Catherine Hubert

Intrahepatic Cholangiocarcinoma: An International Multi-Institutional Analysis of Prognostic Factors and Lymph Node Assessment

PURPOSE To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival. PATIENTS AND METHODS From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. RESULTS Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34). CONCLUSION Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.

Pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy for pancreatic or periampullary tumours: a multicentre randomised trial

BACKGROUND Postoperative pancreatic fistula is the leading cause of death and morbidity after pancreaticoduodenectomy. However, the best reconstruction method to reduce occurrence of fistula is debated. We did a multicentre, randomised superiority trial to compare the outcomes of different reconstructive techniques in patients undergoing pancreaticoduodenectomy for pancreatic or periampullary tumours. METHODS Patients aged 18-85 years with confirmed or suspected neoplasms of the pancreas, distal bile duct, ampulla vateri, duodenum, or periampullary tumours were eligible for inclusion. An internet-based platform was used to randomly assign patients to either pancreaticojejunostomy or pancreaticogastrostomy as reconstruction after pancreaticoduodenectomy, using permuted blocks with six patients per block. Within each centre the randomisation was stratified on the pancreatic duct diameter (≤3 mm vs >3 mm) measured at the time of surgery. The primary endpoint was the occurrence of clinical postoperative pancreatic fistula (grade B or C) as defined by the International Study Group on Pancreatic Fistula. The study was not masked and analyses were done by intention to treat. Patient follow-up was closed 2 months after discharge from the hospital. This study is registered with ClinicalTrials.gov, number NCT00830778. FINDINGS Between June, 2009, and August, 2012, we randomly allocated 167 patients to receive pancreaticojejunostomy and 162 to receive pancreaticogastrostomy. 33 (19.8%) patients in the pancreaticojejunostomy group and 13 (8.0%) in the pancreaticogastrostomy group had clinical postoperative pancreatic fistula (OR 2.86, 95% CI 1.38-6.17; p=0.002). The overall incidence of postoperative complications did not differ significantly between the groups (99 in the pancreaticojejunostomy group vs 100 in the pancreaticogastrostomy group), although more events in the pancreaticojejunostomy group were of grade ≥3a than in the pancreaticogastrostomy group (39 vs 35). INTERPRETATION In patients undergoing pancreaticoduodenectomy for pancreatic head or periampullary tumours, pancreaticogastrostomy is more efficient than pancreaticojejunostomy in reducing the incidence of postoperative pancreatic fistula. FUNDING Funding Johnson & Johnson Medical Devices, Belgium.

Is perioperative chemotherapy useful for solitary, metachronous, colorectal liver metastases?

Background:Chemotherapy is increasingly used in colorectal liver metastases (CRLMs) even when they are initially resectable. The aim of our study was to address the still pending question of whether perioperative chemotherapy is really beneficial in patients developing solitary metastases at a distance from surgery of the primary. Methods:We analyzed a multicentric cohort of 1471 patients resected for solitary, metachronous, primarily resectable CRLMs without extrahepatic disease in the LiverMetSurvey International Registry over a 15-year period. Patients who received at least 3 cycles of oxaliplatin- or irinotecan-based chemotherapy before liver surgery (group CS, n = 169) were compared with those who were resected upfront (group S, n = 1302). Results:Patients of group CS were more frequently females (49% vs 36%, P = 0.001) and had larger metastases (≥5 cm, 33% vs 23%, P = 0.007); no difference was observed with regard to age, site of the primary tumour, time delay to occurrence of metastases, and carcinoembryonic antigen (CEA) levels at the time of diagnosis in the 2 groups. The rate of postoperative complications was significantly higher in group CS (37.2% vs 24% in group S, P = 0.006). At univariate analysis, preoperative chemotherapy did not impact the overall survival (OS) (60% at 5 years in both groups); however, postoperative chemotherapy was associated with better OS (65% vs 55% at 5 years, P < 0.01). At multivariate analysis, age 70 years or older (P = 0.05), lymph node positivity in the primary tumor (P = 0.02), a primary-to-metastases time delay of less than 12 months (P = 0.04), raised CEA levels of more than 5 ng/mL at diagnosis (P < 0.01), a tumor diameter of 5 cm or more (P < 0.01), noncurative liver resection (P < 0.01), and the absence of postoperative chemotherapy (P < 0.01) were independent prognostic factors of survival. The disease-free survival (DFS) was negatively influenced by CEA level of more than 5 ng/mL (P < 0.01), size of the metastases 5 cm or more (P = 0.05), and the absence of postoperative chemotherapy (P < 0.01). When patients with metastases of less than 5 cm in size were compared to those with metastases of size 5 cm or more, preoperative chemotherapy did not influence the OS or DFS in either group. Postoperative chemotherapy, on the other hand, improved OS and DFS in patients with metastases of size 5 cm or more but not in patients with metastases of less than 5 cm in size. Conclusions:Although preoperative chemotherapy does not seem to benefit the outcome of patients with solitary, metachronous CRLM, postoperative chemotherapy is associated with better OS and DFS, mainly when the tumor diameter exceeds 5 cm.

