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Brief Report | Resident's Forum

Reduced Dissemination of Circulating Tumor Cells With No-Touch Isolation Surgical Technique in Patients With Pancreatic Cancer FREE

Tamara M. H. Gall, BSc, MRCS1; Jimmy Jacob, BSc, MSc2; Adam E. Frampton, MSc, MRCS1; Jonathan Krell, BSc, MRCP2; Charis Kyriakides, MD1; Leandro Castellano, BSc, PhD2; Justin Stebbing, MD, MA, FRCP, FRCPath, PhD2; Long R. Jiao, MD, FRCS1
[+] Author Affiliations
1Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, England
2Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, England
JAMA Surg. 2014;149(5):482-485. doi:10.1001/jamasurg.2013.3643.
Text Size: A A A
Published online

Circulating tumor cells (CTCs) disseminate from the primary tumor and travel through the bloodstream and lymphatic system. The detection of and/or increase in the number of CTCs during a patient’s clinical course may be a harbinger of forthcoming overt metastasis. We aimed to examine the impact of 2 different surgical techniques, standard (ST) pancreaticoduodenectomy (PD) and no-touch isolation (NT) PD, on tumor behavior and outcome in patients with pancreatic cancer by using CTCs as biomarkers. In this pilot study, patients were randomized to either ST-PD (n = 6) or NT-PD (n = 6). Intraoperatively, blood samples were taken from the portal vein for measurement of CTCs before and immediately after removal of the tumor. An increase in CTCs was seen in 5 of 6 patients (83%) with ST-PD but no patients with NT-PD (P = .003). In the ST-PD and NT-PD groups, median overall survival was 13.0 and 16.7 months, respectively (P = .33); there was no difference in disease-free survival (P = .42). The use of NT-PD significantly reduced the number of CTCs in the portal vein with no benefit in survival outcomes compared with ST-PD, although more extensive studies are required.

Figures in this Article

Pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) is a dismal disease with a 5-year survival of less than 5%.1 Even after curative resection, most patients develop metastatic disease within 18 months, which is a major cause of mortality.24 The last few years have seen a number of studies documenting circulating tumor cells (CTCs) in the peripheral blood from patients with most types of epithelial cancers.5 Circulating tumor cells may be released from the primary tumor and have the potential to spread to other sites and develop into micrometastatic and subsequently macrometastatic deposits.6 We and others have shown that the routine detection of CTCs can be used in the follow-up of patients with breast,7 pancreatic,811 hepatobiliary,12 and colorectal13 cancers at high risk for relapse. It is possible that handling the tumor at the time of surgery may cause a release of CTCs, hence contributing to future disease recurrence. No-touch isolation (NT) pancreaticoduodenectomy (PD) for pancreatic head resection has been described previously.14 Although it has been shown to be a safe method for PD, it is not widely accepted among pancreatic surgeons owing to its technical difficulties. Our aim was to assess the impact of 2 different surgical resection techniques, standard (ST) PD and NT-PD, on tumor cell spread and patient survival by using portal venous (PV) CTCs as biomarkers. To our knowledge, this is the first report of its kind.

This study was limited to patients who underwent PD for PDAC between September 6, 2010, and April 30, 2012. The main inclusion criteria were those patients undergoing potentially curative resection for PDAC who consented for intraoperative blood sampling. Patients were randomized into 2 groups: ST-PD and NT-PD. All operative procedures were performed by a single surgeon (L.R.J.). Our method for ST-PD has been previously detailed.2 In comparison, the concept of NT-PD is that the tumor must not be manipulated before the vascular and lymphatic drainage vessels are completely isolated; it was performed as previously described.14 This is further explained in the eAppendix in the Supplement. Following identification and exposure of the PV, 7.5 mL of blood was drawn directly using a 21-gauge butterfly needle before dissection and immediately after removal of the PD specimen. Blood samples were taken at each point in a CellSave (Veridex) preservative tube. The samples were then processed in our laboratory within 24 hours using the bead-based fluorescence CellSearch system (Veridex) according to the manufacturer’s protocol. Samples were then scanned on the CellTracks Analyzer II fluorescent microscope (Veridex) for analysis. The cells were evaluated for CTCs independently by 2 operators (eAppendix in Supplement and Figure 1). Statistical analyses were performed using IBM SPSS Statistics version 20 software (IBM Corp). Approval was obtained from a UK national research ethics committee and the Imperial College Healthcare NHS Trust. Written informed consent was obtained from the patients.

