Zahir Soonawalla

Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma

We examined the prognostic value of programmed cell death-1 (PD-1) and its ligand (PD-L1) together with CD8+ tumor-infiltrating lymphocytes (TILs) and FOXP3+ Tregs in resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with adjuvant chemotherapy. Whole-mount FFPE tissue sections from 145 pancreatectomies were immunohistochemically stained for PD-1, PD-L1, CD8 and FOXP3. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin) and in regard to intratumoral lymphoid aggregates. The median OS was 21 months after a mean follow-up of 20 months (range, 2-69 months). In multivariate analysis, high PD-1+ TILs expression was associated with better OS (p = 0.049), LPFS (p = 0.017) and DMFS (p = 0.021). Similar findings were observed for CD8+ TILs, whereas FOXP3 and PD-L1 lacked prognostic significance. Although TIL distribution was heterogeneous, tumors of high stroma density had higher infiltration of CD8+ TILs than loose density stroma and vice versa (p < 0.001), whereas no correlation was found with stromal activity. Sixty (41.4%) tumors contained lymphoid aggregates and the presence of PD-1+ TILs was associated with better OS (p = 0.030), LPFS (p = 0.025) and DMFS (p = 0.033), whereas CD8+ TILs only correlated with superior LPFS (p = 0.039). PD-1+ and CD8+ TILs constitute independent prognostic markers in patients with PDAC treated with adjuvant chemotherapy. Our study provides important insight on the role of PD-1/PD-L1 in the context of desmoplastic stroma and could help guide future immunotherapies in PDAC.

The prognostic role of desmoplastic stroma in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic stroma. We examined the prognostic value of stroma density and activity in patients with resectable PDAC treated with surgery and adjuvant gemcitabine-based chemotherapy. FFPE-tissue from the pancreatectomy of 145 patients was immunohistochemically stained for haematoxylin-eosin and Massons trichrome to assess stroma density, and alpha-smooth muscle actin (αSMA) expression for activated pancreatic stellate cells. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS). After a mean follow-up of 20 months (range, 2–69 months), the median OS was 21 months and the 3-year OS was 35.7%. In multivariate analysis, highly-dense stroma was an independent prognostic parameter for OS (p = 0.001), PFS (p = 0.007), LPFS (p = 0.001) and DMFS (p = 0.002), while αSMA expression lacked significance. Interestingly, highly-dense stroma retained significance for the four clinical endpoints only in early (pT1–2) but not late (pT3–4) stage tumors. Additionally, late pT-stage (pT3–4), the presence of lymph node metastases (pN+ vs pN0), perineural/neural invasion and administration of adjuvant chemotherapy also correlated with prognosis in multivariate analysis. Altogether, stroma density constitutes an independent prognostic marker in PDAC patients treated with adjuvant chemotherapy. Our findings highlight the dynamic complexity of desmoplasia and indicate that highly-dense stroma is correlated with better outcome. Further validation of the prognostic value of stroma as a biomarker and its role in PDAC patients after adjuvant chemotherapy is warranted and will be performed in a prospective study.

A meta-analysis of CXCL12 expression for cancer prognosis

Background:CXCL12 (SDF1) is reported to promote cancer progression in several preclinical models and this is corroborated by the analysis of human tissue specimens. However, the relationship between CXCL12 expression and cancer survival has not been systematically assessed.Methods:We conducted a systematic review and meta-analysis of studies that evaluated the association between CXCL12 expression and cancer survival.Results:Thirty-eight studies inclusive of 5807 patients were included in the analysis of overall, recurrence-free or cancer-specific survival, the majority of which were retrospective. The pooled hazard ratios (HRs) for overall and recurrence-free survival in patients with high CXCL12 expression were 1.39 (95% CI: 1.17–1.65, P=0.0002) and 1.12 (95% CI: 0.82–1.53, P=0.48) respectively, but with significant heterogeneity between studies. On subgroup analysis by cancer type, high CXCL12 expression was associated with reduced overall survival in patients with oesophagogastric (HR 2.08; 95% CI: 1.31–3.33, P=0.002), pancreatic (HR 1.54; 95% CI: 1.21–1.97, P=0.0005) and lung cancer (HR 1.37; 95% CI: 1.08–1.75, P=0.01), whereas in breast cancer patients high CXCL12 expression conferred an overall survival advantage (HR 0.5; 95% CI: 0.38–0.66, P<0.00001).Conclusions:Determination of CXCL12 expression has the potential to be of use as a cancer biomarker and adds prognostic information in various cancer types. Prospective or prospective–retrospective analyses of CXCL12 expression in clearly defined cancer cohorts are now required to advance our understanding of the relationship between CXCL12 expression and cancer outcome.

