ICG-Fluorescence Imaging for Margin Assessment During Minimally Invasive Colorectal Liver Metastasis Resection.

Importance: Unintended tumor-positive resection margins occur frequently during minimally invasive surgery for colorectal liver metastases and potentially negatively influence oncologic outcomes. Objective: To assess whether indocyanine green (ICG)-fluorescence-guided surgery is associated with achieving a higher radical resection rate in minimally invasive colorectal liver metastasis surgery and to assess the accuracy of ICG fluorescence for predicting the resection margin status. Design, Setting, and Participants: The MIMIC (Minimally Invasive, Indocyanine-Guided Metastasectomy in Patients With Colorectal Liver Metastases) trial was designed as a prospective single-arm multicenter cohort study in 8 Dutch liver surgery centers. Patients were scheduled to undergo minimally invasive (laparoscopic or robot-assisted) resections of colorectal liver metastases between September 1, 2018, and June 30, 2021. Exposures: All patients received a single intravenous bolus of 10 mg of ICG 24 hours prior to surgery. During surgery, ICG-fluorescence imaging was used as an adjunct to ultrasonography and regular laparoscopy to guide and assess the resection margin in real time. The ICG-fluorescence imaging was performed during and after liver parenchymal transection to enable real-time assessment of the tumor margin. Absence of ICG fluorescence was favorable both during transection and in the tumor bed directly after resection. Main Outcomes and Measures: The primary outcome measure was the radical (R0) resection rate, defined by the percentage of colorectal liver metastases resected with at least a 1 mm distance between the tumor and resection plane. Secondary outcomes were the accuracy of ICG fluorescence in detecting margin-positive (R1; <1 mm margin) resections and the change in surgical management. Results: In total, 225 patients were enrolled, of whom 201 (116 [57.7%] male; median age, 65 [IQR, 57-72] years) with 316 histologically proven colorectal liver metastases were included in the final analysis. The overall R0 resection rate was 92.4%. Re-resection of ICG-fluorescent tissue in the resection cavity was associated with a 5.0% increase in the R0 percentage (from 87.4% to 92.4%; P < .001). The sensitivity and specificity for real-time resection margin assessment were 60% and 90%, respectively (area under the receiver operating characteristic curve, 0.751; 95% CI, 0.668-0.833), with a positive predictive value of 54% and a negative predictive value of 92%. After training and proctoring of the first procedures, participating centers that were new to the technique had a comparable false-positive rate for predicting R1 resections during the first 10 procedures (odds ratio, 1.36; 95% CI, 0.44-4.24). The ICG-fluorescence imaging was associated with changes in intraoperative surgical management in 56 (27.9%) of the patients. Conclusions and Relevance: In this multicenter prospective cohort study, ICG-fluorescence imaging was associated with an increased rate of tumor margin-negative resection and changes in surgical management in more than one-quarter of the patients. The absence of ICG fluorescence during liver parenchymal transection predicted an R0 resection with 92% accuracy. These results suggest that use of ICG fluorescence may provide real-time feedback of the tumor margin and a higher rate of complete oncologic resection.

Unexpected, complete recovery after emergent thoracic endovascular aortic repair for inoperable type A aortic dissection.

Patients presenting with a Stanford type A acute aortic dissection require immediate surgical treatment; however, up to 30% of patients are deemed inoperable. Here we describe a case of a patient with a complicated type A acute aortic dissection presenting with a severe impact of brain malperfusion. In contrast with open surgery, an emergent thoracic endovascular aortic repair was performed with a Gore cTAG 45 × 150 mm graft and an additional chimney graft Advanta V12 7 × 59 mm graft for the brachiocephalic trunk. After early extubation, unexpected complete neurological recovery was observed. A follow-up computed tomography scan demonstrated complete remodeling of the ascending aorta. This report underlines the potential of thoracic endovascular aortic repair as an alternative for immediate open surgical repair in case of high-risk or inoperable patients.

