BACKGROUND:Venous resection (VR) during left-sided pancreatic resection (LPR) is typically more challenging than during pancreatoduodenectomy, because the pancreatic head remains in situ. Theoretically, converting from LPR to total pancreatectomy (TP) could resolve this issue. This study compared clinical outcomes after LPR and TP with and without VR. METHODS:This nationwide retrospective study included all patients who underwent LPR for all indications or single-stage TP in the Netherlands from 2014 to 2019. RESULTS:One-thousand-seventy-five patients were analyzed: 996 underwent LPR and 79 TP. Twenty-eight (3%) LPRs were with VR (VR+), of which 17 wedge and 11 segmental resections. Of 21 (27%) TPs with VR, 11 were wedge and 10 segmental resections. In the LPR-group, VR+ was associated with a higher incidence of portomesenteric venous thrombosis (PVT) than VR- (3/28 vs. 5/968, p < 0.001), but not with major complications or mortality. Similarly, in the TP-group, higher rates of PVT were reported after VR+ (2/21 vs. 0/58, p = 0.004). The incidence of major complications and PVT were comparable between LPR-VR+ and TP-VR+, but postoperative mortality was higher in TP-VR+ (6/21 vs. 1/28 p = 0.032). CONCLUSION:Our findings suggest that, despite technical impediments of VR during LPR, switching to TP may not benefit patients.

BACKGROUND:Prognostic factors in resected pancreatic ductal adenocarcinoma (PDAC) have been determined under the assumption that hazard ratios (HRs) remain static. However, PDAC is a dynamic disease with evolving conditional survival. The aim of this study was to determine if the impact of prognostic factors in PDAC is time-varying. METHODS:This was a multicenter, retrospective cohort study of the prospectively maintained Dutch Pancreatic Cancer Recurrence Database and New York University and Johns Hopkins Hospital Institutional Databases. Patients with complete macroscopic resection of histopathologically proven PDAC between 2014 and 2019 and available follow-up data were included. The time-varying impact of prognostic factors identified by univariable Cox regression was modeled using Aalen's Additive Regression Models (Aalen's models) and visualized as plots of cumulative hazard. RESULTS:In total, 3104 patients were included, of whom 938 (30.2%) received neoadjuvant therapy (NAT), whereas the rest underwent upfront surgery (US). A total of 201 (6.5%) patients achieved observed long-term survival (>5 years). Aalen's models showed that lymphovascular invasion, perineural invasion, and nodal disease were prognostic up to 2 years postoperatively. At varying points thereafter, these variables lost their impact in the NAT but not US patients. Similarly, during the fourth year of follow-up, American Society of Anesthesiology scores became impactful in the NAT but not in the US patients. CONCLUSION:The impact of prognostic factors in resected PDAC across NAT and US patients is time-varying. Our results suggest that aggressive disease drives early mortality but, after NAT, tumor-biological factors lose prognostic importance to frailty and comorbidities over time.

