Publications by authors named "Emilio Bertani"

53 Publications

Prognostic features of gastro-entero-pancreatic neuroendocrine neoplasms in primary and metastatic sites: Grade, mesenteric tumour deposits and emerging novelties.

J Neuroendocrinol 2021 08 16;33(8):e13000. Epub 2021 Jul 16.

1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Updates in classification of gastro-entero-pancreatic neuroendocrine neoplasms better reflect the biological characteristics of these tumours. In the present study, we analysed the characteristics of neuroendocrine tumours that could aid in a more precise stratification of risk groups. In addition, we have highlighted the importance of grade (re)assessment based on investigation of secondary tumour lesions. Two hundred and sixty-four cases of neuroendocrine tumours of gastro-entero-pancreatic origin from three centres were included in the study. Tumour morphology, mitotic count and Ki67 labelling index were evaluated in specimens of primary tumours, lymph node metastases and distant metastases. These variables were correlated with overall survival (OS) and relapse-free survival (RFS). Tumour stage, number of affected lymph nodes, presence of tumour deposits and synchronous/metachronous metastases were tested as possible prognostic features. Mitotic count, Ki-67 labelling index, primary tumour site, tumour stage, presence of tumour deposits and two or more affected lymph nodes were significant predictors of OS and RFS. At the same time, mitotic count and Ki-67 labelling index can be addressed as continuous variables determining prognosis. We observed a very high correlation between the measures of proliferative activity in primary and secondary tumour foci. The presence of isolated tumour deposits was identified as an important determinant of both RFS and OS for pancreatic (hazard ratio [HR] = 7.61, 95% confidence interval [CI] = 3.96-14.6, P < 0.0001 for RFS; HR = 3.28, 95% CI = 1.56-6.87, P = 0.0017 for OS) and ileal/jejunal neuroendocrine tumours (HR = 1.98, 95% CI = 1.25-3.13, P = 0.0036 for RFS and HR 2.59, 95% CI = 1.27-5.26, P = 0.009 for OS). The present study identifies the presence of mesenterial tumour deposits as an important prognostic factor for gastro-entero-pancreatic neuroendocrine tumours, provides evidence that proliferative parameters need to be treated as continuous variables and further supports the importance of grade determination in all available tumour foci.
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http://dx.doi.org/10.1111/jne.13000DOI Listing
August 2021

Looking for the right TNM staging system for pancreatic neuroendocrine tumors.

Hepatobiliary Surg Nutr 2021 Jun;10(3):382-384

Division of Digestive Surgery, European Institute of Oncology, IEO, IRCCS, Milan, Italy.

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http://dx.doi.org/10.21037/hbsn-2021-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188133PMC
June 2021

First Results of β-Radioguided Surgery in Small Intestine Neuroendocrine Tumors with Y-DOTATOC.

Cancer Biother Radiopharm 2021 Jun 18;36(5):397-406. Epub 2021 Feb 18.

Division of Nuclear Medicine, Istituto Europeo di Oncologia, IRCCS, Milano, Italy.

In neuroendocrine tumor (NET), complete surgery could better the prognosis. Radioguided surgery (RGS) with β-radioisotopes is a novel approach focused on developing a new probe that, detecting electrons and operating with low background, provides a clearer delineation of the lesions with low radiation exposition for surgeons. As a first step to validate this procedure, specimens of tumors expressing somatostatin receptors, as small intestine neuroendocrine tumor (SI-NET), were tested. SI-NET presents a high uptake of a beta-emitting radiotracer, Y-DOTATOC. Five SI-NET patients were enrolled after performing a Ga-DOTATOC positron emission tomography/computed tomography (CT) and a CT enterography; 24 h before surgery, they received 5 mCi of Y-DOTATOC. Surgery was performed as routine. Tumors and surrounding tissue were sectioned in different samples and examined with the beta-detecting probe. All the tumor samples showed high counts of radioactivity that was up to a factor of 18 times higher than the corresponding cutoff value, with a sensitivity of 96% and a specificity of 100%. These first RGS tests showed that this probe can discriminate very effectively between tumor and healthy tissues by the administration of low activities of Y-DOTATOC, allowing more precise surgery.
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http://dx.doi.org/10.1089/cbr.2020.4487DOI Listing
June 2021

Fluorescence-based bowel anastomosis perfusion evaluation: results from the IHU-IRCAD-EAES EURO-FIGS registry.

Surg Endosc 2021 12 25;35(12):7142-7153. Epub 2021 Jan 25.

Ospedale di Vaio, Fidenza, Italy.

Background: Anastomotic leakage (AL) is one of the dreaded complications following surgery in the digestive tract. Near-infrared fluorescence (NIRF) imaging is a means to intraoperatively visualize anastomotic perfusion, facilitating fluorescence image-guided surgery (FIGS) with the purpose to reduce the incidence of AL. The aim of this study was to analyze the current practices and results of NIRF imaging of the anastomosis in digestive tract surgery through the EURO-FIGS registry.

Methods: Analysis of data prospectively collected by the registry members provided patient and procedural data along with the ICG dose, timing, and consequences of NIRF imaging. Among the included upper-GI, colorectal, and bariatric surgeries, subgroup analysis was performed to identify risk factors associated with complications.