Real-time surgical margin assessment using ICG-fluorescence during laparoscopic and robot-assisted resections of colorectal liver metastases.

BACKGROUND: Almost a third of the resections in patients with colorectal liver metastases (CRLM) undergoing curative surgery, end up being tumor-margin positive (≤1 mm margin). Near-infrared fluorescent (NIRF) imaging using the fluorescent contrast agent indocyanine green (ICG) has been studied for many different applications. When administered in a relatively low dose (10 mg) 24 hours prior to surgery, ICG accumulated in hepatocytes surrounding the CRLM. This results in the formation of a characteristic fluorescent 'rim' surrounding CRLM when located at the periphery of the liver. By resecting the metastasis with the entire surrounding fluorescent rim, in real-time guided by NIRF imaging, the surgeon can effectively acquire margin-negative (>1 mm) resections. This pilot study aims to describe the surgical technique for using near-infrared fluorescence imaging to assess tumor-margins in vivo in patients with CRLM undergoing laparoscopic or robot-assisted resections. METHODS: Out of our institutional database we selected 16 CRLM based on margin-status (R0; n=8, R1; n=8), which were resected by a minimally-invasive approach using ICG-fluorescence. NIRF images acquired during surgery, from both the resection specimen and the wound bed, were analysed for fluorescent signal. We hypothesized that a protruding fluorescent rim at the parenchymal side of the resection specimen could indicate a too close proximity to the tumor and could be predictive for a tumor-positive surgical margin. NIRF images were correlated to final histopathological assessment of the resection margin. RESULTS: All lesions with a NIRF positive resection plane in vivo were reported as having a tumor-positive margin. Lesions that showcased no protruding rim in the wound bed in vivo were diagnosed as having a tumor-negative margin in 88% of cases. A 5-step surgical workflow is described to document the NIRF signal was used assess the resection margin in vivo for future clinical studies. CONCLUSIONS: The pilot study shows that image-guided surgery using real-time ICG-fluorescence has the potential to aid surgeons in achieving a tumor-negative margin in minimally invasive liver metastasectomies. The national multi-centre MIMIC-Trial will prospectively study the effect of this technique on surgical tumor-margins (Dutch Trial Register number NL7674).

A zwitterionic near-infrared fluorophore for real-time ureter identification during laparoscopic abdominopelvic surgery.

Iatrogenic injury of the ureters is a feared complication of abdominal surgery. Zwitterionic near-infrared fluorophores are molecules with geometrically-balanced, electrically-neutral surface charge, which leads to renal-exclusive clearance and ultralow non-specific background binding. Such molecules could solve the ureter mapping problem by providing real-time anatomic and functional imaging, even through intact peritoneum. Here we present the first-in-human experience of this chemical class, as well as the efficacy study in patients undergoing laparoscopic abdominopelvic surgery. The zwitterionic near-infrared fluorophore ZW800-1 is safe, has pharmacokinetic properties consistent with an ideal blood pool agent, and rapid elimination into urine after a single low-dose intravenous injection. Visualization of structure and function of the ureters starts within minutes after ZW800-1 injection and lasts several hours. Zwitterionic near-infrared fluorophores add value during laparoscopic abdominopelvic surgeries and could potentially decrease iatrogenic urethral injury. Moreover, ZW800-1 is engineered for one-step covalent conjugatability, creating possibilities for developing novel targeted ligands.

A Prospective Clinical Trial to Determine the Effect of Intraoperative Ultrasound on Surgical Strategy and Resection Outcome in Patients with Pancreatic Cancer.

