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Jesse Vincent Groen,1 SC Boon,2 MW Minderhoud,2 Bert A Bonsing,1 CH Martini,2 H Putter,3 AL Vahrmeijer,1 Monique van Velzen,2 J Vuijk,2 JSD Mieog,1,* A Dahan2,* 1Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; 2Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands; 3Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands*These authors contributed equally to this workCorrespondence: A Dahan, Department of Anesthesiology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2300 RC, The Netherlands, Tel +31 71 526 2301, Email A.Dahan@lumc.nlBackground: The optimal treatment strategy for postoperative pain following pancreatoduodenectomy remains unknown. The aim of this study was to investigate whether sublingual sufentanil tablet (SST) is a non-inferior analgesic compared to our standard-of-care (patient-controlled epidural analgesia [PCEA] or PCA morphine) in the treatment of pain following pancreatoduodenectomy.Methods: This was a pragmatic, strategy, open-label, non-inferiority, parallel group, randomized (1:1) trial. The primary outcome was an overall mean pain score (Numerical Rating Scale: 0– 10) on postoperative days 1 to 3 combined. The non-inferiority margin was − 1.5 since this difference was considered clinically relevant.Results: Between October 2018 and July 2021, 190 patients were assessed for eligibility and 36 patients were included in the final analysis: 17 patients were randomized to SST and 19 patients to standard-of-care. Early treatment failure in the SST group occurred in 2 patients (12%) due to inability to operate the SST system and in 2 patients (12%) due to severe nausea despite antiemetics. Early treatment failure in the standard-of-care group occurred in 2 patients (11%) due to preoperative PCEA placement failure and in 1 patient (5%) due to hemodynamic instability caused by PCEA. The mean difference in pain score on postoperative day 1 to 3 was − 0.10 (95% CI − 0.72– 0.52), and therefore the non-inferiority of SST compared to standard-of-care was demonstrated. The mean pain score, number of patients reporting unacceptable pain (pain score > 4), Overall Benefit of Analgesia Score, and patient satisfaction per postoperative day, perioperative hemodynamics and postoperative outcomes did not differ significantly between groups.Conclusion: This first randomized study investigating the use of SST in 36 patients following pancreatoduodenectomy showed that SST is non-inferior compared to our standard-of-care in the treatment of pain on postoperative days 1 to 3. Future research is needed to confirm that these findings are applicable to other settings.Keywords: postoperative pain, pancreatoduodenectomy, sufentanil, epidural analgesia, morphine

Introduction: Routine treatment with preoperative systemic chemotherapy (CTx) in patients with colorectal liver metastases (CRLM) remains controversial due to lack of consistent evidence demonstrating associated survival benefits. This study aimed to determine the effect of preoperative CTx on overall survival (OS) compared to surgery alone and to assess hospital and oncological network variation in 5-year OS., Methods: This was a population-based study of all patients who underwent liver resection for CRLM between 2014 and 2017 in the Netherlands. After 1:1 propensity score matching (PSM), OS was compared between patients treated with and without preoperative CTx. Hospital and oncological network variation in 5-year OS corrected for case-mix factors was calculated using an observed/expected ratio., Results: Of 2820 patients included, 852 (30.2%) and 1968 (69.8%) patients were treated with preoperative CTx and surgery alone, respectively. After PSM, 537 patients remained in each group, median number of CRLM; 3 [IQR 2-4], median size of CRLM; 28 mm [IQR 18-44], synchronous CLRM (71.1%). Median follow-up was 80.8 months. Five-year OS rates after PSM for patients treated with and without preoperative chemotherapy were 40.2% versus 38.3% (log-rank P = 0.734). After stratification for low, medium, and high tumour burden based on the tumour burden score (TBS) OS was similar for preoperative chemotherapy vs. surgery alone (log-rank P = 0.486, P = 0.914, and P = 0.744, respectively). After correction for non-modifiable patient and tumour characteristics, no relevant hospital or oncological network variation in five-year OS was observed., Conclusion: In patients eligible for surgical resection, preoperative chemotherapy does not provide an overall survival benefit compared to surgery alone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In 2017, the Southampton guideline stated that minimally invasive liver resections (MILR) should considered standard practice for minor liver resections. This study aimed to assess recent implementation rates of minor MILR, factors associated with performing MILR, hospital variation, and outcomes in patients with colorectal liver metastases (CRLM)., Methods: This population-based study included all patients who underwent minor liver resection for CRLM in the Netherlands between 2014 and 2021. Factors associated with MILR and nationwide hospital variation were assessed using multilevel multivariable logistic regression. Propensity-score matching (PSM) was applied to compare outcomes between minor MILR and minor open liver resections. Overall survival (OS) was assessed with Kaplan-Meier analysis on patients operated until 2018., Results: Of 4,488 patients included, 1,695 (37.8%) underwent MILR. PSM resulted in 1,338 patients in each group. Implementation of MILR increased to 51.2% in 2021. Factors associated with not performing MILR included treatment with preoperative chemotherapy (aOR 0.61 CI:0.50-0.75, p < 0.001), treatment in a tertiary referral hospital (aOR 0.57 CI:0.50-0.67, p < 0.001), and larger diameter and number of CRLM. Significant hospital variation was observed in use of MILR (7.5% to 93.0%). After case-mix correction, six hospitals performed fewer, and six hospitals performed more MILRs than expected. In the PSM cohort, MILR was associated with a decrease in blood loss (aOR 0.99 CI:0.99-0.99, p < 0.01), cardiac complications (aOR 0.29, CI:0.10-0.70, p = 0.009), IC admissions (aOR 0.66, CI:0.50-0.89, p = 0.005), and shorter hospital stay (aOR CI:0.94-0.99, p < 0.01). Five-year OS rates for MILR and OLR were 53.7% versus 48.6%, p = 0.21., Conclusion: Although uptake of MILR is increasing in the Netherlands, significant hospital variation remains. MILR benefits short-term outcomes, while overall survival is comparable to open liver surgery., (© 2023. The Author(s).)

