Fluorescence-guided surgery using tumour-targeted imaging agents has emerged over the past decade as a promising and effective method of intraoperative cancer detection. An impressive number of ...fluorescently labelled antibodies, peptides, particles and other molecules related to cancer hallmarks have been developed for the illumination of target lesions. New approaches are being implemented to translate these imaging agents into the clinic, although only a few have made it past early-phase clinical trials. For this translational process to succeed, target selection, imaging agents and their related detection systems and clinical implementation have to operate in perfect harmony to enable real-time intraoperative visualization that can benefit patients. Herein, we review key aspects of this imaging cascade and focus on imaging approaches and methods that have helped to shed new light onto the field of intraoperative fluorescence-guided cancer surgery with the singular goal of improving patient outcomes.
This review summarizes the key applications of a hybrid operating room (HOR) in hepatobiliary surgery and explores the advantages, limitations, and future directions of its utilization. A ...comprehensive literature search was conducted in PubMed to identify articles reporting on the utilization of HORs in liver surgery. So far, the HOR has been limitedly applied in hepatobiliary surgery. It can offer an optimal environment for combining radiological and surgical interventions and for performing image‐guided surgical navigation.
Background
Operative management of pancreatic ductal adenocarcinoma (PDAC) is complicated by several key decisions during the procedure. Identification of metastatic disease at the outset and, when ...none is found, complete (R0) resection of primary tumor are key to optimizing clinical outcomes. The use of tumor-targeted molecular imaging, based on photoacoustic and fluorescence optical imaging, can provide crucial information to the surgeon. The first-in-human use of multimodality molecular imaging for intraoperative detection of pancreatic cancer is reported using cetuximab-IRDye800, a near-infrared fluorescent agent that binds to epidermal growth factor receptor.
Methods
A dose-escalation study was performed to assess safety and feasibility of targeting and identifying PDAC in a tumor-specific manner using cetuximab-IRDye800 in patients undergoing surgical resection for pancreatic cancer. Patients received a loading dose of 100 mg of unlabeled cetuximab before infusion of cetuximab-IRDye800 (50 mg or 100 mg). Multi-instrument fluorescence imaging was performed throughout the surgery in addition to fluorescence and photoacoustic imaging ex vivo.
Results
Seven patients with resectable pancreatic masses suspected to be PDAC were enrolled in this study. Fluorescence imaging successfully identified tumor with a significantly higher mean fluorescence intensity in the tumor (0.09 ± 0.06) versus surrounding normal pancreatic tissue (0.02 ± 0.01), and pancreatitis (0.04 ± 0.01;
p
< 0.001), with a sensitivity of 96.1% and specificity of 67.0%. The mean photoacoustic signal in the tumor site was 3.7-fold higher than surrounding tissue.
Conclusions
The safety and feasibilty of intraoperative, tumor-specific detection of PDAC using cetuximab-IRDye800 with multimodal molecular imaging of the primary tumor and metastases was demonstrated.
Median tube current was 244 mA (IQR 159·5–353·0), consistent with settings for standard radiation dose CT scans in the cited study by Jensen and colleagues.2 Subgroup analyses of two meta-analyses ...(the latter meta-analysis includes the study by Motsugi and collegues, which was cited by Antony Haddad and collegues) showed no difference in detection of colorectal liver metastases between portovenous phase and multi-phase CT.3,4 Hence, we conclude that CT quality was adequate and is highly unlikely to have influenced study outcomes. Furthermore, a shorter time interval between CT and MRI does not seem realistically attainable in many countries, and this therefore reflects clinical practice.5 Although we agree with the authors that the added value of an additional liver MRI for patients with colorectal liver metastases is likely to be higher in specific patient populations, both our data and theory-driven prediction model found no subgroup in which MRI had no or very little effect on the local treatment plan. ...Granata and colleagues also pointed out that liver MRI was assessed by an abdominal radiologist who was not masked to CT results.
