Hepatospecific MR contrast agent uptake on hepatobiliary phase can be used as a biomarker of marked ß-catenin activation in hepatocellular adenoma.

OBJECTIVES: To assess the value of hepatospecific MR contrast agent uptake on hepatobiliary phase (HBP) images to detect marked activation of the ß-catenin pathway in hepatocellular adenomas (HCAs). METHODS: This multicentric retrospective IRB-approved study included all patients with a pathologically proven HCA who underwent gadobenate dimeglumine-enhanced liver MRI with HBP. Tumor signal intensity on HBP was first assessed visually, and lesions were classified into three distinct groups-hypointense, isointense, or hyperintense-according to the relative signal intensity to liver. Uptake was then quantified using the lesion-to-liver contrast enhancement ratio (LLCER). Finally, the accuracy of HBP analysis in depicting marked ß-catenin activation in HCA was evaluated. RESULTS: A total of 124 HCAs were analyzed including 12 with marked ß-catenin activation (HCA B+). Visual analysis classified 94/124 (76%), 12/124 (10%), and 18/124 (14%) HCAs as being hypointense, isointense, and hyperintense on HBP, respectively. Of these, 1/94 (1%), 3/12 (25%), and 8/18 (44%) were HCA B+, respectively (p < 0.001). The LLCER of HCA B+ was higher than that of HCA without marked ß-catenin activation in the entire cohort (means 4.9 ± 11.8% vs. - 19.8 ± 11.4%, respectively, p < 0.001). A positive LLCER, i.e., LLCER ≥ 0%, had 75% (95% CI 43-95%) sensitivity and 97% (95% CI 92-99%) specificity, with a LR+ of 28 (95% CI 8.8-89.6) for the diagnosis of HCA B+. CONCLUSIONS: Hepatospecific contrast uptake on hepatobiliary phase is strongly associated with marked activation of the ß-catenin pathway in hepatocellular adenoma, and its use might improve hepatocellular adenoma subtyping on MRI. KEY POINTS: • Tumor uptake on hepatobiliary phase in both the visual and quantitative analyses had a specificity higher than 90% for the detection of marked ß-catenin activation in hepatocellular adenoma. • However, the sensitivity of visual analysis alone is inferior to that of LLCER quantification on HBP due to the high number of HCAs with signal hyperintensity on HBP, especially those developed on underlying liver steatosis.

Relevance of liver surface nodularity for preoperative risk assessment in patients with resectable hepatocellular carcinoma.

BACKGROUND: Quantification of liver surface nodularity (LSN) on routine preoperative CT images allows detection of cirrhosis and clinically significant portal hypertension. This study aimed to assess the relevance of LSN in preoperative assessment of operative risks for patients with resectable hepatocellular carcinoma (HCC). METHODS: All patients undergoing hepatectomy for HCC between 2012 and 2017 were analysed retrospectively. LSN was assessed at the liver-fat interface on the left liver lobe on preoperative CT images. The feasibility of LSN quantification was assessed. The association between LSN and outcomes (severe complications and posthepatectomy liver failure (PHLF)) was evaluated by multivariable analysis and after propensity score matching. RESULTS: Among 210 patients, LSN measurement was successful in 187 (89·0 per cent). Among these, the median LSN score was 2·42 (i.q.r. 2·21-2·66) and 52·9 per cent had severe fibrosis, including 33·7 per cent with cirrhosis. LSN score increased with hepatic venous pressure gradient (P = 0·048), severity of steatosis (P = 0·011) and fibrosis grade (P = 0·001). LSN score was independently associated with severe complications (odds ratio (OR) 5·25; P = 0·006) and PHLF (OR 6·78; P = 0·003). After matching with respect to model for end-stage liver disease, aspartate aminotransferase-to-platelet ratio index and fibrosis-4 score, patients with a LSN score of 2·63 or higher retained an increased risk of PHLF (OR 5·81; P = 0·018). In the subgroup of patients without severe fibrosis, LSN was accurate in predicting severe complications (P = 0·005). Patients with (P = 0·039) or without (P = 0·018) severe fibrosis with increased LSN score had a higher comprehensive complication index score. Among patients with cirrhosis who had clinically significant portal hypertension, a LSN value below 2·63 ruled out the risk of PHLF. CONCLUSION: LSN measurement represents a practical tool that may allow improvement in the preoperative evaluation and management of patients with HCC.