Background: The International Study Group of Pancreatic Surgery 4-tier (ie, A-D) risk classification for postoperative pancreatic fistula grade B/C is based on pancreatic texture and pancreatic duct size: A (not-soft texture and pancreatic duct >3 mm), B (not-soft texture and pancreatic duct ≤3 mm), C (soft texture and pancreatic duct >3 mm), and D (soft texture and pancreatic duct ≤3 mm). This study aimed to validate the International Study Group of Pancreatic Surgery risk classification for postoperative pancreatic fistula after pancreatoduodenectomy., Methods: Consecutive patients after pancreatoduodenectomy for all indications (2014-2021) were included from the nationwide, mandatory Dutch Pancreatic Cancer Audit. The rate of postoperative pancreatic fistula grade B/C (according to the International Study Group of Pancreatic Surgery 2016 definition) was calculated per risk category. Model performance was assessed using the area under the receiver operating curve (discrimination) and calibration plots., Results: Overall, 3,900 patients were included in risk categories: A (n = 1,046), B (n = 498), C (n = 963), and D (n = 1,393) with corresponding postoperative pancreatic fistula grade B/C rates of 3.8%, 12.2%, 15.6%, and 29.6%. Per category, the in-hospital mortality rates were 1.3%, 3.4%, 2.9%, and 4.1%, P = .001. There was no difference in the rate of postoperative pancreatic fistula between risk categories B and C (12.2% vs 15.6%, P = .101). When simplifying the classification system to a 3-tier classification system (based on 0, 1, and 2 risk factors), the discrimination was not significantly different (area under the receiver operating curve 0.697 vs area under the receiver operating curve 0.701, P = .077)., Conclusion: This validation of the 4-tier International Study Group of Pancreatic Surgery risk classification for postoperative pancreatic fistula after pancreatoduodenectomy confirmed its predictive value. However, as the 2 middle risk categories provide no added predictive value, a simplified 3-tier classification with comparable predictive value is proposed and should be validated in future prospective studies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Early recognition and management of postoperative complications, before they become clinically relevant, can improve postoperative outcomes for patients, especially for high-risk procedures such as pancreatic resection., Methods: We did an open-label, nationwide, stepped-wedge cluster-randomised trial that included all patients having pancreatic resection during a 22-month period in the Netherlands. In this trial design, all 17 centres that did pancreatic surgery were randomly allocated for the timing of the crossover from usual care (the control group) to treatment given in accordance with a multimodal, multidisciplinary algorithm for the early recognition and minimally invasive management of postoperative complications (the intervention group). Randomisation was done by an independent statistician using a computer-generated scheme, stratified to ensure that low-medium-volume centres alternated with high-volume centres. Patients and investigators were not masked to treatment. A smartphone app was designed that incorporated the algorithm and included the daily evaluation of clinical and biochemical markers. The algorithm determined when to do abdominal CT, radiological drainage, start antibiotic treatment, and remove abdominal drains. After crossover, clinicians were trained in how to use the algorithm during a 4-week wash-in period; analyses comparing outcomes between the control group and the intervention group included all patients other than those having pancreatic resection during this wash-in period. The primary outcome was a composite of bleeding that required invasive intervention, organ failure, and 90-day mortality, and was assessed by a masked adjudication committee. This trial was registered in the Netherlands Trial Register, NL6671., Findings: From Jan 8, 2018, to Nov 9, 2019, all 1805 patients who had pancreatic resection in the Netherlands were eligible for and included in this study. 57 patients who underwent resection during the wash-in phase were excluded from the primary analysis. 1748 patients (885 receiving usual care and 863 receiving algorithm-centred care) were included. The primary outcome occurred in fewer patients in the algorithm-centred care group than in the usual care group (73 [8%] of 863 patients vs 124 [14%] of 885 patients; adjusted risk ratio [RR] 0·48, 95% CI 0·38-0·61; p<0·0001). Among patients treated according to the algorithm, compared with patients who received usual care there was a decrease in bleeding that required intervention (47 [5%] patients vs 51 [6%] patients; RR 0·65, 0·42-0·99; p=0·046), organ failure (39 [5%] patients vs 92 [10%] patients; 0·35, 0·20-0·60; p=0·0001), and 90-day mortality (23 [3%] patients vs 44 [5%] patients; 0·42, 0·19-0·92; p=0·029)., Interpretation: The algorithm for the early recognition and minimally invasive management of complications after pancreatic resection considerably improved clinical outcomes compared with usual care. This difference included an approximate 50% reduction in mortality at 90 days., Funding: The Dutch Cancer Society and UMC Utrecht., Competing Interests: Declaration of interests CvdL is the Secretary of the Dutch Society of Interventional Radiology (unpaid position). CHvW's institution received payments from Pfizer, Biomerieux, Da Volterra, and MSD and he has a European Patent Application with Da Volterrra, University Antwerp, and University Medical Centre Utrecht Holdings. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The objective of this study was to validate and update the Amsterdam prediction model including tumor grade, lymph node ratio, margin status and adjuvant therapy, for prediction of overall survival (OS) after pancreatoduodenectomy for pancreatic cancer., Methods: We included consecutive patients who underwent pancreatoduodenectomy for pancreatic cancer between 2000 and 2017 at 11 tertiary centers in 8 countries (USA, UK, Germany, Italy, Sweden, the Netherlands, Korea, Australia). Model performance for prediction of OS was evaluated by calibration statistics and Uno's C-statistic for discrimination. Validation followed the TRIPOD statement., Results: Overall, 3081 patients (53% male, median age 66 years) were included with a median OS of 24 months, of whom 38% had N2 disease and 77% received adjuvant chemotherapy. Predictions of 3-year OS were fairly similar to observed OS with a calibration slope of 0.72. Statistical updating of the model resulted in an increase of the C-statistic from 0.63 to 0.65 (95% CI 0.64-0.65), ranging from 0.62 to 0.67 across different countries. The area under the curve for the prediction of 3-year OS was 0.71 after updating. Median OS was 36, 25 and 15 months for the low, intermediate and high risk group, respectively (P < 0.001)., Conclusions: This large international study validated and updated the Amsterdam model for survival prediction after pancreatoduodenectomy for pancreatic cancer. The model incorporates readily available variables with a fairly accurate model performance and robustness across different countries, while novel markers may be added in the future. The risk groups and web-based calculator www.pancreascalculator.com may facilitate use in daily practice and future trials., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: Our aim was to determine the prognostic significance of the systemic-immune-inflammation index (SIII) in patients with resectable pancreatic cancer, using cancer-specific survival as the primary outcome., Background: Pancreatic cancer is associated with a dysfunctional immune system and poor prognosis. We examined the prognostic significance of the SIII in patients with resectable pancreatic ductal adenocarcinoma (PDAC) and the effects of bilirubin on this index., Methods: We retrospectively assessed all pancreatic resections performed between 2004 and 2015 at 4 tertiary referral centers to identify pathologically confirmed PDAC patients. Baseline clinicopathologic characteristics, preoperative laboratory values such as absolute neutrophil, lymphocyte, and platelet counts, C-reactive protein, albumin, bilirubin, and CA19-9 levels, and also follow-up information, were collected. The associations of the calculated inflammatory indices with outcome were both internally and externally validated., Results: In all, 590 patients with resectable PDAC were included. The discovery and validation cohort included 170 and 420 patients, respectively. SIII >900 [hazard ratio (HR) 2.32, 95% confidence interval (CI) 1.55-3.48], lymph node ratio (HR 3.75, 95% CI 2.08-6.76), and CA19.9 >200 kU/L (HR 1.62, 95% CI 1.07-2.46) were identified as independent predictors of cancer-specific survival. Separate model analysis confirmed that preoperative SIII contributed significantly to prognostication. However, SIII appeared to lose its prognostic significance in patients with bilirubin levels above 200 μmol/L., Conclusions: SIII is an independent predictor of cancer-specific survival and recurrence in patients with resectable PDAC. SIII may lose its prognostic significance in patients with high bilirubin levels. Properly designed prospective studies are needed to further confirm this hypothesis.

