HRG/HER2/HER3 signaling promotes AhR-mediated Memo-1 expression and migration in colorectal cancer.

Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre-screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression. Dissection of the hMemo-1 gene promoter using reporter assays and chromatin IP techniques revealed recruitment of Aryl hydrocarbon receptor (AhR)/Aryl hydrocarbon receptor nuclear-translocator (ARNT) complex, which positively influenced Memo-1 expression in cancer cells. We found that Memo-1 depletion negatively influenced the cellular actin network and that its expression is required for HER2-mediated cell migration and invasion. Moreover, analyses of Memo-1 expression in primary CRC revealed correlation with clinical parameters that point to Memo-1 as a new prognostic factor of aggressive disease in CRC patients. Altogether, these observations demonstrate that Memo-1 is an important downstream regulator of HER2-driven CRC cell migration and invasion through connecting extracellular signals from membrane to the cytoskeletal actin network.

Staging and outcome depending on surgical treatment in adenocarcinomas of the oesophagogastric junction.

BACKGROUND: Owing to controversial staging and classification of adenocarcinoma of the oesophago-gastric junction (AOG) before surgery, the choice of appropriate surgical approach remains problematic. In a retrospective study, preoperative staging of AOG and the impact of preoperative misclassification on outcome were analysed. METHODS: Data from patients with AOG were analysed from a prospectively collected database with regard to surgical treatment, preoperative and postoperative staging, and outcome. RESULTS: One-hundred and thirty patients with Siewert types I and II AOG who did not have neoadjuvant treatment were included in the study: 41 patients with an AOG type I who underwent oesophagectomy, 51 patients with an AOG staged before surgery as type I who underwent oesophagectomy but in whom the final histology showed a type II tumour, and 38 patients whose tumours were staged as AOG type II before and after operation who underwent gastrectomy. Among patients who had an oesophagectomy, lymph node metastases (P = 0.022), tumour relapse (P = 0.009) and recurrent distant metastases (P = 0.028) were significantly more frequent in patients with AOG type II; those with AOG type II had shorter overall survival than those with type I tumours (P = 0.024). Among those with AOG type II, recurrence-free survival was significantly shorter after oesophagectomy compared with extended gastrectomy (P = 0.019). Thoracoabdominal oesophagectomy had a favourable influence on outcome compared with the transhiatal approach. CONCLUSION: Accurate preoperative staging of AOG and appropriate surgical therapy are crucial for outcome. AOG type II is a more aggressive tumour with higher recurrence rates than AOG type I. These patients therefore benefit from more radical surgical treatment.

Arterial en bloc resection for pancreatic carcinoma.

BACKGROUND: Surgery for locally advanced pancreatic cancer with arterial involvement of the hepatic artery, coeliac trunk and superior mesenteric artery (SMA) is highly controversial. In a retrospective review, the benefits and harms of arterial en bloc resection (AEBR) for pancreatic adenocarcinoma with arterial involvement were analysed. METHODS: Patients were divided into three groups: 29 patients who had pancreatic resection and AEBR (group 1), 449 who had pancreatic resection with no arterial resection or reconstruction (group 2), and 40 with unresectable tumours who underwent palliative bypass (group 3). RESULTS: Eighteen patients underwent reconstruction of the hepatic artery, eight of the coeliac trunk and three of the SMA. Additional reconstruction of portal vein was required in 15 patients and of adjacent visceral organs in 19. Perioperative morbidity and mortality rates were higher in group 1 than in group 2 (P = 0·031 and P = 0·037 respectively). Additional portal vein resection was an independent predictor of morbidity (P < 0·001). Median overall survival was similar for groups 1 and 2 (14·0 versus 15·8 months; P = 0·152), and lower for group 3 (7·5 months; P = 0·028 versus group 1). CONCLUSION: In selected patients AEBR can result in overall survival comparable to that obtained with standard resection and better than that after palliative bypass. Nevertheless, AEBR is associated with significantly higher morbidity and mortality rates, counterbalancing the overall gain in survival and limiting the overall oncological benefit.

Pancreatic cancer: a generalized disease--prognostic impact of cancer cell dissemination.

