Jacques Ewald

Two-stage hepatectomy: who will not jump over the second hurdle?

BACKGROUND Two-stage hepatectomy uses compensatory liver regeneration after a first noncurative hepatectomy to enable a second curative resection in patients with bilobar colorectal liver metastasis (CLM). OBJECTIVE To determine the predictive factors of failure of two-stage hepatectomy. METHOD Between 2000 and 2010, 48 patients with irresectable CLM were eligible for two-stage hepatectomy. The planned strategy was a) cleaning of the left hepatic lobe (first hepatectomy), b) right portal vein embolisation and c) right hepatectomy (second hepatectomy). Six patients had occult CLM (n = 5) or extra-hepatic disease (n = 1), which was discovered during the first hepatectomy. Thus, 42 patients completed the first hepatectomy and underwent portal vein embolisation in order to receive the second hepatectomy. Eight patients did not undergo a second hepatectomy due to disease progression. RESULTS Upon univariate analysis, two factors were identified that precluded patients from having the second hepatectomy: the combined resection of a primary tumour during the first hepatectomy (p = 0.01) and administration of chemotherapy between the two hepatectomies (p = 0.03). An independent association with impairment to perform the two-stage strategy was demonstrated by multivariate analysis for only the combined resection of the primary colorectal cancer during the first hepatectomy (p = 0.04). CONCLUSION Due to the small number of patients and the absence of equivalent conclusions in other studies, we cannot recommend performance of an isolated colorectal resection prior to chemotherapy. However, resection of an asymptomatic primary tumour before chemotherapy should not be considered as an outdated procedure.

Transcriptomic Analysis Predicts Survival and Sensitivity to Anticancer Drugs of Patients with a Pancreatic Adenocarcinoma

A major impediment to the effective treatment of patients with pancreatic ductal adenocarcinoma (PDAC) is the molecular heterogeneity of this disease, which is reflected in an equally diverse pattern of clinical outcome and in responses to therapies. We developed an efficient strategy in which PDAC samples from 17 consecutive patients were collected by endoscopic ultrasound-guided fine-needle aspiration or surgery and were preserved as breathing tumors by xenografting and as a primary culture of epithelial cells. Transcriptomic analysis was performed from breathing tumors by an Affymetrix approach. We observed significant heterogeneity in the RNA expression profile of tumors. However, the bioinformatic analysis of these data was able to discriminate between patients with long- and short-term survival corresponding to patients with moderately or poorly differentiated PDAC tumors, respectively. Primary culture of cells allowed us to analyze their relative sensitivity to anticancer drugs in vitro using a chemogram, similar to the antibiogram for microorganisms, establishing an individual profile of drug sensitivity. As expected, the response was patient dependent. We also found that transcriptomic analysis predicts the sensitivity of cells to the five anticancer drugs most frequently used to treat patients with PDAC. In conclusion, using this approach, we found that transcriptomic analysis could predict the sensitivity to anticancer drugs and the clinical outcome of patients with PDAC.

Postoperative sepsis in cancer patients undergoing major elective digestive surgery is associated with increased long-term mortality

BACKGROUND Major postoperative events (acute respiratory failure, sepsis, and surgical complications) are frequent early after elective gastroesophageal and pancreatic surgery. It is unclear whether these complications impact equally on long-term outcome. METHODS Prospective observational study including the patients admitted to the surgical intensive care unit between January 2009 and October 2011 after elective gastroesophageal and pancreatic surgery. Risk factors for 30-day major postoperative events and long-term outcome were evaluated. RESULTS During the study period, 259 patients were consecutively included. Among them, 166 (64%), 54 (21%), and 39 (15%) patients underwent pancreatic surgery, gastric surgery, and esophageal surgery, respectively. Using the Clavien-Dindo classification, 117 patients (45%) developed at least 1 postoperative complication, including 60 (23%) patients with acute respiratory failure, 77 (30%) with sepsis, and 89 (34%) with surgical complications. The median follow-up from the time of intensive care unit admission was 34 months (95% confidence interval, 30-37 months). The 1-year survival was 95% (95% confidence interval, 92-98). Among the perioperative variables, postoperative sepsis and an American Society of Anesthesiologists score higher than 2 were independently associated with long-term mortality. In septic patients, death (n = 16) was significantly associated with cancer recurrence (n = 10; P < .0001). Independent factors associated with postoperative sepsis were a Sequential Organ Failure Assessment score on day 1, a systemic inflammatory response syndrome on day 3, positive intraoperative microbiological samples, Simplified Acute Physiology Score II and an American Society of Anesthesiologists score higher than 2 (P < .005). CONCLUSIONS Postoperative sepsis was the only major postoperative event associated with long-term mortality. Postoperative sepsis may reflect a deep impairment of immune response, which is potentially associated with cancer recurrence and mortality.

Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts

SUMMARY Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

Surgical treatment of acute abdominal complications in hematology patients: outcomes and prognostic factors

Abstract The decision to operate on hematology patients with abdominal emergencies can be difficult, as neutropenia and thrombocytopenia are common and the usual causes of abdominal pain are broad. We conducted a retrospective observational study including all hematology patients undergoing emergency abdominal surgery between January 1998 and January 2013. Of the fifty-eight consecutive patients included in the study, nineteen (33%) underwent an operation during the neutropenia period. In the multivariate analysis, a laparotomy after 2002 was protective (HR: 0.05; 95%CI: 0.001–0.24), whereas preoperative septic shock (HR: 8.58; 95%CI: 2.25–32.63) and use of dialysis (HR: 6.67; 95%CI: 2.11–21.07) were independently associated with hospital mortality. Surgery during neutropenia or thrombocytopenia was not associated with prognosis. In hematology patients, emergency abdominal surgery is associated with encouraging hospital survival rates. Surgery should be performed prior to septic shock, regardless of whether neutropenia or thrombocytopenia is present.

‘Peripheric’ pancreatic cysts: performance of CT scan, MRI and endoscopy according to final pathological examination

OBJECTIVE To assess the accuracy of pre-operative staging in patients with peripheral pancreatic cystic neoplasms (pPCNs). METHODS From 2005 to 2011, 148 patients underwent a pancreatectomy for pPCNs. The pre-operative examination methods of computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS) were compared for their ability to predict the suggested diagnosis accurately, and the definitive diagnosis was affirmed by pathological examination. RESULTS A mural nodule was detected in 34 patients (23%): only 1 patient (3%) had an invasive pPCN at the final histological examination. A biopsy was performed in 79 patients (53%) during EUS: in 55 patients (70%), the biopsy could not conclude a diagnosis; the biopsy provided the correct and wrong diagnosis in 19 patients (24%) and 5 patients (6%), respectively. A correct diagnosis was affirmed by CT, EUS and pancreatic MRI in 60 (41%), 103 (74%) and 80 (86%) patients (when comparing EUS and MRI; P = 0.03), respectively. The positive predictive values (PPVs) of CT, EUS and MRI were 70%, 75% and 87%, respectively. CONCLUSIONS Pancreatic MRI appears to be the most appropriate examination to diagnose pPCNs accurately. EUS alone had a poor PPV. Mural nodules in a PCN should not be considered an indisputable sign of pPCN invasiveness.

The prognostic impact of abdominal surgery in cancer patients with neutropenic enterocolitis: a systematic review and meta-analysis, on behalf the Groupe de Recherche en Réanimation Respiratoire du patient d’Onco-Hématologie (GRRR-OH)

Neutropenic enterocolitis (NE) is a diagnostic and therapeutic challenge associated with high mortality rates, with controversial opinions on its optimal management. Physicians are usually reluctant to select surgery as the first-choice treatment, concerns being raised regarding the potential risks associated with abdominal surgery during neutropenia. Nevertheless, no published studies comforted this idea, literature is scarce and surgery has never been compared to medical treatment. This review and meta-analysis aimed to determine the prognostic impact of abdominal surgery on outcome of neutropenic cancer patients presenting with NE, versus medical conservative treatment. This meta-analysis included studies analyzing cancer patients presenting with NE, treated with surgical or medical treatment, searched by PubMed and Cochrane databases (1983–2016), according to PRISMA recommendations. The endpoint was hospital mortality. Fixed-effects models were used. The meta-analysis included 20 studies (385 patients). Overall estimated mortality was 42.2% (95% CI = 40.2–44.2). Abdominal surgery was associated with a favorable outcome with an OR of 0.41 (95% CI = 0.23–0.74; p = 0.003). Pre-defined subgroups analysis showed that neither period of admission, underlying malignancy nor neutropenia during the surgical procedure, influenced this result. Surgery was not associated with an excess risk of mortality compared to medical treatment. Defining the optimal indications of surgical treatment is needed.Trial registration PROSPERO CRD42016048952

