Improving breast cancer outcome by preoperative systemic therapy and image-guided surgery

This thesis consists of two parts. In part I, we have demonstrated that preoperatively administrated systemic (neoadjuvant) therapy is a feasible treatment strategy in early stage breast cancer to achieve improved surgical options and to assess tumor response. We also demonstrated that overexpression of the breast cancer stem cell marker aldehyde dehydrogenase-1 in early stage breast cancer patients is inversely associated with age and is of prognostic importance. In part II, we have demonstrated proof-of-principle of intraoperative tumor detection and image-guided tumor resection by using the novel technique of near-infrared fluorescence imaging. We have performed two clinical trials to optimize the use of indocyanine green as a near-infrared fluorescence lymphatic tracer for the sentinel lymph node procedure in breast cancer patients.KWF CTMM ZonMw Sacha Swarttouw-Hijmans FoundationUBL - phd migration 201

Near-infrared fluorescence-guided metastasectomy for hepatic gastrointestinal stromal tumor metastases using indocyanine green: a case report

INTRODUCTION AND IMPORTANCE: Gastrointestinal stromal tumors are the most prevalent mesenchymal tumors of the gastrointestinal tract. Distant metastases are most often found in the liver or peritoneum with surgery being the preferred treatment option. In our center, fluorescence-guided surgery with indocyanine green is used as standard-of-care for hepatic metastases in colorectal cancer. This case report describes fluorescence-guided metastasectomy for a hepatic gastrointestinal stromal tumor in two patients undergoing open liver resection and radiofrequency ablation.CASE PRESENTATION: A 69-year old women was seen during follow-up after laparoscopic resection of a GIST in the lesser curvature of the stomach. Contrast-enhanced computed tomography imaging showed two suspicious lesions in liver segment VI and VIII. Intraoperative near-infrared fluorescence imaging of the liver clearly revealed the lesion in segment VIII, and an additional lesion in segment V - which was not seen on preoperative CT-imaging, neither on intraoperative ultrasonography. The lesion in segment VI was not seen with NIRF imaging due to its deeper location in the liver parenchyma. The second case is an 82-year old man who was also diagnosed with liver metastases from a GIST in the stomach and was scheduled for near-infrared fluorescence-guided liver resection and radio frequency ablation.CLINICAL DISCUSSION: In this case report we demonstrated the feasibility of fluorescence-guided surgery in detection of liver metastases and treatment planning of two patients with hepatic GIST metastases using indocyanine green.CONCLUSION: NIRF-imaging with ICG is useful for identification of preoperatively discovered lesions, surgical resection planning and margin evaluation, and for detection of additional hepatic GIST metastases. (C) 2020 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. This is an open access article under the CC BY-NC-ND license (http://creative commons.org/licenses/by-nc-nd/4.0/).Surgical oncolog

The clinical usefulness of optical coherence tomography during cancer interventions

Surgical oncolog

Quantitative dynamic near-infrared fluorescence imaging using indocyanine green for analysis of bowel perfusion after mesenteric resection

Significance: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has proven to be a feasible application for real-time intraoperative assessment of tissue perfusion, although quantification of NIR fluorescence signals is pivotal for standardized assessment of tissue perfusion.Aim: Four patients are described with possible compromised bowel perfusion after mesenteric resection. Based on these patients we want to emphasize the difficulties in the quantification of NIR fluorescence imaging for perfusion analysis.Approach: During image-guided fluorescence assessment, 5 mg of ICG (2.5 mg/ml) was intravenously administered by the anesthesiologist. NIR fluorescence imaging was done with the open camera system of Quest Medical Imaging. Fluorescence data taken from the regions of interest (bowel at risk, transition zone of bowel at risk and adjacent normally perfused bowel, and normally perfused reference bowel) were quantitatively analyzed after surgery for fluorescence intensity-and perfusion time-related parameters.Results: Bowel perfusion, as assessed clinically by independent surgeons based on NIR fluorescence imaging, resulted in different treatment strategies, three with excellent clinical outcome, but one with a perfusion related complication. Post-surgery quantitative analysis of fluorescence dynamics showed different patterns in the affected bowel segment compared to the unaffected reference segments for the four patients.Conclusions: Similar intraoperative fluorescence results could lead to different surgical treatment strategies, which demonstrated the difficulties in interpretation of uncorrected fluorescence signals. Real-time quantification and standardization of NIR fluorescence perfusion imaging could probably aid surgeons in the nearby future. (C) The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License.Surgical oncolog