BACKGROUND: Pancreatic ductal adenocarcinoma is the fifth leading cause of death among all malignancies, leading to approximately 40,000 deaths each year in Europe. The annual incidence rate for all types of pancreatic cancer is approximately nine new cases per 100,000 people, ranking it as the 11th among all cancers. Stage, grade and resection margin status are currently accepted as the most accurate pathologic variables predicting survival. All classification systems fail prognostically to distinguish between different stages. Even in patients with seemingly early tumours (T1, N0), the likelihood of relapse is high. This reflects the shortcomings of the pathologic staging to sufficiently discriminate patients with a high risk to develop tumour recurrence from those that carry a lower risk. RESULTS: On the other hand, none of the currently used systems includes or takes into consideration the role of disseminated tumour cells neither in the lymph nodes nor in the bone marrow. Occult residual tumour disease is suggested when either bone marrow or lymph nodes, from which tumour relapse may originate, are affected by micrometastatic lesions undetectable by conventional histopathology. For detection, antibodies against tumour-associated targets can be used to detect individual epithelial tumour cells both in lymph nodes and in bone marrow. The clinical significance of these immunohistochemical analyses is still controversial. Various monoclonal antibodies are still in use for micrometastatic detection, thus contributing to the incongruity of data and validity of results. These assays have been rarely used in patients with pancreatic carcinoma. CONCLUSION: The presence or absence of lymph-node metastases can predict the likelihood of survival for most, if not all, patients with pancreatic ductal adenocancer and the likelihood that metastases will develop at distant sites.

Late morbidity after duodenum-preserving pancreatic head resection with bile duct reinsertion into the resection cavity.

BACKGROUND: Reinsertion of the distal common bile duct (CBD) into the pancreatic resection cavity during duodenum-preserving pancreatic head excision (DPPHE) may be an alternative option to Whipple resection or bilioenteric anastomosis when chronic pancreatitis is associated with CBD stenosis. METHODS: Outcome in 82 patients with chronic pancreatitis who underwent DPPHE with CBD reinsertion was compared with that in 432 who had DPPHE without reinsertion and 50 who had a Whipple procedure or pylorus-preserving pancreatoduodenectomy (PPPD). RESULTS: There were no deaths after DPPHE with CBD reinsertion, compared with four (0.9 per cent) after DPPHE without reinsertion and three (6 per cent) after classical resection. Overall morbidity rates were 30, 28.9 and 36 per cent respectively. Fifteen patients (18 per cent) who had DPPHE with CBD reinsertion developed a stricture at the reinsertion site, compared with a long-term stricture rate of 2.3 per cent (ten patients) after DPPHE without CBD reinsertion and 4 per cent (two patients) after PPPD/Whipple resection. CONCLUSION: Although associated with a high incidence of anastomotic stricture, reinsertion of the CBD into the resection cavity as part of DPPHE can be used to preserve duodenal passage and offers an alternative to extended resection for chronic pancreatitis.

Laparoscopic gastric tailoring for huge subcardial gastrointestinal stromal tumor.

BACKGROUND: A 67-year-old woman with a gastrointestinal stromal tumor (GIST) of the stomach presented to our outpatient clinic. Preoperative computed tomographic scans and endoscopic examination revealed a spherical submucosal tumor (7.7 x 6.1 x 6 cm) in the posterior wall of the stomach less than 1cm away from the cardia, on the small curvature side. METHODS: The tumor, which endosonographically had a volume of 282 cm(3), was completely resected by a full-thickness laparoscopic wedge excision without discontinuous gastric resection. The whole procedure was performed using 4 working ports (one 12-mm and three 5-mm ports) and 1 camera port (12 mm). Because the resection margins were tumor free on frozen sections and the distance between the resection margin and cardia was wide enough not to compromise food passage, there was no need for total gastrectomy or upper discontinuous gastric resection. The patient was discharged on the fourth postoperative day after an uneventful clinical course. RESULTS: Histological examination revealed a malignant gastrointestinal stroma tumor of the stomach. The patient was therefore enrolled for Imatinib adjuvant therapy. Careful and long-term follow-up of 21 months showed no signs of local or distant tumor recurrence. However, further follow-up is needed to monitor for signs of possible recurrence or distant metastases. CONCLUSION: The described technique prevented proximal gastric resection and a risk of anastomosis without compromising the food passage and radicality.