Gregory Sergeant

Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma

AIMS Despite curative surgery for pancreatic ductal adenocarcinoma (PDAC), most patients develop cancer recurrence and die from metastatic disease. Understanding of the patterns of failure after surgery can lead to new insights for novel therapeutic modalities. The aim of the present study is to describe the patterns of recurrence after curative resection of PDAC. METHODS A retrospective analysis was performed of 145 consecutive resections for PDAC between 1998 and 2005 (M/F 75/70; median (range) age 67 years (32-85 y)). The location of the first and consecutive recurrences, and the time interval to cancer recurrence after surgical resection was studied. The magnitude of tumour-free margin was less than a millimetre in 48 patients, whereas a positive surgical margin was observed in 27 patients. The median duration of follow-up was 18.5 (range 0.3-116.8) months. RESULTS Cancer recurrence was observed in 110 patients. The first location of recurrence was locoregional in 19, extra-pancreatic in 66, and combined locoregional and extra-pancreatic in 25 patients. Extra-pancreatic recurrence developed in the liver in 57, peritoneal in 35, pulmonary in 15, and retroperitoneal in 5 patients. The median (95% CI) overall (OS) and disease-free (DFS) survival was 18.7 (15.7-23.5) and 9.8 (7.5-12.4) months, respectively. The type of cancer recurrence did not significantly influence OS, while the resection margin status had a prognostic effect. CONCLUSION The vast majority of patients who undergo potentially curative surgery for PDAC develop cancer recurrence located in the abdominal cavity. Surgical resection margins with tumour involvement and tumour-free margins of less then 1mm are negative prognostic factors. Further research on better local surgical control, peri-operative locoregional treatment, and more effective adjuvant systemic therapy is necessary to improve long-term survival of patients with curable PDAC.

Perioperative cancer cell dissemination detected with a real-time RT-PCR assay for EpCAM is not associated with worse prognosis in pancreatic ductal adenocarcinoma

BackgroundEpithelial cell adhesion molecule (EpCAM) has been used as surrogate marker for the quantification of circulating tumour cells (CTC). Our aim was to prospectively study the value of a real-time RT-PCR assay for EpCAM detection in the peripheral blood and peritoneal cavity of patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma (PDAC).MethodsFrom 48 patients with PDAC (40 resectable, 8 unresectable) and 10 patients with chronic pancreatitis undergoing pancreatectomy 10 ml of venous blood was drawn preoperatively (PB) and postoperatively (POB, day 1 (D1B), day 7 (D7B) and after 6 weeks (6WB). Of all patients undergoing pancreatectomy, 40 ml peritoneal lavage fluid was taken preoperatively and postoperatively. A real-time RT-PCR assay (TaqMan, ABI Prism 7700) was developed for the detection of EpCAM mRNA. To discriminate between EpCAM-positive and negative samples a cut-off was applied. Median postoperative follow-up was 24.0 months (range: 0.7 - 41.3).ResultsPB was EpCAM-positive (+) in 25% of patients versus 65% of patients in POB (p < 0.0001). EpCAM(+) was noted at D1B, D7B and 6WB was found in 28.6%, 23.1% and 23.5% of patients respectively. Preoperative peritoneal lavage fluid was EpCAM(+) in 10.3% versus 53.8% of patients postoperatively (p < 0.0001).At none of the time-points, an association was found between EpCAM positivity in blood and/or peritoneal cavity and cancer-specific or disease-free survival. Also, no significant associations were found between clinicopathological variables and perioperative EpCAM positivity.ConclusionsDespite a significant increase in EpCAM counts in postoperative blood and peritoneal lavage fluid this was not associated with worse prognosis after pancreatectomy for PDAC.Trial registrationClinicaltrials.gov NCT00495924

Reversed arthroscopic subacromial decompression for symptomatic irreparable rotator cuff tears: mid-term follow-up results in 34 shoulders.