Background: The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is poor and selection of patients for surgery is challenging. This study examined the impact of a positive resection margin (R1) on locoregional recurrence (LRR) and overall survival (OS); and also aimed to identified tumour characteristics and/or technical factors associated with a positive resection margin in patients with PDAC., Methods: Patients scheduled for pancreatic resection for PDAC between 2006 and 2016 were identified from an institutional database. The effect of resection margin status, patient characteristics and tumour characteristics on LRR, distant metastasis and OS was assessed., Results: A total of 322 patients underwent pancreatectomy for PDAC. A positive resection (R1) margin was found in 129 patients (40·1 per cent); this was associated with decreased OS compared with that in patients with an R0 margin (median 15 (95 per cent c.i. 13 to 17) versus 22 months; P < 0·001). R1 status was associated with reduced time to LRR (median 16 versus 36 (not estimated, n.e.) months; P = 0·002). Disease recurrence patterns were similar in the R1 and R0 groups. Risk factors for early recurrence were tumour stage, positive lymph nodes (N1) and perineural invasion. Among 100 patients with N0 disease, R1 status was associated with shorter OS compared with R0 resection (median 17 (10 to 24) versus 45 (n.e.) months; P = 0·002), whereas R status was not related to OS in 222 patients with N1 disease (median 14 (12 to 16) versus 17 (15 to 19) months after R1 and R0 resection respectively; P = 0·068)., Conclusion: Although pancreatic resection with a positive margin was associated with poor survival and early recurrence, particularly in patients with N1 disease, disease recurrence patterns were similar between R1 and R0 groups., (© 2019 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Discrimination of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) or peritumoral inflammation is challenging, both at preoperative imaging and during surgery, but it is crucial for proper therapy selection. Tumor-specific molecular imaging aims to enhance this discrimination and to help select and stratify patients for resection. We evaluated various biomarkers for the specific identification of PDAC and associated lymph node metastases. Using immunohistochemistry (IHC), expression levels and patterns were investigated of integrin αvβ6, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), Cathepsin E (Cath E), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), thymocyte differentiation antigen 1 (Thy1), and urokinase-type plasminogen activator receptor (uPAR). In a first cohort, multiple types of pancreatic tissue were evaluated (n=62); normal pancreatic tissue (n=8), CP (n=7), PDAC (n=9), tumor associated lymph nodes (n=32), and PDAC after neoadjuvant radiochemotherapy (n=6). In a second cohort, tissues were investigated (n=55) with IHC and immunofluorescence (IF) for concordance of biomarker expression in all tissue types, obtained from an individual patient. Integrin αvβ6 and CEACAM5 showed significantly higher expression levels in PDAC versus normal pancreatic tissue (P=0.001 and P<0.001, respectively) and CP (P=0.003 and P<0.001, respectively). Avβ6 and CEACAM5 expression identified tumor-positive lymph nodes correctly in 84% and 68%, respectively, and in 100% of tumor-negative nodes for both biomarkers. In conclusion, αvβ6 and CEACAM5 are excellent biomarkers to differentiate PDAC from surrounding tissue and to identify lymph node metastases. Individually or combined, these biomarkers are promising targets for tumor-specific molecular imaging of PDAC., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

To improve the diagnostic value of fine-needle aspiration (FNA)-derived material, we perform targeted next-generation sequencing (NGS) in patients with a suspect lesion of the pancreas. The NGS analysis can lead to a change in the treatment plan or supports inconclusive or uncertain cytology results. We describe the advantages of NGS using one particular patient with a recurrent pancreatic lesion 7 years after resection of a pancreatic ductal adenocarcinoma (PDAC). Our NGS analysis revealed the presence of a presumed second primary cancer in the pancreatic remnant, which led to a change in treatment: resection with curative intend instead of palliation. Additionally, NGS identified an unexpected germline CDKN2A 19-base pair deletion, which predisposed the patient to developing PDAC. Preoperative NGS analysis of FNA-derived DNA can help identify patients at risk for developing PDAC and define future therapeutic options., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Several infectious processes of intra-abdominal origin may atypically present as skin or soft tissue infections or abscess in the thigh., Case Report: We describe the case of a 73-year-old woman who presented to the emergency department with the clinical picture of a skin infection of the right leg. The patient's condition deteriorated during medical treatment with intravenous antibiotics. Subsequent radiologic imaging revealed that the complaints were caused by a bulging retroperitoneal appendicular abscess along the iliopsoas muscle, although the patient experienced no abdominal symptoms. The patient recovered completely after surgical intervention. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Timely performance of anatomic imaging in patients with unexplained skin or soft tissue infections and thigh abscesses is important because these findings may be manifestations of an abdominal pathology. A correct diagnosis in the emergency department prohibits delays in treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma., Procedures: The expression of eight potential imaging targets was assessed by the target selection criteria (TASC)-score and immunohistochemical analysis in normal pancreatic tissue (n = 9), pancreatic (n = 137), and periampullary (n = 28) adenocarcinoma., Results: Integrin α v β 6 , carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p < 0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients., Conclusions: The results of this study show that integrin α v β 6 , CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma., Competing Interests: The authors declare that they have no conflict of interest.

Background: Quality assurance of cancer care is of utmost importance to detect and avoid under and over treatment. Most cancer data are collected by different procedures in different countries, and are poorly comparable at an international level. EURECCA, acronym for European Registration of Cancer Care, is a platform aiming to harmonize cancer data collection and improve cancer care by feedback. After the prior launch of the projects on colorectal, breast and upper GI cancer, EURECCA's newest project is collecting data on pancreatic cancer in several European countries., Methods: National cancer registries, as well as specific pancreatic cancer audits/registries, were invited to participate in EURECCA Pancreas. Participating countries were requested to share an overview of their collected data items. Of the received datasets, a shared items list was made which creates insight in similarities between different national registries and will enable data comparison on a larger scale. Additionally, first data was requested from the participating countries., Results: Over 24 countries have been approached and 11 confirmed participation: Austria, Belgium, Bulgaria, Denmark, Germany, The Netherlands, Slovenia, Spain, Sweden, Ukraine and United Kingdom. The number of collected data items varied between 16 and 285. This led to a shared items list of 25 variables divided into five categories: patient characteristics, preoperative diagnostics, treatment, staging and survival. Eight countries shared their first data., Conclusions: A list of 25 shared items on pancreatic cancer coming from eleven participating registries was created, providing a basis for future prospective data collection in pancreatic cancer treatment internationally., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Data are currently lacking regarding the quality of life of surgical oncology (SO) trainees. We sought to assess the training conditions and quality of life of SO residents and fellows across Europe., Material and Methods: Members of the European Society for Surgical Oncology were invited to complete a Web-based survey that included a questionnaire specifically designed for SO trainees. Demographics, timing, and incentive to choose for SO, quality of life, and symptoms of fatigue, sleepiness, depression, and burnout, as well as self-reported medical errors, were assessed using validated instruments., Results: The survey was completed by 109 residents and 53 fellows (mean age 34.6 ± 8.2). The mean Linear Analog Scale Assessment score for quality of life was 34.8 ± 8.6 out of a possible 50. A low level of fatigue was declared by 60% of the trainees. However, 44% scored an abnormal Epworth Sleepiness score, which was mostly related to in-hospital work time and lack of educational programs. High positive screenings regarding depression (51%) and burnout (25%) were associated with resident status and lack of mentorship, respectively. Major medical errors during the last 3 months were self-reported by 20% of the trainees., Conclusions: In Europe, the perceived quality of life is overall acceptable among trainees in SO. However, the present study demonstrated a high level of sleepiness, depression, and burnout symptoms. Additional work is required to identify and overcome the underlying causes of these symptoms., (Copyright © 2014 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

In recent years, studies investigating neoadjuvant therapies have been emerging, because of the additional benefits it provides in terms of facilitating less extensive surgery and the possibility of investigating tumor biological features and response. Neoadjuvant hormonal therapy (NHT) is, in general, considered to be a suitable option for hormone receptor (HR)-positive patients who are unfit for chemotherapy or surgery, and is increasingly being utilized to achieve tumor downsizing before surgery in postmenopausal women. Studies investigating NHT were reviewed for tumor response data. NHT demonstrated similar efficacy to neoadjuvant chemotherapy (NCT) in HR-positive breast cancer patients. Clinical responses ranged from 13.5% to 100%, with treatment periods between 3 and 24 months. In studies comparing tamoxifen with aromatase inhibitors, the latter were superior in terms of tumor response and rates of breast-conserving surgery (BCS). In most studies with treatment durations longer than 3 months, tumor response rates increased. Therefore, longer durations of NHT are feasible and should be considered as an alternative to NCT in selected patients., (Copyright © 2013. Published by Elsevier Ltd.)