Pancreaticoduodenectomy: Secondary stenting of the celiac trunk after inefficient median arcuate ligament release and reoperation as an alternative to simultaneous hepatic artery reconstruction

In patients undergoing pancreaticoduodenectomy (PD), unrecognized hemodynamically significant celiac axis (CA) stenosis impairs hepatic arterial flow by suppressing the collateral pathways supplying arterial flow from the superior mesenteric artery and leads to serious hepatobiliary complications due to liver and biliary ischemia, with a high rate of mortality. CA stenosis is usually due to an extrinsic compression by a previously asymptomatic median arcuate ligament (MAL). MAL is diagnosed by computerized tomography in about 10% of the candidates for PD, but only half are found to be hemodynamically significant during the gastroduodenal artery clamping test with Doppler assessment, which is mandatory before any resection. MAL release is usually efficient to restore an adequate liver blood inflow and prevent ischemic complications. In cases of failure in MAL release, postponed PD with secondary stenting of the CA and reoperation for PD should be considered as an alternative to immediate hepatic artery reconstruction, which involves the risk of postoperative thrombosis of the arterial reconstruction. We recently used this two-stage strategy in a patient undergoing surgery for pancreatic adenocarcinoma.

Use of partially covered and uncovered metallic prosthesis for endoscopic ultrasound-guided hepaticogastrostomy: Results of a retrospective monocentric study.

Background and Objectives: Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) represents an option to treat obstructive jaundice when endoscopic retrograde cholangiopancreatography (ERCP) fails. The success rate of this procedure has been shown to be very high. Up to now, plastic and self-expandable metallic stents (SEMSs) have been employed, each of them presenting some limitations. The aims of this study were to evaluate the technical and functional success rates of EUS-HGS using a dedicated biliary SEMS with a half-covered part (Giobor® stent). Methods: We retrospectively reviewed data of patients, who underwent EUS-HGS at our center, with at least 6 months of follow-up. Demographic, clinical, and laboratory data were extracted from the patients charts and electronic records. Technical success rate was defined as the successful passage of the Giobor stent across the stomach, along with the flow of contrast medium and/or bile through the stent. Functional success rate was considered achieved when the decrease of bilirubin value of at least 25% within the 1st week was obtained. The rate of early and late complications was assessed. Results: A total of 41 patients were included (21F/20M, [mean age 66, range 45–85]). Technical success rate was obtained in 37 (90.2%) of patients. Functional success rate, analyzable in 29 patients, occurred in 65%. Between the 37 patients in whom HGS was technically feasible, 13 patients (31.7%) presented an early complication, mostly infective. At 6-month follow-up, 10/37 patients (27.0%) required a new biliary drainage (BD) and 11/37 (29.7%) died because of their disease. Conclusions: EUS-HGS using Giobor® stent is technically feasible, clinical effective, safe, and may be an alternative to percutaneous transhepatic BD in case of ERCP failure for biliary decompression.

Patients with resectable pancreatic adenocarcinoma: A 15-years single tertiary cancer center study of laparotomy findings, treatments and outcomes

BACKGROUND To describe, in patients with resectable pancreatic ductal adenocarcinoma (PDAC), the laparotomy findings, treatments and outcomes before (period 1) and after 2010 (period 2). METHODS From 2000 to 2015, patients newly diagnosed with resectable PDAC at Paoli-Calmettes Institute, France, were evaluated. Survival was examined using the Kaplan-Meier method, and statistical comparisons were conducted using log rank tests. RESULTS Among 1175 patients diagnosed with pancreatic mass, 164 underwent laparotomy with an intention of pancreatic resection. Some of them did not undergo pancreatic resection due to peroperative discovery of advanced disease. For those who were finally resected (n = 119), there were fewer pancreaticoduodenectomies (p = 0.045), shorter operation times (p < 0.01), lower mortality rates (p = 0.02), more advanced-stage tumors (T3), more frequent perineural invasion and R1 resection in period 2. This group had a trend of better outcomes after 2010 (51 months vs. 36 months (p = 0.065)). CONCLUSION Improvement in surgical procedures and postoperative management led to prolonged survival of those who underwent surgery for resectable pancreatic cancer since 2010, despite a higher frequency of advanced tumors at the diagnosis in our institution.