Surgical exploration in patients with pancreatic or periampullary cancer is often performed without intraoperative image guidance. Although intraoperative ultrasound (IOUS) may enhance visualization during resection, this tool has not been investigated in detail until now. Here, we performed a prospective cohort study to evaluate the effect of IOUS on surgical strategy and to evaluate whether vascular involvement and radicality of the resection could be correctly assessed with IOUS. IOUS was performed by an experienced abdominal radiologist during surgical exploration in 31 consecutive procedures. IOUS affected surgical strategy by either (i) having no effect, (ii) determining tumor localization, (iii) evaluating vascular involvement or (iv) waiving surgery. Radicality of the resections and vascular contact were determined during pathologic analysis and compared with preoperative imaging and IOUS findings. Overall, IOUS influenced surgical strategy in 61% of procedures. In 21 out of 27 malignant tumors, a radical resection was achieved (78%). Vascular contact was assessed correctly using IOUS in 89% compared with 74% of patients using preoperative imaging. IOUS can help the surgical team to assess the resectability and to visualize the tumor and possible vascular contact in real time during resection. IOUS may therefore increase the likelihood of achieving a radical resection.

A dual-labeled cRGD-based PET/optical tracer for pre-operative staging and intraoperative treatment of colorectal cancer.

cRGD peptides target integrins associated with angiogenesis (e.g., αvß3) and cancer, and have been used as binding ligands for both positron emission tomography (PET) and near-infrared fluorescence (NIRF) optical imaging. This study introduces the hybrid tracer cRGD-ZW800-1-Forte-[89Zr]Zr-DFO, which is based on a novel zwitterionic fluorophore structure that reduces non-specific background uptake during molecular imaging of tumors. An in vitro binding assay was used to validate tracer performance. 10 nmol ZW800F-cRGD-Zr-DFO was injected in mice (n=7) bearing orthotopic human colorectal tumors (HT29-luc2) for tumor detection with NIRF imaging. Subsequently, ZW800F-cRGD-Zr-DFO was loaded with 89Zr and 10 nmol cRGD-ZW800-1-Forte-[89Zr]Zr-DFO (3 MBq) was injected in mice (n=8) for PET/CT imaging. Imaging and biodistribution was performed at 4 and 24 h. NIRF imaging was performed up to 168 h after administration. Sufficient fluorescent signals were measured in the tumors of mice injected with ZW800F-cRGD-Zr-DFO (emission peak ~800 nm) compared to the background. The signal remained stable for up to 7 days. The fluorescence signal of cRGD-ZW800-1-Forte-[89Zr]Zr-DFO remained intact after labeling with 89Zr. PET/CT permitted clear visualization of the colorectal tumors at 4 and 24 h. Biodistribution at 4 h showed the highest uptake of the tracer in kidneys and sufficient uptake in the tumor, remaining stable for up to 24 h. A single molecular imaging agent, ZW800F-cRGD-[89Zr]Zr-DFO, permits serial PET and NIRF imaging of colorectal tumors, with the latter permitting image-guided treatment intraoperatively. Due to its unique zwitterionic structure, the tracer is rapidly renally cleared and fluorescent background signals are low.

[Intraoperative imaging using fluorescence, 5 years later]. / Intraoperatieve beeldvorming met fluorescentie, 5 jaar later.

Fluorescence imaging is a technique that uses near-infrared light combined with a fluorescent contrast agent to visualise specific tissue structures. This technique can be used to visualise vital anatomical structures, sentinel nodes, primary tumours and metastases during surgery or laparoscopic procedures. The development of various tumour-specific contrast agents has led to an increase in indications for the use of fluorescence imaging.

Image-Guided Surgery in Patients with Pancreatic Cancer: First Results of a Clinical Trial Using SGM-101, a Novel Carcinoembryonic Antigen-Targeting, Near-Infrared Fluorescent Agent.