Recurrence after operative management of intrahepatic cholangiocarcinoma

INTRODUCTION Data on recurrence after operation for intrahepatic cholangiocarcinoma (ICC) are limited. We sought to investigate rates and patterns of recurrence in patients after operative intervention for ICC. METHODS We identified 301 patients who underwent operation for ICC between 1990 and 2011 from an international, multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed. RESULTS During the median follow up duration of 31 months (range 1-208), 53.5% developed a recurrence. Median RFS was 20.2 months and 5-year actuarial disease-free survival, 32.1%. The most common site for initial recurrence after operation of ICC was intrahepatic (n = 98; 60.9%), followed by simultaneous intra- and extrahepatic disease (n = 30; 18.6%); 33 (21.0%) patients developed extrahepatic recurrence only as the first site of recurrence. Macrovascular invasion (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.34-3.21; P < .001), nodal metastasis (HR, 1.55; 95% CI, 1.01-2.45; P = .04), unknown nodal status (HR, 1.57; 95% CI, 1.10-2.25; P = .04), and tumor size ≥ 5 cm (HR, 1.84; 95% CI, 1.28-2.65; P < .001) were independently associated with increased risk of recurrence. Patients were assigned a clinical score from 0 to 3 according to the presence of these risk factors. The 5-year RFS for patients with scores of 0, 1, 2, and 3 was 61.8%, 36.2%, 19.5%, and 9.6%, respectively. CONCLUSION Recurrence after operative intervention for ICC was common. Disease recurred both at intra- and extrahepatic sites with roughly the same frequency. Factors such as lymph node metastasis, tumor size, and vascular invasion predict highest risk of recurrence.

A survival analysis of the liver-first reversed management of advanced simultaneous colorectal liver metastases: a LiverMetSurvey-based study.

Background:Liver-first reversed management (RM) for the treatment of patients with simultaneous colorectal liver metastases (CRLM) includes liver-directed chemotherapy, the resection of the CRLM, and the subsequent resection of the primary cancer. Retrospective data have shown that up to 80% of patients can successfully undergo a complete RM, whereas less than 30% of those undergoing classical management (CM) do so. This registry-based study compared the 2 approaches. Methods:The study was based on the LiverMetSurvey (January 1, 2000 to December 31, 2010) and included patients with 2 or more metastases. All patients had irinotecan and/or oxaliplatin-based chemotherapy before liver surgery. Patients undergoing simultaneous liver and colorectal surgery were excluded. Results:A total of 787 patients were included: 729 in the CM group and 58 in the RM group. Patients in the 2 groups had similar numbers of metastases (4.20 vs 4.80 for RM and CM, P = 0.231) and Fong scores of 3 or more (79% vs 87%, P = 0.164). Rectal cancer, neoadjuvant rectal radiotherapy, and the use of combined irinotecan/oxaliplatin chemotherapy were more frequent in the RM group (P < 0.001), whereas colorectal lymph node involvement was more frequent in the CM group (P < 0.001). Overall survival and disease-free survival were similar in the RM and CM groups (48% vs 46% at 5 years, P = 0.965 and 30% vs 26%, P = 0.992). Conclusions:Classical and reversed managements of metastatic liver disease in colorectal cancer are associated with similar survival when successfully completed.