Prognosis of patients with pancreatic cancer is poor. Even the small minority that undergoes resection with curative intent has low 5-year survival rates. This may partly be explained by the high number of irradical resections, which results in local recurrence and impaired overall survival. Currently, ultrasonography is used during surgery for resectability assessment and frozen-section analysis is used for assessment of resection margins in order to decrease the number of irradical resections. The introduction of minimal invasive techniques in pancreatic surgery has deprived surgeons from direct tactile information. To improve intraoperative assessment of pancreatic tumor extension, enhanced or novel intraoperative imaging technologies accurately visualizing and delineating cancer cells are necessary. Emerging modalities are intraoperative near-infrared fluorescence imaging and freehand nuclear imaging using tumor-specific targeted contrast agents. In this review, we performed a meta-analysis of the literature on laparoscopic ultrasonography and we summarized and discussed current and future intraoperative imaging modalities and their potential for improved tumor demarcation during pancreatic surgery.

Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has the potential to improve the sentinel lymph node (SLN) procedure by facilitating percutaneous and intraoperative identification of lymphatic channels and SLNs. Previous studies suggested that a dose of 0.62 mg (1.6 mL of 0.5 mM) ICG is optimal for SLN mapping in breast cancer. The aim of this study was to evaluate the diagnostic accuracy of NIR fluorescence for SLN mapping in breast cancer patients when used in conjunction with conventional techniques. Study subjects were 95 breast cancer patients planning to undergo SLN procedure at either the Dana-Farber/Harvard Cancer Center (Boston, MA, USA) or the Leiden University Medical Center (Leiden, the Netherlands) between July 2010 and January 2013. Subjects underwent the standard-of-care SLN procedure at each institution using (99)Technetium-colloid in all subjects and patent blue in 27 (28 %) of the subjects. NIR fluorescence-guided SLN detection was performed using the Mini-FLARE imaging system. SLN identification was successful in 94 of 95 subjects (99 %) using NIR fluorescence imaging or a combination of both NIR fluorescence imaging and radioactive guidance. In 2 of 95 subjects, radioactive guidance was necessary for initial in vivo identification of SLNs. In 1 of 95 subjects, NIR fluorescence was necessary for initial in vivo identification of SLNs. A total of 177 SLNs (mean 1.9, range 1-5) were resected: 100 % NIR fluorescent, 88 % radioactive, and 78 % (of 40 nodes) blue. In 2 of 95 subjects (2.1 %), SLNs-containing macrometastases were found only by NIR fluorescence, and in one patient this led to upstaging to N1. This study demonstrates the safe and accurate application of NIR fluorescence imaging for the identification of SLNs in breast cancer patients, but calls into question what technique should be used as the gold standard in future studies.

Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to β1 integrins. asTF promotes oncogenic gene expression, anchorage-independent growth, and strongly up-regulates tumor expansion in a luminal BrCa model. In basal BrCa cells that constitutively express both TF isoforms, asTF blockade reduces tumor growth and proliferation in vivo. We propose that asTF plays a major role in BrCa progression acting as an autocrine factor that promotes tumor progression. Targeting asTF may comprise a previously unexplored therapeutic strategy in BrCa that stems tumor growth, yet does not impair normal hemostasis.

Neoadjuvant chemotherapy (NAC) is an increasingly important component in the treatment of both locally advanced and early-stage breast cancer. With this, a debate on the timing of the sentinel lymph node biopsy (SLNB) has emerged. At the end of the last century, the SLNB was introduced as an axillary staging modality, and this paper aims to further elucidate this issue in the context of NAC. We compiled available data on the SLNB after NAC and provide clinical guidance for timing the SLNB in this context. On the basis of our findings, we recommend that the SLNB can be performed after NAC in all cases. In patients with a clinically node-negative (cN0) status prior to NAC, the SLNB should be performed after NAC, and in case of a histologically confirmed negative SLNB, a completion axillary lymph node dissection (ALND) has no added value and can be omitted. In patients with clinically positive nodal involvement (cN+) prior to NAC, all axillary surgery can also be performed after NAC., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has the potential to improve sentinel lymph node (SLN) mapping of breast cancer. We performed a randomized clinical trial to assess the value of blue dyes when used in combination with NIR fluorescence. We also preliminarily examined the possibility of performing SLN mapping without radiotracers., Methods: Clinical trial subjects were 24 consecutive breast cancer patients scheduled to undergo SLN biopsy. All patients received standard of care using 99(m) technetium-nanocolloid and received 1.6 mL of 500 μM ICG injected periareolarly. Patients were randomly assigned to undergo SLN biopsy with or without patent blue. To assess the need for radiocolloids to localize the SLN or SLNs, the surgeon did not use the handheld gamma probe during the first 15 min after the axillary skin incision., Results: SLN mapping was successful in 23 of the 24 patients. No significant difference was found in signal-to-background ratio between the groups with and without patent blue (8.3 ± 3.8 vs. 10.3 ± 5.7, respectively, P = 0.32). In both groups, 100 % of SLNs were radioactive and fluorescent, and in the patent blue group, only 84 % of SLNs were stained blue. In 25 % of patients, the use of the gamma probe was necessary to localize the SLN within the first 15 min., Conclusions: This study shows that there is no benefit of using patent blue for SLN mapping in breast cancer patients when using NIR fluorescence and 99(m) technetium-nanocolloid. NIR fluorescence imaging outperformed patent blue in all patients.