ANTECEDENTES: La cuantificación de la nodularidad de la superficie hepática (liver surface nodularity, LSN) en las imágenes de la tomografía computarizada (TC) de rutina preoperatoria permite detectar la cirrosis y la hipertensión portal clínicamente significativa (clinically significant portal hypertension, CSPH). Este estudio tuvo como objetivo evaluar la relevancia de la LSN en la evaluación preoperatoria del riesgo quirúrgico en pacientes con carcinoma hepatocelular resecable (hepatocellular carcinoma, HCC). MÉTODOS: Todos los pacientes sometidos a hepatectomía por HCC entre 2012 y 2017 fueron analizados de forma retrospectiva. La LSN se evaluó en la interfase hígado-grasa en el lóbulo hepático izquierdo en la TC preoperatoria. Se evaluó la viabilidad de la cuantificación de la LSN. La asociación entre la LSN y los resultados (complicaciones graves e insuficiencia hepática poshepatectomía (post-hepatectomy liver failure, PHLF) se analizó en un análisis multivariable y después del método de emparejamiento por puntaje de propensión. RESULTADOS: Del total de 210 pacientes, la medición de la LSN fue exitosa en 187 (89,0%). En estos pacientes, la mediana de LSN fue de 2,42 (rango intercuartílico 2,21-2,66) y el 53,0% tenía fibrosis severa, incluyendo un 33,7% con cirrosis. La LSN aumentó con el gradiente de presión venosa hepática (P = 0,048), la gravedad de la esteatosis (P = 0,011) y el grado de fibrosis (P = 0,001). La LSN se asoció de forma independiente con complicaciones graves (razón de oportunidades, odds ratio, OR = 5,25; P = 0,006) y PHLF (OR = 6,78; P = 0,003). Después de emparejar para el modelo de enfermedad hepática terminal, el índice de relación aspartato amino transferase-plaquetas y el grado de fibrosis-4, los pacientes con LSN ≥ 2,63 mantuvieron un mayor riesgo de PHLF (OR = 5,81; P = 0,018). Dentro del subgrupo de pacientes sin fibrosis severa, la LSN fue precisa en predecir complicaciones graves (P = 0,005). Los pacientes con (P = 0,039) y sin (P = 0,018) fibrosis severa con aumento de la LSN tuvieron un índice de complicación global más alto. De los pacientes cirróticos con CSPH, un valor de LSN de 2,63 descartó el riesgo de PHLF. CONCLUSIÓN: La LSN representa una herramienta práctica, que puede permitir mejorar la evaluación preoperatoria y el manejo de pacientes con HCC.

Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver.

BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. OBJECTIVE: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. METHODS: A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs-/- mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. RESULTS: The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. CONCLUSION: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti-inflammatory therapies should be considered in patients with recurrent AIP.

Comparison of transient elastography (FibroScan), FibroTest, APRI and two algorithms combining these non-invasive tests for liver fibrosis staging in HIV/HCV coinfected patients: ANRS CO13 HEPAVIH and FIBROSTIC collaboration.

OBJECTIVES: Combining noninvasive tests increases diagnostic accuracy for staging liver fibrosis in hepatitis C virus (HCV)-infected patients, but this strategy remains to be validated in HIV/HCV coinfection. We compared the performances of transient elastography (TE), Fibrotest (FT), the aspartate aminotransferase-to-platelet ratio index (APRI) and two algorithms combining TE and FT (Castera) or APRI and FT (SAFE) in HIV/HCV coinfection. METHODS: One hundred and sixteen HIV/HCV-coinfected patients (64% male; median age 44 years) enrolled in two French multicentre studies (the HEPAVIH cohort and FIBROSTIC) for whom TE, FT and APRI data were available were included in the study. Diagnostic accuracies for significant fibrosis (METAVIR F ≥ 2) and cirrhosis (F4) were evaluated by measuring the area under the receiver-operating characteristic curve (AUROC) and calculating percentages of correctly classified (CC) patients, taking liver biopsy as a reference. RESULTS: For F ≥ 2, both TE and FT (AUROC = 0.87 and 0.85, respectively) had a better diagnostic performance than APRI (AUROC = 0.71; P < 0.005). Although the percentage of CC patients was significantly higher with Castera's algorithm than with SAFE (61.2% vs. 31.9%, respectively; P < 0.0001), this percentage was lower than that for TE (80.2%; P < 0.0001) or FT (73.3%; P < 0.0001) taken separately. For F4, TE (AUROC = 0.92) had a better performance than FT (AUROC = 0.78; P = 0.005) or APRI (AUROC = 0.73; P = 0.025). Although the percentage of CC patients was significantly higher with the SAFE algorithm than with Castera's (76.7% vs. 68.1%, respectively; P < 0.050), it was still lower than that for TE (85.3%; P < 0.033). CONCLUSIONS: In HIV/HCV-coinfected patients, TE and FT have a similar diagnostic accuracy for significant fibrosis, whereas for cirrhosis TE has the best accuracy. The use of the SAFE and Castera algorithms does not seem to improve diagnostic performance.

