Damien Bergeat

The true prognosis of resected distal cholangiocarcinoma.

Prognosis of distal cholangiocarcinoma (DCC) after pancreaticoduodenectomy (PD) remains poorly assessed. The aims of this study were to describe the oncological results of PD in DCC and to compare its prognosis to pancreatic ductal adenocarcinoma (PDAC).

“Fibrous nests” in human hepatocellular carcinoma express a Wnt-induced gene signature associated with poor clinical outcome

Hepatocellular carcinoma (HCC) is the 3rd cause of cancer-related death worldwide. Most cases arise in a background of chronic inflammation, extracellular matrix (ECM) remodeling, severe fibrosis and stem/progenitor cell amplification. Although HCCs are soft cellular tumors, they may contain fibrous nests within the tumor mass. Thus, the aim of this study was to explore cancer cell phenotypes in fibrous nests. Combined anatomic pathology, tissue microarray and real-time PCR analyses revealed that HCCs (n=82) containing fibrous nests were poorly differentiated, expressed Wnt pathway components and target genes, as well as markers of stem/progenitor cells, such as CD44, LGR5 and SOX9. Consistently, in severe liver fibroses (n=66) and in HCCs containing fibrous nests, weighted correlation analysis revealed a gene network including the myofibroblast marker ACTA2, the basement membrane components COL4A1 and LAMC1, the Wnt pathway members FZD1; FZD7; WNT2; LEF1; DKK1 and the Secreted Frizzled Related Proteins (SFRPs) 1; 2 and 5. Moreover, unbiased random survival forest analysis of a transcriptomic dataset of 247 HCC patients revealed high DKK1, COL4A1, SFRP1 and LAMC1 to be associated with advanced tumor staging as well as with bad overall and disease-free survival. In vitro, these genes were upregulated in liver cancer stem/progenitor cells upon Wnt-induced mesenchymal commitment and myofibroblast differentiation. In conclusion, fibrous nests express Wnt target genes, as well as markers of cancer stem cells and mesenchymal commitment. Fibrous nests embody the specific microenvironment of the cancer stem cell niche and can be detected by routine anatomic pathology analyses.

De novo HAPLN1 expression hallmarks Wnt-induced stem cell and fibrogenic networks leading to aggressive human hepatocellular carcinomas.

About 20% hepatocellular carcinomas (HCCs) display wild-type β-catenin, enhanced Wnt signaling, hepatocyte dedifferentiation and bad outcome, suggesting a specific impact of Wnt signals on HCC stem/progenitor cells. To study Wnt-specific molecular pathways, cell fates and clinical outcome, we fine-tuned Wnt/β-catenin signaling in liver progenitor cells, using the prototypical Wnt ligand Wnt3a. Cell biology assays and transcriptomic profiling were performed in HepaRG hepatic progenitors exposed to Wnt3a after β-catenin knockdown or Wnt inhibition with FZD8_CRD. Gene expression network, molecular pathology and survival analyses were performed on HCCs and matching non-tumor livers from 70 patients by real-time PCR and tissue micro-array-based immunohistochemistry. Wnt3a reprogrammed liver progenitors to replicating fibrogenic myofibroblast-like cells displaying stem and invasive features. Invasion was inhibited by 30 nM FZD7 and FZD8 CRDs. Translation of these data to human HCCs revealed two tight gene networks associating cell surface Wnt signaling, stem/progenitor markers and mesenchymal commitment. Both networks were linked by Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1), that appeared de novo in aggressive HCCs expressing cytoplasmic β-catenin and stem cell markers. HAPLN1 was independently associated with bad overall and disease-free outcome. In vitro, HAPLN1 was expressed de novo in EPCAM−/NCAM+ mesoderm-committed progenitors, upon spontaneous epithelial-mesenchymal transition and de-differentiation of hepatocyte-like cells to liver progenitors. In these cells, HAPLN1 knockdown downregulated key markers of mesenchymal cells, such as Snail, LGR5, collagen IV and α-SMA. In conclusion, HAPLN1 reflects a signaling network leading to stemness, mesenchymal commitment and HCC progression.

A novel transforming growth factor beta‐induced long noncoding RNA promotes an inflammatory microenvironment in human intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a deadly liver primary cancer associated with poor prognosis and limited therapeutic opportunities. Active transforming growth factor beta (TGFβ) signaling is a hallmark of the iCCA microenvironment. However, the impact of TGFβ on the transcriptome of iCCA tumor cells has been poorly investigated. Here, we have identified a specific TGFβ signature of genes commonly deregulated in iCCA cell lines, namely HuCCT1 and Huh28. Novel coding and noncoding TGFβ targets were identified, including a TGFβ‐induced long noncoding RNA (TLINC), formerly known as cancer susceptibility candidate 15 (CASC15). TLINC is a general target induced by TGFβ in hepatic and nonhepatic cell types. In iCCA cell lines, the expression of a long and short TLINC isoform was associated with an epithelial or mesenchymal phenotype, respectively. Both isoforms were detected in the nucleus and cytoplasm. The long isoform of TLINC was associated with a migratory phenotype in iCCA cell lines and with the induction of proinflammatory cytokines, including interleukin 8, both in vitro and in resected human iCCA. TLINC was also identified as a tumor marker expressed in both epithelial and stroma cells. In nontumor livers, TLINC was only expressed in specific portal areas with signs of ductular reaction and inflammation. Finally, we provide experimental evidence of circular isoforms of TLINC, both in iCCA cells treated with TGFβ and in resected human iCCA. Conclusion: We identify a novel TGFβ‐induced long noncoding RNA up‐regulated in human iCCA and associated with an inflammatory microenvironment. (Hepatology Communications 2018;2:254‐269)