Results: A total of 1240 patients were included in the study. The included patients, 74.8% of whom were operated on for cancer, originated from 8 European countries and 30 hospitals. A total of 54 surgeons performed the procedures. In 83.8% of cases, a pre-anastomotic ICG dose was administered, and in 60.1% of cases, a post-anastomotic ICG dose was administered. A significant difference (p < 0.001) was found in the ICG dose given in the four pathology groups registered (range: 0.013-0.89 mg/kg) and a significant (p < 0.001) negative correlation was found between the ICG dose and BMI. In 27.3% of the procedures, the choice of the anastomotic level was guided by means of NIRF imaging which means that in these cases NIRF imaging changed the level of anastomosis which was first decided based on visual findings in conventional white light imaging. In 98.7% of the procedures, the use of ICG partly or strongly provided a sense of confidence about the anastomosis. A total of 133 complications occurred, without any statistical significance in the incidence of complications in the anastomoses, whether they were ICG-guided or not.

Conclusion: The EURO-FIGS registry provides an insight into the current clinical practice across Europe with respect to NIRF imaging of anastomotic perfusion during digestive tract surgery.
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http://dx.doi.org/10.1007/s00464-020-08234-8DOI Listing
December 2021

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study.

Front Med (Lausanne) 2020 23;7:598438. Epub 2020 Dec 23.

National NET Centre and ENETS Centre of Excellence, St Vincent's University Hospital, Dublin, Ireland.

The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017-2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at Gallium DOTATOC-PET scan. The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach.
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http://dx.doi.org/10.3389/fmed.2020.598438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785972PMC
December 2020

Fluorescence-guided D3 lymphadenectomy in robotic right colectomy with complete mesocolic excision.

Int J Med Robot 2021 Jun 21;17(3):e2217. Epub 2021 Jan 21.

Division of Hepatobiliary and Colorectal Surgery, Candiolo Cancer Institute IRCCS, Candiolo, Italy.

Background: In robotic right hemicolectomy for cancer, appropriate lymphadenectomy is essential. Visualization of draining lymph nodes and blood flow with near-infrared (NIR) fluorescence DaVinci imaging system is a recent development. We present the technique of robotic right colectomy with complete mesocolic excision (CME) and D3 lymphadenectomy using Indocyanine Green (ICG) endoscopic submucosal injection to intraoperatively identify tumour lymphatic basin.

Methods: The day before surgery, in patients scheduled for robotic right colectomy an endoscopic submucosal injection of 3 mg of ICG solution around the tumor is realized. Robotic right hemicolectomy is performed with suprapubic trocars layout and "bottom to up dissection", realizing a CME with central vessel ligation and D3 lymphadenectomy. Site of primary tumor and lymphatic basin are visible with the FireflyTM camera modality.

Results: From July 2016 to July 2020, 85 patients received a robotic right colectomy with CME and D3 lymphadenectomy. In 50 patients, ICG submucosal injection was performed: visualisation of the site of primary tumour and of LN in the D3 area was possible in all cases; in 17/50 patients (34%), LN out from anatomical lymphatic basin were identified. No side effects were observed.

Conclusions: In this series, submucosal ICG injection showed to be feasible and safe. The accuracy in identification of D3 lymphatic basin was high, thus permitting an image-guided radical lymphadenectomy. Fluorescent technology represents an interesting innovation to ameliorate surgery of colon cancer.
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http://dx.doi.org/10.1002/rcs.2217DOI Listing
June 2021

Cisplatin plus capecitabine concomitant with intensity-modulated radiation therapy in non-metastatic anal squamous cell carcinoma: the experience of a single research cancer center.

Ther Adv Med Oncol 2020 15;12:1758835920940945. Epub 2020 Jul 15.

Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology IRCCS, Milan, Italy.

Background And Aims: The standard treatment of non-metastatic anal squamous cell carcinoma (ASCC) consists of chemotherapy with mitomycin (MMC) plus 5-fluorouracil (5FU) for 1-2 cycles concomitant with pelvic radiotherapy. Subsequent studies introduced cisplatin (CDDP) combined with 5FU, with unclear results. We evaluated the doublet capecitabine (C) and CDDP as a possible alternative to MMC-5FU regimen concomitant with intensity-modulated radiation therapy (IMRT).

Patients And Methods: We carried out a retrospective study on 67 patients affected by stage I-III ASCC, treated with CDDP (60-70 mg/m every 21 days for two courses) plus C (825 mg/m twice daily for 5 days/week) chemotherapy concomitant with IMRT for curative intent.

Results: At a median follow up of 41 months, the clinical complete response calculated at the 6-month time-point (6-moCR), the 6-month objective response rate and the 6-month disease control rate were 93%, 94%, and 99%, respectively.Disease-free survival rates at 1, 2, and 3 years were 89%, 87%, and 85%, while the overall survival rates at 1 and 2 years were 100% and 95%. The colostomy-free survival rates were 90% at 1 year and 88% at 2 years. Grade 3-4 acute adverse events were reported in 61% of patients; predominantly skin toxicity (46%) and limited hematological toxicity (12%).

Conclusion: In this retrospective study, chemotherapy with C plus CDDP concomitant with IMRT proved safe and effective, and may represent a possible alternative option to standard MMC-containing regimen for curative intent.
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http://dx.doi.org/10.1177/1758835920940945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364808PMC
July 2020

Histopathological and Immunophenotypic Changes of Pancreatic Neuroendocrine Tumors after Neoadjuvant Peptide Receptor Radionuclide Therapy (PRRT).

Endocr Pathol 2020 Jun;31(2):119-131

Pathology Unit, Pancreas Translational and Clinical Research Center, ENETS Center of Excellence, IRCCS San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy.