BACKGROUND In the elderly, there is no guideline for the treatment of irreparable rotator cuff lesions. The results of open or arthroscopic repair are variable. We hypothesized that the use of a reversed arthroscopic subacromial decompression (RASD) would yield comparable results. MATERIAL AND METHODS Between January 2004 and December 2006, thirty-eight patients underwent a RASD for irreparable cuff tears in 39 shoulders. The surgical procedure consisted of a tenotomy of the long head of the biceps tendon, a debridement of the torn rotator cuff and a tuberoplasty, without violation of the coracoacromial arch and the acromion. RESULTS Thirty-three patients (age 69.9 +/- 7.3 years) were available for clinical and radiological evaluation of 34 shoulders (male/female ratio: 11/22), at a mean follow-up of 38 months (range: 21 months-52 months). Two of 33 patients had required revision surgery, and were excluded from further statistical analysis. In the remaining 31 patients (32 shoulders), the modified Constant-Murley score (CMS) improved from 34.9% +/- 11.6 to 84.0% +/- 11.6 (p < 0.0001). The preoperative mobility did not correlate with the final result. Preoperative pain was found to correlate negatively to the modified CMS at follow-up (p= 0.0038). Although the acromiohumeral height decreased with 2.58 mm +/- 1.68 and the severity of glenohumeral osteoarthritis increased with one grade (Samilson-Prieto classification), there was no correlation with the functional outcome. CONCLUSION We conclude that for irreparable rotator cuff tears in the elderly, excellent mid-term results can be achieved with a RASD.

Pancreatic cancer circulating tumour cells express a cell motility gene signature that predicts survival after surgery

BackgroundMost cancer deaths are caused by metastases, resulting from circulating tumor cells (CTC) that detach from the primary cancer and survive in distant organs. The aim of the present study was to develop a CTC gene signature and to assess its prognostic relevance after surgery for pancreatic ductal adenocarcinoma (PDAC).MethodsNegative depletion fluorescence activated cell sorting (FACS) was developed and validated with spiking experiments using cancer cell lines in whole human blood samples. This FACS-based method was used to enrich for CTC from the blood of 10 patients who underwent surgery for PDAC. Total RNA was isolated from 4 subgroup samples, i.e. CTC, haematological cells (G), original tumour (T), and non-tumoural pancreatic control tissue (P). After RNA quality control, samples of 6 patients were eligible for further analysis. Whole genome microarray analysis was performed after double linear amplification of RNA. ‘Ingenuity Pathway Analysis’ software and AmiGO were used for functional data analyses. A CTC gene signature was developed and validated with the nCounter system on expression data of 78 primary PDAC using Cox regression analysis for disease-free (DFS) and overall survival (OS).ResultsUsing stringent statistical analysis, we retained 8,152 genes to compare expression profiles of CTC vs. other subgroups, and found 1,059 genes to be differentially expressed. The pathway with the highest expression ratio in CTC was p38 mitogen-activated protein kinase (p38 MAPK) signaling, known to be involved in cancer cell migration. In the p38 MAPK pathway, TGF-β1, cPLA2, and MAX were significantly upregulated. In addition, 9 other genes associated with both p38 MAPK signaling and cell motility were overexpressed in CTC. High co-expression of TGF-β1 and our cell motility panel (≥ 4 out of 9 genes for DFS and ≥ 6 out of 9 genes for OS) in primary PDAC was identified as an independent predictor of DFS (p=0.041, HR (95% CI) = 1.885 (1.025 – 3.559)) and OS (p=0.047, HR (95% CI) = 1.366 (1.004 – 1.861)).ConclusionsPancreatic CTC isolated from blood samples using FACS-based negative depletion, express a cell motility gene signature. Expression of this newly defined cell motility gene signature in the primary tumour can predict survival of patients undergoing surgical resection for pancreatic cancer.Trial RegistrationClinical trials.gov NCT00495924