OBJECTIVE:To compare the incidence of major surgical complications between patients with (borderline) resectable pancreatic cancer treated with neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy. SUMMARY OF BACKGROUND DATA:There are ongoing concerns regarding the possible adverse impact of neoadjuvant treatment on postoperative complication rates following pancreatectomy. METHODS:This study was a predefined analysis within the investigator-initiated nationwide randomized controlled PREOPANC-2 trial. Patients with (borderline) resectable pancreatic cancer were randomized to receive neoadjuvant FOLFIRINOX (FFX group) or neoadjuvant gemcitabine-based chemoradiotherapy (CRT group), both followed by surgery, and adjuvant gemcitabine only in the CRT group. Surgical complications including postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, postoperative interventions, and 90-day mortality were compared, with major complications defined as Clavien-Dindo grade ≥3. RESULTS:Between June 5, 2018, and January 28, 2021, in total 375 patients were randomized, of whom 280 (74.7%) underwent pancreatic resection. A pancreatoduodenectomy was performed in 238 patients (85.0%), left pancreatectomy in 41 patients (14.6%), and total pancreatectomy in one patient (0.4%). The incidence of major surgical complications was similar between the FFX and CRT groups (26.8% versus 27.5%, P=0.884). No differences were observed in the risk of postoperative pancreatic fistula grade B/C (9.9% versus 4.4%, P=0.076), postpancreatectomy hemorrhage grade B/C (7.7% versus 3.6%, P=0.137), bile leakage grade B/C (2.5% versus 2.5%, P>0.999), and postoperative interventions (26.1% versus 26.8%, P=0.886). Surgical reoperation was performed in nine patients (6.3%) in the FFX group and eight patients (5.8%) in the CRT group (P=0.850). The postoperative 90-day mortality was 1.4% in the FFX group (2/142 patients) and 2.9% in the CRT group (4/138 patients) (P=0.442). CONCLUSIONS:In the PREOPANC-2 randomized trial, the risk of major surgical complications after pancreatic resection following neoadjuvant FOLFIRINOX or neoadjuvant gemcitabine-based chemoradiotherapy was similar with an overall low 90-day mortality.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of approximately 5-7%, and complete surgical resection remains the only curative treatment but is often unfeasible. Fluorescence-guided surgery (FGS) using tumor-targeted probes may improve tumor visualization and facilitate complete resection. This study aimed to identify and validate tumor targets for FGS during PDAC resection procedures. RNA expression data from over 4000 cell surface genes, obtained from public genomic databases, were analyzed to identify genes encoding PDAC-associated proteins. Eleven potential tumor targets were identified, including CEACAM5, TMPRSS4, COL17A1, CLDN18, and AQP5. Protein expression was evaluated by immunohistochemistry (IHC) in tissues from 44 PDAC and 7 chronic pancreatitis (CP) patients. All targets, except COL17A1, showed significantly higher expression in PDAC tissue compared to healthy pancreatic, CP, and duodenal tissue (p < 0.001), as well as in tumor-positive versus tumor-negative lymph nodes. Especially CEACAM5, TMPRSS4, and AQP5 were identified as the most promising targets for distinguishing PDAC from healthy tissues and detecting lymph node metastasis during FGS. The development of probes targeting multiple markers, such as AQP5 with CEACAM5 and/or TMPRSS4, may help overcome interpatient variability and enhance detection across patients.

Abstract Background The introduction of (m)FOLFIRINOX and gemcitabine-nab-paclitaxel has changed the perspective for patients with locally advanced pancreatic cancer (LAPC). Consequently, in experienced centres 23% of patients with LAPC undergo a resection with 5-year overall survival (OS) rates of up to 25%. In the Netherlands, the nationwide resection rate for LAPC remains low at 8%. The PREOPANC-4 program aims for a nationwide implementation of the international multidisciplinary best-practice to improve patient outcome. Methods Nationwide program implementing the international multidisciplinary best-practice for LAPC. In the training phase, multidisciplinary and surgical webinars are given by 4 international experts, leading to a clinical protocol, followed by surgical off-site and on-site proctoring sessions. In the implementation phase, the clinical protocol will be implemented in all centres, including a nationwide expert panel (2022–2024). Healthcare professionals will be trained in shared decision-making. Consecutive patients diagnosed with pathology-proven LAPC (i.e., arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion [DPCG criteria]) are eligible. Primary outcomes are median and 5-year OS from diagnosis, resection rate, in-hospital/30-day mortality and major morbidity (i.e., Clavien-Dindo grade ≥ IIIa), and radical resection (R0) rate. Secondary outcomes include quality of life, functioning, side effects, and patients’ healthcare satisfaction in all included patients. Outcomes will be compared with patients with borderline resectable pancreatic cancer (BRPC) treated with neoadjuvant FOLFIRINOX in the PREOPANC-2 trial (EudraCT: 2017–002036-17) and a historical cohort of patients with LAPC from the PACAP registry (NCT03513705). The existing prospective LAPC Registry and PACAP PROMs (NCT03513705) will be used for data collection. In qualitative interviews, treatment preferences, values, and experiences of LAPC patients, their relatives, and healthcare professionals will be assessed for the development of shared decision-making supportive tools. It is hypothesized that the program will double the nationwide LAPC resection rate to 16% with major morbidity < 50% and mortality ≤ 5%, and OS following resection similar to that observed in patients with BRPC. Discussion The PREOPANC-4 program aims to safely implement the international multidisciplinary best-practice for LAPC leading to benchmark outcomes for both short-term morbidity, mortality, and OS. Trial registration PREOPANC-4 program was registered at ClinicalTrials.gov (NCT05524090) on September 1, 2022.