Intracystic concentrations of tumour markers for the diagnosis of cystic liver lesions.

BACKGROUND: Imaging occasionally fails to differentiate hepatic simple cysts from malignant or premalignant mucinous cystic lesions such as biliary cystadenomas. Hepatic simple cysts can be treated conservatively, whereas malignant or premalignant cysts require complete resection. This study assessed the ability of intracystic tumour marker concentrations to differentiate these disease entities. METHODS: Intracystic fluid was sampled in patients undergoing partial or complete resection of a cystic lesion of the liver. The indication for surgery in hepatic simple cysts was symptoms or suspicion of a biliary cystadenoma. Intracystic concentrations of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9 and tumour-associated glycoprotein (TAG) 72 were measured to assess the diagnostic accuracy of these tumour markers. Cut-off values were defined by receiver operating characteristic (ROC) curves. RESULTS: The study population comprised 118 patients (94 women) with a median age of 59 years. There were 75 patients with hepatic simple cysts, 27 with mucinous cysts (19 biliary cystadenomas, 4 biliary cystadenocarcinomas, 4 intraductal papillary mucinous neoplasms of the bile duct) and 16 with miscellaneous cysts. Unlike CEA and CA19-9, a TAG-72 concentration of more than 25 units/ml differentiated hepatic simple cysts from mucinous cysts with a sensitivity and a specificity of 0·79 and 0·97 respectively. The area under the ROC curve was 0·98 for mucinous versus hepatic simple cysts. CONCLUSION: The concentration of TAG-72 in cyst fluid accurately identified hepatic cysts that required complete resection.

Surgical treatment of hepatocellular carcinoma associated with the metabolic syndrome.

BACKGROUND: The incidence of metabolic syndrome-associated hepatocellular carcinoma (MS-HCC) is increasing. However, the results following liver resection in this context have not been described in detail. METHODS: Data for all patients with metabolic syndrome as a unique risk factor for HCC who underwent liver resection between 2000 and 2011 were retrieved retrospectively from an institutional database. Pathological analysis of the underlying parenchyma included fibrosis and non-alcoholic fatty liver disease activity score. Patients were classified as having normal or abnormal underlying parenchyma. Their characteristics and outcomes were compared. RESULTS: A total of 560 resections for HCC were performed in the study interval. Sixty-two patients with metabolic syndrome, of median age 70 (range 50-84) years, underwent curative hepatectomy for HCC, including 32 major resections (52 per cent). Normal underlying parenchyma was present in 24 patients (39 per cent). The proportion of resected HCCs labelled as MS-HCC accounted for more than 15 per cent of the entire HCC population in more recent years. Mortality and major morbidity rates were 11 and 58 per cent respectively. Compared with patients with normal underlying liver, patients with abnormal liver had increased rates of mortality (0 versus 18 per cent; P = 0·026) and major complications (13 versus 42 per cent; P = 0·010). In multivariable analysis, a non-severely fibrotic yet abnormal underlying parenchyma was a risk factor for major complications (hazard ratio 5·66, 95 per cent confidence interval 1·21 to 26·52; P = 0·028). The 3-year overall and disease-free survival rates were 75 and 70 per cent respectively, and were not influenced by the underlying parenchyma. CONCLUSION: HCC in patients with metabolic syndrome is becoming more common. Liver resection is appropriate but carries a high risk, even in the absence of severe fibrosis. Favourable long-term outcomes justify refinements in the perioperative management of these patients.

Congenital portosystemic shunts associated with liver tumours.