Peptide Receptor Radionuclide Therapy (PRRT) is an emerging therapeutic option for pancreatic neuroendocrine tumors (PanNETs). A possible role for PRRT as a neoadjuvant agent is still largely undetermined, explored only in case reports or small case series. Likewise, the histopathological and immunophenotypic changes induced by PRRT are poorly characterized. In the present study, 24 patients who underwent neoadjuvant PRRT on the basis of their disease's characteristics were retrospectively matched with 24 patients who underwent upfront surgery. A comprehensive morphological and immunohistochemical evaluation was conducted to identify the differences in the two groups. The most significant findings were that the total percentage of stroma increased significantly in patients who underwent PRRT (p < 0.0001) and the characteristics of the stroma were different in the two groups. The somatostatin receptors type 2A (SSTR2A) were retained in most patients (87%) after PRRT. The density of CD163+ M2-polarized macrophages was greater in the PRRT group (p = 0.022), and M2-polarized macrophages tended to assume an epithelioid morphology (p = 0.043). In the neoadjuvant PRRT group, none of the histological parameters considered were associated with progression-free survival (PFS). Neoadjuvant PRRT in PanNETs is associated with reduced tumor diameter, an increased percentage of stroma, preserved SSTR2A expression in most of the cases, and an increased CD163+ M2-polarized macrophages density.
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http://dx.doi.org/10.1007/s12022-020-09623-4DOI Listing
June 2020

Systemic therapies in patients with advanced well-differentiated pancreatic neuroendocrine tumors (PanNETs): When cytoreduction is the aim. A critical review with meta-analysis.

Cancer Treat Rev 2018 Dec 13;71:39-46. Epub 2018 Oct 13.

Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy. Electronic address:

Introduction: Cytoreduction is sometimes an important aim of systemic anti-tumor therapies in well-differentiated pancreatic neuroendocrine tumors (PanNETs). As there is not a gold standard treatment for these tumors in this field, we conducted a literature review in order to identify objective criteria for treatment choice.

Materials And Methods: We critically reviewed and performed a meta-analysis of all published clinical studies of systemic therapies in patients with well-differentiated unresectable PanNETs, selecting only those articles which reported tumor shrinkage (TS) with a waterfall plot (WP). Tumor downsizing of ≥10% was considered as objective response.

Results: We selected 17 out of 2758 studies, comprising 1118 patients with tumor response reported as WP. Proliferation index, tumor burden and anti-tumor therapies were heterogeneous. Chemotherapy alone (mainly, capecitabine/temozolomide) or in combination showed the best results, with ≥10% TS ranging from 65% to 93%. Peptide receptor radionuclide therapy combined with chemotherapy (Chemo-PRRT) and sunitinib appeared promising by inducing objective response in a significant proportion of patients (93% and 60%, respectively). Time to tumor response was reported in only two trials. No clear clinical and/or biological predictive factors emerged.

Conclusion: Based on response criteria used in our retrospective analysis, systemic chemotherapy alone or in combination appeared to have the main cytoreductive impact. However no conclusions regarding either a specific regimen or combination can be drawn. Furthermore, tumor population selection and/or choice of regimen may have a significant influence. Further analysis should be also conducted to identify potential predictive biomarkers of responses, in order to design future prospective interventional clinical trials enrolling more homogenous populations of advanced well-differentiated PanNETs.
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http://dx.doi.org/10.1016/j.ctrv.2018.10.008DOI Listing
December 2018

Robotic Versus Laparoscopic Right Colectomy with Complete Mesocolic Excision for the Treatment of Colon Cancer: Perioperative Outcomes and 5-Year Survival in a Consecutive Series of 202 Patients.

Ann Surg Oncol 2018 Nov 14;25(12):3580-3586. Epub 2018 Sep 14.

Division of Gastrointestinal Surgery, European Institute of Oncology, Milan, Italy.

Background: During the past decade, the concept of complete mesocolic excision (CME) has emerged as a possible strategy to minimize recurrence for right colon cancers. The purpose of this study was to compare robotic versus laparoscopic CME in performing right colectomy for cancer.

Methods: Pertinent data of all patients who underwent robotic or laparoscopic right colectomy with CME using a Pfannenstiel incision and intracorporeal anastomosis performed between October 2005 and November 2015 were entered in a prospectively maintained database.

Results: A total of 202 patients underwent robotic (n = 101) or laparoscopic (n = 101) right colectomy within the study period. Patient characteristics were equivalent between groups. The robotic group showed a statistically significant reduction in conversion rate (0% vs. 6.9%, p = 0.01) but a longer operative time (279 min vs. 236 min, p < 0.001) compared with the laparoscopic group. There were no other differences in perioperative clinical or pathological outcomes. Five-years overall survival was 77 versus 73 months for the robotic versus laparoscopic groups (p = 0.64). The disease-free survival (DFS) rates were 85% and 83% for the robotic versus laparoscopic groups (p = 0.58). Among UICC stage III patients, there was a slight but not significant difference in 5-year DFS for the robotic group (81 vs. 68 months; p = 0.122).

Conclusions: Both approaches for right colectomy with CME were safe and feasible and resulted in excellent survival. Robotic assistance was beneficial for performing intracorporeal anastomosis and dissection as evidenced by the lower conversion rates. Further robotic experience may shorten the operative time.
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http://dx.doi.org/10.1245/s10434-018-6752-7DOI Listing
November 2018

Green indocyanine fluorescence in robotic abdominal surgery.

Updates Surg 2018 Sep 29;70(3):375-379. Epub 2018 Aug 29.

Department of Hepatobiliary and Digestive Surgery, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, Milan, Italy.