Background: In oral cancer surgery, intraoperative optical imaging could help the surgeon to determine adequate tumor-free margins., Methods: Tumor-specific near-infrared fluorescence agents targeting epidermal growth factor receptor (CW800 EGF) or glucose transporter system (CW800 2-DG) were administered to mice with tongue carcinoma and cervical lymph node metastases. Tumor growth was followed by bioluminescence imaging. Fluorescence signals were compared with a control group of healthy animals., Results: Significantly higher fluorescence was found in tongue tumors and cervical lymph node metastases compared with that in control animals. Fluorescence correlated with histopathology. Tumor-to-background ratio of CW800 EGF in the tongue was 13.8 (SD = 6.1) and in the lymph nodes 15.7 (SD = 8.8). For CW800 2-DG, the tumor-to-background ratio in the tongue was 4.6 (SD = 2.1) and in the lymph nodes 33.9 (SD = 18.4)., Conclusions: Optical imaging can be used to detect oral cancer and cervical lymph node metastases and could potentially improve complete surgical resection by real-time image-guided surgery., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) is a promising technique to obtain real-time assessment of the extent and number of colorectal liver metastases during surgery. The current study aims to optimize dosage and timing of ICG administration., Materials and Methods: Liver tumors were induced in 18 male WAG/Rij rats by subcapsular inoculation of CC531 rat colorectal cancer cells into three distinct liver lobes. Rats were divided in two groups: imaging after 24 and 48 h or 72 and 96 h after intravenous ICG administration. In each time group, rats were allocated to three dose groups: 0.04, 0.08, or 0.16 mg ICG. Intraoperative imaging and ex vivo measurements were performed using the Mini-FLARE imaging system and confirmed by fluorescence microscopy. Fluorescence intensity was quantified using the Mini-FLARE software and the difference between tumor signal and liver signal (tumor-to-liver ratio; TLR) was calculated., Results: In all 18 rats, all colorectal liver metastases (n = 34), some as small as 1.2 mm, were identified using ICG and the Mini-FLARE imaging system. Average tumor-to-liver ratio (TLR) over all groups was 3.0 ± 1.2. TLR was significantly higher in the 72 h time group compared with other time points. ICG dose did not significantly influence TLR, but a trend was found favoring the 0.08 mg dose group. Fluorescence microscopy demonstrated a clear fluorescent rim around the tumor., Conclusions: This study demonstrates that colorectal cancer liver metastases can be clearly identified during surgery using ICG and the Mini-FLARE imaging system, with optimal timing of 72 h post-injection and an optimal dose of 0.08 mg (0.25 mg/kg) ICG. NIR fluorescence imaging has the potential to improve intraoperative detection of micrometastases and, thus, the completeness of resection., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Aromatase inhibitors are more effective than is tamoxifen in prevention of breast-cancer recurrence, but at the expense of increased musculoskeletal side-effects, such as carpal tunnel syndrome. The aim of this study was to assess risk factors and the prognostic value of musculoskeletal symptoms during treatment with the steroidal aromatase inhibitor exemestane or with tamoxifen after 2-3 years of tamoxifen., Methods: In the Intergroup Exemestane Study, postmenopausal women treated for early invasive breast cancer who remained disease free and on treatment after 2-3 years of tamoxifen were randomised to switch to exemestane or to continue tamoxifen for the remainder of the 5-year period of endocrine treatment. The primary endpoint for this retrospective analysis was occurrence of carpal tunnel syndrome and any musculoskeletal events, analysed in the safety population, which consisted of all patients who had received any trial treatment. As well as case-report forms, questionnaires were distributed retrospectively to gain more details of cases of carpal tunnel syndrome. The relation between musculoskeletal symptoms reported by 6 months from randomisation and survival from 9 months onwards was assessed by Cox proportional hazards models. The trial is registered, number ISRCTN11883920. It has completed accrual and follow-up is continuing for enrolled participants., Findings: After a median follow-up of 91·0 months (IQR 83·0-99·2), carpal tunnel syndrome had been reported for 66 (2·8%) of 2319 patients in the exemestane group compared with 13 (0·6%) of 2338 in the tamoxifen group (odds ratio [OR] 5·23, 99% CI 2·39-11·49; p<0·0001). More events occurred during treatment in the exemestane group than in the tamoxifen group (66 [2·8%] vs seven [0·3%], adjusted OR 9·90, 99% CI 3·52-27·82; p<0·0001). There was no significant difference between groups in events in the post-treatment period (ten with exemestane [0·4%] vs seven with tamoxifen [0·3%]; p=0·46). More patients in the exemestane group (1082 of 2319 patients, 46·7%) had musculoskeletal symptoms than in the tamoxifen group (901 of 2338, 38·5%; OR 1·48, 99% CI 1·32-1·67, p<0·0001). More events occurred during treatment in the exemestane group than in the tamoxifen group (984 [42·4%] vs 776 [33·2%], adjusted OR 1·59, 99% CI 1·32-1·91; p<0·0001), with this difference persisting to some extent in the post-treatment period (449 [19·4%] vs 390 [16·7%]; p=0·017). Of 73 on-treatment cases of carpal tunnel syndrome, 58 (79·5%) completed questionnaires were available. 27 patients (46·6%) had bilateral carpal tunnel syndrome and 31 (53·4%) had unilateral disease; 40 (69·0%) underwent surgical release. The disorder greatly affected daily-life activities in 21 (36·2%) cases. Occurrence of musculoskeletal symptoms, including carpal tunnel syndrome, was associated with improved disease-free survival in unadjusted analysis (p=0·023), but not with overall survival (p=0·36). However, after adjustment for possible confounding factors, musculoskeletal symptoms were not associated with disease-free survival (hazard ratio [HR] 0·96, 95% CI 0·82-1·14, p=0·67) or overall survival (HR 1·02, 95% CI 0·84-1·25, p=0·82)., Interpretation: Occurrence of carpal tunnel syndrome is higher in patients with breast cancer given exemestane than in those treated with tamoxifen, and surgical release might be necessary in most cases. Development of musculoskeletal symptoms in the first 6 months of treatment is not an independent biomarker of improved disease outcome. Further investigation is warranted into the relation between treatment-emergent musculoskeletal symptoms and clinical outcome in patients with breast cancer receiving hormonal therapy., Funding: Pfizer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The purpose of this study was to compare the expression and the prognostic effect of the breast cancer stem cell marker aldehyde dehydrogenase-1 (ALDH1) in young and elderly breast cancer patients., Methods: The study population (N = 574) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Median follow-up was 17.9 years (range: 0.1 to 23.5). Tissue microarray slides were immunohistochemically stained for ALDH1 expression and quantified by two independent observers who were blinded to clinical outcome. Assessment of the prognostic effect of ALDH1 expression was stratified according to age and systemic treatment., Results: Complete lack of expression of ALDH1 was found in 40% of tumors. With increasing age more tumors showed complete absence of ALDH1 expression (P < .001). In patients aged > 65 years, ALDH1 status was not associated with any clinical outcome. Conversely, in patients aged < 65 years, ALDH1 positivity was an independent risk factor of worse outcome for relapse free period (hazard ratio = 1.71 (95% CI, 1.09 to 2.68); P = .021) and relative survival (relative excess risks of death = 2.36 (95% CI, 1.22 to 3.68); P = .016). Ten-year relative survival risk was 57% in ALDH1-positive patients compared to 83% in ALDH1-negative patients., Conclusion: ALDH1 expression and its prognostic effect are age-dependent. Our results support the hypothesis that breast cancer biology is different in elderly patients compared to their younger counterparts and emphasizes the importance of taking into consideration age-specific interactions in breast cancer research.

Objectives: Near-infrared fluorescence imaging has the potential to improve sentinel lymph node mapping in vulvar cancer, which was assessed in the current study. Furthermore, dose optimization of indocyanine green adsorbed to human serum albumin was performed., Study Design: Nine vulvar cancer patients underwent the standard sentinel lymph node procedure using (99m)technetium-nancolloid and patent blue. In addition, intraoperative imaging was performed after peritumoral injection of 1.6 mL of 500, 750, or 1000 μM of indocyanine green adsorbed to human serum albumin., Results: Near-infrared fluorescence sentinel lymph node mapping was successful in all patients. A total of 14 sentinel lymph nodes (average, 1.6; range, 1-4) were detected: 14 radioactive (100%), 11 blue (79%), and 14 near-infrared fluorescent (100%)., Conclusion: This study demonstrates feasibility and accuracy of sentinel lymph node mapping using indocyanine green adsorbed to human serum albumin. Considering safety, cost, and pharmacy preferences, an indocyanine green adsorbed to human serum albumin concentration of 500 μM appears optimal for sentinel lymph node mapping in vulvar cancer., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: In early cervical cancer, a total pelvic lymphadenectomy is the standard of care, even though most patients have negative nodes and thus undergo lymphadenectomy unnecessarily. Although the value of sentinel lymph node (SLN) mapping in early-stage cervical cancer has not yet been established, near-infrared (NIR) fluorescence imaging is a promising technique to perform this procedure. Near-infrared fluorescence imaging is based on invisible NIR light and can provide high sensitivity, high-resolution, and real-time image guidance during surgery., Methods: Clinical trial subjects were 9 consecutive cervical cancer patients undergoing total pelvic lymphadenectomy. Before surgery, 1.6 mL of indocyanine green adsorbed to human serum albumin (ICG:HSA) was injected transvaginally and submucosally in 4 quadrants around the tumor. Patients were allocated to 500-, 750-, or 1000-μM ICG:HSA concentration groups. The Mini-FLARE imaging system was used for NIR fluorescence detection and quantitation., Results: Sentinel lymph nodes were identified in all 9 patients. An average of 3.4 ± 1.2 SLNs was identified per patient. No differences in signal to background of the SLNs between the 500-, 750-, and 1000-μM dose groups were found (P = 0.73). In 2 patients, tumor-positive lymph nodes were found. In both patients, tumor-positive lymph nodes confirmed by pathology were also NIR fluorescent., Conclusions: This study demonstrated preliminary feasibility to successfully detect SLNs in cervical cancer patients using ICG:HSA and the Mini-FLARE imaging system. When considering safety, cost-effectiveness, and pharmacy preferences, an ICG:HSA concentration of 500 μM was optimal for SLN mapping in cervical cancer patients.