Place holder to copy figure label and caption
Figure 1.
Identification of Pancreatic Circulating Tumor Cells (CTCs) in the Portal Venous Circulation

A, True CTC that is positive for epithelial cell adhesion molecule, pan-cytokeratin (pan-CK), and 4′,6-diamidino-2-phenylindole (DAPI) but negative for CD45. B, Leukocyte that is positive for CD45. Images are from the CellTracks Analyzer II, which uses fluorescent optics to capture and analyze CTCs that have been immunomagnetically selected.

Graphic Jump Location

During the 2-year period, 91 patients underwent PD, 30 of whom had a histological diagnosis of PDAC. Based on the availability of the CellSearch system to perform the assay, 12 patients with preoperative suspicion of PDAC were randomized into this study (ST-PD, n = 6; NT-PD, n = 6). All patients had stage II disease (potentially resectable) and none had received neoadjuvant chemotherapy. There were no differences between the 2 groups with regard to age, operative time, length of hospital stay, complication rate, metastatic to examined lymph node ratio,15 or tumor characteristics (Table). Only 1 patient (in the ST-PD group) required a perioperative blood transfusion (2 units). For pancreatic duct reconstruction, 5 patients in each group had a longitudinal ventral pancreaticojejunostomy anastomosis16 and 1 in each group had a pancreaticogastrostomy. Major complications included 1 biliary leak in the ST-PD group and 1 pancreatic leak (pancreaticogastrostomy anastomosis) in the NT-PD group. Both cases were treated conservatively. All tumors were confirmed histologically as PDAC and American Joint Committee on Cancer stage IIB (pT3N1M0). An R1 resection was defined as cancer cells within 1 mm of a circumferential or transectional margin. A negative resection margin (R0) was achieved for 6 patients (50%), with 3 in each group having R1 medial resection margins. Prior to resection of the pancreatic head, there was no difference in the number of CTCs between the 2 groups (range, 0-4 CTCs in the ST-PD group vs 1-6 CTCs in the NT-PD group; P = .31). Following resection, an increase in the number of CTCs was seen in 5 of 6 patients (83%) in the ST-PD group but 0 of 6 patients in the NT-PD group (P = .003) (eTable in Supplement). The median follow-up period for the entire cohort was 14.6 months (range, 10.5-27.9 months). At the end of follow-up, there were 7 deaths and 5 survivors. Median overall survival (OS) was 13.0 months (95% CI, 10.1-15.9) in the ST-PD group and 16.7 months (95% CI, 12.6-20.8) in the NT-PD group (P = .33) (Figure 2). Three patients in the ST-PD group and 2 patients in the NT-PD group developed disease recurrence in the liver (n = 2) and lung (n = 3). There was no difference in disease-free survival (DFS) between the 2 groups (P = .42). However, correlations with outcomes become unstable with small numbers of patients.

Table Graphic Jump LocationTable.  Clinicopathological Characteristics of Patients Undergoing Pancreaticoduodenectomy for Pancreatic Cancer
Place holder to copy figure label and caption
Figure 2.
Kaplan-Meier Curve of Overall Survival Comparing No-Touch Isolation Pancreaticoduodenectomy With Standard Pancreaticoduodenectomy

Comparison between groups was made by log-rank test (P = .33).

