Most solid cancers are treated by surgical resections to reduce the burden of disease. Surgeons often face the challenge of detecting small areas of residual neoplasm after resection or finding... Show moreMost solid cancers are treated by surgical resections to reduce the burden of disease. Surgeons often face the challenge of detecting small areas of residual neoplasm after resection or finding small primary tumors for the initial resection. Intraoperative molecular imaging (IMI) is an emerging technology with the potential to dramatically improve cancer surgery operations by allowing surgeons to better visualize areas of neoplasm using fluorescence imaging. Over the last two years, two molecular optical contrast agents received U.S. Food and Drug Administration approval, and several more drugs are now on the horizon. Thus a conference was organized at the University of Pennsylvania to bring together oncologic surgeons from different specialties to discuss the current clinical status of IMI trials with a specific focus on phase 2 and phase 3 studies. In addition, phase 1 and experimental trials were also discussed briefly, to highlight other novel techniques. Our review summarizes the discussions from the conference and delves into the types of cancers discussed, different contrast agents in human trials, and the clinical value being studied. (C) The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Show less
Background The use of epidural analgesia (EA) in pancreatic surgery remains under debate. This study compares patients treated with EA versus non-EA after open pancreatectomy in a tertiary referral... Show moreBackground The use of epidural analgesia (EA) in pancreatic surgery remains under debate. This study compares patients treated with EA versus non-EA after open pancreatectomy in a tertiary referral center.Methods All patients undergoing open pancreatectomy from 2013 to 2017 were retrospectively reviewed. (Non-)EA was terminated on postoperative day (POD) 3 or earlier if required.Results In total, 190 (72.5%) patients received EA and 72 (27.5%) patients received non-EA (mostly intravenous morphine). EA was terminated prematurely in 32.6% of patients and non-EA in 10.5% of patients. Compared with non-EA patients, EA patients had significantly lower pain scores on POD 0 (1.10 (0-3.00) versus 3.00 (1.67-5.00), P < 0.001) and POD 1 (2.00 (0.50-3.41) versus 3.00 (2.00-3.80), P = 0.001), though significantly higher pain scores on POD 3 (3.00 (2.00-4.00) versus 2.33 (1.50-4.00), P < 0.001) and POD 4 (2.50 (1.50-3.67) versus 2.00 (0.50-3.00), P = 0.007). EA patients required more vasoactive medication perioperatively and had higher cumulative fluid balances on POD 1-3. Postoperative complications were similar between groups.Conclusions In our cohort, patients with EA experienced significantly lower pain scores in the first PODs compared with nonEA, yet higher pain scores after EA had been terminated. Although EA patients required more vasoactive medication and fluid therapy, the complication rate was similar. Show less
Deken, M.M.; Bos, D.L.; Tummers, W.S.F.J.; March, T.L.; Velde, C.J.H. van de; Rijpkema, M.; Vahrmeijer, A.L. 2019
Background Combining modalities using dual-labeled antibodies may allow preoperative and intraoperative tumor localization and could be used in image-guided surgery to improve complete tumor... Show moreBackground Combining modalities using dual-labeled antibodies may allow preoperative and intraoperative tumor localization and could be used in image-guided surgery to improve complete tumor resection. Trastuzumab is a monoclonal antibody against the human epidermal growth factor-2 (HER2) receptor and dual-labeled trastuzumab with both a fluorophore (IRDye800CW) and a radioactive label (In-111) can be used for multimodal imaging of HER2-positive breast cancer. The aim of this study was to demonstrate the feasibility of HER2-targeted multimodal imaging using [In-111]In-DTPA-trastuzumab-IRDye800CW in an orthotopic breast cancer model. Methods Trastuzumab was conjugated with p-isothiocyanatobenzyl (ITC)-diethylenetriaminepentaacetic acid (DTPA) and IRDye800CW-NHS ester and subsequently labeled with In-111. In a dose escalation study, the biodistribution of 10, 30, and 100 mu g [In-111]In-DTPA-trastuzumab-IRDye800CW was determined 48 h after injection in BALB/c nude mice with orthotopic high HER2-expressing tumors. Also, a biodistribution study was performed in a low HER2-expressing breast cancer model. In addition, multimodal image-guided surgery was performed in each group. Autoradiography, fluorescence microscopy, and immunohistochemically stained slices of the tumors were compared for co-localization of tumor tissue, HER2 expression, fluorescence, and radiosignal. Results Based on the biodistribution data, a 30 mu g dose of dual-labeled trastuzumab (tumor-to-blood ratio 13 +/- 2) was chosen for all subsequent studies. [In-111]In-DTPA-trastuzumab-IRDye800CW specifically accumulated in orthotopic HER2-positive BT474 tumors (101 +/- 7 %IA/g), whereas uptake in orthotopic low HER2-expressing MCF7 tumor was significantly lower (1.2 +/- 0.2 %IA/g, p = 0.007). BT474 tumors could clearly be visualized with both micro-SPECT/CT, fluorescence imaging and subsequently, image-guided resection was performed. Immunohistochemical analyses of BT474 tumors demonstrated correspondence in fluorescence, radiosignal, and high HER2 expression. Conclusions Dual-labeled trastuzumab showed specific accumulation in orthotopic HER2-positive BT474 breast tumors with micro-SPECT/CT and fluorescence imaging and enabled image-guided tumor resection. In the clinical setting, [In-111]In-DTPA-trastuzumab-IRDye800CW could be valuable for preoperative detection of (metastatic) tumors by SPECT/CT imaging, and intraoperative localization by using a gamma probe and fluorescence image-guided surgery to improve radical resection of tumor tissue in patients with HER2-positive tumors. Show less