The prognostic relevance of tumor hypoxia markers in resected carcinoma of the gallbladder

BACKGROUND Intratumoral hypoxia has been suggested to drive more aggressive tumor behavior. Our aim was to define whether markers of tumor hypoxia are predictors of outcome in patients with gallbladder carcinoma. PATIENTS AND METHODS From 1996 to 2006, 34 patients underwent resection for gallbladder carcinoma. The median follow-up was 12.6 months. Immunohistochemical stains for VEGF, HIF1α, GLUT1, GLUT3, CA9 and EGFR were performed on archival tissue. Immunohistochemical results were correlated with clinical and histopathological parameters. Cumulative overall survival (OS) rates were estimated using the Kaplan-Meier method. Multivariable Cox regression models were used to identify predictors of OS. RESULTS The median OS was 11.9 (IQR: 3.4-22.0) months. Ubiquitous VEGF staining was observed in all gallbladder carcinomas. High (>50% of tumor cells) EGFR expression was associated with worse OS (p0.03). CA9 expression was less prevalent in poorly differentiated tumors (p0.02). GLUT3, GLUT1 and HIF1α expression were not associated with survival, but did correlate with the presence of lymph node metastasis (p0.02), tumor differentiation (p0.04) and tumor stage (p0.03) respectively. High EGFR expression, TNM stage and preoperative serum CA19.9 were retained as independent predictors of OS in multivariable analysis. CONCLUSION In gallbladder cancer high expression of EGFR is an independent predictor of survival.

Extended Lymphadenectomy in Patients With Pancreatic Cancer Is Debatable

Lymph node staging is one of the most important factors in determining the prognosis after resection of pancreatic ductal adenocarcinoma. Despite ongoing efforts to further refine lymph node staging, the debate on the extent of lymphadenectomy during pancreaticoduodenectomy is still open. The purpose of this review was to summarize the evidence about performing standard lymphadenectomy during curative resection of pancreatic cancer. All four prospective randomized controlled trials published concluded that extended lymphadenectomy does not contribute to better oncologic outcome for patients with adenocarcinoma of the pancreatic head. Indeed, one major drawback of extended lymphadenectomy is the higher risk of persistent postoperative diarrhea. No prospective randomized studies could be found on the role of extended lymphadenectomy in patients with adenocarcinoma of the corpus and tail. Based on current evidence there is no indication that extended lymphadenectomy should be performed routinely during resection of pancreatic cancer.

Variations in Serum Electrolyte Concentrations and Renal Function After Therapeutic Hip Arthroscopy: A Pilot Study

PURPOSE The purpose of this study was to analyze changes in serum electrolyte concentration and renal function after hip arthroscopy. METHODS We studied 10 consecutive patients (4 men and 6 women; median age, 30.5 years [range, 20 to 50 years]) undergoing hip arthroscopy. Operating time, traction time, and perfusion volume of lactated Ringer solution (in milliliters) were recorded. Preoperative and postoperative levels of sodium (Na(+)), potassium (K(+)), cloride (Cl(-)), calcium (Ca(2+)), magnesium (Mg(2+)), phosphorous (P), creatinine, and blood urea nitrogen (BUN) were compared. RESULTS The median operating time was 80 minutes (range, 60 to 150 minutes). The median perfusion volume of lactated Ringer solution was 15,000 mL (range, 6,000 to 30,000 mL). The median traction time was 37.5 minutes (range, 30 to 105 minutes). None of the patients had postoperative complications develop. With a mean decrease of 0.84 +/- 0.68 mg/dL, only serum calcium levels were found to decrease significantly (P = .01). There was a mean decrease of 1.50 +/- 2.07 mEq/L in sodium concentrations (P = .06). Hip arthroscopy was associated with a mean postoperative decrease in creatinine and BUN concentrations of 0.05 +/- 0.06 mg/dL (P = .19) and 9.84 +/- 10.36 mg/dL (P = .13), respectively. Although the mean decrease in BUN concentration was important, this was not shown to be significant. No correlations were found between operating time, perfusion volume, and postoperative changes. CONCLUSIONS Lengthy therapeutic hip arthroscopy under high intra-articular pressure has only a minimal effect on electrolyte balance and renal function. We therefore conclude that performing routine preoperative and postoperative blood analysis of electrolyte concentrations and renal function is unnecessary. LEVEL OF EVIDENCE Level IV, therapeutic case series.