BACKGROUND:In patients with malignant gastric outlet obstruction, endoscopic ultrasonography-guided gastroenterostomy might be superior to surgical gastroenterostomy, but randomised trials are scarce. We aimed to assess time to resumption of oral intake and the rate of persistent or recurrent obstructive symptoms requiring re-intervention following endoscopic ultrasonography-guided gastroenterostomy compared with surgical gastroenterostomy. METHODS:ENDURO was a multicentre, randomised controlled trial conducted at 12 Dutch academic and teaching hospitals. Hospitals with experience in at least 20 LAMS placements of any indication, at least ten endoscopic gastroenterostomies, and approved competence were eligible to perform endoscopic gastroenterostomy independently within the trial. Adults aged 18 years and older with symptomatic, malignant gastric outlet obstruction in a palliative setting were randomly assigned (1:1) to endoscopic or surgical gastroenterostomy. Randomisation was performed with an electronic data capture system using randomly generated permuted blocks of 2 and 4 and stratified by WHO performance status (0-1 and 2-3). The first coprimary outcome was time to resumption of solid oral intake (Gastric Outlet Obstruction Scoring System score ≥2). The second coprimary outcome was non-inferiority for persistent or recurrent obstructive symptoms requiring re-intervention. The predefined non-inferiority margin of the risk difference was 20%. All outcomes were analysed in all randomly assigned participants. This trial was registered in the International Clinical Trials Registry Platform, NL9592, and is completed. FINDINGS:Between Feb 18, 2022, and Feb 26, 2024, 250 patients were screened, 98 of whom were randomly assigned to endoscopic gastroenterostomy (n=48) or surgical gastroenterostomy (n=50). 43 (44%) patients were female and 55 (56%) were male. Endoscopic gastroenterostomy had a shorter time to solid oral intake than surgical gastroenterostomy (median 1 day [IQR 1-3] vs 3 days [1-6], hazard ratio 2·21 [95% CI 1·43-3·42]; p=0·0003). Endoscopic gastroenterostomy was non-inferior to surgical gastroenterostomy for persistent or recurrent obstructive symptoms requiring re-intervention (five [10%] vs six [12%], risk difference 1·6% [upper limit of 90% CI 8·9]). Overall adverse events were reported in 28 (58%) patients in the endoscopic gastroenterostomy group and 32 (64%) in the surgical gastroenterostomy group (relative risk 0·91 [95% CI 0·66-1·25]). One fatal event occurred in the endoscopic gastroenterostomy group and three fatal events occurred in the surgical gastroenterostomy group. INTERPRETATION:In patients with malignant gastric outlet obstruction, palliative treatment with endoscopic gastroenterostomy was superior to surgical gastroenterostomy for time to resumption of solid oral intake and was non-inferior for the rate of persistent or recurrent obstructive symptoms requiring re-intervention. Based on these results, endoscopic gastroenterostomy should be the preferred palliative treatment for patients with malignant gastric outlet obstruction. FUNDING:KWF Dutch Cancer Society.