Suker, M.; Koerkamp, B.G.; Coene, P.P.; Harst, E. van der; Bonsing, B.A.; Vahrmeijer, A.L.; ... ; Eijck, C.H.J. van 2019
Introduction: Locally advanced pancreatic cancer (LAPC) is found in 35% of patients with pancreatic cancer. However, these patients often have occult metastatic disease. Patients with occult... Show moreIntroduction: Locally advanced pancreatic cancer (LAPC) is found in 35% of patients with pancreatic cancer. However, these patients often have occult metastatic disease. Patients with occult metastases are unlikely to benefit from locoregional treatments. This study evaluated the yield of occult metastases during staging laparoscopy in patients with LAPC.Methods: Between January 2013 and January 2017 all patients with LAPC underwent a staging laparoscopy after a recent tri-phasic CT-scan of the chest and abdomen. Data were retrospectively reviewed from a prospectively maintained database. Univariate and multivariable logistic regression analysis was conducted to predict metastasis found at laparoscopy.Results: A total of 91 (41% male, median age 64 years) LAPC patients were included. The median time between CT-scan and staging laparoscopy was 21 days. During staging laparoscopy metastases were found in 17 patients (19%, 95% CI: 12%-28%). Seven (8%) patients had liver-only, 9 (10%) patients peritoneal-only, and 1 (1%) patient both liver and peritoneal metastases. Univariate logistic regression analysis showed that CEA (OR 1.056, 95% CI 1.007-1.107, p = 0.02) was the only preoperative predictor for occult metastases. In a multivariable logistic regression analysis of the preoperative risk factors again only CEA was an independent predictor for occult metastatic disease (p = 0.03). Patients with a CEA above 5 mu g/l. had a risk of occult metastasis of 91%. FOLFIRINOX was given to 69 (76%) of the patients with a median number of cycles of 8. Subsequent radiotherapy was given to 44 (48%) patients after the FOLFIRINOX treatment. Six (14%) patients underwent a resection after FOLFIRINOX and radiotherapy. The overall 1-year survival was 53% in patients without occult metastasis versus 29% with occult metastasis (p = 0.11). The 1-year OS for patients that completed FOLFIRINOX and radiotherapy was 84%.Conclusion: The yield of staging laparoscopy for occult intrahepatic or peritoneal metastases in patients with locally advanced pancreatic cancer was 19%. Staging laparoscopy is recomended for patients with LAPC for accurate staging to determine optimal treatment. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Show less
Kuninty, P.R.; Bansal, R.; Geus, S.W.L. de; Mardhian, D.F.; Schnittert, J.; Baarlen, J. van; ... ; Prakash, J. 2019
Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to... Show moreAbundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin alpha 5 (ITGA5) receptor in the PDAC stroma. ITGA5 was over-expressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models. Show less
Surgical exploration in patients with pancreatic or periampullary cancer is often performed without intraoperative image guidance. Although intraoperative ultrasound (IOUS) may enhance... Show moreSurgical 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. (C) 2019 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Show less
Background: Although most patients with PDAC experience distant failure after resection, a significant portion still present with local recurrence. Intraoperative fluorescent imaging can... Show moreBackground: Although most patients with PDAC experience distant failure after resection, a significant portion still present with local recurrence. Intraoperative fluorescent imaging can potentially facilitate the visualization of involved peritumoral LNs and guide the locoregional extent of nodal dissection. Here, the efficacy of targeted intraoperative fluorescent imaging was examined in the detection of metastatic lymph nodes (LNs) during resection of pancreatic ductal adenocarcinoma (PDAC).Methods: A dose-escalation prospective study was performed to assess feasibility of tumor detection within peripancreatic LNs using cetuximab-IRDye800 in PDAC patients. Fluorescent imaging of dissected LNs was analyzed ex vivo macroscopically and microscopically and fluorescence was correlated with histopathology.Results: A total of 144 LNs (72 in the low-dose and 72 in the high-dose cohort) were evaluated. Detection of metastatic LNs by fluorescence was better in the low-dose (50 mg) cohort, where sensitivity and specificity was 100% and 78% macroscopically, and 91% and 66% microscopically. More importantly, this method was able to detect occult foci of tumor (measuring < 5 mm) with a sensitivity of 88% (15/17 LNs).Conclusion: This study provides proof of concept that intraoperative fluorescent imaging with cetuximab-IRDye800 can facilitate the detection of peripancreatic lymph nodes often containing subclinical foci of disease. Show less