AIM: To evaluate the diagnosis and presentation of liver tumours in patients with congenital portosystemic shunts (CPS). MATERIALS AND METHODS: Eight patients were diagnosed in Hôpital Beaujon as having CPS. All patients underwent Doppler ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and histological examination of liver tumours. CPS were classified according to anatomy and the amount of portal flow deviated to the systemic circulation as: total, subtotal, or partial. Liver tumours were diagnosed by needle core biopsy (n = 5) or surgery (n = 3). Clinical follow-up was available in all patients but one (mean follow-up 36 months; range 1-5 years). RESULTS: Six patients had total CPS, one patient had a subtotal CPS, and the last had a partial CPS. All patients presented with multiple liver nodules (range four to >15). The tumours were characterized as focal nodular hyperplasia (FNH; n = 4), FNH with hepatocellular adenoma (n = 2), and regenerative nodular hyperplasia (n = 2). In four of seven patients (57%) that had follow-up, tumours showed enlargement or new lesions appeared. CONCLUSION: In this series of CPS patients, tumours were all benign, multiple, and of hepatocellular origin, and different tumours were present simultaneously in two patients. Tumour enlargement or new nodules were common during follow-up.

Serum proteomic profiling of obese patients: correlation with liver pathology and evolution after bariatric surgery.

OBJECTIVE: Chronic liver diseases, including cirrhosis, may develop in obese patients. Steatosis and non-alcoholic steatohepatitis (NASH) are risk factors for progression to fibrosis. To date, diagnosis of steatosis and NASH relies on liver biopsy. The aim of the study was to identify serum markers of steatosis and NASH in obese patients using SELDI-TOF ProteinChip. PATIENTS: Eighty obese non-alcoholic patient candidates for bariatric surgery and devoid of hepatitis B and C infection were selected. Serum samples were collected before surgery and at 6 months after surgery for 33 of these patients. Wedge liver biopsy was performed at the time of bariatric surgery. Twenty-four serum samples from healthy blood donors served as controls. The protein profiles of each serum were assessed using SELDI-TOF ProteinChip technology and were compared according to liver histological lesions. RESULTS: Twenty-four obese patients (30%) had non-significant liver lesions, 32 (40%) had significant steatosis and 24 (30%) had NASH. Comparison of serum protein profiles according to liver lesions identified three peaks (CM10-7558.4, CM10-7924.2 and Q10-7926.9) the intensity of which significantly increased according to the severity of the liver lesions (steatosis and NASH) and returned to normal after bariatric surgery. None was correlated with either liver function tests or metabolic parameters. Identification using immunoSELDI assay characterised these peaks as the double charged ions of alpha- and beta-haemoglobin subunits. CONCLUSION: The differential proteomic method demonstrated changes in serum protein profiles in obese patients according to severity of liver lesions. Free haemoglobin subunits may serve as a serum biomarker of the severity of liver damages.

Metabolic syndrome and hepatic surgery.

In Europe, the prevalence of metabolic syndrome (MS) has reached the endemic rate of 25%. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of MS. Its definition is histological, bringing together the different lesions associated with hepatic steatosis (fat deposits on more than 5% of hepatocytes) without alcohol consumption and following exclusion of other causes. MS and NAFLD are implicated in the carcinogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). At present, HCC and ICC involving MS represent 15-20% and 20-30% respectively of indications for hepatic resection in HCC and ICC. Moreover, in the industrialized nations NAFLD is tending to become the most frequent indication for liver transplantation. MS patients combine the operative risk associated with their general condition and comorbidities and the risk associated with the presence and/or severity of NAFLD. Following hepatic resection in cases of HCC and ICC complicating MS, the morbidity rate ranges from 20 to 30%, and due to cardiovascular and infectious complications, post-transplantation mortality is heightened. The operative risk incurred by MS patients necessitates appropriate management including: (i) precise characterization of the subjacent liver; (ii) an accurately targeted approach privileging detection and optimization of treatment taking into account the relevant cardiovascular risk factors; (iii) a surgical strategy adapted to the histology of the underlying liver, with optimization of the volume of the remaining (postoperative) liver.

PD-L1 expression in the microenvironment and the response to checkpoint inhibitors in head and neck squamous cell carcinoma.

In head and neck squamous cell carcinoma (HNSCC), data from studies using checkpoint-inhibiting antibodies that target programmed death 1 (PD-1) or its ligand the programmed death ligand 1 (PD-L1) demonstrated outstanding clinical activity. Translational investigations also suggested some correlations between therapeutic response and PD-L1 expression in tumor tissue. We comprehensively summarize results that have evaluated PD-L1 expression in HNSCC. We discuss flaws and strength of current PD-1/PD-L1 detection, quantification methods and the evaluation of PD-L1 as a prognostic and theragnostic biomarker. Understanding tumor microenvironment may help understanding resistance to checkpoint inhibitors, designing clinical trials that can exploit drug combinations.