Phenotypic diversity spanning the spectrum of hepatocyte differentiation impacts the outcome of patients with beta-catenin-mutated hepatocellular carcinomas.

Body: Background: Clinical and radiological features are used for prognostication in patients with hepatocellular carcinoma (HCC) . The present study aimed to prospectively evaluate the impact of HCC treatment in patients with HCC bearing a transcriptomic signature (TS) (Gut 2016 .doi: 10 .1136/gutjnl-2014-308483) associated with aggressive tumour behaviour and worse survival . Methods: Candidates for HCC treatment were prospectively subjected to histological HCC evaluation, both for diagnosis and for performance of the TS (qRT/PCR) . Physicians deciding and performing treatment were blinded to the presence of TS . Outcome results were matched with TS presence only after follow up finished . Results: 237 patients were enrolled, 81% were male, median age 65 years; 39 .7% of them were alive at the end of follow-up in March 2017 . Overall median survival was 31 months; 26 .6% of patients bearing the TS, had significantly worst survival (median survival: 12 vs . 42 months; p <0 .001) . The 80% of entire population underwent at least one treatment for HCC . The cohort with TS showed a significant lower survival independently from having a therapeutic option (HCC with TS vs . no-signature: median survival: 20 vs . 48 months; p<0 .001) or undergoing supportive therapy only (median survival: 5 vs . 13 months; p<0 .001) . The presence of TS was always associated with worse survival independently from undergoing surgical resection (33 vs . 68 months; p<0 .001), multiple loco-regional treatments (33 vs . 69 months; p<0 .001) or systemic drug therapy alone (8 vs . 19 months; p<0 .001) . Twenty patients (11 .8%) undergoing liver transplant (LT) had the best survival of the entire cohort (98 vs . 36 months; p< 0 .001), however, the 3 patients with TS undergoing LT had a significantly lower survival within the LT group (75±19 vs . 101±58 months, p<0 .001) . One out of 3 (33 .3%) HCCs with TS recurred vs . 1 out of 17 (5 .8%) without TS . At Cox Regression analysis, the presence of transcriptomic signature (HR 2 .636,95% CI 1 .676-4 .145), no treatment vs . performance of any treatment (HR .361, 95% CI .217.601), and liver function (Child-Pugh score: HR:1 .263, 95% CI 1 .0631 .490)) were independently related with worse survival . Conclusion: HCCs bearing the transcriptomic signature have an extremely aggressive clinical course that ultimately impacts on survival despite the application of all the available treatment for HCC . Liver transplant could be the only real therapeutic option but this should be prospectively assessed, as in HCC with transcriptomic signature, a high rate of recurrence is biologically extremely plausible .

An unusual case of adrenocortical carcinoma with liver metastasis that occurred at 23 years after surgery

Adrenocortical carcinoma (ACC) is an uncommon and aggressive cancer occurring more frequently in women; local or distant recurrences occur in 80% of cases, typically within 1 year after curative resection. Liver is the preferred metastatic site. Herein, we report the case of a unique liver metastasis from ACC occurring 23 years after the curative prior tumor surgery. A 45-year-old woman was operated in 1991 for adrenocortical stage II without microvascular involvement or capsular infiltration. At that time, no adjuvant treatment was indicated. The initial surgery consisted on a left adrenalectomy with contemporaneous left nephrectomy and regional lymphadenectomy. Five years after surgery, the patient was considered cured. However, 23 years later, the patient presented an atypical right subcostal pain. A 4 cm liver ACC metastasis involving the segment 4 and initially diagnosed as a hemangioma was discovered. A curative resection of the segment 4 was performed. Final pathological examination confirmed the diagnosis of ACC metastasis with a complete R0 resection; no lymph node metastases were observed. This case is the latest metachronous ACC metastasis ever reported in literature. To date, the patient is alive with no signs of recurrence after a post-surgical follow-up of 13 months.

