients (13.1%). Severe symptomatic adverse events occurred in 12 patients (19.7%), mainly ascites (n=7). CONCLUSION: In BCLC-A Child-Pugh A HCC patients ineligible to surgery or thermoablation, TACE-hRT is a safe and effective treatment. Prospective studies are needed to compare this association with radioembolization, TACE-stereotactic radiotherapy, and systemic treatments combinations.

[Radiation therapy of hepatic haemangiomas: Review from a case report]. / Radiothérapie externe des angiomes hépatiques : revue de la littérature, à partir d'un cas.

Haemangioma is the most frequent benign hepatic tumour. Haemangioma is generally asymptomatic but it can sometimes cause disabling symptoms depending on its size and location. Surgery and interventional radiology are the cornerstone of the treatment in this situation. Radiation therapy, already used with good efficacy and safety to treat hepatic malignant lesions as hepatocarcinoma and metastases, is a relevant option in case of contraindication to surgery because of multiple or very large lesions. In this context, we report the case of a patient presenting with multiple symptomatic hepatic haemangiomas, successfully treated by radiation therapy in our department. These good results justified a review of the literature to report series of patients treated in this indication and to describe the main treatment regimens used.

Xanthogranulomatous cholecystitis: Diagnosis and management.

Xanthogranulomatous cholecystitis (XGC) is a rare form of cholecystitis, characterized by the presence of xanthogranuloma, prominent yellow structures within the gallbladder wall that is very often lithiasic. When XGC presents in its pseudo-tumoral form with occasional adjacent organ involvement, it can mimic gallbladder carcinoma (GBC). The etiopathogenesis of XGC is inflammatory destruction of Rokitansky-Aschoff sinuses containing biliary and cholesterol pigments within the gallbladder wall; this leads to a florid granulomatous histiocytic inflammatory reaction. The prevalence ranges from 1.3% to 8.8% of all cholecystectomies and varies from country to country; XGC occurs predominantly in patients over 50 years of age, and is equally distributed between males and females. Its association with GBC remains a topic of debate in the literature (between 0 and 20%). Symptoms are non-specific and generally similar to those of acute or chronic cholecystitis. XGC, when associated with altered health status, leads to the suspicion of GBC. XGC can also come to light due to an acute complication of cholecystolithiasis, in particular, gallstone migration. Imaging by sonography and CT scan is suggestive, but magnetic resonance imaging is more specific. In difficult cases, biopsy may be necessary to eliminate the diagnosis of tumor. In case of pre- or intra-operative diagnostic doubt, the opinion of a hepatobiliary specialty center can be of help. When diagnosis of GBC has been eliminated, laparoscopic cholecystectomy is recommended, although with a high risk of conversion to laparotomy and complications.

Defining the Contribution of CYP1A1 and CYP1A2 to Drug Metabolism Using Humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 Knockout Mice.

Cytochrome P450s CYP1A1 and CYP1A2 can metabolize a broad range of foreign compounds and drugs. However, these enzymes have significantly overlapping substrate specificities. To establish their relative contribution to drug metabolism in vivo, we used a combination of mice humanized for CYP1A1 and CYP1A2 together with mice nulled at the Cyp1a1 and Cyp1a2 gene loci. CYP1A2 was constitutively expressed in the liver, and both proteins were highly inducible by 2,3,7,8-tetrachlorodibenzodioxin (TCDD) in a number of tissues, including the liver, lung, kidney, and small intestine. Using the differential inhibition of the human enzymes by quinidine, we developed a method to distinguish the relative contribution of CYP1A1 or CYP1A2 in the metabolism of drugs and foreign compounds. Both enzymes made a significant contribution to the hepatic metabolism of the probe compounds 7-methoxy and 7-ehthoxyresorufin in microsomal fractions from animals treated with TCDD. This enzyme kinetic approach allows modeling of the CYP1A1, CYP1A2, and non-CYP1A contribution to the metabolism of any substrate at any substrate, inhibitor, or enzyme concentration and, as a consequence, can be integrated into a physiologically based pharmacokinetics model. The validity of the model can then be tested in humanized mice in vivo. SIGNIFICANCE STATEMENT: Human CYP1A1 and CYP1A2 are important in defining the efficacy and toxicity/carcinogenicity of drugs and foreign compounds. In light of differences in substrate specificity and sensitivity to inhibitors, it is of central importance to understand their relative role in foreign compound metabolism. To address this issue, we have generated mice humanized or nulled at the Cyp1a gene locus and, through the use of these mouse lines and selective inhibitors, developed an enzyme kinetic-based model to enable more accurate prediction of the fate of new chemicals in humans and which can be validated in vivo using mice humanized for cytochrome P450-mediated metabolism.