Clinical translation and implementation of optical imaging agents for precision image-guided cancer surgery

Introduction The field of tumor-specific fluorescence-guided surgery has seen a significant increase in the development of novel tumor-targeted imaging agents. Studying patient benefit using intraoperative fluorescence-guided imaging for cancer surgery is the final step needed for implementation in standard treatment protocols. Translation into phase III clinical trials can be challenging and time consuming. Recent studies have helped to identify certain waypoints in this transition phase between studying imaging agent efficacy (phase I-II) and proving patient benefit (phase III). Trial initiation Performing these trials outside centers of expertise, thus involving motivated clinicians, training them, and providing feedback on data quality, increases the translatability of imaging agents and the surgical technique. Furthermore, timely formation of a trial team which oversees the translational process is vital. They are responsible for establishing an imaging framework (camera system, imaging protocol, surgical workflow) and clinical framework (disease stage, procedure type, clinical research question) in which the trial is executed. Providing participating clinicians with well-defined protocols with the aim to answer clinically relevant research questions within the context of care is the pinnacle in gathering reliable trial data. Outlook If all these aspects are taken into consideration, tumor-specific fluorescence-guided surgery is expected be of significant value when integrated into the diagnostic work-up, surgical procedure, and follow-up of cancer patients. It is only by involving and collaborating with all stakeholders involved in this process that successful clinical translation can occur. Aim Here, we discuss the challenges faced during this important translational phase and present potential solutions to enable final clinical translation and implementation of imaging agents for image-guided cancer surgery.Surgical oncolog

Gadoxetic acid-enhanced magnetic resonance imaging significantly influences the clinical course in patients with colorectal liver metastases

Surgical oncolog

Robot-assisted and fluorescence-guided remnant-cholecystectomy: a prospective dual-center cohort study

Background: Abdominal symptoms after cholecystectomy may be caused by gallstones in a remnant gallbladder or a long cystic duct stump. Resection of a remnant gallbladder or cystic duct stump is associated with an increased risk of conversion and bile duct or vascular injuries. We prospectively investigated the additional value of robotic assistance and fluorescent bile duct illumination in redo biliary surgery.Methods: In this prospective two-centre observational cohort study, 28 patients were included with an indication for redo biliary surgery because of remnant stones in a remnant gallbladder or long cystic duct stump. Surgery was performed with the da Vinci X & REG; and Xi & REG; robotic system. The biliary tract was visualised in the fluorescence Firefly & REG; mode shortly after intravenous injection of indocyanine green.Results: There were no conversions or perioperative complications, especially no vascular or bile duct injuries. Fluorescence-based illumination of the extrahepatic bile ducts was successful in all cases. Symptoms were resolved in 27 of 28 patients. Ten patients were treated in day care and 13 patients were discharged the day after surgery.Conclusion: Robot-assisted fluorescence-guided surgery for remnant gallbladder or cystic duct stump resection is safe, effective and can be done in day-care setting.Surgical oncolog

Clinical implications of bile cultures obtained during pancreatoduodenectomy: a cohort study and meta-analysis

Background: The association between intraoperative bile cultures and infectious complications after pancreatoduodenectomy remains unclear. This cohort study and meta-analysis aimed to determine the predictive role of intraoperative bile cultures in abdominal infectious complications after pancreatoduodenectomy. Methods: The cohort study included 114 patients undergoing pancreatoduodenectomy. Regression analyses were used to estimate the odds to develop an organ space infection (OSI) or isolated OSI (OSIs without a simultaneous complication potentially contaminating the intraabdominal space) after a positive bile culture. A systematic review and meta-analysis was performed on abdominal infectious complications (Mantel-Haenszel fixed-effect model). Results: The positive bile culture rate was 61%, predominantly in patients after preoperative biliary drainage (98% vs 26%, p < 0.001). OSIs occurred in 35 patients (31%) and isolated OSIs in nine patients (8%) and were not associated with positive bile cultures (OSIs: odds ratio = 0.6, 95% CI = 0.25-1.23, isolated OSIs: odds ratio = 0.77, 95% CI = 0.20-3.04). In the meta-analysis, 15 studies reporting on 2047 patients showed no association between positive bile cultures and abdominal infectious complications (pooled odds ratio = 1.3, 95% CI = 0.98-1.65). Conclusion: Given the rare occurrence of isolated OSIs and similar odds for patients with positive and negative bile cultures to develop abdominal infectious complications, routine performance of bile cultures should be reconsidered.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Novel Molecular Targets for Tumor-Specific Imaging of Epithelial Ovarian Cancer Metastases

