Pancreatology 14 (2014) 321e323

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Snapshots AprileAugust 2014

Effects of needle-size and biopsy technique on the results of Endoscopic Ultrasound Guided Fine Needle aspiration (EUSFNA). Varadarajulu S, Bang JY, Holt BA, Hasan MK, Logue A, Hawes RH, Hebert-Magee S. The 25-gauge EUS-FNA needle: Good for on-site but poor for off-site evaluation? Results of a randomized trial. Gastrointest Endosc. 2014 Jun 25. doi:pii: S0016-5107(14)01755-6. 10.1016/j.gie.2014.05.304. [Epub ahead of print] PMID: 24973173. Nakai Y, Isayama H, Chang KJ, Yamamoto N, Hamada T, Uchino R, Mizuno S, Miyabayashi K, Yamamoto K, Kawakubo K, Kogure H, Sasaki T, Hirano K, Tanaka M, Tada M, Fukayama M, Koike K. Slow pull versus suction in endoscopic ultrasound-guided fine-needle aspiration of pancreatic solid masses. Dig Dis Sci. 2014 Jul; 59(7):1578e85. doi: 10.1007/s10620-013-3019-9. Epub 2014 Jan 16. EUS-FNA has an established place in the diagnosis and staging of pancreatic diseases, but is still evolving through advances in equipment and technique. Needle-gauge is an important determinant of outcome: finer needles are easier to manipulate in the duodenum and a recent meta-analysis concluded that 25 g needles are superior to 23 g in centres where Rapid On-Site Evaluation of cytology (ROSE) is available. ROSE improves diagnostic yield, decreases inadequate samples and reduces the number of passes required, but is not available at centres lacking an on-site cytopathologist. Two different approaches to this problem have been reported recently. One approach is to make cell blocks by fixing and centrifuging needle aspirate for histological aspiration. A group from Florida prospectively studied the number of passes required to obtain a diagnostic cell-block from a solid intra-pancreatic lesion using a 25 g needle. For all patients an initial aspiration was evaluated by ROSE, then either 2 or 4 further passes were made (according to prior randomization) for cell-block preparation. Samples were obtained without suction (see below). 73 patients were considered for the study; 11 without solid intra-pancreatic lesions were excluded at EUS. All 62 subjects had a preliminary ROSE diagnosis: adenocarcinoma 72.6%; other tumour 11.3%; chronic pancreatitis 16.1%. There were no significant differences between 2 or 4 FNA passes respectively for pellet yield (93.5 vs 96.8%, p ¼ 0.99) or median pellet size (0.006 mm2 vs 0.05 mm2, respectively; p ¼ 0.12). 25 subjects (81%) of each group gave a cell-block core which was of diagnostic quality and agreed with both the ROSE and final surgical diagnosis. There was 100% concordance between the ROSE diagnosis and the final diagnosis. The authors conclude that “although the 25-gauge FNA needle appears to have an excellent diagnostic yield at ROSE, its performance is suboptimal for cell-block preparation”, and that there is no benefit from making more than 2 passes using a 25 g needle. Where tissue diagnosis depends exclusively on a cell block, they recommend that larger-calibre 19- or 22-gauge needles should be

