Michael Bau Mortensen

Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells

Pancreatic cancer (PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts (CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and non-cellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a context-dependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.

TNM staging and assessment of resectability of pancreatic cancer by laparoscopic ultrasonography.

AbstractBackground: Laparoscopic ultrasonography (LUS) is an imaging modality that combines laparoscopy and ultrasonography. The purpose of this prospective blinded study was to evaluate the TNM stage and assessment of resectability by LUS in patients with pancreatic cancer. Methods: Of the 71 consecutive patients admitted to our department, 36 were excluded from the study, mainly due to evident signs of metastatic disease or another condition that would preclude surgery. Thus, a total of 35 patients were enrolled in the study. All patients underwent abdominal CT scan, ultrasonography, endoscopic ultrasonography (EUS), diagnostic laparoscopy, and LUS. Histopathologic examination was considered to be the final evaluation for LUS in all but three patients, where EUS was used as the reference. Results: The accuracy of LUS in T staging was 29/33 (80%); in N staging it was 22/34 (76%); in M staging, it was 23/34 (68%); and in overall TNM staging, it was 23/34 (68%). In assessment of nonresectability, distant metastases, and lymph node metastases, the sensitivity was 0.86, 0.43 and 0.67, respectively, for LUS alone. Combining the information gleaned from laparoscopy and LUS, the accuracy in finding nonresectable tumors was 89%. Conclusions: Diagnostic laparoscopy with LUS is highly accurate in TNM staging and assessment of resectability of pancreatic cancer and should be considered an important modality in the assessment algorithm.

Combined Endoscopic Ultrasonography and Laparoscopic Ultrasonography in the Pretherapeutic Assessment of Resectability in Patients with Upper Gastrointestinal Malignancies

BACKGROUND Even though endoscopic ultrasonography (EUS) has improved the pretherapeutic staging and assessment of resectability in patients with upper gastrointestinal (GI) tract malignancies, a considerable number of patients still have to undergo unnecessary explorative laparotomy to obtain the final assessment of resectability. The aim of the present study was to evaluate laparoscopic ultrasonography (LUS) and the combination of EUS and LUS in the pretherapeutic study of these patients with special reference to resectability. METHODS Each of 44 patients with esophageal, gastric, or pancreatic cancer was assigned to a treatment-related resectability group based on five different imaging modalities: computer tomography (CT) + ultrasonography (US), EUS, laparoscopy, LUS, and EUS + LUS. The findings with these imaging modalities were compared with intraoperative findings. RESULTS Overall group assignment accuracy showed significantly better results for EUS, LUS, and EUS + LUS than for CT + US and laparoscopy. EUS + LUS identified all non-resectable patients, whereas the sensitivity of CT + US, laparoscopy, and EUS were 14%, 36%, and 79%, respectively. Median time consumption for each EUS, laparoscopy, or LUS procedure was less than 25 min, and no complications were seen during or after the EUS, laparoscopy, or LUS procedures. CONCLUSION Preliminary experience with the combination of EUS and LUS for pretherapeutic assessment of upper GI tract malignancies showed that this combination was superior to CT + US, laparoscopy, and EUS. EUS + LUS correctly identified all non-resectable patients, but two overstaged patients also indicated the need for larger prospective studies to identify the indications and the limitations of this new approach.

Impact of endoscopic ultrasonography (EUS) on surgical decision-making in upper gastrointestinal tract cancer : An international multicenter study