Graphic Jump Location

To our knowledge, this is the first study to examine CTC numbers in the PV circulation during PD for PDAC. The NT-PD technique has been adopted as the standard for pancreatic head resection in our patients with PDAC. There was a significant increase in the number of CTCs following ST-PD but not following NT-PD. Although the NT-PD group trended toward better OS and DFS, there was no significant difference. The log-rank test performs poorly with small sample sizes, so this may be a type II error.17 The NT technique was first described as a way of preventing the spread of cancer cells in colorectal and eye cancer by limiting the handling of the tumors.18,19 In colorectal cancer, a tendency for a reduction in the number and time to liver metastases over 5 years has been seen using the NT technique compared with conventional resection.20 More recently, the NT technique has been shown to be safe for PD14,21 and distal pancreatectomy,22 with comparable operative morbidity and mortality. In a small pilot study,23 carcinoembryonic antigen messenger RNA (mRNA) was identified in PV blood samples from 5 of 10 patients (50%) undergoing ST-PD compared with only 1 of 8 patients (13%) having NT-PD. The latter also had reduced disease recurrence and a longer OS. This study provided the first evidence for the biological benefit of this technique, even though mRNA levels were not isolated from a specific cell type.

The detection of CTCs is extremely difficult, as they are rare and samples are often contaminated by leukocytes. However, the ability to detect, enumerate, and characterize CTCs is important for the study of the metastatic cascade and improved clinical management of patients with cancer. To date, most studies have used the CellSearch system, the only one with US Food and Drug Administration approval. In recent years, other reproducible methods of CTC detection and analysis have been developed.24 However, the CellSearch system has been shown to be the most reliable tool in clinical trials using CTCs as a prognostic marker.2530 Limitations to this method and the functional significance of detected CTCs are further discussed in the eAppendix in the Supplement.

Peripheral CTCs have been detected using a low cutoff (≥1 CTC/7.5 mL) in 11% of patients with locally advanced PDAC31 and 40% to 80.5% with metastatic disease,8,11,32 compared with none in healthy individuals and those with chronic pancreatitis. While we did not assess CTCs in the peripheral circulation, it appears that CTCs are easier to detect in the PV circulation, even in earlier-stage disease, as 11 of our 12 patients (92%) had 1 or more CTCs per 7.5 mL in the PV prior to PD. The clinical implications of detecting CTCs in PDAC are under investigation; however, reports are divided regarding the association between enumeration and survival outcomes.33 Indeed, Kurihara et al11 found that in stage III to IV disease, CTC-positive patients (11 of 26 patients) had worse OS compared with those who were CTC negative (15 of 26 patients). Similarly, Bidard et al31 showed that in patients with stage III disease, CTC positivity at any point (baseline or after 2 months of chemotherapy) was associated with shorter OS (hazard ratio = 2.5; 95% CI, 1.2-5.4), although CTC detection did not influence DFS. Conversely, Khoja et al34 and Negin et al32 failed to correlate CTC number with OS or DFS in metastatic PDAC. Plausible explanations for these findings include small sample sizes or low statistical power of many of these studies, different detection methods and markers used, and heterogeneous patient groups.31,33 However, most studies do show a trend toward an association between CTC positivity and poor survival; thus, their role in metastatic development is still debated.

Our pilot study, albeit in a small number of patients, showed that NT-PD is comparable to ST-PD with regard to perioperative morbidity and long-term outcome. In addition, we provide further evidence that CTCs can be detected in patients with PDAC in the PV circulation and that the count is increased following tumor manipulation. This may affect disease recurrence and survival, but larger studies are needed for a definitive answer with regard to outcome.

Section Editor: Richard D. Schulick, MD, MBA; Pamela A. Lipsett, MD, MPHE.

Corresponding Author: Long R. Jiao, MD, FRCS, Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London, W12 0HS England (l.jiao@imperial.ac.uk).

Accepted for Publication: July 8, 2013.

Published Online: March 5, 2014. doi:10.1001/jamasurg.2013.3643.

Author Contributions: Dr Jiao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Jacob, Frampton, Stebbing, Jiao.