Fluorescent imaging with indocyanine green (ICG) is an emerging technology that is gaining acceptance for being a valid tool in surgeons' decision making. ICG binds to plasma lipoproteins if injected intravenously and, when excited by near-infrared light, provides anatomic information about organs vascularization and tissues perfusion. If injected in tissues, it migrates in the lymphatic system, therefore enabling the identification of lymphatic draining pathways of different organs. In this paper we address specific applications of ICG fluorescence in robotic general surgery.
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http://dx.doi.org/10.1007/s13304-018-0585-6DOI Listing
September 2018

Robotic right colectomy with complete mesocolic excision and indocyanine green guidance.

Minerva Chir 2019 Apr 23;74(2):165-169. Epub 2018 Jul 23.

Division of Gastrointestinal Surgery, European Institute of Oncology, Milan, Italy -

Background: Robotic complete mesocolic excision (CME) has recently emerged as promising technique to enhance oncologic results in hemicolectomy for cancer. The potential near-infrared (NIR) fluorescence with indocyanine-green (ICG) dye for lymphatic mapping is under investigation and few small case-series are reported.

Methods: ICG solution was endoscopically injected the day before surgery in patients undergoing robotic right colectomy with CME using the Da Vinci Xi® system and the bottom to up technique. During surgery the ICG was excited by light in the near-infrared (NIR) spectrum of the Firefly™ system, of the Da Vinci Xi® system for image comparison in standard white light and NIR, and real-time visualization of the lymphatic drainage.

Results: Twenty patients affected by right colon cancer underwent robotic right colectomy with the bottom to up technique. No cases converted to open surgery were observed. During surgery, a fluorescent mapping of draining lymph nodes, was visualized in all the 20 patients. In seven patients (35%), lymph nodes outside the standard lymphatic basin were identified and removed.

Conclusions: The association of robotic right colectomy with the bottom to up technique and ICG-guided lymphadenectomy is a feasible and safe procedure. ICG lymphatic mapping may help to perform a correct CME, although the independent impact of these procedures on oncologic outcome deserves further investigations.
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http://dx.doi.org/10.23736/S0026-4733.18.07831-8DOI Listing
April 2019

Double indocyanine green technique of robotic right colectomy: Introduction of a new technique.

J Minim Access Surg 2019 Oct-Dec;15(4):357-359

European Institute of Oncology (IEO), Hepatobiliary, Pancreatic and Digestive Program, Milan, Italy.

In robotic right hemicolectomy for colorectal cancer (CRC), appropriate lymphadenectomy and anastomotic leak prevention are critical. Visualisation of lymph nodes and blood flow with near-infrared (NIR) fluorescence DaVinci imaging system is a recent development. Herein, we present an improved robotic modified complete mesocolic excision (mCME) technique using indocyanine green (ICG) fluorescence. Before surgery, ICG is injected into the submucosa around the tumour with endoscopy for intraoperative detection of lymph nodes. Robotic mCME with central vascular ligation is performed, supplemented in most of the cases with selective extended lymphadenectomy. Intestinal blood flow before anastomosis is evaluated by administering ICG intravenously and NIR visualisation. Visualisation of the lymph nodes with ICG facilitates standard mCME lymphadenectomy and enables extended lymphadenectomy. Blood flow of the intestinal walls of the anastomotic site can be assessed and determines the extent of intestinal resection. Robotic double ICG technique for robotic right hemicolectomy enables improved lymphadenectomy and warrants the extent of intestinal resection; thus, becoming a strong candidate for gold standard in robotic resections of the right colon for CRC.
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http://dx.doi.org/10.4103/jmas.JMAS_127_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839355PMC
July 2018

Aggressive Surgical Approach for Treatment of Primary and Recurrent Retroperitoneal Soft Tissue Sarcoma.

Indian J Surg 2018 Apr 31;80(2):154-162. Epub 2018 Jan 31.

6Division of Digestive-Tract Surgery, European Institute of Oncology, via Ripamonti, 435, 20141 Milan, Italy.

To analyze treatment and survival in a series of resected patients with primary or recurrent retroperitoneal sarcoma (RPS) treated and prospectively followed at a single institution. Between July 1994 and December 2015, 89 patients (36 M, 53 F; mean age 60 years, range 25-79) were evaluated. For the purpose of analysis, complete resection was defined as removal of gross tumor with histologically confirmed clear resection margins. Eighty-three out of the 89 patients (93%), 46 of whom affected by primary RPS, and 37 by recurrent RPS, underwent surgical exploration. Sixty-two had a grossly and microscopically complete resection. Fifty-three out of 83 patients (64%) underwent removal of contiguous intra-abdominal organs. Preoperative mortality was nil and significant preoperative complications occurred in six cases only (7%). High-grade tumor pointed out to be a significant variable for a worse survival in all 83 patients amenable to undergo surgical resection (57% 5 years survival for low grade vs 14% for high grade;  = 0.0004). Among completely resected patients, only histologic grade clearly affected disease-free survival (72% 5 years survival for low grade vs 50% for high grade;  = 0.04), while the role of preoperative blood transfusions (67% 5 years survival for non-transfused patients vs 29% for transfused patients;  = 0.05) has to be evaluated in connection to patient complexity. Histological grade and recurrence are the most valuable prognostic predictors; in this clinical subset, an aggressive surgical approach in both primary and recurrent RPS is associated with a best long-term survival and disease-free survival.
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http://dx.doi.org/10.1007/s12262-018-1722-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991015PMC
April 2018

Neuroendocrine neoplasms of rectum: A management update.

Cancer Treat Rev 2018 May 6;66:45-55. Epub 2018 Apr 6.

Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milano, Italy.