Definition and natural history of metabolic steatosis: histology and cellular aspects.

In patients with diabetes and metabolic syndrome, liver changes may be observed on histology that are characterized as non-alcoholic fatty liver disease (NAFLD). The NAFLD spectrum covers a variety of histological features, including steatosis, necroinflammation and fibrosis. Although steatosis usually follows a benign course, steatohepatitis is prone to progress to fibrosis and cirrhosis. Establishing the degree of severity of liver lesions, the main endpoint of the disease, can identify patients at risk of disease progression. This may be achieved by liver biopsy. For that purpose, a scoring system for both activity (grade) and fibrosis (stage) is available with good reproducibility. In addition to the commonly seen histopathological patterns of lesions, additional changes are reported in patients with diabetes, including glycogenic hepatopathy and hepatic hepatosclerosis.

[Cholangiocarcinoma: epidemiology and global management]. / Cholangiocarcinomes: épidémiologie et prise en charge globale.

SCOPE: Cholangiocarcinoma, or biliary tract tumors, are rare tumors for which survival is short, as diagnosis is often made at an advanced stage. Indeed, diagnosis remains difficult, since symptoms are often unspecific and appear at latest stages. This article presents an update of recent data and therapeutic options. CURRENT SITUATION AND SALIENT POINTS: Several etiologic factors have been identified, but for most patients, none of these factors can be found. Prognosis is often poor, and remains difficult to establish because of the lack of sufficient large-scale studies looking at the impact on preexisting tumor characteristics on overall survival. Surgery remains when possible the gold standard. When tumor removal is impossible, due to a local extension, the appropriate care of patients remains to be defined. Chemotherapy has been proposed with evidence of objective response but limited data on its ability to prolong overall survival and to enhance quality of life. Active chemotherapies appear to be made from combination of an antimetabolite, such as 5-fluorouracile or gemcitabine, and a platinum drug. PERSPECTIVES: In the near future, indications of chemotherapy could be enlarged and targeted therapy might also be used, since several molecules have been tested in preclinical studies, and be offered to patients in clinical trials.

[Neoplastic portal vein thrombosis and hepatic metastasis from colorectal cancer. A rare association]. / Thrombose portale tumorale et métastase hépatique de cancer colorectal. Une association peu connue.

It is rare for portal vein thrombosis to complicate colorectal liver metastases. However malignant portal vein thrombosis must be anticipated when considering hepatic resection. While this finding may influence long-term survival, it does not absolutely contraindicate hepatic resection. We report here a case of colorectal metastasis to the liver with associated macroscopic malignant portal vein thrombosis treated with hepatic resection; the patient is free from recurrence at 5-year follow-up.

Volumetric measurement of hepatic tumors: Accuracy of manual contouring using CT with volumetric pathology as the reference method.

PURPOSE: The purpose of this study was to assess the accuracy of liver tumor volumetry by manual contouring on computed tomography (CT) compared to pathological tumor volume determined from surgical specimen that served as a reference method. PATIENTS AND METHOD: Thirty-eight patients with planned liver surgery and a total of 41 liver tumors were included. There were 24 men and 14 women (mean age: 57 years; range: 32-85 years). Two readers calculated tumor volume by manual contouring on axial CT images. The reference tumor volume was calculated by manual contouring with dedicated software applied to the liver specimen slice. CT and pathology volumes were compared and the percentage of error (PE%) was calculated. Intraobserver and interobserver variabilities were calculated using Bland and Altman plots, and intraclass correlation coefficients (ICC). RESULTS: A strong correlation was found between CT tumor volumes and pathology tumor volumes (r=0.994; P<0.001 for both readers). The mean (±SD) and median (range) PE% were 19%±12% and 16% (1%, +42%) and 19%±15% and 17% (0%, +55%) for readers 1 and 2, respectively. Readers 1 and 2 significantly overestimated tumor volume (i.e., PE%>40%) in 3 (7%) and 2 (5%) tumors on CT, respectively. Tumor volume was not significantly underestimated in any of the patients (i.e. PE%>33%). Tumor size, CT attenuation, time between imaging and surgery, contours and margin definition did not influence the results of PE% values (all P values>0.05 for both readers). The bias and limits of agreement between the two readers were +4.6% and (-24%, +33%) with an ICC of 0.997. CONCLUSION: There was a strong correlation between tumor volume measured on CT and that assessed with surgical specimen. Tumor size, visibility of contours and tumor margins and the time between CT and surgery did not influence the results.