An Extensively Humanized Mouse Model to Predict Pathways of Drug Disposition and Drug/Drug Interactions, and to Facilitate Design of Clinical Trials.

Species differences in drug metabolism and disposition can confound the extrapolation of in vivo PK data to man and also profoundly compromise drug efficacy studies owing to differences in pharmacokinetics, in metabolites produced (which are often pharmacologically active), and in differential activation of the transcription factors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), which regulate the expression of such enzymes as P450s and drug transporters. These differences have gained additional importance as a consequence of the use of genetically modified mouse models for drug-efficacy testing and also patient-derived xenografts to predict individual patient responses to anticancer drugs. A number of humanized mouse models for cytochrome P450s, CAR, and PXR have been reported. However, the utility of these models has been compromised by the redundancy in P450 reactions across gene families, whereby the remaining murine P450s can metabolize the compounds being tested. To remove this confounding factor and create a mouse model that more closely reflects human pathways of drug disposition, we substituted 33 murine P450s from the major gene families involved in drug disposition, together with Car and Pxr, for human CAR, PXR, CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4, and CYP3A7. We also created a mouse line in which 34 P450s were deleted from the mouse genome. Using model compounds and anticancer drugs, we demonstrated how these mouse lines can be applied to predict drug-drug interactions in patients and discuss here their potential application in the more informed design of clinical trials and the personalized treatment of cancer.

Low-Phospholipid Associated Cholelithiasis (LPAC) syndrome: A synthetic review.

Low-Phospholipid Associated Cholelithiasis (LPAC) is a genetic disease responsible for the development of intrahepatic lithiasis. It is associated with a mutation of the ABCB4 gene which codes for protein MDR3, a biliary carrier. As a nosological entity, it is defined by presence of two of the three following criteria: age less than 40 years at onset of biliary symptoms, recurrence of biliary symptoms after cholecystectomy, and intrahepatic hyperechogenic foci detected by ultrasound. While the majority of clinical forms are simple, there also exist complicated forms, involving extended intrahepatic lithiasis and its consequences: lithiasis migration, acute cholangitis, intrahepatic abscess. Chronic evolution can lead to secondary sclerosing cholangitis or secondary biliary cirrhosis. In unusual cases, degeneration into cholangiocarcinoma may occur. Treatment is built around ursodeoxycholic acid, which yields dissolution of biliary calculi. Complicated forms may call for interventional, radiological, endoscopic or surgical treatment. This synthetic review illustrates and summarizes the different aspects of this entity, from simple gallbladder lithiasis to cholangiocarcinoma, as well as secondary biliary cirrhosis requiring liver transplant, on the basis of clinical cases and the iconography of patients treated in our ward.

Gallbladder adenomyomatosis: Diagnosis and management.