In Response to: “The Outcome of Bariatric Surgery in Patients Aged 75 Years and Older”

We readwith great interest the recently publishedmonocentric study coming from a center of excellence focusing on obesity surgery in the older [1]. This paper is of interest, since even the number of patients included in the analysis is small (n = 19), and data concerning results of obesity in patients over 75 years old are scarce. In this much-selected population, the authors report that obesity surgery could lead to interesting results about weight loss (median %EWL = 47.1%) at 1 year and remission of obesity-related diseases. As it was previously reported, results about weight loss and diabetes resolution are still encouraging but overall less good than those obtained with younger patients [2]. Due to the high expertise of the operating center, postoperative morbidity and mortality were impressive and lower than expected from patient age. Considering the good results of obesity surgery in older people and the increased prevalence of obesity even in older people, obesity surgery should be considered in national public health policies. In current obesity surgery French national guidelines, Bthe indication of obesity surgery over 60 years of age should be discussed case by case according to physiological age and obesity-related comorbidities^, as there are currently no strong criteria to select the best candidates. In the study by Nor Hanipah et al., we were intrigued by the selection criteria and how the preoperative medical care was optimized to promote the adherence of patients and finally guide them to surgery. We are convinced that multidisciplinary psychological, behavioral, and nutritional care are the key for the success of obesity surgery. The use of specific selection criteria and careful exploration of the benefit-risk ratio are of great importance in this vulnerable population, especially given the higher risk of malnutrition related to frailty and sarcopenia. Therefore, in the older people, as the relation between obesity and mortality is still debated [3], massive weight loss could lead to malnutrition, thus could be more risky than maintain an obesity weight. In the older patients, weight loss is always happening together with loss of muscle mass, and then, muscle function. The two latter could be prevented by preand postoperative daily-adapted physical activity. This could be one of the key for the success of obesity surgery. We wonder if the authors did include a preoperative body composition assessment, especially of skeletal muscle mass, e.g., by CT scan as shown by Carnero et al. [4], and functional tests to assess muscle function (e.g., 6-min walking test), and if they plan to do so during postoperative follow-up. We also wonder if patients were integrated before surgery into a dedicated physical activity program in order to prevent muscle loss. Indeed, muscle mass and function are closely related to quality of life, which is a key endpoint in obesity surgery that should be considered, especially in older people, at the same level than obesity-related complications remission. Muscle mass and function can condition the ability for physical activity during the first postoperative year where massive weight loss occurs. The gain of quality of life on social and physical mobility items should be considered to evaluate obesity surgery success in the older people. We believe that, given the annual number of operated patients in the center, drastic criteria were applied to select operated patients, as only 19 patients in 9 years were selected to surgery. How many patients over 75 years of age were screened without being operated? * Damien Bergeat damien.bergeat@chu-rennes.fr

Diagnosis, assessment, and management of surgical complications following esophagectomy

Despite improvements in operative strategies for esophageal resection, anastomotic leaks, fistula, postoperative pulmonary complications, and chylothorax can occur. Our review seeks to identify potential risk factors, modalities for early diagnosis, and novel interventions that may ameliorate the potential adverse effects of these surgical complications following esophagectomy.

Adénocarcinome du pancréas : quelles tumeurs opérer et quand ?

Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis even if some progresses have been made in the standardization of the surgery and perioperative care. Survival is conditioned by clear margins or not and by the occurrence of postoperative complications that can hamper the start of adjuvant chemotherapy before 8 weeks. Non curative resection rates without clear margin remain high (70%), even in case of an initially resectable pancreatic cancer. Those poor results questions the role of the primary tumor resection strategy in case of potentially curable PDAC. Only a comprehensive radiologic evaluation showing no arterial or vein involvement without metastatic spread can classify a pancreatic cancer as potentially curable. The line between borderline and locally advanced PDAC is currently a matter of debate. For borderline tumors, a preoperative treatment should be systematically discussed because of the high rates of R1 resection. For locally advanced PDAC, an aggressive strategy must be encouraged to maximize chances to get clear margins. Currently, identifying patients with a locally advanced but potentially curable PDAC after aggressive treatment is the therapeutic challenge. The expertise of multidisciplinary teams is crucial in order to choose the best strategy of treatment. The aim of this minireview is to redefine the good timing and the place of surgery in the modern era of PDAC management by focusing on potentially curable or locally advanced but potentially curable tumours.

Pancreatic adenocarcinoma: what is the best time for surgery?

Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis even if some progresses have been made in the standardization of the surgery and perioperative care. Survival is conditioned by clear margins or not and by the occurrence of postoperative complications that can hamper the start of adjuvant chemotherapy before 8 weeks. Non curative resection rates without clear margin remain high (70%), even in case of an initially resectable pancreatic cancer. Those poor results questions the role of the primary tumor resection strategy in case of potentially curable PDAC. Only a comprehensive radiologic evaluation showing no arterial or vein involvement without metastatic spread can classify a pancreatic cancer as potentially curable. The line between borderline and locally advanced PDAC is currently a matter of debate. For borderline tumors, a preoperative treatment should be systematically discussed because of the high rates of R1 resection. For locally advanced PDAC, an aggressive strategy must be encouraged to maximize chances to get clear margins. Currently, identifying patients with a locally advanced but potentially curable PDAC after aggressive treatment is the therapeutic challenge. The expertise of multidisciplinary teams is crucial in order to choose the best strategy of treatment. The aim of this minireview is to redefine the good timing and the place of surgery in the modern era of PDAC management by focusing on potentially curable or locally advanced but potentially curable tumours.