considered. Editor comment: the median pellet size is an order of magnitude greater with 4 passes: the failure to demonstrate statistical significance presumably reflects the relatively small number of subjects. It is fascinating that despite this the diagnostic yields were identical, which suggests that the problem is with the quality rather than the quantity of some samples. science/article/pii/S0016510714017556. Nakai and colleagues from Tokyo report a retrospective study of aspiration technique as a factor in diagnostic yield. Conventionally suction is applied to the needle: this increases sample cellularity but may also increase blood contamination. The “capillary action” or “slow-pull” technique relies on passage of material into the needle as the tip is passed to and fro within the lesion 10e20 times, either with no suction or with minimal suction obtained by withdrawing the trochar. Studies using special reversebevel 22 g and 25 g core biopsy needles have shown superior yields with “slow-pull”. The authors report the results of the technique using conventional needles. Having changed from aspiration to “slow-pull” in. May 2012, they accessed notes on 113 consecutive pancreatic EUS-FNA patients from April 2011 to January 2013. 93 patients met the inclusion criteria of having had EUS-FNA performed by one or other technique to a solid intra-pancreatic lesion (of whom two had two sessions and one three sessions) resulting in 97 procedures with a total of 367 passes. Needle type and size was the operator's choice. Cytology slides were made but ROSE (see above) was not used. Visible tissue fragments were however removed from the slide and put in formalin for histology. For the trial, two cytologists blinded to the technique assessed the slides for cellularity and blood contamination. Diagnosis was made on the combination of cytology and histology of the fragments (where available). Accuracy was assessed against final diagnosis. Passes made for 19 g/22 g/25 g needles respectively were 01/90/ 90 (total 181) for Suction and 01/129/56 (Total 186) for Slow-pull. 53 patients had Suction and 44 Slow-pull: male sex and median tumour size were significantly greater in the Suction group. Median (range) passes were 3 (1e5) for Suction vs. 4 (2e6) for Slow pull (p < 0.001). For all 367 passes, Slow-pull was superior in accuracy (83.9% vs. 75.1%, P ¼ 0.039) and sensitivity (82.5% vs. 71.9%, P ¼ 0.025). Cellularity score was higher for Suction, but blood contamination score also tended to be higher for the suction technique. Comparing needle gauge, for the 22 g needle, diagnostic yield, cellularity and blood contamination were similar for the two groups. In the 25-gauge needle group, there was greater cellularity but also greater blood contamination (p < 0.001) for Suction; accuracy (91.1% vs. 70.0%, p ¼ 0.004), sensitivity (90.0% vs. 67.9%, p ¼ 0.003), and negative predictive value (54.5% vs. 18.2%, 1424-3903/Copyright © 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.


Editorial / Pancreatology 14 (2014) 321e323

P ¼ 0.045) were all better for Slow-pull. Histology contributed significantly to the diagnostic accuracy for this group. The authors concluded that Slow-pull gave less blood contamination and potentially increased the diagnostic yield compared to Suction technique in EUS-FNA of pancreatic solid masses using a regular FNA needle, especially for a 25-gauge needle. However because of the retrospective design they recommend a prospective trial to confirm their findings. Editor comment: this group obtained fragments of tissue from the slides and fixed them for histological analysis. This significantly improved diagnostic accuracy, particularly for the 25 g needle. It would be interesting to see a comparison of this technique and the cell-block technique described above. http://link. Lymph node numbers as a marker of prognosis and resection adequacy in pancreatic surgery: moving goalposts? Gleisner AL [1], Spolverato G, Ejaz A, Pawlik TM. Time-related changes in the prognostic significance of the total number of examined lymph nodes in node-negative pancreatic head cancer. J Surg Oncol. 2014 Jun 29. doi: 10.1002/jso.23715. [Epub ahead of print]. Total number of lymph nodes examined (TNLE) is used as a prognostic tool as well as being an indicator of excisional adequacy in GI and other cancers. For pancreatic cancer the US National Comprehensive Cancer Network (NCCN) recommends that at least 11e17 nodes should be examined to optimise staging. Gleisner and colleagues used retrospective data from a data-base covering 26% of the US population to look at changes in TNLE and survival following resection for adenocarcinoma of the head of the pancreas between 1988 and 2007. The paper considers only node-negative patients. A total of 3406 node-negative patients were divided into two cohorts by date of diagnosis: 1998e2002 (1886 patients) and 2003e2007 (1540 patients). Unadjusted KaplaneMeier survival estimates showed a lower median survival for the 1998e2002 cohort (20 months vs. 24 months, p < 0.001). 3 and 5 year survivals were similarly better in the 2003e2007 cohort. TNLE was divided into 3 cohorts, 12. Over the entire study period survival probability was, as expected, significantly lower for both TNLE 12. The same pattern was seen in the 1988e2002 cohort, but for the 2003e2007 cohort there was no difference between TNLE 4e12 and the TNLE>12 groups, both of which had superior survival probability to the TNLE1 week after the onset of pancreatitis or if the patient was discharged without further imaging it was assumed that there was no necrosis. For a score of >4 (necrosis probably present), the best performing radiologist scored Sensitivity 64%, Specificity 97%, Accuracy 90%, ROC 0.96 for CECT alone and 82%, 100%, 96%, ROC1.00 for CECT þ Color. The worst performer (a fellow with less experience) scored 73%, 87%, 83%, ROC 0.90 for CECT alone and 82%, 92%, 90%, ROC 0.96, for CECT þ Color. CECT þ Color significantly improved the performance vs. CECT alone for 2 readers and the third showed a non-significant improvement. The authors conclude that, “subtraction color-map images of CECT and unenhanced CT obtained using 3D nonrigid registration significantly improves the detection of pancreatic necrosis in early stage of acute pancreatitis”. Editor comment: whilst the image processing helped all three radiologists to improve their performance, the hierarchy of performance between them persisted. This shows the importance of skill and experience in interpreting imaging tests, a fact rarely appreciated by managers and other non-clinicians. full/10.2214/AJR.13.10957. Desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC): protective after-all? € Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014 Jun 16; 25(6):719e34. doi: 10.1016/ j.ccr.2014.04.005. Epub 2014 May 22. Desmoplasia and immunocyte infiltration were classically viewed as protective host reactions to the presence of carcinoma cells, but in recent years the thinking has moved towards the concept of myofibroblasts being a component of the malignant phenotype and immunosuppressive cells have been recognised within the tumour micro-environment. The concept of fibrous