Gallbladder (GB) adenomyomatosis (ADM) is a benign, acquired anomaly, characterized by hypertrophy of the mucosal epithelium that invaginates into the interstices of a thickened muscularis forming so-called Rokitansky-Aschoff sinuses. There are three forms of ADM: segmental, fundal and more rarely, diffuse. Etiology and pathogenesis are not well understood but chronic inflammation of the GB is a necessary precursor. Prevalence of ADM in cholecystectomy specimens is estimated between 1% and 9% with a balanced sex ratio; the incidence increases after the age of 50. ADM, although usually asymptomatic, can manifest as abdominal pain or hepatic colic, even in the absence of associated gallstones (50% to 90% of cases). ADM can also be revealed by an attack of acalculous cholecystitis. Pre-operative diagnosis is based mainly on ultrasound (US), which identifies intra-parietal pseudo-cystic images and "comet tail" artifacts. MRI with MRI cholangiography sequences is the reference examination with characteristic "pearl necklace" images. Symptomatic ADM is an indication for cholecystectomy, which results in complete disappearance of symptoms. Asymptomatic ADM is not an indication for surgery, but the radiological diagnosis must be beyond any doubt. If there is any diagnostic doubt about the possibility of GB cancer, a cholecystectomy is justified. The discovery of ADM in a cholecystectomy specimen does not require special surveillance.

Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis.

Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared with tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.

Shear wave elastography: An accurate technique to stage liver fibrosis in chronic liver diseases.

OBJECTIVES: The goals of this study were to assess the diagnostic accuracy of shear wave elastography (SWE) using the results of histopathological analysis as a standard of reference and compare the results of SWE and those of transient elastography (TE) to the degree of fibrosis as evaluated by histomorphometry. PATIENTS AND METHODS: Adult patients who were scheduled to undergo liver biopsy were prospectively enrolled in the study. The diagnostic performances of SWE were assessed using AUROC curve analysis according to fibrosis thresholds defined by ≥F2 (significant fibrosis), ≥F3 (advanced fibrosis) and F4 (cirrhosis). Additional analyses using the Obuchowski measures for pairwise comparisons of fibrosis stages were performed. In a subgroup of 55 patients, the relationships between stiffness as measured using SWE and TE and the percentage of fibrosis were compared using Spearman's rank coefficient. RESULTS: Among the initially enrolled 170 patients, 148/170 (87%) had successful SWE acquisition and formed the study population. SWE sensitivity and specificity were respectively 85.1% and 82.7% (≥F2), 88.9% and 90.3% (≥F3), 93.3% and 98.3% (F4). The AUROC curves of SWE along with their 95% confidence intervals (CI) were respectively 0.904 (95%CI: 0.845-0.946) for fibrosis ≥F2; 0.958 (95%CI: 0.912-0.984) for fibrosis ≥F3 and 0.988 (95%CI: 0.955-0.999) for fibrosis=F4. The global Obuchowski measure was 0.953±0.007. In the subgroup study, a significant correlation was found between the percentage of fibrosis and stiffness as assessed by SWE (r=0.77; 95%CI: 0.63-0.86; P<0.0001) and by TE (r=0.65; 95%CI: 0.47-0.78; P<0.01). CONCLUSION: SWE is accurate to assess liver fibrosis in patients with chronic liver disease.

Surgical Management of Large Spontaneous Portosystemic Splenorenal Shunts During Liver Transplantation: Splenectomy or Left Renal Vein Ligation?

OBJECTIVE: Management of splenorenal shunt (SRS) during whole liver transplantation is still controversial. Splenectomy (SP) permits its radical removal, at the price of a specific related morbidity. Left renal vein ligation (LRVL) performs a downstream ligation with potential renal repercussions. This study aimed to compare these techniques regarding portal revascularization and postoperative outcomes. METHODS: From 1994 to 2012, 22 SPs and 7 LRVLs were performed for large SRS (>1 cm) management. RESULTS: There was no difference in operating times or transfusion rates. In both groups, efficient portal flow was initially obtained in all cases. After a median follow-up of 79 months, 2 patients in the SP group presented an altered portal flow owing to persistence of a not disconnected mesentericogonadic or splenorenal shunt. Postoperative morbidity, including infection and portal vein thrombosis, was not significantly different (32% vs 14%). SP allowed a faster correction of the thrombocytopenia. The LRVL group had a moderate and temporary impairment of renal function. CONCLUSIONS: SP and LRVL represent 2 effective procedures to avoid vascular steal in the presence of SRS, but they require a patent portal vein. SP appears to be associated to specific but acceptable intraoperative morbidity, permits treatment of associated splenic artery aneurysm, and enables a faster correction of thrombocytopenia. However, the presence of a remote hilum SRS or another large portosystemic shunt represents a cause of failure of the procedure. LRVL is a safer and less demanding procedure that can suppress portal steal whatever the location of the SRS, but at the price of moderate renal morbidity.