Real-time intraoperative guidance is essential during oncological surgery for complete and safe tumour resection. Fluorescence imaging in the near-infrared spectrum has shown potential for guiding... Show moreReal-time intraoperative guidance is essential during oncological surgery for complete and safe tumour resection. Fluorescence imaging in the near-infrared spectrum has shown potential for guiding surgeons during complex interventions. Recently, there has been a shift towards the use of fluorescence contrast agents for molecular imaging. The first targeted fluorescent agents, of which most consist of approved therapeutic antibodies conjugated to a fluorescent dye, have been evaluated in several early-phase clinical trials. Moreover, advances in protein engineering and drug design have led to the development of a variety of tracers suitable for molecular fluorescence image-guided surgery. In this Review, we discuss preclinical and clinical evidence, ongoing clinical trials, and the latest developments in the field of molecular near-infrared tracers for fluorescence-guided cancer surgery. Show less
Hoven, P. van den; Ooms, S.; Manen, L. van; Bogt, K.E.A. van der; Schaik, J. van; Hamming, J.F.; ... ; Mieog, J.S.D. 2019
Objective: In the diagnosis of peripheral artery disease (PAD), the ankle-brachial index plays an important role. However, results of the ankle-brachial index are unreliable in patients with severe... Show moreObjective: In the diagnosis of peripheral artery disease (PAD), the ankle-brachial index plays an important role. However, results of the ankle-brachial index are unreliable in patients with severe media sclerosis. Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) can provide information about tissue perfusion and has already been studied in oncologic, reconstructive, and cardiac surgery. For patients with PAD, this technique might give insight into skin perfusion and thereby guide treatment. We performed a systematic review of the literature on the use of NIR fluorescence imaging in patients with PAD.Methods: PubMed, MEDLINE, Embase, and Cochrane were searched for articles and abstracts on the application of NIR fluorescence imaging using ICG as fluorescent dye in patients with PAD. Our search strategy combined the terms "fluorescence," "ICG," or synonyms and "peripheral artery disease" or synonyms. The extracted data included fluorescence parameters and test characteristics for diagnosis of PAD.Results: Twenty-three articles were found eligible for this review using 18 different parameters for evaluation of the fluorescence signal intensity. NIR fluorescence imaging was used for four main indications: diagnosis, quality control in revascularization, guidance in amputation surgery, and visualization of vascular structures. For the diagnosis of PAD, NIR fluorescence imaging yields a sensitivity ranging from 67% to 100% and a specificity varying between 72% and 100%. Significant increases in multiple fluorescence parameters were found in comparing patients before and after revascularization.Conclusions: NIR fluorescence imaging can be used for several indications in patients with PAD. NIR fluorescence imaging seems promising in diagnosis of PAD and guidance of surgeons in treatment, especially in patients in whom current diagnostic methods are not applicable. Further standardization is needed to reliably use this modality in patients with PAD. Show less
Meijer, T.S.; Burgmans, M.C.; Fiocco, M.; Geus-Oei, L.F. de; Kapiteijn, E.; Leede, E.M. de; ... ; Vahrmeijer, A.L. 2019
Background: Postpancreatectomy haemorrhage (PPH) and venous thromboembolism (VTE) are serious complications following pancreatic surgery. The aim was to assess the timing, occurrence and predictors... Show moreBackground: Postpancreatectomy haemorrhage (PPH) and venous thromboembolism (VTE) are serious complications following pancreatic surgery. The aim was to assess the timing, occurrence and predictors of PPH and VTE.Methods: Elective pancreatic resections undertaken in a single university hospital between November 2013 and September 2017 were assessed. Three intervals were reviewed, each with a different routine regimen of nadroparin: 2850 units once daily (single dose) administered in hospital only, or 5700 units once daily (double dose) or 2850 units twice daily (split dose) administered in hospital and continued for 6weeks after surgery. Clinically relevant PPH (CR-PPH) was classified according to International Study Group of Pancreatic Surgery criteria. VTE was defined according to a number of key diagnostic criteria within 6weeks of surgery. Cox regression analyses were performed to test the hypotheses that the double-dose group would experience more PPH than the other two groups, the single-dose group would experience more VTE than the other two groups, and the split-dose group would experience the fewest adverse events (PPH or VTE).Results: In total, 240 patients were included, 80 per group. The double-dose group experienced significantly more CR-PPH (hazard ratio (HR) 2.14, 95 per cent c.i. 1.16 to 3.94; P = 0.015). More relaparotomies due to CR-PPH were performed in the double-dose group (16 versus 3.8 per cent; P = 0.002). The single-dose group did not experience more VTE (HR 1.41, 0.43 to 4.62; P = 0.570). The split dose was not associated with fewer adverse events (HR 0.77, 0.41 to 1.46; P = 0.422). Double-dose low molecular weight heparin (LMWH), high BMI and pancreatic fistula were independent predictors of CR-PPH.Conclusion: A double dose of LMWH prophylaxis continued for 6weeks after pancreatic resection was associated with a twofold higher rate of CR-PPH, resulting in four times more relaparotomies. Patients receiving a single daily dose of LMWH in hospital only did not experience a higher rate of VTE. Show less
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