Editorial / Pancreatology 14 (2014) 321e323

tissue as a barrier to chemotherapeutic agents further suggested that myofibroblast depletion should be beneficial in PDAC. The failure of Saridgebib, a Hedgehog (Hh) inhibitor expected to reduce myofibroblast proliferation, to improve survival in a phase 2 PDAC trial was disappointing. Now a trial in mice suggests that depleting fibroblastic cells may worsen the survival of PDAC and that the relationship between tumour cells, myofibroblasts, matrix and immunocytes is more complicated and nuanced than previously suspected. € Ozdemir and colleagues crossed the PKT mouse, which spontaneously develops PDAC, with the a-SMA-tk transgenic mouse to produce animals (PKT; a-SMA-tk mice) in which a-SMA-expressing cells can be targeted by injecting Gancyclovir (GCV). GCV injection at both the PanIN and PDAC stages reduced proliferating myofibroblasts in tumours by 80% but did not deplete other a-SMA positive cells either in the tumour and local blood vessels or in extrapancreatic tissue. Tumours were significantly more invasive, undifferentiated and necrotic in myofibroblast depleted mice. There was an increase in EMT program markers including YFPþa-SMAþ cells and in positivity for CD44þCD133þ, suggestive of cancer stem cell activity. Tuveson's group previously reported that the Hh pathway inhibitor IP-926 increased vessel density, depleted desmoplastic stroma and improved delivery of Gemcitabine (GEM) to tumours € [1]; by contrast, Ozdemir et al. found none of these features in


the PKT a-SMA-tk model and GEM did not improve survival. Myofibroblast depletion was however associated with significant suppression of effector T cells (Teff, CD4þFoxp3), an increase in regulator T cells (Treg, CD4þFoxp3þ), and a decrease in the Teff/ Treg ratio. Administration of an antibody to CTLA-4 (a T-helper protein which inhibits T-cell activity) significantly improved tumour scores without changing myofibroblast depletion and improved survival by an average of 60% of lifespan. In support of the animal experiments a supplementary study of human archival tumours correlated a-SMA expression and classical features of differentiation with survival. In 53 patients, 27 poorly differentiated tumours were associated with worse survival than 26 moderate/well differentiated tumours (p ¼ 0.0139, Kaplan Meier) whereas low a-SMA in 17 correlated even better with poor survival (p ¼ 0.0053). The authors discuss the implications of their findings for the treatment of PDAC. S1535610814001755

Reference [1] Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324:1457e61.

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