Purpose: It is suggested that tumour markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) could be used to predict the stage of pancreatic cancer. However, optimal cut-off ...values for CEA and CA19-9 are disputable. This study aimed to assess the value of CEA and CA19-9 serum levels at diagnosis of pancreatic ductal adenocarcinoma (PDAC) as predictors for the advanced stage of PDAC in patients discussed at pancreatic multidisciplinary team (MDT) meetings.
Methods: Patients with suspected PDAC discussed at MDT meetings from 2013 to 2017 were reviewed, in order to determine optimal cut-off values of both CEA and CA19-9.
Results: In total, 375 patients were included. Optimal cut-off values for predicting advanced PDAC were 7.0 ng/ml for CEA and 305.0 U/ml for CA19-9, resulting in positive predictive values of 83.3%, 73.6%, and 91.4% for CEA, CA19-9 and combined, respectively. Both tumour markers were independent predictors of advanced PDAC, demonstrated by an odds ratio of 4.21 (95% CI:1.85-9.56; p = 0.001) for CEA and 2.58 for CA19-9 (95% CI:1.30-5.14; p = 0.007).
Conclusions: CEA appears to be a more robust predictor of advanced PDAC than CA19-9. Implementing CEA and CA19-9 serum levels during MDT meetings as an additional tool for establishing tumour resectability is worthwhile for tailored diagnostics.
Given their self-renewing and pluripotent capabilities, human embryonic stem cells (hESCs) are well poised as a cellular source for tissue regeneration therapy. However, the host immune response ...against transplanted hESCs is not well characterized. In fact, controversy remains as to whether hESCs have immune-privileged properties. To address this issue, we used in vivo bioluminescent imaging to track the fate of transplanted hESCs stably transduced with a double-fusion reporter gene consisting of firefly luciferase and enhanced GFP. We show that survival after transplant is significantly limited in immunocompetent as opposed to immunodeficient mice. Repeated transplantation of hESCs into immunocompetent hosts results in accelerated hESC death, suggesting an adaptive donor-specific immune response. Our data demonstrate that transplanted hESCs trigger robust cellular and humoral immune responses, resulting in intragraft infiltration of inflammatory cells and subsequent hESC rejection. Moreover, we have found CD4⁺ T cells to be an important modulator of hESC immune-mediated rejection. Finally, we show that immunosuppressive drug regimens can mitigate the anti-hESC immune response and that a regimen of combined tacrolimus and sirolimus therapies significantly prolongs survival of hESCs for up to 28 days. Taken together, these data suggest that hESCs are immunogenic, trigger both cellular and humoral-mediated pathways, and, as a result, are rapidly rejected in xenogeneic hosts. This process can be mitigated by a combined immunosuppressive regimen as assessed by molecular imaging approaches.
Background
During laparoscopic cholecystectomy, common bile duct (CBD) injury is a rare but severe complication. To reduce the risk of injury, near-infrared (NIR) fluorescent cholangiography using ...indocyanine green (ICG) has recently been introduced as a novel method of visualizing the biliary system during surgery. To date, several studies have shown feasibility of this technique; however, liver background fluorescence remains a major problem during fluorescent cholangiography. The aim of the current study was to optimize ICG dose and timing for NIR cholangiography using a quantitative intraoperative camera system during open hepatopancreatobiliary (HPB) surgery. Subsequently, these results were validated during laparoscopic cholecystectomy using a laparoscopic fluorescence imaging system.
Methods
Twenty-seven patients who underwent NIR imaging using the Mini-FLARE image-guided surgery system during open HPB surgery were analyzed to assess optimal dosage and timing of ICG administration. ICG was intravenously injected preoperatively at doses of 5, 10, and 20 mg, and imaged at either 30 min (early) or 24 h (delayed) post-injection. Next, the optimal doses found for early and delayed imaging were applied to two groups of seven patients (
n
= 14) undergoing laparoscopic NIR fluorescent cholangiography during laparoscopic cholecystectomy.