Acquisition of data: Gall, Jacob, Frampton, Kyriakides, Castellano, Jiao.

Analysis and interpretation of data: Gall, Frampton, Krell, Stebbing, Jiao.

Drafting of the manuscript: Gall, Frampton, Krell, Stebbing, Jiao.

Critical revision of the manuscript for important intellectual content: Jacob, Frampton, Krell, Kyriakides, Castellano, Stebbing, Jiao.

Statistical analysis: Gall, Frampton, Jiao.

Obtained funding: Castellano, Stebbing, Jiao.

Administrative, technical, and material support: Jacob, Kyriakides, Jiao.

Study supervision: Krell, Stebbing, Jiao.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by the Alliance Family Foundation.

Role of the Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Poruk  KE, Firpo  MA, Adler  DG, Mulvihill  SJ.  Screening for pancreatic cancer. Ann Surg. 2013;257(1):17-26.
PubMed   |  Link to Article
Sommerville  CA, Limongelli  P, Pai  M,  et al.  Survival analysis after pancreatic resection for ampullary and pancreatic head carcinoma. J Surg Oncol. 2009;100(8):651-656.
PubMed   |  Link to Article
Barugola  G, Falconi  M, Bettini  R,  et al.  The determinant factors of recurrence following resection for ductal pancreatic cancer. JOP. 2007;8(1)(suppl):132-140.
PubMed
Neoptolemos  JP, Stocken  DD, Friess  H,  et al; European Study Group for Pancreatic Cancer.  A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200-1210.
PubMed   |  Link to Article
Paterlini-Brechot  P, Benali  NL.  Circulating tumor cells (CTC) detection. Cancer Lett. 2007;253(2):180-204.
PubMed   |  Link to Article
Müller  V, Stahmann  N, Riethdorf  S,  et al.  Circulating tumor cells in breast cancer. Clin Cancer Res. 2005;11(10):3678-3685.
PubMed   |  Link to Article
Slade  MJ, Payne  R, Riethdorf  S,  et al.  Comparison of bone marrow, disseminated tumour cells and blood-circulating tumour cells in breast cancer patients after primary treatment. Br J Cancer. 2009;100(1):160-166.
PubMed   |  Link to Article
Ren  C, Han  C, Zhang  J,  et al.  Detection of apoptotic circulating tumor cells in advanced pancreatic cancer following 5-fluorouracil chemotherapy. Cancer Biol Ther. 2011;12(8):700-706.
PubMed   |  Link to Article
de Albuquerque  A, Kubisch  I, Breier  G,  et al.  Multimarker gene analysis of circulating tumor cells in pancreatic cancer patients. Oncology. 2012;82(1):3-10.
PubMed   |  Link to Article
Mudan  S, Giakoustidis  A, Thillainayagam  AV, Jacob  J, Stebbing  J.  Clinical utility of circulating tumor cell measurement in the diagnosis of indeterminate lesions of the pancreas. Future Oncol. 2010;6(1):177-179.
PubMed   |  Link to Article
Kurihara  T, Itoi  T, Sofuni  A,  et al.  Detection of circulating tumor cells in patients with pancreatic cancer. J Hepatobiliary Pancreat Surg. 2008;15(2):189-195.
PubMed   |  Link to Article
Jiao  LR, Apostolopoulos  C, Jacob  J,  et al.  Unique localization of circulating tumor cells in patients with hepatic metastases. J Clin Oncol. 2009;27(36):6160-6165.
PubMed   |  Link to Article
Rahbari  NN, Aigner  M, Thorlund  K,  et al.  Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology. 2010;138(5):1714-1726.
PubMed   |  Link to Article
Hirota  M, Kanemitsu  K, Takamori  H,  et al.  Pancreatoduodenectomy using a no-touch isolation technique. Am J Surg. 2010;199(5):e65-e68.
PubMed   |  Link to Article
Berger  AC, Watson  JC, Ross  EA, Hoffman  JP.  The metastatic/examined lymph node ratio is an important prognostic factor after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am Surg. 2004;70(3):235-240.
PubMed