Grading of small hepatocellular carcinomas (≤2 cm): correlation between histology, T2 and diffusion-weighted imaging.

OBJECTIVE: To evaluate the capacity of diffusion-weighted imaging (DWI) to determine the histological grade of small-sized hepatocellular carcinomas (HCCs) in liver cirrhosis in comparison with T2 weighted imaging. METHODS: 51 cirrhotic patients with 63 histologically proven HCCs ≤2 cm underwent abdominal MRI, including DWI (b-values 50, 400 and 800 s mm(-2)) and T2 weighted sequences. HCCs were classified into well-differentiated HCCs (n = 37) and moderately differentiated HCCs (n = 26). Relative contrast ratios (RCRs) between the lesions and the surrounding liver were performed and compared between the two groups for T2 weighted images, each b-value and apparent diffusion coefficients (ADCs). A receiver operating characteristic (ROC) analysis was performed to compare RCRs in T2 and diffusion-weighted images. RESULTS: We found significant differences in RCRs between well-differentiated vs moderately differentiated HCCs for b = 50, 400 and 800 s mm(-2) and T2 weighted images (1.35 ± 0.36 vs 1.86 ± 0.62; 1.35 ± 0.38 vs 1.82 ± 0.60; 1.27 ± 0.30 vs 1.74 ± 0.53; 1.14 ± 0.18 vs 1.43 ± 0.28, respectively; p < 0.001), whereas no significant differences were observed in ADC and ADC RCR (1.05 ± 0.19 vs 0.99 ± 0.15 and 1.1 ± 0.22 vs 1.09 ± 0.23; p = 0.16 and p = 0.82, respectively). No significant difference was found in the areas under the ROC curve for RCRs of T2 weighted images and every DWI b-value (p = 0.18). CONCLUSION: The RCR measurement performed in DWI 50, 400 and 800 b-values and T2 demonstrated a significant difference between well-differentiated and moderately differentiated small-sized HCCs. Furthermore, no difference was shown by using either ADC or ADC RCR. ADVANCES IN KNOWLEDGE: DWI with RCR measurement may be a valuable tool for non-invasively predicting the histological grade of small HCCs.

Management of bleeding liver tumors.

Liver tumors bleed rarely; management has changed radically during the last 20years, advancing from emergency surgery with poor results to multidisciplinary management. The first steps are the diagnosis and control of bleeding. Abdominopelvic CT scan should be performed as soon as patient hemodynamics allow. When active bleeding is visualized, arterial embolization, targeted as selectively as possible, is preferable to surgery, which should be reserved for severe hemodynamic instability or failure of interventional radiology. When surgery is unavoidable, abbreviated laparotomy (damage control) with perihepatic packing is recommended. The second step is determination of the etiology and treatment of the underlying tumor. Adenoma and hepatocellular carcinoma (HCC) are the two most frequently encountered tumors in this context. Liver MRI after control of the bleeding episode generally leads to the diagnosis although sometimes the analysis can be difficult because of the hematoma. Prompt resection is indicated for HCC, atypical adenoma or lesions at risk for degeneration to hepatocellular carcinoma. For adenoma with no suspicion of malignancy, it is best to wait for the hematoma to resorb completely before undertaking appropriate therapy.

Segment I intrahepatic biliary cystadenocarcinoma impinging on the hepatic vein.