The estimated annual incidence of R-NENs is 1.04 per 100,000 persons although the real incidence may be underestimated, as not all R-NEN are systematically reported in registers. Also the prevalence has increased substantially, reflecting the rising incidence and indolent nature of R-NENs, showing the highest prevalence increase among all site of origin of NENs. The size of the tumor reveals the behavior of R-NENs where the risk for metastatic spread increases for lesions > 10 mm. Applying the WHO 2010 grading system to whole NENs originating in the gastroenteropancreatic system, R-NENs are classified as Well-Differentiated Neuroendocrine Tumors (WD-NET), which contain NET G1 and NET G2, and Poorly-Differentiated Carcinomas (PD-NEC) enclosing only G3 neoplasms for which the term carcinoma is applied. The treatment is endoscopic resection in most cases: conventional polypectomy or endoscopic mucosal resection (EMR) for smaller lesions or endoscopic submucosal resection with a ligation device (ESMR-L), cap-assisted EMR (EMR-C) and endoscopic submucosal dissection (ESD). However it is important to know when the endoscopic treatment is not enough, and surgical treatment is indicated, or when the latter could be unnecessary. For PD-NECs, it has recently been demonstrated that chemoradiotherapy is associated with a similar long-term survival to that obtained with surgery. As well, new targeted-agents chemotherapy may be indicated for metastatic WD-NETs.
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http://dx.doi.org/10.1016/j.ctrv.2018.04.003DOI Listing
May 2018

Peptide receptor radionuclide therapy as neoadjuvant therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms.

Surgery 2018 04 25;163(4):761-767. Epub 2017 Dec 25.

Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. Electronic address:

Background: Peptide receptor radionuclide therapy is a valid therapeutic option for pancreatic neuroendocrine neoplasms. The aim of this study was to describe an initial experience with the use of peptide receptor radionuclide therapy as a neoadjuvant agent for resectable or potentially resectable pancreatic neuroendocrine neoplasms.

Methods: The postoperative outcomes of 23 patients with resectable or potentially resectable pancreatic neuroendocrine neoplasms at high risk of recurrence who underwent neoadjuvant peptide receptor radionuclide therapy (peptide receptor radionuclide therapy group) were compared with 23 patients who underwent upfront surgical operation (upfront surgery group). Patients were matched for tumor size, grade, and stage. Median follow-up was 61 months.

Results: The size (median greatest width) of the primary pancreatic neuroendocrine neoplasms decreased after neoadjuvant peptide receptor radionuclide therapy (59 to 50 mm; P=.047). There were no differences in intraoperative and postoperative outcomes and there were no operative deaths, but the risk of developing a pancreatic fistula tended to be less in the peptide receptor radionuclide therapy group when compared to the upfront surgery group (0/23 vs 4/23; P < .02). The incidence of nodal metastases at the time of resection was also less in the peptide receptor radionuclide therapy group (n= 9/23 vs 17/23; P<.02). Neither median disease-specific survival (not reached in either group; P=.411) nor progression-free survival (52 vs 37 months; P>.2) differed between groups, but progression-free survival in the 31 patients who had an R0 resection seemed to be greater in the 15 patients in the peptide receptor radionuclide therapy group versus 16 patients the upfront group (median progression-free survival not reached vs 36 months; P<.05).

Conclusion: Neoadjuvant peptide receptor radionuclide therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms in patients with high-risk features of recurrence seems to be beneficial, but well-designed and much larger prospective trials are needed to confirm the safety and the oncologic value of this approach.
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http://dx.doi.org/10.1016/j.surg.2017.11.007DOI Listing
April 2018

Directional probe for radio-guided surgery: A pilot study.

Med Phys 2018 Feb 2;45(2):622-628. Epub 2018 Jan 2.

Institute of Biostructure and Bioimaging, National Research Council of Italy, Via Salaria km 29, 300, 00015 Monterotondo Scalo, Rome, Italy.

Purpose: The sentinel lymph node (SLN) biopsy technique has highly evolved during the last 20 yr. Consequently, the intraoperative use of Gamma Probes (GPs) for SLN mapping is increased. This preliminary study evaluates a novel directional GP prototype. This proof-of-concept prototype is designed to identify the direction of radiopharmaceuticals uptakes, by combining the information from multiple detectors. The purpose of this work is to develop a tool able to effectively guide the surgeon reducing the surgery time.

Methods: The proposed prototype consists of three CsI(Tl) scintillation crystals, each coupled with an S10931 silicon photomultiplier (Hamamatsu Photonics K.K., Hamamatsu, JP). The three detectors lie on the same plane with an angle of 30° between them. The central detector is placed as in a common GP, so it can be used to pinpoint the target tissue. Meanwhile, the lateral sensors provide a broader view of the surgical field. A dedicated data acquisition system digitizes and processes the signals from the front-end electronics. Finally, an embedded system, based on ARM processor, calculates and displays the acquired count rates. In order to assess the prototype behavior, the isosensitivity curves for the three detectors were measured. Meanwhile, for the central one, the main quality criteria measurements were also performed (i.e., sensitivity, radial sensitivity, and spatial resolution).

Results: For the central detector, the measured sensitivity at the tip of the probe is better than 5 cps/kBq. The full width at half maximum (FWHM) of the radial sensitivity is less than 30° and the FWHM of the lateral sensitivity (spatial resolution) is about 7.2 mm. The central detector measured isosensitivity distribution shows a narrow profile in agreement with the spatial resolution measured. On the contrary, the two lateral detectors exhibit widespread isosensitivity distributions that mean a larger field of view. The system had shown satisfactory performance and reliability, meeting the minimal requirements of gamma probe systems.

