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Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2′-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.

BACKGROUND AND STUDY AIMS:

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is now performed routinely in many advanced endoscopy centers and has enhanced the ability to diagnose pancreatic masses. However, there is uncertainty about which needle size is optimal for EUS-FNA of pancreatic masses. We aimed to evaluate the performance of the 22-gauge and 25-gauge needles in obtaining cytologic diagnosis of pancreatic masses.

METHODS:

All cases that were referred for EUS-FNA for pancreatic masses between February 2001 and June 2007 were reviewed, and patients who underwent EUS-FNA using the 22-gauge and 25-gauge needle system were identified. In patients who underwent surgery, operative histopathological findings were compared with the cytopathological findings from EUS-FNA.

RESULTS:

A total of 842 patients with pancreatic masses detected on computed tomography (CT) and/or magnetic resonance imaging (MRI) and confirmed by EUS underwent EUS-FNA with the 22-gauge needle (n = 540) or the 25-gauge needle (n = 302). Results of EUS-FNA cytology findings were compared with the gold standard of surgical histopathological findings or long-term clinical follow-up. The sensitivity, specificity, PPV, and NPV of FNA were respectively 84%, 100%, 100%, and 73% [corrected] for the 22-gauge needle compared with 92%, 97%, 98%, and 87%, [corrected] respectively for the 25-gauge needle. No complications were noted in the 25-gauge needle group, compared with pancreatitis in 2% of the 22-gauge needle group.

CONCLUSIONS:

This retrospective comparative study shows that EUS-FNA with a 25-gauge needle system is a safe and reliable method for tissue sampling in pancreatic masses. The system is more sensitive and has a slightly [corrected] higher NPV than the standard 22-gauge needle. Our study suggests that perhaps the smaller caliber FNA needle causes less trauma during EUS-FNA and hence less complications. Further studies including randomized trials are needed.

BACKGROUND:

Upper-GI vascular ectasias, including angiodysplasia and gastric antral vascular ectasia may present with either acute or chronic bleeding. Endoscopic thermal modalities have been used to control acute bleeding and reduce transfusion requirements.

METHODS:

Endoscopic experience was reviewed for a 6-year period during which 32 patients requiring blood transfusions for upper-GI angiodysplasia or gastric antral vascular ectasia were evaluated. Patients seen during the first 5 years were treated with either Nd:YAG laser photocoagulation or multipolar electrocoagulation. During the most recent 12 months, all patients were treated by argon plasma coagulation. Response to therapy was assessed by change in mean Hb and transfusion requirements.

RESULTS:

Overall, 16 patients were treated by laser photoablation alone; 9, argon plasma coagulation with or without laser; and 7, multipolar electrocoagulation with or without laser. Mean follow-up for all patients was 19 months. After therapy, mean Hb concentration rose from 76 to 114 g/L for patients with gastric antral vascular ectasia and from 85 to 118 g/L for those with angiodysplasia. Endoscopic therapy abolished or reduced transfusion requirements in 93% of patients with gastric antral vascular ectasia and 76% with angiodysplasia. Patients with gastric antral vascular ectasia required a mean of 6 treatment sessions, while those with angiodysplasia required one to two sessions.

CONCLUSIONS:

Endoscopic thermal ablation effectively controls acute bleeding and reduces transfusion requirements in most patients with upper-GI vascular ectasias. Patients with gastric antral vascular ectasia require significantly more treatment sessions to achieve this effect.