BACKGROUND: Biliary cystadenoma is a rare cystic tumor; prognosis is dependent on the completeness of the surgical resection. CASE REPORT: The case of a 65-year-old woman with a multilocular cystic hepatic tumor is reported. Radiological and laboratory findings suggested the diagnosis of cystadenoma with localized malignant degeneration. RESULTS: A surgical resection of hepatic Segment I was performed, requiring total vascular exclusion (TVE) of the liver and a needle aspiration of a non-degenerated cyst to permit total resection. CONCLUSIONS: TVE and decompression of a cyst presumed to be benign may be warranted to achieve a safe and complete resection of biliary cystadenoma.

Superinfection of focal liver lesions after bile duct procedures.

OBJECTIVES: Pyogenic liver abscess is a rare condition in the general population. The source of infection is most often biliary, and more rarely gastrointestinal via the portal tract, or even hematogenic. Other than in special contexts (scarring after radiofrequency ablation), focal liver lesions are not a usual risk factor for hepatic abscesses in patients with a history of bile duct procedures (sphincterotomy, biliary stenting, biliary enteric anastomosis). MATERIALS AND METHOD - RESULTS: We report four cases of focal liver lesions (two patients with benign lesions of the biliary cyst type and two other patients with lesions due to pancreatic cancer) complicated by a superinfection in patients with a history of bile duct procedures. There were no predisposing factors other than a context of cancer or diabetes. CONCLUSION: Superinfection of a focal liver lesion should be considered when there is a suggestive clinical picture and a change in the appearance of the lesion in patients with a history of bile duct procedures in a context of cancer or diabetes.

Transthoracic approach for liver tumors.

Abdominal approach is commonly used for resection of liver tumors. However, in rare cases, transthoracic approach may be a valuable option for management of lesions located in the hepatic dome or involving the cavo-hepatic junction for very selected patients. This approach can be an open procedure (thoracotomomy), a video-assisted minimally invasive technique (thoracoscopy), or a strictly percutaneously treatment (CT-guided radiofrequency ablation). This approach seems useful for high-risk patients, with previous major abdominal surgery, or awaiting for liver transplantation (bridge concept) with cranially located single lesions. A limited liver resection (tumorectomy or segmentectomy) can be performed, but this approach is also suitable for percutaneous ablation therapy (radiofrequency or cryotherapy), with an acceptable morbidity.

Management of postoperative chylothorax.

Chylothorax is a rare but severe complication of thoracic and esophageal surgery. The anatomical relations of the thoracic duct and its highly variable anatomy may explain the occurrence of thoracic duct injury during dissection of the posterior mediastinum. At an early stage, chylothorax can lead to severe cardiorespiratory and volemic complications. In case of chronicization, malnutrition and immunologic complications can occur, responsible for a mortality rate of up to 50%. Optimal management of chylothorax can decrease mortality. It is based on three options: conservative treatment, surgery and radiological treatment. Conservative treatment must be initiated at diagnosis and results in resolution of the chylothorax is achieved in 50 to 70% of cases. In case of either high flow rate chylothorax or failure of conservative treatment, reoperation is indicated. Percutaneous embolization is an interesting and minimally invasive alternative to surgery.

[Radiological diagnosis of hepatocellular carcinoma in 2010]. / Diagnostic radiologique du carcinome hépatocellulaire sur foie de cirrhose en 2010.

The aim of diagnosis imaging is to detect hepatocellular carcinoma at an early stage, when a curative treatment is available. Biopsy is no longer required prior to treatment, and diagnosis of hepatocellular carcinoma is heavily dependent of imaging characteristics. Therefore, the purpose of this article is to describe the typical features of small (<20mm) and larger hepatocellular carcinomas with noninvasive diagnostic criteria, including ultrasound, computed tomography and MRI. Advances in these imaging modalities have greatly improved the detection of small hepatic nodules on liver cirrhosis, including the different steps of carcinogenesis, from regenerative to dysplastic nodules, and we emphasize the difficulties of radiological differentiation of precancerous lesions and small hepatocellular carcinomas.