Bitsakou  G, Frampton  AE, Pai  M, Jiao  LR.  An alternative pancreatic anastomosis following pancreaticoduodenectomy. Arch Surg. 2011;146(6):752-754.
PubMed   |  Link to Article
Wang  R, Lagakos  SW, Gray  RJ.  Testing and interval estimation for two-sample survival comparisons with small sample sizes and unequal censoring. Biostatistics. 2010;11(4):676-692.
PubMed   |  Link to Article
Barnes  JP.  Physiologic resection of the right colon. Surg Gynecol Obstet. 1952;94(6):722-726.
PubMed
Turnbull  RB  Jr, Kyle  K, Watson  FR, Spratt  J.  Cancer of the colon. Ann Surg. 1967;166(3):420-427.
PubMed   |  Link to Article
Wiggers  T, Jeekel  J, Arends  JW,  et al.  No-touch isolation technique in colon cancer. Br J Surg. 1988;75(5):409-415.
PubMed   |  Link to Article
Kobayashi  S, Asano  T, Ochiai  T.  A proposal of no-touch isolation technique in pancreatoduodenectomy for periampullary carcinomas. Hepatogastroenterology. 2001;48(38):372-374.
PubMed
Hirota  M, Hashimoto  D, Ishiko  T,  et al.  Distal pancreatectomy using a no-touch isolation technique. Scand J Surg. 2012;101(3):156-159.
PubMed   |  Link to Article
Hirota  M, Shimada  S, Yamamoto  K,  et al.  Pancreatectomy using the no-touch isolation technique followed by extensive intraoperative peritoneal lavage to prevent cancer cell dissemination. JOP. 2005;6(2):143-151.
PubMed
O’Flaherty  JD, Gray  S, Richard  D,  et al.  Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer. Lung Cancer. 2012;76(1):19-25.
PubMed   |  Link to Article
Onstenk  W, Gratama  JW, Foekens  JA, Sleijfer  S.  Towards a personalized breast cancer treatment approach guided by circulating tumor cell (CTC) characteristics. Cancer Treat Rev. 2013;39(7):691-700.
PubMed   |  Link to Article
Schindlbeck  C, Andergassen  U, Hofmann  S,  et al.  Comparison of circulating tumor cells (CTC) in peripheral blood and disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients. J Cancer Res Clin Oncol. 2013;139(6):1055-1062.
PubMed   |  Link to Article
Munzone  E, Botteri  E, Sandri  MT,  et al.  Prognostic value of circulating tumor cells according to immunohistochemically defined molecular subtypes in advanced breast cancer. Clin Breast Cancer. 2012;12(5):340-346.
PubMed   |  Link to Article
Gazzaniga  P, Gradilone  A, de Berardinis  E,  et al.  Prognostic value of circulating tumor cells in nonmuscle invasive bladder cancer. Ann Oncol. 2012;23(9):2352-2356.
PubMed   |  Link to Article
Naito  T, Tanaka  F, Ono  A,  et al.  Prognostic impact of circulating tumor cells in patients with small cell lung cancer. J Thorac Oncol. 2012;7(3):512-519.
PubMed   |  Link to Article
Shamash  J, Jacob  J, Agrawal  S,  et al.  Whole blood stem cell reinfusion and escalated dose melphalan in castration-resistant prostate cancer. Clin Cancer Res. 2012;18(8):2352-2359.
PubMed   |  Link to Article
Bidard  FC, Huguet  F, Louvet  C,  et al.  Circulating tumor cells in locally advanced pancreatic adenocarcinoma. Ann Oncol. 2013;24(8):2057-2061.
PubMed   |  Link to Article
Negin  BP, Meropol  NJ, Alpaugh  RK,  et al.  Characterization and prognostic significance of circulating tumor cells in the peripheral blood of patients with metastatic pancreatic cancer. J Clin Oncol. 2010;28(suppl):15s.
Tjensvoll  K, Nordgård  O, Smaaland  R.  Circulating tumor cells in pancreatic cancer patients. Int J Cancer. 2014;134(1):1-8.
PubMed   |  Link to Article
Khoja  L, Backen  A, Sloane  R,  et al.  A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br J Cancer. 2012;106(3):508-516.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Identification of Pancreatic Circulating Tumor Cells (CTCs) in the Portal Venous Circulation

