Jérôme Cros

Sonic Hedgehog and Gli1 Expression Predict Outcome in Resected Pancreatic Adenocarcinoma

Purpose: Aberrant activation of the hedgehog (Hh) pathway is implicated in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. We investigated the prognostic and predictive value of four Hh signaling proteins and of the tumor stromal density. Experimental Design: Using tissue microarray and immunohistochemistry, the expression of Shh, Gli1, SMO, and PTCH1 was assessed in 567 patients from three independent cohorts who underwent surgical resection for PDAC. In 82 patients, the tumor stromal index (SI) was calculated, and its association with overall survival (OS) and disease-free survival (DFS) was investigated. Results: Shh and Gli1 protein abundance were independent prognostic factors in resected PDACs; low expressors for those proteins experiencing a better OS and DFS. The combination of Shh and Gli1 levels was the most significant predictor for OS and defined 3 clinically relevant subgroups of patients with different prognosis (Gli1 and Shh low; HR set at 1 vs. 3.08 for Shh or Gli1 high vs. 5.69 for Shh and Gli1 high; P < 0.001). The two validating cohorts recapitulated the findings of the training cohort. After further stratification by lymph node status, the prognostic significance of combined Shh and Gli1 was maintained. The tumor SI was correlated with Shh levels and was significantly associated with OS (P = 0.023). Conclusions: Shh and Gli1 are prognostic biomarkers for patients with resected PDAC. Clin Cancer Res; 21(5); 1215–24. ©2014 AACR.

Human equilibrative nucleoside transporter 1 testing in pancreatic ductal adenocarcinoma: a comparison between murine and rabbit antibodies.

The human equilibrative nucleoside transporter 1 (hENT1) expression level in pancreatic ductal adenocarcinoma (PDAC) may predict survival in gemcitabine‐treated patients after resection. These results have been obtained with a murine anti‐hENT1 antibody (10D7G2) that is not commercially available. Another antibody, which is rabbit‐derived (SP120), appears to have no predictive value in local, advanced or metastatic PDAC. We aimed to study whether the two antibodies are equivalent.

Assessment of chronic rejection in liver graft recipients receiving immunosuppression with low-dose calcineurin inhibitors

BACKGROUND & AIMS Calcineurin inhibitors represent the cornerstone immunosuppressants after liver transplantation despite their side effects. As liver graft is particularly well tolerated, low doses may be proposed. The aim of this study was to assess the prevalence of chronic rejection in patients with low calcineurin inhibitors regimen and to compare their characteristics with patients under standard doses. METHODS All patients with liver transplantation between 1997 and 2004 were divided into two groups. Low-dose patients (n=57) had tacrolimus baseline levels <5ng/ml or cyclosporine levels <50ng/ml at t0 or <100ng/ml at t+2h and were prospectively proposed a liver biopsy, searching for chronic rejection according to Banff criteria. The remaining patients constituted the standard-doses group (n=40). RESULTS Among the low-dose group, 36 patients in the low-dose group were assessed by biopsy. No chronic rejection was found. Fifty-six percent had only calcineurin inhibitors and 8% received other immunosuppressants only. The median time between liver transplantation and biopsy was 90 months (64-157) and between IS regimen decrease and biopsy was 41 months (11-115). Liver tests were normal in 72% of the patients. Low-dose patients had more often hepatitis B (p=0.045), less past acute rejection episodes (p=0.028), and better renal function (p=0.040). Decrease of calcineurin inhibitors failed in 15% of standard-dose patients without impacting the graft function. In the low-dose group, co-prescription of other immunosuppressants facilitated the decrease (p=0.051). CONCLUSIONS The minimization, or even cessation, of calcineurin inhibitors may be an achievable goal in the long term for most of the liver graft recipients.

Asparagine Synthetase Expression and Phase I Study With L-Asparaginase Encapsulated in Red Blood Cells in Patients With Pancreatic Adenocarcinoma.