Prognostic role and correlation of CA9, CD31, CD68 and CD20 with the desmoplastic stroma in pancreatic ductal adenocarcinoma

We assessed the prognostic value of hypoxia (carbonic anhydrase 9; CA9), vessel density (CD31), with macrophages (CD68) and B cells (CD20) that can interact and lead to immune suppression and disease progression using scanning and histological mapping of whole-mount FFPE pancreatectomy tissue sections from 141 primarily resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with surgery and adjuvant chemotherapy. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin). The median OS was 21 months after a mean follow-up of 20 months (range, 2–69 months). The median tumor surface area positive for CA9 and CD31 was 7.8% and 8.1%, respectively. Although total expression of these markers lacked prognostic value in the entire cohort, nevertheless, high tumor compartment CD68 expression correlated with worse PFS (p = 0.033) and DMFS (p = 0.047). Also, high CD31 expression predicted for worse OS (p = 0.004), PFS (p = 0.008), LPFS (p = 0.014) and DMFS (p = 0.004) in patients with moderate density stroma. High stromal and peripheral compartment CD68 expression predicted for significantly worse outcome in patients with loose and moderate stroma density, respectively. Altogether, in contrast to the current notion, hypoxia levels in PDAC appear to be comparable to other malignancies. CD31 and CD68 constitute prognostic markers in patient subgroups that vary according to tumor compartment and stromal density. Our study provides important insight on the pathophysiology of PDAC and should be exploited for future treatments.

Intraductal papillary neoplasm of the bile duct (IPN-B): also a disease of western Caucasian patients. A literature review and case series

Cholangiocarcinoma (CCa) is an aggressive malignancy, which often presents with advanced, inoperable disease. Early detection of any premalignant condition could improve the dismal prognosis of cholangiocarcinoma (5% 5-year survival). There are two premalignant precursors of CCa: biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPN-B). BilIN is only visible microscopically; imaging has no role in identification. IPN-B is a recent diagnostic entity, arising from a World Health Organization (WHO) reclassification of tumours. IPN-B is visible macroscopically, and can be identified on imaging. With its propensity to spread preferentially along the biliary epithelium, only infiltrating the duct wall at a late stage, it may be more amenable to complete resection than typical CCa. The lead time with early detection, during which dysplasia could progress to invasive carcinoma, is an opportunity where resection may be curative. The literature on IPN-B has originated from Asia, but awareness of this condition in the western world is limited. We report a case series of IPN-B occurring in Caucasian patients from the UK, with radiological-pathological correlation. The protean imaging appearances present a unique challenge, but also a great opportunity, for radiologists. Early identification and resection of lesions, even in asymptomatic or minimally symptomatic patients, should be considered.

Endoscopic ultrasound-guided drainage of pancreatic walled-off necrosis using self-expanding metal stents without fluoroscopy

AIM To investigate whether endoscopic ultrasound (EUS)-guided insertion of fully covered self-expandable metal stents in walled-off pancreatic necrosis (WOPN) is feasible without fluoroscopy. METHODS Patients with symptomatic pancreatic WOPN undergoing EUS-guided transmural drainage using self-expandable and fully covered self expanding metal stents (FCSEMS) were included. The EUS visibility of each step involved in the transmural stent insertion was assessed by the operators as “visible” or “not visible”: (1) Access to the cyst by needle or cystotome; (2) insertion of a guide wire; (3) introducing of the diathermy and delivery system; (4) opening of the distal flange; and (5) slow withdrawal of the delivery system until contact of distal flange to cavity wall. Technical success was defined as correct positioning of the FCSEMS without the need of fluoroscopy. RESULTS In total, 27 consecutive patients with symptomatic WOPN referred for EUS-guided drainage were included. In 2 patients large traversing arteries within the cavity were detected by color Doppler, therefore the insertion of FCSEMS was not attempted. In all other patients (92.6%) EUS-guided transgastric stent insertion was technically successful without fluoroscopy. All steps of the procedure could be clearly visualized by EUS. Nine patients required endoscopic necrosectomy through the FCSEMS. Adverse events were two readmissions with fever and one self-limiting bleeding; there was no procedure-related mortality. CONCLUSION The good endosonographic visibility of the FCSEMS delivery system throughout the procedure allows safe EUS-guided insertion without fluoroscopy making it available as bedside intervention for critically ill patients.

Management of pancreaticojejunal strictures after pancreaticoduodenectomy: clinical experience and review of literature

Symptomatic pancreaticojejunal anastomotic stricture (PJS) is a rare complication following pancreaticoduodenectomy. The incidence, presentation and management of this condition are infrequently reported in the literature. Revision surgery is thought to be an effective treatment. Recent literature shows some success from endoscopic management.

Surgeons opinions of legal practice in bile duct injury following cholecystectomy.

INTRODUCTION Litigation for bile duct injury following laparoscopic cholecystectomy places financial strain on the health service, causes significant patient morbidity and adversely affects the patient and surgeon. Claimants argue that the injury itself is evidence of negligence. METHODS A questionnaire addressing views on BDI causation was sent to members of AUGIS working in the National Health Service, UK. Response themes and responses were compared between groups of surgeons. RESULTS Of 117 respondents, 45% experienced BDI and 22% had medicolegal experience. 47% of respondents identified factors outside the surgeons control as being relevant to BDI. Those that had experienced BDI from their own surgery were less likely to identify surgeon/systems errors as the primary cause for BDI than those that had not (34% vs 74%, p < 0.001). Medicolegal expert surgeons were more likely to report that substandard technique should be presumed (50% vs 19%, p = 0.002), however, 25% of medicolegal experts indicated that not all BDIs caused by their own surgery could have been avoided. CONCLUSION A significant number of experienced surgeons indicated that BDI following LC should not be assumed to result from surgeon negligence or institutional failure. This suggests that negligence should not be inferred from the act of BDI alone.