BACKGROUND:Randomized trials have demonstrated the superiority of surgery over endoscopy in patients with symptomatic chronic pancreatitis. However, large international studies quantifying the impact of surgery on chronic pancreatitis are lacking. The aim of this study was to evaluate current practice across Europe regarding indications, surgical techniques, and outcomes of surgery for chronic pancreatitis. METHODS:A prospective multicentre study of consecutive patients undergoing surgery for symptomatic chronic pancreatitis from 22 centres in 13 countries from 1 June 2021 to 30 November 2022 was conducted. The outcome of interest in patients with pain as an indication was the Izbicki pain score at 6-month follow-up, with complete pain relief defined as an Izbicki pain score ≤10 and partial pain relief defined as an Izbicki pain score >10, but with a >50% decrease compared with the baseline score. Quality of life was assessed using Pancreatitis Quality of Life Instrument (PANQOLI) and 12-Item Short-Form (SF-12) surveys. Predictors of pain relief were analysed using multivariable analysis. RESULTS:Overall, 207 patients underwent surgery (24.6% underwent surgical drainage procedures, 29.5% underwent duodenum-preserving head resections, and 45.9% underwent formal pancreatic resections). Before surgery, 48.8% used opioids and 51.2% had undergone prior endoscopic treatment. Major morbidity occurred in 14.0% and the 90-day mortality rate was 1.4%. Among 113 patients operated on for pain, the median Izbicki pain score decreased from 61.3 to 19.0 at 6 months (P < 0.001). Pain relief was achieved in 72.6% (43 patients reported complete pain relief and 39 patients reported partial pain relief). PANQOLI and SF-12 Physical Component Summary scores improved significantly (P < 0.001). Longer symptom duration (OR 0.95 (95% c.i. 0.90 to 1.00), P = 0.045) and use of opioids before surgery (OR 3.16 (95% c.i. 1.04 to 9.64), P = 0.043) predicted less pain relief. CONCLUSION:Surgery for chronic pancreatitis across Europe was performed with low morbidity. Patients reported good pain relief and improvements in quality-of-life scores. Multidisciplinary consultation is recommended for all patients with chronic pancreatitis before undergoing any intervention.

Objective: To identify learning curves for robotic gastroenterostomy (RGE) during robotic pancreatoduodenectomy (RPD) and the predictive value of the objective structured assessment of technical skills (OSATS) score for delayed gastric emptying (DGE) according to the Birkmeyer and colleagues and University of Pittsburgh Medical Center method. Background: In some series, RPD has been associated with an increased risk of DGE. It is unclear whether this is attributable to learning curve. Improved surgical performance and experience have not yet been linked to a decrease in DGE in RPD. Methods: Post hoc study of the prospective multicenter (LAELAPS-3) training program, including videos of RGE during RPD. Surgical performance was scored with OSATS by 2 blinded graders. The main outcomes are the combined OSATS scores of 2 blinded graders over time (learning curve). Secondary outcome is the correlation between OSATS scores and clinically relevant DGE (grade B/C). Results: Videos from 192 RGE anastomoses were included. DGE occurred in 42/192 (21.9%) patients. The mean OSATS score was 22.4 (SD ± 5.1) and predicted DGE Area under the curve (AUC): 0.668, P < 0.001). The predictive OSATS elements for DGE were gentleness (AUC: 0.719, P < 0.001), instrument handling (AUC: 0.595 P = 0.043), tissue exposure (AUC: 0.625, P = 0.009), and summary score (AUC: 0.665, P < 0.001). An OSATS score >25 was associated with a 59.9% reduced relative risk of grade B/C DGE [11.3% (8/71) vs 28.1% (34/121); odds ratio (OR): 0.325, P = 0.006]. Cumulative sum analysis of RGE-OSATS identified a turning point at 34 procedures [25.7% (36/140) before vs 11.5% (6/52) after; OR: 0.156, P = 0.035]. On multivariable analysis for grade B/C DGE, OSATS ≤25 remained an independent risk factor (OR: 2.907, P = 0.028). Conclusions: Better surgical performance during gastroenteric anastomosis in RPD, as assessed by OSATS, is associated with a reduced rate of grade B/C DGE. OSATS could serve as a tool for competency-based training programs and quality-controlled implementation of RPD.

Background: Preoperative planning of patients diagnosed with pancreatic head cancer is difficult and requires specific expertise. This pilot study assesses the added value of three-dimensional (3D) patient models and computer-aided detection (CAD) algorithms in determining the resectability of pancreatic head tumors. Methods: This study included 14 hepatopancreatobiliary experts from eight hospitals. The participants assessed three radiologically resectable and three radiologically borderline resectable cases in a simulated setting via crossover design. Groups were divided in controls (using a CT scan), a 3D group (using a CT scan and 3D models), and a CAD group (using a CT scan, 3D and CAD). For the perceived fulfillment of preoperative needs, the quality and confidence of clinical decision-making were evaluated. Results: A higher perceived ability to determine degrees and the length of tumor–vessel contact was reported in the CAD group compared to controls (p = 0.022 and p = 0.003, respectively). Lower degrees of tumor–vessel contact were predicted for radiologically borderline resectable tumors in the CAD group compared to controls (p = 0.037). Higher confidence levels were observed in predicting the need for vascular resection in the 3D group compared to controls (p = 0.033) for all cases combined. Conclusions: “CAD (including 3D) improved experts’ perceived ability to accurately assess vessel involvement and supports the development of evolving techniques that may enhance the diagnosis and treatment of pancreatic cancer”.