Conclusions: The prototype presented in this paper allows a rapid localization by the use of the whole system, while the sole central detector can be used to pinpoint the target source. This device, unlike common GPs, allows localizing simultaneously different areas of radiopharmaceuticals uptake, thus precisely guiding the surgeon to the region of interest. These preliminary results encourage to develop a further prototype for intraoperative validation.
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http://dx.doi.org/10.1002/mp.12726DOI Listing
February 2018

Should cT2N0M0 be managed as a localized or locally advanced esophageal carcinoma?

J Thorac Dis 2017 Sep;9(9):2829-2834

Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy.

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http://dx.doi.org/10.21037/jtd.2017.08.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708429PMC
September 2017

The role of multimodal treatment in patients with advanced lung neuroendocrine tumors.

J Thorac Dis 2017 Nov;9(Suppl 15):S1501-S1510

Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy.

Lung neuroendocrine tumors (NETs) comprise typical (TC) and atypical carcinoids (AC). They represent the well differentiated (WD) or low/intermediate grade forms of lung neuroendocrine neoplasms (NENs). Unlike the lung poorly differentiated NENs, that are usually treated with chemotherapy, lung NETs can be managed with several different therapies, making a multidisciplinary interaction a key point. We critically discussed the multimodal clinical management of patients with advanced lung NETs. Provided that no therapeutic algorithm has been validate so far, each clinical case should be discussed within a NEN-dedicated multidisciplinary team. Among the systemic therapies available for metastatic lung NETs everolimus is the only approved drug, on the basis of the results of the phase III RADIANT-4 trial. Another phase III trial, the SPINET, is ongoing comparing lanreotide with placebo. Peptide receptor radionuclide therapy and chemotherapy were not studied within phase III trials for lung NETs, and they have been reported to be active within retrospective or phase II prospective studies. Temozolomide and oxaliplatin are two interesting chemotherapeutic agents in lung NETs. While some European Institutions were certificated as Centers of Excellence for gastroenteropancreatic NENs by the European Neuroendocrine Tumor Society (ENETS), an equivalent ENETS certification for lung NENs does not exist yet. Ideally a lung NEN-dedicated multidisciplinary tumor board should include NEN-dedicated medical oncologists, thoracic medical oncologist, thoracic surgeons, pathologists, interventional radiologists, endocrinologists, radiotherapists, interventional pneumologists, nuclear physician.
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http://dx.doi.org/10.21037/jtd.2017.06.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690950PMC
November 2017

Predictive Markers of Response to Everolimus and Sunitinib in Neuroendocrine Tumors.

Target Oncol 2017 10;12(5):611-622

Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, 20141 via Ripamonti, 435, Milan, Italy.

Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques.
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http://dx.doi.org/10.1007/s11523-017-0506-5DOI Listing
October 2017

Metronomic and metronomic-like therapies in neuroendocrine tumors - Rationale and clinical perspectives.

Cancer Treat Rev 2017 Apr 24;55:46-56. Epub 2017 Feb 24.

Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, Milan, Italy. Electronic address:

Metronomic therapy is characterized by the administration of regular low doses of certain drugs with very low toxicity. There have been numerous debates over the empirical approach of this regimen, but fewest side effects are always something to consider in order to improve patients' quality of life. Neuroendocrine tumors (NETs) are rare malignancies relatively slow-growing; therefore their treatment is often chronic, involving several different therapies for tumor growth control. Knowing that these tumors are highly vascularized, the anti-angiogenic aspect is highly regarded as something to be targeted in all patients harboring NETs. Additionally the metronomic schedule has proved to be effective on an immunological level, rendering this approach as a multi-targeted therapy. Rationalizing that advanced NETs are in many cases a chronic disease, with which patients can live for as long as possible, a systemic therapy with regular low doses and a very low toxicity is in many cases a judicious manner of pursuing stabilization. Metronomic schedule is usually correlated with chemotherapy in oncology, but other therapies, such as radiotherapy and biotherapy can be delivered in a metronomic like manner. This review describes clinical trials and case series involving metronomic therapies alone or in combination in patients with advanced NETs. Nowadays level of evidence about metronomic therapy in NETs is quite low, therefore future prospective clinical studies are needed to validate the metronomic approach in specific clinical settings.
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http://dx.doi.org/10.1016/j.ctrv.2017.02.007DOI Listing
April 2017

Resection of the Primary Tumor Followed by Peptide Receptor Radionuclide Therapy as Upfront Strategy for the Treatment of G1-G2 Pancreatic Neuroendocrine Tumors with Unresectable Liver Metastases.

Ann Surg Oncol 2016 12 9;23(Suppl 5):981-989. Epub 2016 Sep 9.

Division of Pancreatic Surgery, Ospedale San Raffaele IRCCS, Università Vita e Salute, Milan, Italy.

Background: A low burden of disease represents an independent favorable prognostic factor of response to peptide receptor radionuclide therapy (PRRT) in patients affected by gastro-entero-pancreatic neuroendocrine tumors. However, it is not clear whether this is due to a lower diffusion of the disease or thanks to debulking surgery.

Methods: From 1996 to 2013 those patients diagnosed with G1-G2 pancreatic neuroendocrine tumor (PNET) and synchronous liver metastases who were not deemed eligible for liver radical surgery but were eligible to receive upfront PRRT were prospectively included in the study. Two groups of comparison were identified: those submitted for primary tumor resection before PRRT and those who were not. The outcome was evaluated as: objective response to PRRT (OR), progression-free survival (PFS), and overall survival (OS).