Background: Near-infrared (NIR) fluorescent sentinel lymph node (SLN) mapping in breast cancer requires optimized imaging systems and lymphatic tracers., Materials and Methods: A small, portable version of the FLARE imaging system, termed Mini-FLARE, was developed for capturing color video and two semi-independent channels of NIR fluorescence (700 and 800 nm) in real time. Initial optimization of lymphatic tracer dose was performed using 35-kg Yorkshire pigs and a 6-patient pilot clinical trial. More refined optimization was performed in 24 consecutive breast cancer patients. All patients received the standard of care using (99m)Technetium-nanocolloid and patent blue. In addition, 1.6 ml of indocyanine green adsorbed to human serum albumin (ICG:HSA) was injected directly after patent blue at the same location. Patients were allocated to 1 of 8 escalating ICG:HSA concentration groups from 50 to 1000 μM., Results: The Mini-FLARE system was positioned easily in the operating room and could be used up to 13 in. from the patient. Mini-FLARE enabled visualization of lymphatic channels and SLNs in all patients. A total of 35 SLNs (mean = 1.45, range 1-3) were detected: 35 radioactive (100%), 30 blue (86%), and 35 NIR fluorescent (100%). Contrast agent quenching at the injection site and dilution within lymphatic channels were major contributors to signal strength of the SLN. Optimal injection dose of ICG:HSA ranged between 400 and 800 μM. No adverse reactions were observed., Conclusions: We describe the clinical translation of a new NIR fluorescence imaging system and define the optimal ICG:HSA dose range for SLN mapping in breast cancer.

Optical imaging using near-infrared (NIR) fluorescence provides new prospects for general and oncologic surgery. ICG is currently utilised in NIR fluorescence cancer-related surgery for three indications: sentinel lymph node (SLN) mapping, intraoperative identification of solid tumours, and angiography during reconstructive surgery. Therefore, understanding its advantages and limitations is of significant importance. Although non-targeted and non-conjugatable, ICG appears to be laying the foundation for more widespread use of NIR fluorescence-guided surgery., (Copyright © 2011 Wiley-Liss, Inc.)

Tumor involvement of resection margins is found in a large proportion of patients who undergo breast-conserving surgery. Near-infrared (NIR) fluorescence imaging is an experimental technique to visualize cancer cells during surgery. To determine the accuracy of real-time NIR fluorescence imaging in obtaining tumor-free resection margins, a protease-activatable NIR fluorescence probe and an intraoperative camera system were used in the EMR86 orthotopic syngeneic breast cancer rat model. Influence of concentration, timing and number of tumor cells were tested in the MCR86 rat breast cancer cell line. These variables were significantly associated with NIR fluorescence probe activation. Dosing and tumor size were also significantly associated with fluorescence intensity in the EMR86 rat model, whereas time of imaging was not. Real-time NIR fluorescence guidance of tumor resection resulted in a complete resection of 17 out of 17 tumors with minimal excision of normal healthy tissue (mean minimum and a mean maximum tumor-free margin of 0.2 ± 0.2 mm and 1.3 ± 0.6 mm, respectively). Moreover, the technique enabled identification of remnant tumor tissue in the surgical cavity. Histological analysis revealed that the NIR fluorescence signal was highest at the invasive tumor border and in the stromal compartment of the tumor. In conclusion, NIR fluorescence detection of breast tumor margins was successful in a rat model. This study suggests that clinical introduction of intraoperative NIR fluorescence imaging has the potential to increase the number of complete tumor resections in breast cancer patients undergoing breast-conserving surgery.

Introduction: Young age at the time of diagnosis of breast cancer is an independent factor of poor prognosis. In many treatment guidelines, the recommendation is to treat young patients with adjuvant chemotherapy regardless of tumor characteristics. However, limited data on prognostic factors are available for young breast cancer patients. The purpose of this study was to determine the prognostic value of established clinical and pathological prognostic factors in young breast cancer patients., Methods: Data from four European Organisation for Research and Treatment of Cancer (EORTC) clinical trials were pooled, resulting in a dataset consisting of 9,938 early breast cancer patients with a median follow-up of 11 years. For 549 patients aged less than 40 years at the time of diagnosis, including 341 node negative patients who did not receive chemotherapy, paraffin tumor blocks were processed for immunohistochemistry using a tissue microarray. Cox proportional hazard analysis was applied to assess the association of clinical and pathological factors with overall and distant metastasis free survival., Results: For young patients, tumor size (P = 0.01), nodal status (P = 0.006) and molecular subtype (P = 0.02) were independent prognostic factors for overall survival. In the node negative subgroup, only molecular subtype was a prognostic factor for overall survival (P = 0.02). Young node negative patients bearing luminal A tumors had an overall survival rate of 94% at 10 years' follow-up compared to 72% for patients with basal-type tumors., Conclusions: Molecular subtype is a strong independent prognostic factor in breast cancer patients younger than 40 years of age. These data support the use of established prognostic factors as a diagnostic tool to assess disease outcome and to plan systemic treatment strategies in young breast cancer patients.

Objective: To assess the feasibility of optical imaging using activatable near-infrared fluorescence (NIRF) agents to detect oral cancer and cervical lymph node metastasis in vivo., Design: In vivo study., Setting: University medical center., Subjects: Female nude mice aged 4 to 6 weeks., Intervention: Luciferase-expressing OSC-19-luc cells were injected into the tongues of nude mice. A control group of nude mice was injected in the tongue with a physiologic saline solution. Tumor growth was followed by bioluminescence imaging. After 3 weeks, animals were randomly allocated to intravenous administration of 1 of 2 activatable NIRF agents: ProSense680 or MMPSense680. Fluorescence imaging of the mice was performed, and the tumor to background ratio (TBR) was determined on histologic sections of the tongue and cervical lymph nodes after resection at necropsy., Main Outcome Measure: Fluorescence signals., Results: The fluorescence signals in tongue tumor and cervical lymph node metastases were significantly higher than those in control animals. The mean (SD) TBR of ProSense680 in the tongue was 15.8 (8.1) and in the lymph nodes was 11.8 (3.6). For MMPSense680, the mean (SD) TBR in the tongue was 18.6 (9.4) and in the lymph nodes was 10.5 (4.0)., Conclusions: Oral cancer and cervical lymph node metastases can be detected by targeting increased proteolytic activity at the tumor borders using NIRF optical imaging. These NIRF agents could be used for real-time image-guided surgery, which has the potential to improve the complete surgical resection of oral cancer.

Near-infrared (NIR) fluorescence imaging has the potential to improve sentinel lymph node (SLN) mapping in breast cancer. Indocyanine green (ICG) is currently the only clinically available fluorophore that can be used for SLN mapping. Preclinically, ICG adsorbed to human serum albumin (ICG:HSA) improves its performance as a lymphatic tracer in some anatomical sites. The benefit of ICG:HSA for SLN mapping of breast cancer has not yet been assessed in a clinical trial. We performed a double-blind, randomized study to determine if ICG:HSA has advantages over ICG alone. The primary endpoint was the fluorescence brightness, defined as the signal-to-background ratio (SBR), of identified SLNs. Clinical trial subjects were 18 consecutive breast cancer patients scheduled to undergo SLN biopsy. All patients received standard of care using (99m)Technetium-nanocolloid and patent blue. Patients were randomly assigned to receive 1.6 ml of 500 μM ICG:HSA or ICG that was injected periareolarly directly after patent blue. The Mini-Fluorescence-Assisted Resection and Exploration (Mini-FLARE) imaging system was used for NIR fluorescence detection and quantitation. SLN mapping was successful in all patients. Patient, tumor, and treatment characteristics were equally distributed over the treatment groups. No significant difference was found in SBR between the ICG:HSA group and the ICG alone group (8.4 vs. 11.3, respectively, P = 0.18). In both groups, the average number of detected SLNs was 1.4 ± 0.5 SLNs per patient (P = 0.74). This study shows that there is no direct benefit of premixing ICG with HSA prior to injection for SLN mapping in breast cancer patients, thereby reducing the cost and complexity of the procedure. With these optimized parameters that eliminate the necessity of HSA, larger trials can now be performed to determine patient benefit.