Assessment of tissue perfusion using near-infrared fluorescence (NIR) with indocyanine green (ICG) is gaining popularity, however reliable and objective interpretation remains a challenge. Therefore, this study aimed to establish reference curves for vital tissue perfusion across target tissues using this imaging modality. Data from five prospective study cohorts conducted in three Dutch academic medical centres between December 2018 and June 2023 was included. Quantitative analysis using time-intensity curves was performed in ten target tissues, including the colon, ileum, gastric conduit, deep inferior epigastric artery perforator (DIEP) flap, skin of the foot, trachea, sternocleidomastoid muscle (SCM), carotid artery, parathyroid gland, and skin of the neck. A total of 178 patients were included in this study, representing 303 target tissues. Three different patterns of reference curves were identified based on a subjective assessment. Seven out of ten tissues showed a reference curve with rapid inflow (median time-to-max (tmax): 13.0–17.8 s, median maximum-normalized-slope (slope norm): 10.6–12.6

OBJECTIVE:To identify learning curves for robotic gastroenterostomy (RGE) during robotic pancreatoduodenectomy (RPD) and the predictive value of the objective structured assessment of technical skills (OSATS) score for delayed gastric emptying (DGE) according to the Birkmeyer and colleagues and University of Pittsburgh Medical Center method. BACKGROUND:In some series, RPD has been associated with an increased risk of DGE. It is unclear whether this is attributable to learning curve. Improved surgical performance and experience have not yet been linked to a decrease in DGE in RPD. METHODS:Post hoc study of the prospective multicenter (LAELAPS-3) training program, including videos of RGE during RPD. Surgical performance was scored with OSATS by 2 blinded graders. The main outcomes are the combined OSATS scores of 2 blinded graders over time (learning curve). Secondary outcome is the correlation between OSATS scores and clinically relevant DGE (grade B/C). RESULTS:Videos from 192 RGE anastomoses were included. DGE occurred in 42/192 (21.9%) patients. The mean OSATS score was 22.4 (SD ± 5.1) and predicted DGE Area under the curve (AUC): 0.668, P < 0.001). The predictive OSATS elements for DGE were gentleness (AUC: 0.719, P < 0.001), instrument handling (AUC: 0.595 P = 0.043), tissue exposure (AUC: 0.625, P = 0.009), and summary score (AUC: 0.665, P < 0.001). An OSATS score >25 was associated with a 59.9% reduced relative risk of grade B/C DGE [11.3% (8/71) vs 28.1% (34/121); odds ratio (OR): 0.325, P = 0.006]. Cumulative sum analysis of RGE-OSATS identified a turning point at 34 procedures [25.7% (36/140) before vs 11.5% (6/52) after; OR: 0.156, P = 0.035]. On multivariable analysis for grade B/C DGE, OSATS ≤25 remained an independent risk factor (OR: 2.907, P = 0.028). CONCLUSIONS:Better surgical performance during gastroenteric anastomosis in RPD, as assessed by OSATS, is associated with a reduced rate of grade B/C DGE. OSATS could serve as a tool for competency-based training programs and quality-controlled implementation of RPD.