Results: Of the 94 subjects, 31 were previously submitted for primary tumor resection. After propensity score adjustments, patients who underwent surgery before PRRT showed higher stabilization or objective responses after PRRT (p = .006), and this translated into a better median PFS (70 vs. 30 months; p = .002) and OS (112 vs. 65 months; p = .011), for operated versus nonoperated patients, respectively. At multivariate analysis, operated patients showed a statistically significantly improved PFS: HR, 5.11 (95 % CI 1.43-18.3); p = .012, whereas Ki-67 in continuous fashion was correlated significantly with OS: 1.13 (95 % CI 1-1.27); p = .048.

Conclusions: Primary tumor resection prior to PRRT can be safely proposed in G1-G2 PNETs with diffuse liver metastases because it seems to enhance response to PRRT and to improve significantly PFS.
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http://dx.doi.org/10.1245/s10434-016-5550-3DOI Listing
December 2016

Notes of robotic surgical technique: four ways to mobilize splenic flexure.

Minerva Chir 2016 Oct 14;71(5):345-8. Epub 2016 Jul 14.

Division of Hepatobiliary and Pancreatic Surgery, European Institute of Oncology, Milan, Italy -

Splenic flexure mobilization is a challenging surgical procedure, but is it necessary to safely perform left colon and rectal resections. This paper is a technical focus detailing the four ways to mobilize splenic flexure in robotic surgery. The medial approach involves an extensive dissection of the medial plane separating descending mesocolon form Toldt fascia; the sovramesocolic approach starts with gastrocolic ligament section; the lateral approach starts with coloparietal detachment and the "one inch-one inch" approach starts with section of transverse mesocolon.
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October 2016

Open, laparoscopic, and robotic surgery for rectal cancer: medium-term comparative outcomes from a multicenter study.

Tumori 2016 Aug 2;102(4):414-21. Epub 2016 Jul 2.

General Surgery Residency, School of Medicine, University of Milan, Milan - Italy.

Purpose: Several studies have demonstrated the oncologic equivalence of laparoscopic (LS) and open (OS) rectal cancer surgeries and have shown how challenging LS may become. Robotic surgery (RS) has emerged as a practical alternative, offering interesting advantages in comparison to both LS and OS. The aim of this study is to resolve the clinicopathologic outcome advantages of RS with respect to OS and LS techniques.

Methods: Patients with rectal cancer undergoing OS, RS, or LS were evaluated within the period from April 2009 to August 2011. The evaluations were carried out in 4 Italian hospitals. Perioperative clinicopathologic data, postoperative complications, and 3-year overall and disease-free survival (DFS) rates were analyzed.

Results: A total of 160 patients (94 male, 66 female) were included. A total of 105 patients underwent mini-invasive procedure (40 LS; 65 RS), whereas OS was performed in 55 patients. Anterior resection of rectal cancer was the most performed surgical procedure (139; 87%). Median operation time was significantly longer in the RS group (p<0.01). Regarding complication rates and quality of the surgical specimen evaluation, no statistical difference was found among the 3 groups. The shortest hospital stay (p<0.01) was obtained from the LS and RS groups. The median follow-up was 33 months without any significant difference in overall and DFS rates.

Conclusions: Although RS for rectal cancer requires more time to be performed than LS and OS techniques, the analysis shows comparatively the feasibility and safety of RS in terms of perioperative clinicopathologic and medium-term outcomes.
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http://dx.doi.org/10.5301/tj.5000533DOI Listing
August 2016

Optimizing treatment of hepatic metastases from colorectal cancer: Resection or resection plus ablation?

Int J Oncol 2016 Mar 5;48(3):1280-9. Epub 2016 Jan 5.

Digestive Surgery, European Institute of Oncology, Milan, Italy.

The present study determines the oncologic outcome of the combined resection and ablation strategy for colorectal liver metastases (CRLM). Between January 1994 and December 2014, 360 patients underwent surgery for CRLM. There were 280 patients who underwent hepatic resection only (group 1) and 80 hepatic resection plus ablation (group 2). group 2 patients had a higher incidence of multiple metastases than group 1 cases (100% in group 2 vs. 28.2% in group 1; P<0.001) and bilobar involvement (76.5% in group 2 vs. 12.9% in group 1; P<0.001). Perioperative mortality was nil in either group with a higher postoperative complication rate amongst group 1 vs. group 2 cases (18 vs. 0, respectively). The median follow-up was 90 months (range, 1-180) with a 5-year overall survival for group 1 and group 2 of 49 and 80%, respectively (P=0.193). The median disease-free survival for patients with R0 resection was 50, 43 and 34% at 1, 2 and 3 years, respectively, and remained steadily higher (at 50%) in those patients treated with resection combined with ablation up to 5 years (P=0.069). The only intraoperative ablation failure was for a large lesion (≥5 cm). Our data support the use of intraoperative ablation when complete hepatic resection cannot be achieved.
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http://dx.doi.org/10.3892/ijo.2016.3324DOI Listing
March 2016

Histologically-Proven Efficacy of Bland Embolization in a Patient with Net Liver Metastasis.

Cardiovasc Intervent Radiol 2016 Jun 29;39(6):948-52. Epub 2015 Dec 29.

Department of Interventional Radiology, European Institute of Oncology, Via Ripamonti 435, 20100, Milan, Italy.

We present a case of 57-year-old patient with three liver metastases from a primary neuroendocrine duodenal tumor, who underwent bland embolization with excellent response to therapy, followed by surgical resection. The purpose of our case report is to describe the histological characteristics of tumoral response to therapy after bland embolization focusing on intralesional necrosis and microsphere distribution.
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http://dx.doi.org/10.1007/s00270-015-1284-zDOI Listing
June 2016

Small intestinal neuroendocrine tumors with liver metastases and resection of the primary: Prognostic factors for decision making.