BACKGROUND: Near-infrared (NIR) fluorescence is a promising novel imaging technique that can aid in intraoperative demarcation of pancreatic cancer (PDAC) and thus increase radical resection rates. This study investigated SGM-101, a novel, fluorescent-labeled anti-carcinoembryonic antigen (CEA) antibody. The phase 1 study aimed to assess the tolerability and feasibility of intraoperative fluorescence tumor imaging using SGM-101 in patients undergoing a surgical exploration for PDAC. METHODS: At least 48 h before undergoing surgery for PDAC, 12 patients were injected intravenously with 5, 7.5, or 10 mg of SGM-101. Tolerability assessments were performed at regular intervals after dosing. The surgical field was imaged using the Quest NIR imaging system. Concordance between fluorescence and tumor presence on histopathology was studied. RESULTS: In this study, SGM-101 specifically accumulated in CEA-expressing primary tumors and peritoneal and liver metastases, allowing real-time intraoperative fluorescence imaging. The mean tumor-to-background ratio (TBR) was 1.6 for primary tumors and 1.7 for metastatic lesions. One false-positive lesion was detected (CEA-expressing intraductal papillary mucinous neoplasm). False-negativity was seen twice as a consequence of overlying blood or tissue that blocked the fluorescent signal. CONCLUSION: The use of a fluorescent-labeled anti-CEA antibody was safe and feasible for the intraoperative detection of both primary PDAC and metastases. These results warrant further research to determine the impact of this technique on clinical decision making and overall survival.

Risk of multiple pancreatic cancers in CDKN2A-p16-Leiden mutation carriers.

CDKN2A-p16-Leiden mutation carriers have a substantial risk of developing pancreatic ductal adenocarcinoma (PDAC). One of the main clinical features of hereditary cancer is the development of multiple cancers. Since 2000, we have run a surveillance program for CDKN2A-p16-Leiden mutation carriers. The patients are offered a yearly MRI with optionally endoscopic ultrasound. In patients with a confirmed lesion, usually, a partial resection of the pancreas is recommended. A total of 18 PDAC (8.3%) were detected in 218 mutation carriers. In this report, we describe two CDKN2A-p16-Leiden patients with a synchronous and metachronous PDAC. Including two previously-reported cases, we identified four patients with multiple PDAC: two of 18 patients within the surveillance program (11%) and two patients with a proven CDKN2A-p16-Leiden mutation not participating in the surveillance program. In conclusion, this study demonstrated a high risk of developing multiple PDAC in CDKN2A-p16-Leiden mutation carriers. After detecting a primary tumor, it is very important to exclude the presence of a second synchronous tumor. Moreover, after a partial pancreatectomy for PDAC, close surveillance is necessary. In view of the current findings, offering a total pancreatectomy might be an appropriate option in patients with an early PDAC.

Diagnostic value of targeted next-generation sequencing in patients with suspected pancreatic or periampullary cancer.

AIMS: Radiological imaging and morphological assessment of cytology material have limitations for preoperative classification of pancreatic or periampullary lesions, often resulting in surgical resection without definitive diagnosis. Our prospective study aims to define the diagnostic value of targeted next-generation sequencing (NGS) of DNA from cytology material. METHODS: Patients with a suspect pancreatic or periampullary lesion underwent standard diagnostic evaluation including preoperative morphological cytology assessment. Treatment options for suspect lesions were surgical exploration with possible resection, follow-up or palliation. The cytology samples were analysed with NGS, in which 50 genes were sequenced for the presence of pathogenic variants. The NGS results were integrated with the clinical information during multidisciplinary team meetings, and changes in the treatment plan were scored. Diagnostic accuracy of NGS analysis (malignancy vs benign disease) was calculated. RESULTS: NGS results of the cytology samples were confirmed in the resection specimens of the first 10 included patients. The integration of the NGS results led to a change in treatment plan in 7 out of 70 patients (from exploration to follow-up, n=4; from follow-up to exploration and resection, n=2; from palliation to resection, n=1). In four patients, the NGS results were contradictory, but did not affect the treatment plan. In the remaining 59 patients, NGS analysis supported the initial treatment plan. The diagnostic accuracy of NGS analysis was 94% (sensitivity=93%; specificity=100%). CONCLUSIONS: NGS can change the treatment plan in a significant portion of patients with suspect pancreatic or periampullary lesions. Application of NGS can optimise treatment selection and diminish unnecessary surgeries.