Endoscopic ultrasound-guided transluminal drainage of pancreatic duct obstruction: long-term outcome

BACKGROUND AND STUDY AIMS Endoscopic ultrasound-guided pancreatic drainage (EUS-PD) has been reported as an alternative to surgery, when transpapillary access to the main pancreatic duct (MPD) is impossible. The aim of the study was to investigate the feasibility of the procedure and long-term clinical outcome in patients treated with EUS-PD. PATIENTS AND METHODS We retrospectively analyzed our single-center experience over a 10-year period. RESULTS EUS-PD was attempted in 20 patients (24 interventions), with a median age of 64 years (range 36 - 78). Indications for the procedure were post-Whipple symptomatic anastomotic stricture (n = 10) and chronic pancreatitis (n = 10). EUS-PD was performed by a transgastric (n = 16) or transbulbar (n = 3) route or with a rendezvous technique (n = 5). Wirsungography was performed in all interventions and successful drainage was achieved in 18 / 20 (90 %) patients. There were two minor procedure-related complications: bleeding that was treated endoscopically, and a perigastric collection that resolved spontaneously. Median follow up was 37 months (range 3 - 120 months), stent dysfunction occurred in 9 / 18 (50 %) patients. Out of 18 patients with successful EUS-PD, long-term pain resolution was observed in 13 (72 %). At the last follow-up visit, there were significant decreases in pain scores, from 7.5 to 1.6, and in MPD size from 8.1 mm to 3.9 mm. Failure was associated with cancer presence or recurrence. CONCLUSIONS Technical success rate of EUS-PD and clinical long-term pain resolution were 90 % and 72 %, respectively. EUS-PD is a reliable procedure with a low complication rate. It might therefore replace surgery at expert centers.

Pancreatic neuroendocrine tumour grading on endoscopic ultrasound-guided fine needle aspiration: high reproducibility and inter-observer agreement of the Ki-67 labelling index

Assessment of proliferation by the Ki‐67 labelling index (Ki67‐LI) is an important parameter of pancreatic neuroendocrine tumour (pNET) prognosis on resection specimens. Ki67‐LI values for grading are not fully established on endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA). The aim of the study was to determine the accuracy of Ki67‐LI on EUS‐FNA to predict a final grade of pNET and to analyse the relationship between cytological grading and progression‐free survival (PFS).

Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases?

Aims: This report describes three patients suffering from nodular regenerative hyperplasia (NRH).

Management of congenital bile duct cysts.

Bile duct cysts (BDC) are rare congenital anomalies of the biliary tree that are characterized by cystic dilatation of the extrahepatic and/or intrahepatic bile ducts. Presence of an anomalous bilio-pancreatic junction allowing pancreatic juice to reflux into the biliary tree is the most widely aetiopathogenic concept currently accepted. BDC are associated with biliary stasis and lithiasis, and the whole biliary epithelium is considered at risk of malignant transformation. Magnetic resonance cholangio-pancreatography is currently the most accurate preoperative imaging study to assess cyst anatomy and classify the disease according to the standard Todani classification. Complete cyst excision with cholecystectomy followed by biliary reconstruction using a Roux-en-Y hepatico-jejunostomy is the treatment of choice for the extrahepatic component of the disease (type I and IV BDC), but cystic involvement up to the roof of the main biliary convergence represents a real surgical challenge to perform complete resection. The optimal treatment of intrahepatic bile duct dilatations remains controversial, especially for type IV-A BDC. In type V BDC (Caroli’s disease), extent of the liver resection is tailored to intrahepatic disease extent and takes into consideration the presence and severity of underlying chronic liver (congenital hepatic fibrosis) and kidney disease. Late postoperative cholangitis secondary to intrahepatic strictures and lithiasis, as well as the risk of metachronous cholangiocarcinoma that can occur throughout the whole biliary tree even after complete cyst excision, represent serious complications justifying careful long-term follow-up.

Liver transplantation and neuroendocrine tumors: lessons from a single centre experience and from the literature review.

Neuroendocrine tumor (NET) metastases represent at this moment the only accepted indication of liver transplantation (LT) for liver secondaries. Between 1984–2007, nine (1.1%) of 824 adult LTs were performed because of NET. There were five well differentiated functioning NETs (four carcinoids and one gastrinoma), three well differentiated non functioning NETs and one poorly differentiated NET. Indications for LT were an invalidating unresectable tumor (4×), and/or a diffuse tumor localization (3×) and/or a refractory hormonal syndrome (5×). Median post‐LT patient survival is 60.9 months (range 4.8–119). One‐, 3‐ and 5‐year actuarial survival rates are 88%, 77% and 33%; 1, 3 and 5 years disease free survival rates are 67%, 33% and 11%. Due to a more rigorous selection procedure, results improved since 2000; three out of five patients are alive disease‐free at 78, 84 and 96 months. Review of these series together with a review of the literature reveals that results of LT for this oncological condition can be improved using better selection criteria, adapted immunosuppression and neo‐ and adjuvant surgical as well as medical tretament. LT should be considered earlier in the therapeutic algorithm of selected NET patients as it is the only therapy that can offer a cure.