Objectives Asparaginase encapsulated in erythrocytes (ERY-ASP) is a potentially effective drug in patients with pancreatic adenocarcinoma (PAC) with null/low asparagine synthetase (ASNS) expression. Our aims were to assess ASNS expression in PAC from a large cohort and its prognostic and/or predictive value and to conduct a phase I trial with ERY-ASP in patients with metastatic PAC. Methods Asparagine synthetase expression was evaluated using immunohistochemistry in resected PAC (471 patients) and in pairs of primary tumor and metastases (55 patients). Twelve patients were included in the phase I trial and received a single administration of ERY-ASP (25-150 IU/kg). Results Null/low ASNS expression was found in 79.4% of the resected PAC with a high concordance between primary tumor and metastases. Asparagine synthetase expression was significantly correlated with sex and CXCR4 expression. In the phase I trial, ERY-ASP was well tolerated by patients with metastatic PAC. No patient had DLTs, and 6 patients had at least 1 ERY-ASP causally related adverse event out of the 12 adverse events reported. Conclusions Given the high rate of PAC with null/low ASNS expression and the good tolerability profile of ERY-ASP, ERY-ASP should be evaluated in further clinical studies in metastatic PAC.

Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution.

Solid tumors often display chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of resistant tumors as current chemotherapies are inefficient. The tumor stroma and extracellular matrix (ECM) are key contributors to PDAC aggressiveness and to limiting the efficacy of chemotherapy. Lysyl oxidase (LOX) family members mediate collagen cross-linking and thus promote ECM stiffening. Our data demonstrate increased LOX, LOXL1, and LOXL2 expression in PDAC, and that the level of fibrillar collagen, which is directly dependent of LOX family activity, is an independent predictive biomarker of adjuvant “Gemcitabine-based chemotherapy” benefit. Experimentally in mice, increased LOX family activity through LOXL2 promotes chemoresistance. This effect of LOX family activity seems to be due to decreased gemcitabine intra-tumoral diffusion. This observation might be explained by increased fibrillar collagen and decreased vessel size observed in tumors with increased LOX family activity. In conclusion, our data support that LOX family activity is both a novel target to improve chemotherapy as well as a novel biomarker to predict gemcitabine benefit in PDAC. Beyond the PDAC, it is possible that targeting LOX family activity might improve efficacy of chemotherapies against different kinds of solid tumors.

Homicidal deaths in the Western suburbs of Paris: a 15-year-study.

AbstractThe aim of our study was to analyze the homicide pattern in the Western suburbs of Paris and its evolution between 1994 and 2008. All autopsy reports regarding homicides from the period January 1, 1994, to December 31, 2008, were retrospectively reviewed. Five hundred eleven homicide cases were selected of 4842 autopsy cases. The following data were recorded: assailants and victims characteristics, crime scene location, homicide motive, cause of death, and victim’s postmortem toxicological results. Homicide rate steadily declined over the period at the exception of the number of homicide-suicide per year, which remained constant. Homicide victims remained unidentified after medicolegal investigations in 2% of the cases. Child and elder homicide cases represented, respectively, 10.7% and 8.2% of the cases. Offenders were male in 88% of the cases. Male and female assailants showed distinct homicide patterns: females were involved more frequently in familial quarrel and child abuse. They never killed a stranger and committed homicide exclusively in a private place with a predominance of sharp weapons. Males, in contrast, assaulted almost equally a stranger or an acquaintance, often in a public place with a predominance of firearm. Victim knew the assailant(s) in 57% of the cases. Homicides mostly took place at the residence of the assailant or the victim. Homicide motive was clearly determined in 71% of the cases. Argument was the most common motive in 44% of the cases. Sexual assault was rarely found (10 cases). Gunshot wounds were the most common cause of death (37%), followed by stab wounds (27%), blunt trauma (19%), and asphyxia (13%). A decrease of gunshot wounds as a cause of death was found over the studied period. Alcohol was the most common toxic detected in blood of the victim, in 48.5% of the cases when toxicological results were available. Blood alcohol concentration ranged from 1 to 500 mg/dL with a mean value of 150 mg/dL.