A, True CTC that is positive for epithelial cell adhesion molecule, pan-cytokeratin (pan-CK), and 4′,6-diamidino-2-phenylindole (DAPI) but negative for CD45. B, Leukocyte that is positive for CD45. Images are from the CellTracks Analyzer II, which uses fluorescent optics to capture and analyze CTCs that have been immunomagnetically selected.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Kaplan-Meier Curve of Overall Survival Comparing No-Touch Isolation Pancreaticoduodenectomy With Standard Pancreaticoduodenectomy

Comparison between groups was made by log-rank test (P = .33).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Clinicopathological Characteristics of Patients Undergoing Pancreaticoduodenectomy for Pancreatic Cancer

References

Poruk  KE, Firpo  MA, Adler  DG, Mulvihill  SJ.  Screening for pancreatic cancer. Ann Surg. 2013;257(1):17-26.
PubMed   |  Link to Article
Sommerville  CA, Limongelli  P, Pai  M,  et al.  Survival analysis after pancreatic resection for ampullary and pancreatic head carcinoma. J Surg Oncol. 2009;100(8):651-656.
PubMed   |  Link to Article
Barugola  G, Falconi  M, Bettini  R,  et al.  The determinant factors of recurrence following resection for ductal pancreatic cancer. JOP. 2007;8(1)(suppl):132-140.
PubMed
Neoptolemos  JP, Stocken  DD, Friess  H,  et al; European Study Group for Pancreatic Cancer.  A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200-1210.
PubMed   |  Link to Article
Paterlini-Brechot  P, Benali  NL.  Circulating tumor cells (CTC) detection. Cancer Lett. 2007;253(2):180-204.
PubMed   |  Link to Article
Müller  V, Stahmann  N, Riethdorf  S,  et al.  Circulating tumor cells in breast cancer. Clin Cancer Res. 2005;11(10):3678-3685.
PubMed   |  Link to Article
Slade  MJ, Payne  R, Riethdorf  S,  et al.  Comparison of bone marrow, disseminated tumour cells and blood-circulating tumour cells in breast cancer patients after primary treatment. Br J Cancer. 2009;100(1):160-166.
PubMed   |  Link to Article
Ren  C, Han  C, Zhang  J,  et al.  Detection of apoptotic circulating tumor cells in advanced pancreatic cancer following 5-fluorouracil chemotherapy. Cancer Biol Ther. 2011;12(8):700-706.
PubMed   |  Link to Article
de Albuquerque  A, Kubisch  I, Breier  G,  et al.  Multimarker gene analysis of circulating tumor cells in pancreatic cancer patients. Oncology. 2012;82(1):3-10.
PubMed   |  Link to Article
Mudan  S, Giakoustidis  A, Thillainayagam  AV, Jacob  J, Stebbing  J.  Clinical utility of circulating tumor cell measurement in the diagnosis of indeterminate lesions of the pancreas. Future Oncol. 2010;6(1):177-179.
PubMed   |  Link to Article
Kurihara  T, Itoi  T, Sofuni  A,  et al.  Detection of circulating tumor cells in patients with pancreatic cancer. J Hepatobiliary Pancreat Surg. 2008;15(2):189-195.
PubMed   |  Link to Article
Jiao  LR, Apostolopoulos  C, Jacob  J,  et al.  Unique localization of circulating tumor cells in patients with hepatic metastases. J Clin Oncol. 2009;27(36):6160-6165.
PubMed   |  Link to Article
Rahbari  NN, Aigner  M, Thorlund  K,  et al.  Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology. 2010;138(5):1714-1726.
PubMed   |  Link to Article