Int J Surg 2015 Aug 11;20:58-64. Epub 2015 Jun 11.

Gastrointestinal and Neuroendocrine Cancer Medical Treatment Unit, European Institute of Oncology, Milano, Italy.

Introduction: Patients with small intestine neuroendocrine tumors present with liver metastases in 50-75% of cases at diagnosis. The aim of the present study was to assess prognostic factors in patients with liver metastases from intestinal neuroendocrine tumor after primary tumor surgical removal with or without liver surgery or radiofrequency ablation. The primary endpoint was disease-specific survival.

Methods: Data regarding seventy-eight consecutive patients with liver metastases who undergone primary tumor surgical removal between 1996 and 2011 were extracted from the institutional tumor registry and retrospectively analyzed.

Results: Liver tumor burden was <25% in 43 (55.1%) 25-50% in 30 (38.5%) and >50% in 5 (6.4%) patients. For the whole cohort of patients disease-specific survival at 3, 5 and 8 years was 93.2%, 83.6% and 77.3%, respectively. Fifteen patients who underwent radical liver surgery were all alive with a median survival of 106 months (range 18-152 months). In multivariate analysis the Ki-67 index in a continuous fashion significantly correlate with prognosis (p = 0.021). Liver tumor burden (p = 0.036) and extrahepatic involvement (p = 0.03), were the most powerful prognosticators for patients who underwent only debulking surgery.

Conclusion: The Ki-67 index, the liver tumor burden and the presence of extrahepatic metastases should be carefully considered in the selection criteria for liver debulking in asymptomatic patients.
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http://dx.doi.org/10.1016/j.ijsu.2015.06.019DOI Listing
August 2015

The Impact of pelvimetry on anastomotic leakage in a consecutive series of open, laparoscopic and robotic low anterior resections with total mesorectal excision for rectal cancer. .

Hepatogastroenterology 2014 Sep;61(134):1574-81

Background/aims: Recently, pelvic anatomy has been taken into consideration and related to surgical outcome indicators after low anterior resection (LAR). Several pelvimetric parameters have been matched with conversion rate, postoperative complications and duration of surgery in laparoscopic series, and with the quality of specimen and pathologic outcomes in further open surgical series.

Methodology: In 97 consecutive patients submitted to sphincter-saving LAR with total mesorectal excision (TME) five pelvic dimensions were measured by abdominal computed tomography scan: anteroposterior and transverse diameters in the pelvic inlet (IAP and ITRA), anteroposterior and transverse diameters in the pelvic outlet (OAP and OTRA), and the pelvic depth. The endpoint evaluated was anastomotic leakage (AL) rate.

Results: There were 51 open, 12 laparoscopic and 34 robotic LARs. The sum of IAP OAP and OTRA (Pelvic Index) significantly predicted AL showing that starting from the cut-point of 290 mm down to a PI of 278 mm the odds-ratio of having an AL increased from 2.63 (95% CI: 1.10,5.47) to 5.07 (95% CI: 1.35,8.02).

Conclusions: The sum of the 3 pelvic dimensions which we termed “Pelvic Index” was associated to AL following sphinctersaving LAR. This may be considered in planning the surgical strategy for rectal cancer patients.
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September 2014

Detection of circulating tumor cells in patients with locally advanced rectal cancer undergoing neoadjuvant therapy followed by curative surgery.

Int J Colorectal Dis 2014 Sep 10;29(9):1053-9. Epub 2014 Jul 10.

Gastrointestinal and Neuroendocrine Tumors Unit, European Institute of Oncology, via Ripamonti 435, 20141, Milan, Italy,

Purpose: Circulating tumor cells (CTCs) represent an independent prognostic factor in metastatic colorectal cancer, while their significance in early stages is still an open issue. The aim of the study is to investigate the role of CTCs in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (CT-RT).

Methods: In this prospective single institutional study, cT3-4 and/or N+ rectal cancer was treated with neoadjuvant CT-RT. The primary endpoints were as follows: evaluation of CTCs at baseline (t0), after CT-RT (t1), within 7 days after surgery (t2), and at 6 months from surgery (t3) and correlation with main patient/tumor characteristics, CEA, response to neoadjuvant therapy, and disease-free survival (DFS). CTCs were enumerated with the CellSearch System in 22.5 ml peripheral blood. A repeated measure analysis for binary outcome was used to evaluate over time changes in the percentage of CTCs detectable in blood samples.

Results: Of the 90 patients enrolled in this study, 85 were eligible consisting of 52 males and 33 females. Median age was 63 years and median follow-up was 38 months. CTCs were available for all patients at t0, for 67 at t1, for 68 at t2, and for 62 at t3. CTCs >0 were reported on 16 (19%) at t0, on 5 (7.5%) at t1, on 6 (9%) at t2, and on 3 (5%) at t3 (P value for trend 0.039). Only for CT-RT responders, CTCs reduced from t0 to t1. No statistically significant association was found between CTCs and main patient/tumor characteristics and DFS.

Conclusions: Sixteen patients (19%) had CTCs ≥1 at t0 with reduction in CTC number in case of objective remissions. The proportion of patients with CTCs ≥1 decreased over the time as the therapeutic course proceeded. Much effort should be oriented toward increasing CTC detection rate by enhancing technical tests and achieving better patient characterization.
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http://dx.doi.org/10.1007/s00384-014-1958-zDOI Listing
September 2014
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