In cancer surgery, intra-operative assessment of the tumor-free margin, which is critical for the prognosis of the patient, relies on the visual appearance and palpation of the tumor. Optical imaging techniques provide real-time visualization of the tumor, warranting intra-operative image-guided surgery. Within this field, imaging in the near-infrared light spectrum offers two essential advantages: increased tissue penetration of light and an increased signal-to-background-ratio of contrast agents. In this article, we review the various techniques, contrast agents, and camera systems that are currently used for image-guided surgery. Furthermore, we provide an overview of the wide range of molecular contrast agents targeting specific hallmarks of cancer and we describe perspectives on its future use in cancer surgery.

Background: Sentinel lymph node (SLN) mapping in colorectal cancer may have prognostic and therapeutic significance; however, currently available techniques are not optimal. We hypothesized that the combination of invisible near-infrared (NIR) fluorescent light and ex vivo injection could solve remaining problems of SLN mapping in colorectal cancer., Methods: The FLARE imaging system was used for real-time identification of SLNs after injection of the NIR lymphatic tracer HSA800 in the colon and rectum of (n = 4) pigs. A total of 32 SLN mappings were performed in vivo and ex vivo after oncologic resection using an identical injection technique. Guided by these results, SLN mappings were performed in ex vivo tissue specimens of 24 consecutive colorectal cancer patients undergoing resection., Results: Lymph flow could be followed in real-time from the injection site to the SLN using NIR fluorescence. In pigs, the SLN was identified in 32 of 32 (100%) of SLN mappings under both in vivo and ex vivo conditions. Clinically, SLNs were identified in all patients (n = 24) using the ex vivo strategy within 5 min after injection of fluorescent tracer. Also, 9 patients showed lymph node involvement (N1 disease). In 1 patient, a 3-mm mesenteric metastasis was found adjacent to a tumor-negative SLN., Conclusions: The current pilot study shows proof of principle that ex vivo NIR fluorescence-guided SLN mapping can provide high-sensitivity, rapid, and accurate identification of SLNs in colon and rectum. This creates an experimental platform to test optimized, non-FDA-approved NIR fluorescent lymphatic tracers in a clinical setting.

Aim: Near-infrared (NIR) fluorescence optical imaging is a promising technique to assess the extent of colorectal metastases during curative-intended surgery. However, NIR fluorescence imaging of liver metastases is highly challenging due to hepatic uptake and clearance of many fluorescent dyes. In the current study, the biodistribution and the ability to demarcate liver and peritoneal metastases were assessed during surgery in a syngeneic rat model of colorectal cancer using an integrin α(v)β(3)-directed NIR fluorescence probe., Methods: Liver tumors and peritoneal metastases were induced in 7 male WAG/Rij rats by subcapsular inoculation of 0.5 × 10(6) CC531 colorectal cancer rat cells into three distinct liver lobes. Intraoperative and ex vivo fluorescence measurements were performed 24 (N = 3 rats, 7 tumors) and 48 h (N = 4 rats, 9 tumors) after intravenous administration of the integrin α(v)β(3)-directed NIR fluorescence probe., Results: Colorectal metastases had a minimal two-fold higher NIR fluorescence signal than healthy liver tissue and other abdominal organs (p < 0.001). The tumor-to-background ratio was independent of time of imaging (24 h vs. 48 h post-injection; p = 0.31), which facilitates flexible operation planning in future clinical applications. Total fluorescence intensity was significantly correlated with the size of metastases (R(2) = 0.92 for the 24 h group, R(2) = 0.96 for the 48 h group)., Conclusion: These results demonstrate that colorectal intra-abdominal metastases can be clearly demarcated during surgery using an integrin α(v)β(3) targeting NIR fluorescence probe. Translating these findings to the clinic will have an excellent potential to substantially improve the quality of cancer surgery., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Intraoperative visualization of pancreatic tumors has the potential to improve radical resection rates. Intraoperative visualization of the common bile duct and bile duct anastomoses could be of added value. In this study, we explored the use of indocyanine green (ICG) for these applications and attempted to optimize injection timing and dose., Methods: Eight patients undergoing a pancreaticoduodenectomy were injected intravenously with 5 or 10 mg ICG. During and after injection, the pancreas, tumor, common bile duct and surrounding organs were imaged in real time using the Mini-FLARE™ near-infrared (NIR) imaging system., Results: No clear tumor-to-pancreas contrast was observed, except for incidental contrast in 1 patient. The common bile duct was clearly visualized using NIR fluorescence, within 10 min after injection, with a maximal contrast between 30 and 90 min after injection. Patency of biliary anastomoses could be visualized due to biliary excretion of ICG., Conclusion: No useful tumor demarcation could be visualized in pancreatic cancer patients after intravenous injection of ICG. However, the common bile duct and biliary anastomoses were clearly visualized during the observation period. Therefore, these imaging strategies could be beneficial during biliary surgery in cases where the surgical anatomy is aberrant or difficult to identify., (Copyright © 2011 S. Karger AG, Basel.)

Current methods of intraoperative tumor margin detection using palpation and visual inspection frequently result in incomplete resections, which is an important problem in surgical oncology. Therefore, real-time visualization of cancer cells is needed to increase the number of patients with a complete tumor resection. For this purpose, near-infrared fluorescence (NIRF) imaging is a promising technique. Here we describe a novel, handheld, intraoperative NIRF camera system equipped with a 690 nm laser; we validated its utility in detecting and guiding resection of cancer tissues in two syngeneic rat models. The camera system was calibrated using an activated cathepsin-sensing probe (ProSense, VisEn Medical, Woburn, MA). Fluorescence intensity was strongly correlated with increased activated-probe concentration (R2= .997). During the intraoperative experiments, a camera exposure time of 10 ms was used, which provided the optimal tumor to background ratio. Primary mammary tumors (n = 20 tumors) were successfully resected under direct fluorescence guidance. The tumor to background ratio was 2.34 using ProSense680 at 10 ms camera exposure time. The background fluorescence of abdominal organs, in particular liver and kidney, was high, thereby limiting the ability to detect peritoneal metastases with cathepsin-sensing probes in these regions. In conclusion, we demonstrated the technical performance of this new camera system and its intraoperative utility in guiding resection of tumors.

Background: Neoadjuvant chemotherapy defines the preoperative administration of systemic therapy in order to downstage the primary tumor and affected lymph nodes to improve the surgical approach. Neoadjuvant chemotherapy is increasingly being used in the treatment of early operable breast cancer., Objective: We reviewed the available data of neoadjuvant chemotherapy with emphasis on tumor response assessment and prediction, and locoregional management., Methods: We searched the databases of MEDLINE and EMBASE using the search terms breast cancer, neoadjuvant or preoperative or primary or induction, and chemotherapy from 1950 to 1 March 2009., Results/conclusion: Compared with adjuvant chemotherapy, neoadjuvant chemotherapy increases breast conservation with equal survival and locoregional control. Tumor response assessment during neoadjuvant chemotherapy allows identification of in vivo tumor sensitivity to different agents which will help determine predictive factors for improved selection criteria. Randomized trials assessing the timing of sentinel lymph node biopsy in initially lymph node positive patients are warranted. In the near future, intraoperative fluorescent imaging and targeting of cancer stem cells will become important avenues of research.