Results
Median liver-to-background contrast was 23.5 (range 22.1–35.0), 16.8 (range 11.3–25.1), 1.3 (range 0.7–7.8), and 2.5 (range 1.3–3.6) for 5 mg/30 min, 10 mg/30 min, 10 mg/24 h, and 20 mg/24 h, respectively. Fluorescence intensity of the liver was significantly lower in the 10 mg delayed-imaging dose group compared with the early imaging 5 and 10 mg dose groups (
p
= 0.001), which resulted in a significant increase in CBD-to-liver contrast ratio compared with the early administration groups (
p
< 0.002). These findings were qualitatively confirmed during laparoscopic cholecystectomy.
Conclusion
This study shows that a prolonged interval between ICG administration and surgery permits optimal NIR cholangiography with minimal liver background fluorescence.
Whereas mortality rates improved for breast and prostate cancer as a result of successful tumour biology-based therapies and biomarkers, mortality rates for pancreatic cancer patients remained stable ......
Background
Improved imaging methods and surgical techniques have created a new era in hepatopancreatobiliary (HPB) surgery. Despite these developments, visual inspection, palpation, and ...intraoperative ultrasound remain the most utilized tools during surgery today. This is problematic, though, especially in laparoscopic HPB surgery, where palpation is not possible. Optical imaging using near-infrared (NIR) fluorescence can be used for the real-time assessment of both anatomy (e.g., sensitive detection and demarcation of tumours and vital structures) and function (e.g., assessment of luminal flow and tissue perfusion) during both open and minimally invasive surgeries.
Methods
This article reviews the published literature related to preclinical development and clinical applications of NIR fluorescence imaging during HPB surgery.
Results
NIR fluorescence imaging combines the use of otherwise invisible NIR fluorescent contrast agents and specially designed camera systems, which are capable of detecting these contrast agents during surgery. Unlike visible light, NIR fluorescent light can penetrate several millimetres through blood and living tissue, thus providing improved detectability. Applications of this technique during HPB surgery include tumour imaging in liver and pancreas, and real-time imaging of the biliary tree.
Conclusions
NIR fluorescence imaging is a promising new technique that may someday improve surgical accuracy and lower complications.
There is no consensus on the optimal systemic conversion therapy in patients with unresectable colorectal cancer liver-only metastases (CRLM) to achieve a complete resection. Interpretation of trials ...is complicated by heterogeneity of patients caused by emerging prognostic and predictive characteristics, such as RAS/BRAF mutation status, lack of consensus on unresectability criteria and lack of data on clinical outcome of secondary resections. A systematic review was performed of characteristics of study populations and methodology of trials regarding patients with initially unresectable colorectal cancer liver-only metastases.
Phase II/III randomised trials, published after 2008, regarding first-line systemic conversion therapy in patients or subgroups of patients with CRLM were included. Data on secondary resection outcomes were collected.
Overall, 20 trials were included for analysis: seven prospective trials in patients with unresectable CRLM and 13 trials in the overall population of unresectable metastatic colorectal cancer (mCRC) with retrospective subgroup analysis of CRLM patients. Fourteen trials did not provide unresectability criteria at baseline, and criteria differed among the remaining studies. Trials and study populations were heterogeneous in prognostic/predictive factors, use of primary end-points, and reporting on long-term clinical outcomes. R0-resection rates in CRLM patients varied between CRLM studies and mCRC studies, with rates of 22–57% and 11–38%, respectively.
Cross-study comparison of (subgroups of) studies regarding first-line systemic treatment in patients with unresectable CRLM is hampered by heterogeneity in study populations, trial designs, use of (K)RAS/BRAF mutational tumour status, and differences/absence of unresectability criteria. No optimal conversion systemic regimen can be selected from available data. Prospective studies with well-defined criteria of these issues are warranted.
•Cross-study comparison of systemic conversion therapies in CRLM patients is complicated.•Study populations and resection rates vary considerably between CRLM studies.•No preferential systemic regimen for conversion therapy can be given.•Transparent baseline (un)resectability criteria for CRLM are needed.•Long-term survival outcomes after resection were not reported in the majority of studies.
PDF