PTU-002 EUS-Guided Insertion of Fully Covered Self-Expandable Metal Stents for Drainage of Pancreatic Walled-Off Necrosis Does Not Require Fluoroscopy

Introduction Transgastric placement of specially designed fully covered self-expandable metal stent (FCSMS) has improved the management and the outcome of walled-off necrosis (WON) after severe pancreatitis. Reduction of radiation exposure is of increasing importance. Therefore, we investigated whether transgastric insertion of FCMS for drainage of WON is possible only by EUS-guidance. Methods Patients with symptomatic pancreatic walled-off necrosis referred for endoscopic drainage were included. EUS-guided stent insertion was performed under concious sedation or endotracheal intubation. The pancreatic collection was accessed from the stomach using a linear echoendoscope with a 19 G access needle, a cystotome or directly using the hot Axios® device. After insertion of a guidewire and enlargement of the transgastric access by diathermy a fully covered self-expandable metal stent was inserted under EUS guidance without fluoroscopy. As clinically indicated, endoscopic necrosectomy was performed through the large diameter metal stent. When the collection had shrunk to less than 4 cm, symptoms and inflammatory parametrs had improved, the stent was endoscopically removed. Results 18 patients (median age: 55 years; range 48–63 years) with symptomatic WON (median diameter: 14 cm; range 8–18 cm) were referred for EUS-guided drainage. In 2 patients large traversing arteries within the cavity were detected by colour Doppler imaging during EUS, therefore the insertion of FCSMS was not attempted to avoid possible erosion of the vessels by the stent edges with reducing collection size. In all other patients (88.9%) the completely EUS-guided transgastric stent insertion without fluoroscopy was technically successful (6 AXIOS® and 10 Nagi® stents were inserted). The stent insertion into the cavity and the opening of the distal flange could be clearly visualised by EUS in all cases. After correct positioning of the FCSMS by EUS the proximal stent flange was deployed under endoscopic guidance. Two patients were readmitted with fever when the stent was blocked with debris. Seven patients required endoscopic necrosectomy through the FCSMS. One patient developed self-limiting bleeding. WON resolved in all patients within 8 weeks. Conclusion The good sonographic visibility of the FCSMS throughout the procedure allows safe and easy insertion of transgastric drainage under EUS-guidance without fluoroscopy. Reference 1 Seifert H, Wehrmann T, Schmitt T, Zeuzem S, Caspary WF. Retroperito-neal endoscopic debridement for infected peripancreatic necrosis. Lancet 2000; 356:653–5. Disclosure of Interest None Declared

PTU-030 Eus-guided insertion of self-expandable metal stents facilitates access for endoscopic necrosectomy in walled-off necrosis

Introduction Wide flange fully covered self-expandable metallic stents (FCSEMS) have recently been developed for EUS-guided transmural drainage of pancreatic fluid collections. We used these wide calibre stents for transgastric access for endoscopic necrosectomy in patients requiring necrotic debridement. Method Patients referred with large, symptomatic walled off-necrosis for endoscopic therapy were included. Under EUS guidance, the necrotic cavity was accessed using the needle knife of a cystotome. After securing the access with a guidewire the new tract was enlarged to 10 F using the ring diathermy of the cystotome. This allowed a 2 or 3 cm long 14 mm diameter FCSEMS to be placed transmurally. If clinically required, endoscopic necrosectomy sessions were performed through the FCSEMS in weekly intervals. Results Six patients (5 men, median age 50 years) had a walled off-necrosis with a median size of 16 cm (range 12–17 cm) causing gastric outlet obstruction (5) or biliary compression (1). One patient with an endosonographically visible artery transversing the necrotic cavity was declined due to bleeding risk. In the other five patients, the insertion of a transgastric FCSEMS under EUS guidance was successful without immediate complications. In all five patients, the cavity reduced to <3 cm after a mean of 3 (range 2–5) endoscopic necrosectomy sessions. There were no major complications. One stent migration occurred after the cavity had reduced to less than 3 cm. Conclusion EUS-guided insertion of FCSEMS into walled-off necrosis appears safe and results in effective drainage. Endoscopic necrosectomy can be performed through the transmural FCSEMS which provides endoscopic access for repeated debridement and flushing of the necrotic cavity. Disclosure of interest None Declared. References Seifert H, Wehrmann T, Schmitt T, Zeuzem S, Caspary WF. Retroperitoneal endoscopic debridement for infected peripancreatic necrosis. Lancet 2000;356(9230):653–5 Braden B, Dietrich CF. Endoscopic ultrasonography-guided endoscopic treatment of pancreatic pseudocysts and walled-off necrosis: new technical developments. World J Gastroenterol. 2014;20(43):16191–6. doi: 10.3748/wjg.v20.i43.16191