Real-time near-infrared fluorescence imaging using cRGD-ZW800-1 for intraoperative visualization of multiple cancer types.

Incomplete resections and damage to critical structures increase morbidity and mortality of patients with cancer. Targeted intraoperative fluorescence imaging aids surgeons by providing real-time visualization of tumors and vital structures. This study evaluated the tumor-targeted zwitterionic near-infrared fluorescent peptide cRGD-ZW800-1 as tracer for intraoperative imaging of multiple cancer types. cRGD-ZW800-1 was validated in vitro on glioblastoma (U-87 MG) and colorectal (HT-29) cell lines. Subsequently, the tracer was tested in orthotopic mouse models with HT-29, breast (MCF-7), pancreatic (BxPC-3), and oral (OSC-19) tumors. Dose-ranging studies, including doses of 0.25, 1.0, 10, and 30 nmol, in xenograft tumor models suggest an optimal dose of 10 nmol, corresponding to a human equivalent dose of 63 µg/kg, and an optimal imaging window between 2 and 24 h post-injection. The mean half-life of cRGD-ZW800-1 in blood was 25 min. Biodistribution at 4 h showed the highest fluorescence signals in tumors and kidneys. In vitro and in vivo competition experiments showed significantly lower fluorescence signals when U-87 MG cells (minus 36%, p = 0.02) or HT-29 tumor bearing mice (TBR at 4 h 3.2 ± 0.5 vs 1.8 ± 0.4, p = 0.03) were simultaneously treated with unlabeled cRGD. cRGD-ZW800-1 visualized in vivo all colorectal, breast, pancreatic, and oral tumor xenografts in mice. Screening for off-target interactions, cRGD-ZW800-1 showed only inhibition of COX-2, likely due to binding of cRGD-ZW800-1 to integrin αVß3. Due to its recognition of various integrins, which are expressed on malignant and neoangiogenic cells, it is expected that cRGD-ZW800-1 will provide a sensitive and generic tool to visualize cancer during surgery.

No association between metformin use and survival in patients with pancreatic cancer: An observational cohort study.

Several studies have suggested an association between use of metformin and an increased overall survival in patients diagnosed with pancreatic cancer, however with several important methodological limitations. The aim of the study was to assess the association between overall survival, pancreatic cancer, and metformin use.A retrospective cohort study of 1111 patients with pancreatic cancer was conducted using data from The Netherlands Comprehensive Cancer Organization (1998-2011). Data were linked to the PHARMO Database Network containing drug-dispensing records from community pharmacies. Patients were classified as metformin user or sulfonylurea derivatives user from the moment of first dispensing until the end of follow up. The difference in overall survival between metformin users and nonusers was assessed, and additionally between metformin users and sulfonylurea derivatives users. Univariable and multivariable parametric survival models were used and use of metformin and sulfonylurea derivatives was included as time-varying covariates.Of the 1111 patients, 91 patients were excluded because of differences in morphology, 48 patients because of using merely metformin before diagnosis, and 57 metformin-users ever used contemporary sulfonylurea derivatives and were therefore excluded. Lastly, 8 patients with a survival of zero months were excluded. This resulted in 907 patients for the analysis. Overall, 77 users of metformin, 43 users of sulfonylurea derivatives, and 787 nonusers were identified. The adjusted rate ratio for overall survival for metformin users versus nonusers was 0.86 (95% CI: 0.66-1.11; P = 0.25). The difference in overall survival between metformin users and sulfonylurea derivatives users showed an adjusted rate ratio of 0.90 (95% CI: 0.59-1.40; P = 0.67).No association was found between overall survival, pancreatic cancer, and metformin use. This was in concordance with 2 recently published randomized controlled trials. Future research should focus on the use of adjuvant metformin in other cancer types and the development or repurposing of other drugs for pancreatic cancer.

Targeted next-generation sequencing of FNA-derived DNA in pancreatic cancer.

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.