BackgroundEndoscopic ultrasonography (EUS) is an integrated part of the pretherapeutic evaluation program for patients with upper gastrointestinal (GI) tract cancer. Whether the clinical impact of EUS differs between surgeons from different countries is unknown. The same applies to the potential clinical influence of EUS misinterpretations. The aim of this study was to evaluate the interobserver agreement on predefined treatment strategies between surgeons from four different countries, with and without EUS, and to evaluate the clinical consequences of EUS misinterpretations.MethodsOne hundred patients with upper GI tract cancer were randomly selected from all upper GI tract cancer patients treated at Odense University Hospital between 1997 and 2000. Based on patient records and EUS database results, a case story was created with and without the EUS result for each patient. Four surgeons were asked to select the relevant treatment strategy in each case, at first without knowledge of the EUS and thereafter with the EUS result available. Interobserver agreement and impact of EUS misinterpretations were evaluated using the actual final treatment of each patient as reference.ResultsThree of four or all four surgeons agreed on the same treatment strategy for nearly 60% of the patients with and without the EUS results. Treatment decisions were changed in 34% based on the EUS results, and the majority of these changes were toward nonsurgical and palliative treatments (85%). Interobserver agreement was relatively low, but overall EUS increased kappa values from 0.16 (“poor”) to 0.33 (“fair”), thus indicating increased overall agreement after the EUS results were available. EUS conclusion regarding stage or resectability was wrong in 17% of the cases, but only one serious event would have been the clinical result of EUS misinterpretations.ConclusionDespite being used in different ways by different surgeons, EUS did change patient management in one third of the cases. The impact of EUS misinterpretations seemed very low, and this study confirmed one of the strongest clinical possibilities of EUS, i.e., the ability to detect nonresectable cases. EUS is an important imaging modality for oncosurgeons from different countries.

Lethal necrosis and perforation of the stomach and the aorta after multiple EUS-guided celiac plexus neurolysis procedures in a patient with chronic pancreatitis.

2 Celiac plexus neurolysis (CPN) may be an effective means of reducing pain in selected patients with chronic pancreatitis. Several studies have shown that EUS-guided injection of alcohol, local anesthetic, and steroids is effective and safe.1-4 Frequent complications include transient arterial hypotension, diarrhea, and pain. Death resulting from EUS-guided CPN has not been reported so far, to our knowledge.5,6 We report a case in which a patient expeienced lethal necrosis of the stomach and aorta after ultiple CPN procedures.

Endoscopic ultrasound, endoscopic sonoelastography, and strain ratio evaluation of lymph nodes with histology as gold standard

BACKGROUND AND STUDY AIMS Accurate lymph node staging is essential for the selection of an optimal treatment in patients with upper gastrointestinal cancer. Endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) are considered to be the most accurate method for locoregional staging. Endoscopic sonoelastography (ESE) assesses the elasticity of lymph nodes and has been used to differentiate lymph nodes with promising results. The aim of this study was to evaluate the use of EUS, EUS - FNA, ESE, and ESE-strain ratio using histology as the gold standard. PATIENTS AND METHODS Patients with upper gastrointestinal cancer who were referred for EUS examination were enrolled if surgical treatment was planned and the patient had a lymph node that was accessible for EUS - FNA and EUS-guided fine-needle marking (FNM). The lymph node was classified using EUS, ESE, and ESE-strain ratio. Finally, EUS - FNA and EUS - FNM were performed. The marked lymph node was isolated during surgery for histological examination. RESULTS The marked lymph node was isolated for separate histological examination in 56 patients, of whom 22 (39 %) had malignant lymph nodes and 34 (61 %) had benign lymph nodes. There were no complications of EUS - FNM. The sensitivity of EUS for differentiation between malignant and benign lymph nodes was 86 % compared with 55 % - 59 % for the different ESE modalities. The specificity of EUS was 71 % compared with 82 % - 85 % using ESE modalities. CONCLUSION The use of the EUS - FNM technique enabled the identification of a specific lymph node and thereby the use of histology as gold standard. ESE and ESE-strain ratio were no better than standard EUS in differentiating between malignant and benign lymph nodes in patients with resectable upper gastrointestinal cancer.

Cost-effectiveness of endoscopic ultrasonography, magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography in patients suspected of pancreaticobiliary disease.

Background: It is not known whether initial endoscopic ultrasonography (EUS) or magnetic resonance cholangiopancreatography (MRCP) is more cost effective than endoscopic retrograde cholangiopancreatography (ERCP). Methods: A cost‐effectiveness analysis of EUS, MRCP and ERCP was performed on 163 patients. The effectiveness of an investigation was defined as the percentage of patients with no need for further evaluation after the investigation in question had been performed. Costs were assumed from the budget‐holders point of view. Results: MRCP, EUS and ERCP had a total accuracy of 0.91, 0.93 and 0.92, respectively. Eighty‐four (52%) patients needed endoscopic therapy in combination with ERCP, giving an effectiveness of MRCP, EUS, and ERCP of 0.44, 0.45 and 0.92, respectively. The cost‐effectiveness of MRCP, EUS, and ERCP was 6622, 7353 and 4246 Danish Kroner (DKK) per fully investigated and treated patient (1 DKK = 0.14 EUR). Conclusion: Within a patient population with a probability of therapeutic ERCP in 50% of the patients, ERCP was the most cost‐effective strategy.