Accuracy of 2012 International Consensus Guidelines for the prediction of malignancy of branch-duct intraductal papillary mucinous neoplasms of the pancreas

Objective To determine accuracy of 2012 International Consensus Guidelines (ICG) predicting malignancy in a surgical cohort of branch-duct intraductal papillary mucinous neoplasms (BD-IPMN). Methods This study included all consecutive patients with final pathological diagnosis of pure BD-IPMN resected between 2006 and 2014 at Beaujon Hospital. Neoplasms were classified as malignant in presence of high-grade dysplasia (HGD) or invasive carcinoma. Medical, pathological, and radiological data were retrospectively recorded. Results One hundred and twenty patients (65 males, mean age: 57.9 ± 10.8 years) were included. Malignant BD-IPMN accounted for 30% (HGD: 18%, invasive: 12%). Thickened cyst walls (odds ratio (OR): 3.058, 95% confidence interval (CI 95%): 1.102–8.484, p = 0.032), main duct diameter 5–9 mm (OR: 3.395, CI 95%: 1.349–8.543, p = 0.007), and mural nodule (OR: 3.802, CI 95%: 1.156–12.511, p = 0.028) were independently associated with malignancy in multivariate analysis. Among the 89 patients (74%) who underwent surgical resection with ICG criteria, the malignancy rate was 38%, compared with 6% in the 31 ICG-negative group. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for malignancy of having at least one ICG criteria were 94%, 34%, 38%, 94%, and 53%, respectively. Patients with malignant tumors had more ICG criteria than those with benign lesions (2.06 ± 0.98 vs. 0.99 ± 0.95, p < 0.001). Conclusions 2012 ICG criteria are useful to manage BD-IPMN permitting not to miss a malignant form (NPV of 94%), but frequently point out unnecessary surgery (PPV of 38%). Malignancy rate increases with the number of ICG criteria. In patients with only one criterion, additional criteria would be necessary.

Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas

Microsatellite instability (MSI) caused by mismatch repair deficiency (dMMR) is detected in a small proportion of pancreatic ductal adenocarcinomas (PDACs). dMMR and MSI have been associated with responses of metastatic tumors, including PDACs, to immune checkpoint inhibitor therapy. We performed immunohistochemical analyses of a 445 PDAC specimens, collected from consecutive patients at multiple centers, to identify those with dMMR, based on loss of mismatch repair proteins MLH1, MSH2, MSH6, and/or PMS2. We detected dMMR in 1.6% of tumor samples; we found dMMR in a larger proportion of intraductal papillary mucinous neoplasms-related tumors (4/58, 6.9%) than non- intraductal papillary mucinous neoplasms PDAC (5/385, 1.3%) (P = .02). PDACs with dMMR contained potentially immunogenic mutations because of MSI in coding repeat sequences. PDACs with dMMR or MSI had a higher density of CD8+ T cells at the invasive front than PDACs without dMMR or MSI (P = .08; Fisher exact test). A higher proportion of PDACs with dMMR or MSI expressed the CD274 molecule (PD-L1, 8/9) than PDACs without dMMR or MSI (4/10) (P = .05). Times of disease-free survival and overall survival did not differ significantly between patients with PDACs with dMMR or MSI vs without dMMR or MSI. Studies are needed to determine whether these features of PDACs with dMMR or MSI might serve as prognostic factors.

Contribution of virtual biopsy to the screening of microvascular invasion in hepatocellular carcinoma: A pilot study

Microvascular invasion (mVI) is a major prognostic factor in hepatocellular carcinoma (HCC) that cannot be detected before surgery. Predictive biomarkers of mVI are thus urgently needed. We have developed an original approach of virtual biopsy to assess the performance of an immunohistochemical panel comprising three biomarkers of mVI (H4K16ac, H4K20me2, PIVKA‐II) for the prediction of mVI in HCC core needle biopsies (CNB).

Survival time estimation using Injury Severity Score (ISS) in homicide cases

The aim of our study was to assess the value of ISS to estimate survival time in a retrospective study of all homicidal deaths in the Western suburbs of Paris between 1994 and 2008. Stab wounds were the most common cause of death. Survival time between assault and death, determined in 107 cases out of 511 homicide cases, ranged from 0 min to 25 days (mean 39 h). There was an overall significant association between the survival time and the ISS score. ISS and survival time were strongly associated with male victims and a clear trend was seen with women. Regarding the type of wounds, a trend was seen with gunshot wounds and blunt injuries, but not with stab wounds. There was no influence of blood toxicological results and resuscitation attempts. Overall, ISS was a good predictor of a survival under 30 min.