In epithelial ovarian cancer (EOC), the strongest prognostic factor is the completeness of surgery. Intraoperative molecular imaging that targets cell-surface proteins on tumor cells may guide surgeons to detect metastases otherwise not visible to the naked eye. Previously, we identified 29% more metastatic lesions during cytoreductive surgery using OTL-38, a fluorescent tracer targeting folate receptor-α (FRα). Unfortunately, eleven out of thirteen fluorescent lymph nodes were tumor negative. The current study evaluates the suitability of five biomarkers (EGFR, VEGF-A, L1CAM, integrin αvβ6 and EpCAM) as alternative targets for molecular imaging of EOC metastases and included FRα as a reference. Immunohistochemistry was performed on paraffin-embedded tissue sections of primary ovarian tumors, omental, peritoneal and lymph node metastases from 84 EOC patients. Tumor-negative tissue specimens from these patients were included as controls. EGFR, VEGF-A and L1CAM were highly expressed in tumor-negative tissue, whereas αvβ6 showed heterogeneous expression in metastases. The expression of EpCAM was most comparable to FRα in metastatic lesions and completely absent in the lymph nodes that were false-positively illuminated with OTL-38 in our previous study. Hence, EpCAM seems to be a promising novel target for intraoperative imaging and may contribute to a more reliable detection of true metastatic EOC lesions.Surgical oncolog

An immunohistochemical evaluation of tumor-associated glycans and mucins as targets for molecular imaging of Pancreatic Ductal Adenocarcinoma

Simple Summary: Distinguishing pancreatic cancer from healthy tissue before and during surgery can be enhanced by using molecular tracers directed at molecules on tumor cells allowing high-contrast visualization of tumor tissue, eventually improving diagnosis and surgical removal. Albeit sugar molecules and proteins carrying a large amount of sugars-mucins- have gained significant interest as tumor-specific targets, their relative presence on structures surrounding tumor tissues and lymph node metastases is unknown. The current study shows that the presence of several, but not all, investigated sugar molecules and mucins on pancreatic cancer cells is higher compared to surrounding tissues. Moreover, given their abundance on tumor cells in lymph nodes and their absence on normal lymph nodes, all investigated targets are high-potential targets for visualization of lymph node metastases. This study paves the way for the development of molecular tracers against the targets evaluated herein to allow improvement of pancreatic cancer treatment.Targeted molecular imaging may overcome current challenges in the preoperative and intraoperative delineation of pancreatic ductal adenocarcinoma (PDAC). Tumor-associated glycans Le(a/c/x), sdi-Le(a), sLe(a), sLe(x), sTn as well as mucin-1 (MUC1) and mucin-5AC (MU5AC) have gained significant interest as targets for PDAC imaging. To evaluate their PDAC molecular imaging potential, biomarker expression was determined using immunohistochemistry on PDAC, (surrounding) chronic pancreatitis (CP), healthy pancreatic, duodenum, positive (LN+) and negative lymph node (LN-) tissues, and quantified using a semi-automated digital image analysis workflow. Positive expression on PDAC tissues was found on 83% for Le(a/c/x), 94% for sdi-Le(a), 98% for sLe(a), 90% for sLe(x), 88% for sTn, 96% for MUC1 and 67% for MUC5AC, where all were not affected by the application of neoadjuvant therapy. Compared to PDAC, all biomarkers were significantly lower expressed on CP, healthy pancreatic and duodenal tissues, except for sTn and MUC1, which showed a strong expression on duodenum (sTn tumor:duodenum ratio: 0.6, p 0.9999), respectively. All biomarkers are suitable targets for correct identification of LN+, as well as the distinction of LN+ from LN- tissues. To conclude, this study paves the way for the development and evaluation of Le(a/c/x)-, sdi-Le(a)-, sLe(a)-, sLe(x)- and MUC5AC-specific tracers for molecular imaging of PDAC imaging and their subsequent introduction into the clinic.Surgical oncolog