Characteristics, therapy and outcome in an unselected and prospectively registered cohort of pancreatic cancer patients

PURPOSE Pancreatic cancer (PC) is associated with a dismal prognosis. Few studies have examined characteristics and outcome in an unselected population-based cohort of PC patients. Therefore, we investigated patient baseline characteristics, therapy choices and survival in a complete cohort of patients with PC. METHODS All cases diagnosed with PC between 2007 and 2009 in the Region of Southern Denmark (pop: 1,200,000) were prospectively registered. Patient characteristics including performance status, information about haematology, liver function and therapy were retrieved from patient charts, and used to compare differently treated and untreated groups. RESULTS Six-hundred-eighteen cases were registered as PC; 25 of which did not have adenocarcinomas. Patients were divided in 3 clinical groups based on initial therapy; group 1: resection (n=64), group 2: chemotherapy or chemo-radiotherapy (n=191), group 3: no tumour directed therapy (n=324). Median survival (mOS) (95% confidence interval (CI)) in the three groups was 25.7 months (18-30), 8.1 months (7.0-9.5) and 1.1 months (1.0-1.3) respectively. Three percent of patients participated in clinical trials. An evaluation of baseline factors prognostic value suggested that treated patients differed significantly from non-treated patients. CONCLUSION This study reports survival in treated groups comparable to results obtained from clinical trials with highly selected patients. However the majority of patients with PC do not receive cancer directed therapy. This group was significantly different in several baseline factors, which could suggest a different biology. Improving the outcome of PC patients calls for research into the large group of untreated patients, as only a minority of patients receive cancer directed therapy.

Long-term results of concurrent radiotherapy and UFT in patients with locally advanced pancreatic cancer.

BACKGROUND Definition and treatment options for locally advanced non-resectable pancreatic cancer (LAPC) vary. Treatment options range from palliative chemotherapy to chemoradiotherapy (CRT). Several studies have shown that a number of patients become resectable after complementary treatment prior to surgery. METHODS From 2001 to 2005, 63 consecutive patients with unresectable LAPC received CRT. CRT was given at a dose of 50 Gy/27 fractions, combined with UFT (300 mg/m(2)/day) and folinic acid. Re-evaluation of resectability was planned 4-6 weeks after completion of CRT. RESULTS Fifty-eight patients completed all 27 treatment fractions. Toxicity was generally mild, with 18 patients experiencing CTCAE grade 3 or worse acute reactions. One patient died following a treatment-related infection. Two patients developed grade 4 upper GI bleeding. Median survival was 10.6 (8-13) months. Eleven patients underwent resection, leading to a resection rate of 17%, and a median survival of 46 (23-nr) months. All 11 patients had a R0 resection. Median survival for the patients not resected was 8.8 (8-12) months. CONCLUSION CRT with 50 Gy combined with UFT, is a well-tolerated and effective treatment for patients with LAPC. R0 resection was possible in 17% leading to a long median survival of 46 months in resected patients.

Impact of upper gastrointestinal endoscopic ultrasound in children

The impact and feasibility of upper gastrointestinal endoscopic ultrasound (EUS) in younger children are unknown. We retrospectively reviewed the EUS procedures we had performed in children younger than 16 years with regard to feasibility, safety, and impact on further treatment. In all, 18 patients (12 boys, 6 girls; median age 12 years, range 0.5–15) underwent EUS. The indications were as follows: tumor (9), epigastric pain (3), recurrent pancreatitis (2), unexplained jaundice (2), hypoglycemia (1), and von Hippel-Lindau disease (1). We concluded that EUS had a significant impact in 78% of the cases. EUS seems to be a safe, feasible, and valuable diagnostic tool.