Hirota  M, Kanemitsu  K, Takamori  H,  et al.  Pancreatoduodenectomy using a no-touch isolation technique. Am J Surg. 2010;199(5):e65-e68.
PubMed   |  Link to Article
Berger  AC, Watson  JC, Ross  EA, Hoffman  JP.  The metastatic/examined lymph node ratio is an important prognostic factor after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am Surg. 2004;70(3):235-240.
PubMed
Bitsakou  G, Frampton  AE, Pai  M, Jiao  LR.  An alternative pancreatic anastomosis following pancreaticoduodenectomy. Arch Surg. 2011;146(6):752-754.
PubMed   |  Link to Article
Wang  R, Lagakos  SW, Gray  RJ.  Testing and interval estimation for two-sample survival comparisons with small sample sizes and unequal censoring. Biostatistics. 2010;11(4):676-692.
PubMed   |  Link to Article
Barnes  JP.  Physiologic resection of the right colon. Surg Gynecol Obstet. 1952;94(6):722-726.
PubMed
Turnbull  RB  Jr, Kyle  K, Watson  FR, Spratt  J.  Cancer of the colon. Ann Surg. 1967;166(3):420-427.
PubMed   |  Link to Article
Wiggers  T, Jeekel  J, Arends  JW,  et al.  No-touch isolation technique in colon cancer. Br J Surg. 1988;75(5):409-415.
PubMed   |  Link to Article
Kobayashi  S, Asano  T, Ochiai  T.  A proposal of no-touch isolation technique in pancreatoduodenectomy for periampullary carcinomas. Hepatogastroenterology. 2001;48(38):372-374.
PubMed
Hirota  M, Hashimoto  D, Ishiko  T,  et al.  Distal pancreatectomy using a no-touch isolation technique. Scand J Surg. 2012;101(3):156-159.
PubMed   |  Link to Article
Hirota  M, Shimada  S, Yamamoto  K,  et al.  Pancreatectomy using the no-touch isolation technique followed by extensive intraoperative peritoneal lavage to prevent cancer cell dissemination. JOP. 2005;6(2):143-151.
PubMed
O’Flaherty  JD, Gray  S, Richard  D,  et al.  Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer. Lung Cancer. 2012;76(1):19-25.
PubMed   |  Link to Article
Onstenk  W, Gratama  JW, Foekens  JA, Sleijfer  S.  Towards a personalized breast cancer treatment approach guided by circulating tumor cell (CTC) characteristics. Cancer Treat Rev. 2013;39(7):691-700.
PubMed   |  Link to Article
Schindlbeck  C, Andergassen  U, Hofmann  S,  et al.  Comparison of circulating tumor cells (CTC) in peripheral blood and disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients. J Cancer Res Clin Oncol. 2013;139(6):1055-1062.
PubMed   |  Link to Article
Munzone  E, Botteri  E, Sandri  MT,  et al.  Prognostic value of circulating tumor cells according to immunohistochemically defined molecular subtypes in advanced breast cancer. Clin Breast Cancer. 2012;12(5):340-346.
PubMed   |  Link to Article
Gazzaniga  P, Gradilone  A, de Berardinis  E,  et al.  Prognostic value of circulating tumor cells in nonmuscle invasive bladder cancer. Ann Oncol. 2012;23(9):2352-2356.
PubMed   |  Link to Article
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eAppendix. Pancreaticoduodenectomy Techniques, Identification of Circulating Tumor Cells (CTCs) Using the CellSearch System, and Limitations of CellSearch and the Functional Significance of Detected CTCs in PDAC

eReferences

eTable. Number of CTCs Detected Within the Portal Venous Circulation Before and After Pancreaticoduodenectomy

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