CT diagnosis of a post-embolization ischemic diverticulitis of Meckel.

A 23-year-old man presented with hypovolemic shock due to a lower gastrointestinal bleeding. Radiological and endoscopic investigation did not reveal the bleeding site. Emergency visceral angiography showed contrast extravasation at a right-sided branch of the superior mesenteric artery (SMA). Embolization of the bleeding point was performed, resulting in bleeding cessation. One week later, the patient presented with a new episode of moderate anal blood loss associated with diffuse abdominal pain. Computed tomography (CT) revealed an ischemic small bowel diverticulum that was treated by a laparoscopically-assisted segmental small bowel resection. Intraoperative and pathologic analysis confirmed a post-embolization ischemic diverticulitis of Meckel.

Hepatic Artery Embolization prior to En Bloc Resection of an Encased Common Hepatic Artery in Adenocarcinoma of the Head of the Pancreas

A 64-year-old female patient with adenocarcinoma of the head of the pancreas with encasement of the common hepatic artery and portal vein stenosis was reexplored after six cycles of gemcitabine (1000 mg/m2). Prior to surgery, the patient underwent balloon dilation and stenting of the portal vein in addition to successful coil embolisation of the common hepatic artery, proper hepatic artery, and proximal gastroduodenal artery. After embolisation, a pylorus-preserving pancreaticoduodenectomy was performed with resection of the common hepatic artery and portal vein confluens. Pathological examination showed a moderately differentiated pT3N0 (Stage IIa, TNM 7th edition) tumor with negative section margins. We show with this case that in selected cases of periampullary cancer with encasement of the common hepatic artery, it is technically feasible to perform pancreaticoduodenectomy with hepatic artery resection and negative surgical margins. Nevertheless, the oncological benefit of extended arterial resections remains controversial.

Citius Altius Fortius: A Case for Superspecialization

t s m u c Citius, Altius, Fortius (Faster, Higher, Stronger). It was carved in stone at the main entrance of the Lycee Albert Legrand and later cited by Father Dideon and Baron de Coubertin to eulogize the human ambition to excel. Finally it became the official motto of the Olympic Games. Citius, Altius, Fortius could be impersonated by Mark Cavendish, Samuel Sanchez, and Thor Hushovd, winners of different jerseys or stages at the Tour de France 2011. All three are brilliant cyclists; all three ride on similar bikes, but they differ in anatomy, attitude, and mental and physical skills. Their career-long training and race-specific preparation were also totally different. Their superspecialization allowed them to achieve top performances, but nevertheless, the Tour de France was won by the Australian Cadel Evans, who was up with the best in flat and mountain stages as well as time trials. These 4 riders are perfect metaphors in favor and against superspecialization. The education and practice of medicine were structured in 1910 by the report by Flexner.1 Medicine became a specialized training, differentiating itself from osteopathic, chiropractic, and homeopathic medicine. It took 25 years to witness further specialization through the creation of different boards.2 Driven by the recognition that all, most, or some patients would benefit from a highly focused clinical knowledge and the organization and delivery of care, the process of differentiation continued. As an example, more than 20 further subspecialties3 were recognized between 1936 and 2011 by the American Board of Internal Medicine. There are different organizational levels toward superspecialty. The first level is the specialist from a recognized specialty who focuses his practice on one subject. Through a number of processes he becomes a superspecialist in this focused domain. Finally he