Neoadjuvant systemic therapy is administered preoperatively in order to provide a better preparation for surgery by down sizing the tumour. A recent meta-analysis comparing neoadjuvant and adjuvant chemotherapy demonstrated a 17% (95% CI: 15.1-18.1) increase in breast-conserving operations with equal survival rates and maintenance of local control providing adequate surgery was performed. Comparable results have been reported with neoadjuvant hormonal therapy. However, in the case of hormonal therapy the tumour-shrinking effects persisted when treatment was sustained. Research has shown that the sentinel lymph node procedure continues to be reliable after neoadjuvant therapy. Therefore, axillary lymph node dissection is not necessary if the lymph node metastases have disappeared as a result of the neoadjuvant therapy: down staging. However, further research is needed to confirm the safety of this treatment approach. Assessment oftumour sensitivity during neoadjuvant therapy facilitates analysis of the prognostic value of tumour markers. The aim of this translational research is to provide better selection criteria to identify patients in which the systemic treatment will be beneficial.

Isolated inflammatory aneurysm of the common iliac artery is a rare condition. Previously reported cases presented with urologic complications owing to entrapment of the ureter in the perianeurysmal fibrosis. We report a case of a healthy young man who presented with acute abdominal pain in the right lower quadrant without urologic complications mimicking acute appendicitis. The pain was caused by an isolated inflammatory aneurysm of the right common iliac artery measuring 4 cm in diameter. Three years after open aneurysmal resection and graft interposition, the patient is doing well, with excellent peripheral circulation. The available literature on presentation, diagnosis, and treatment is reviewed.

Background: Neoadjuvant chemotherapy for early breast cancer can avoid mastectomy by shrinkage of tumour volume. This review assesses the effectiveness of neoadjuvant chemotherapy on clinical outcome., Methods: All randomized trials comparing neoadjuvant and adjuvant chemotherapy for early breast cancer were reviewed systematically and meta-analyses were performed., Results: Fourteen studies randomizing 5500 women were eligible for analysis. Overall survival was equivalent in both groups. In the neoadjuvant group, the mastectomy rate was lower (relative risk 0.71 (95 per cent confidence interval (c.i.) 0.67 to 0.75)) without hampering local control (hazard ratio 1.12 (95 per cent c.i. 0.92 to 1.37)). Neoadjuvant chemotherapy was associated fewer adverse effects., Conclusion: Neoadjuvant chemotherapy is an established treatment option for early breast cancer., (Copyright (c) 2007 British Journal of Surgery Society Ltd.)

Background: Currently, preoperative chemotherapy is the standard of care in locally advanced breast cancer to achieve local tumour downsizing in order to make surgery possible. Since the early 1980s, the role of preoperative chemotherapy in early stage (or operable) breast cancer has been the subject of study. Potential advantages are early introduction of systemic therapy, determination of chemosensitivity, reduction of tumour volume and downstaging of surgical requirement. Concerns exist about local control after downsized surgery and the delay of local treatment in patients with tumours resistant to chemotherapy., Objectives: To assess the effectiveness of preoperative chemotherapy in women with operable breast cancer when compared to postoperative chemotherapy., Search Strategy: The Specialised Register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 4th of August 2005., Selection Criteria: Randomised trials comparing preoperative chemotherapy with postoperative in women with operable breast cancer., Data Collection and Analysis: Studies were assessed for eligibility and quality, and data were extracted by two independent review authors. Hazard ratios were derived for time-to-event outcomes directly or indirectly using the methods described by Parmar. Relative risks were derived for dichotomous outcomes. Meta-analyses were performed using fixed effect model., Main Results: We identified 14 eligible studies which randomised a total of 5,500 women. Median follow-up ranged from 18 to 124 months. Eight studies described a satisfactory method of randomisation.Data, based on 1139 estimated deaths in 4620 women available for analysis, show equivalent overall survival rates with a HR of 0.98 (95% CI, 0.87 to 1.09; p, 0.67; no heterogeneity). Preoperative chemotherapy increases breast conservation rates, yet at the associated cost of increased loco regional recurrence rates. However, this rate was not increased as long as surgery remains part of the treatment even after complete tumour regression (HR, 1.12; 95% CI, 0.92 to 1.37; p, 0.25; no heterogeneity. Preoperative chemotherapy was associated with fewer adverse effects. Pathological complete response is associated with better survival than residual disease (HR, 0.48; 95% CI, 0.33 to 0.69; p, < 10-4)., Authors' Conclusions: This review suggests safe application of preoperative chemotherapy in the treatment of women with early stage breast cancer in order to down-stage surgical requirement, to evaluate chemosensitivity and to facilitate translational research.

Introduction: Breast cancer at a young age is associated with an unfavorable prognosis. Very young patients with breast cancer therefore are advised to undergo adjuvant chemotherapy irrespective of tumor stage or grade. However, chemotherapy alone may not be adequate in young patients with hormone receptor-positive breast cancer. Therefore, we studied the effect of adjuvant chemotherapy in young patients with breast cancer in relation to hormone receptor status., Methods: Paraffin-embedded tumor material was collected from 480 early-stage breast cancer patients younger than 41 years who participated in one of four European Organization for Research and Treatment of Cancer trials. Using immunohistochemistry on the whole series of tumors, we assessed estrogen receptor (ER) status and progesterone receptor (PgR) status in a standardized way. Endpoints in this study were overall survival (OS) and distant metastasis-free survival (DMFS). The median follow-up period was 7.3 years., Results: Overall, patients with ER-positive tumors had better OS rates (hazard ratio [HR] 0.63; P = 0.02) compared with those with ER-negative tumors. However, in the subgroup of patients who received chemotherapy, no significant difference in OS (HR 0.87; P = 0.63) and DMFS (HR 1.36; P = 0.23) was found between patients with ER-positive tumors or those with ER-negative tumors. These differences were similar for PgR status., Conclusion: Young patients with hormone receptor-positive tumors benefit less from adjuvant systemic chemotherapy than patients with hormone receptor-negative tumors. These results confirm that chemotherapy alone cannot be considered optimal adjuvant systemic treatment in breast cancer patients 40 years old or younger with hormone receptor-positive tumors.

The aim of this retrospective study was to identify markers capable of predicting pathological complete (pCR) and overall clinical tumour response to preoperative anthracycline-based chemotherapy and clinical outcome in women with operable breast cancer. Therefore, we used the pre-treatment core biopsies from 107 patients who were enrolled in the EORTC trial 10902 to analyse tumour characteristics and the oncogenic markers Bcl-2, p53, ER, PgR, HER2, and p21. Median follow-up was 7 years (95% confidence interval [CI], 6.89-7.45). pCR was seen in seven patients (6.5%) and was associated with improved overall survival (hazards ratio, 0.39; 95% CI, 0.05-2.56; P = 0.30). In multivariate logistic regression analysis, pCR was independently predicted by p53 overexpression estimated by immunohistochemistry (odds ratio [OR], 16.83; 95% CI, 1.78-159.33; P = 0.01). Fifty-eight patients showed clinical tumour response (>50% decrease in tumour size), however responders experienced no benefit in clinical outcome. Clinical tumour response was independently predicted by p53 overexpression (OR, 5.57; 95% CI, 1.58-19.65; P = 0.008) and small clinical tumour size (OR, 10.26; 95% CI, 2.01-52.48; P = 0.005). In multivariate Cox regression analysis, negative pathological lymph node status, low tumour grade and use of tamoxifen showed improved overall survival. In conclusion, our data suggest p53 expression is of predictive significance in anthracycline-containing chemotherapeutic regimens.