Diagnostic value of serum protein profiling by SELDI-TOF ProteinChip compared with a biochemical marker, FibroTest, for the diagnosis of advanced fibrosis in patients with chronic hepatitis C.

BACKGROUND: FibroTest has been validated for the diagnosis of liver fibrosis in patients with chronic hepatitis C. AIM: To compare FibroTest with a new proteome-based model for the prediction of advanced liver fibrosis. METHODS: Sera from 191 consecutive patients with simultaneous liver biopsy and FibroTest on fresh sera were used for retrospective mass spectrometry analysis. A new fibrosis index was constructed combining proteomic peaks, selected on differential expression according to fibrosis stages in logistic regression analyses. The main end point was the diagnosis of advanced fibrosis on liver biopsy. RESULTS: Eight out of 1000 peaks were selected for the construction of the proteomic index. The area under the receiver operating curve (AUROC) of the proteomic index was 0.88 (95% CI: 0.82-0.92), significantly greater than the FibroTest AUROC of 0.81 (95% CI: 0.74-0.86; P = 0.04); the AUROC of the proteomic and FibroTest combination was 0.88 (95% CI: 0.83-0.92). Seven of the eight selected peaks were highly associated with the FibroTest score, with different patterns of association with the five components of FibroTest. CONCLUSIONS: A proteomic index combining eight peaks had an excellent accuracy value for the diagnosis of advanced fibrosis in patients with chronic hepatitis C. However, despite a statistical significance, the small improvement delivered by proteomics impairs clinical applications because of its cost and its variability compared with the well validated FibroTest.

Aurora-A/STK-15 is a predictive factor for recurrent behaviour in non-invasive bladder carcinoma: a study of 128 cases of non-invasive neoplasms.

Aurora-A, a member of serine/threonine kinase, is implied in mitosis and centrosome maturation. Increasing levels of Aurora-A have been shown to be present in several malignancies and especially in bladder cancer. No immunohistochemical marker has shown to be able to predict the clinical outcome of patients with superficial bladder cancer, except MIB-1, as a predictive marker of relapse and progression. The aim was to investigate the expression of Aurora-A and MIB-1 in tissue micro arrays of superficial bladder cancer representative of pTa papillary urothelial neoplasm with different degrees of aggressiveness (low malignant potential [PUNLMP], non-invasive papillary urothelial carcinoma low grade [NILGC], non-invasive papillary urothelial carcinoma high grade [NIHGC] and carcinoma in situ). We analysed predictive values of both markers, their specificity and sensitivity in tumor recurrence. Aurora-A was a sensitive marker to predict tumor recurrence especially for pTa (PUNLMP, NILGC; PUNLMP p<0.001, NILGC p<0.001) with statistical significant correlation between immunohistochemical staining and clinical outcome. MIB-1 expression displayed statistical difference p=0.002 in the PUNLMP group and p=0.03 in the NILGC group. Aurora-A is a more sensitive marker than MIB-1 to predict relapse in pTa bladder neoplasias. The combination of both markers seems to have a very powerful predictive value of recurrence (p<0.001).

Malignant transformation of nontrophoblastic cells is associated with the expression of chorionic gonadotropin beta genes normally transcribed in trophoblastic cells.

The beta subunit of human chorionic gonadotropin (hCGbeta) is encoded by four nonallelic CGbeta genes. An assay was developed for distinguishing type I CGbeta allelic genes beta7 and beta6, which possess a GCC codon corresponding to an alanine at position 117 of hCGbeta, from type II CGbeta genes beta8, beta5, and beta3 and its allele beta9, which possess a GAC codon corresponding to an aspartic acid at the same position. In normal trophoblast, hCGbeta is encoded by type II CGbeta genes, whereas normal nontrophoblastic tissues of differing histological origin (breast, prostate, skeletal muscle, bladder, adrenal glands, thyroid, colon, and uterus) express only type I CGbeta genes. We studied the expression of CGbeta genes in 86 tumor specimens collected from patients with breast, bladder, prostate, and thyroid cancer and found that up to 61% of these nontrophoblastic tumors expressed type II CGbeta genes. Experiments performed on tumor tissues and their normal counterparts confirmed that the malignant transformation of nontrophoblastic cells is associated with the expression of type II CGbeta genes. These findings provide the basis for a simple test (the CG117 assay) that may be useful for the diagnosis of the most frequent malignancies.

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.

Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.