Objective: To determine if video grading using Objective Structured Assessment of Technical Skills (OSATS) could estimate the risk of postoperative bile leak (BL) after robotic pancreatoduodenectomy (RPD) and to identify a learning curve effect. Summary Background Data: The hepaticojejunostomy (HJ) bile leak rate after RPD is rather high with 10% and may be improved by structured training and skills. Robotic HJ therefore requires confirmation of adequate performance. Grading of surgical performance during HJ could be used in competency-based surgical training. Methods: Post-hoc analysis of patients included the Dutch LAELAPS-3 RPD training program in 6 centers. Technical performance during robotic HJ was graded by two blinded graders using OSATS (attainable scores 6-30). Primary outcome was grade B/C bile leak according to the ISGLS. Logistic regression determined the performance cut-off and CUSUM analysis identified the learning curve. Results: Videos from robotic HJ in 259 patients were included with a 6.9% rate of grade B/C bile leak (n=18/259). The median OSATS for the HJ was 25.0 [22–27], with an OSATS score>21 associated with a reduced risk of BL. The rate of BL was 5.1% in patients for OSATS>21 and 12.5% for OSATS ≤21, amounting to a relative reduction of 59.2% and an absolute reduction of 7.4% (8/64 vs. 10/195, OR 0.378, P =0.013). These findings remained similar when only including grade C BL: OR 0.076, P =0.004. On multivariable analysis for grade B/C BL, the only significant predictive factor was OSATS>21: OR 0.273, P =0.025. Stabilization of the CUSUM learning curve for grade B/C BL was reached at 19 RPD procedures, and after 44 procedures the learning curve showed a continuous downward trend. The rate of grade B/C BL was significantly lower beyond 19 RPD: 5.6% versus 8.6% (8/143 vs. 10/116, OR 0.710, P =0.040). Conclusions: The risk of postoperative BL after RPD is strongly associated with surgical performance during robotic HJ as objectified using OSATS. This approach can be used for rapid assessment of the learning curve and competency-based surgical training, aiming for a safe implementation RPD.

Background: Unfavorable intraoperative findings or incidents during minimally invasive liver surgery may necessitate conversion to open surgery. This study aimed to identify predictors for conversion in minimally invasive liver surgery and gain insight into outcomes following conversions. Methods: This nationwide, retrospective cohort study compared converted and non-converted minimally invasive liver surgery procedures using data from 20 centers in the Dutch Hepatobiliary Audit (2014-2022). Propensity score matching was applied. Subgroup analyses of converted robotic liver resection versus laparoscopic liver resection and emergency versus non-emergency conversions were performed. Predictors for conversions were identified using backward stepwise multivariable logistic regression. Results: Of 3,530 patients undergoing minimally invasive liver surgery (792 robotic liver resection, 2,738 laparoscopic liver resection), 408 (11.6%) were converted (4.9% robotic liver resection, 13.5% laparoscopic liver resection). Conversion was associated with increased blood loss (580 mL [interquartile range 250-1,200] vs 200 mL [interquartile range 50-500], P < .001), major blood loss (>= 500 mL, 58.8% vs 26.7%, P < .001), intensive care admission (19.0% vs 8.4%, P = .005), overall morbidity (38.9% vs 21.0%, P < .001), severe morbidity (17.9% vs 9.6%, P = .002), and a longer hospital stay (6 days [interquartile range 5-8] vs 4 days [interquartile range 2-5], P < .001) but not mortality (2.2% vs 1.2%, P = .387). Emergency conversions had increased intraoperative blood loss (1,500 mL [interquartile range 700-2,800] vs 525 mL [interquartile range 208-1,000], P < .001), major blood loss (87.5% vs 59.3%, P = .005), and intensive care admission (27.9% vs 10.6%, P = .029), compared with non-emergency conversions. Robotic liver resection was linked to lower conversion risk, whereas American Society of Anesthesiologists grade >= 3, larger lesion size, concurrent ablation, technically major, and anatomically major resections were risk factors. Conclusion: Both emergency and non-emergency conversions negatively impact perioperative outcomes in minimally invasive liver surgery. Robotic liver resection reduces conversion risk compared to laparoscopic liver resection. (c) 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

In our previous phase 2 trial, patients with locally advanced (LARC) or locally recurrent rectal cancer (LRRC) received SGM-101, a CEA-targeted fluorescent agent, to enable real-time near-infrared fluorescence (NIRF) guided surgery. This study demonstrated that SGM-101 enabled additional tumor removal in some patients and supported less invasive surgery in others. Despite this positive intraoperative effect, the impact on long-term tumor control is unknown. Therefore, in this article we report the long-term outcomes of all rectal cancer patients that participated to the trial. For all 29 LARC and LRRC patients that participated in the SGM-101 phase 2 trial, follow-up data were collected. Main outcome measure was 5-year local tumor control. The median follow-up of all patients was 5.0 years (IQR 4.5–5.5). Of the 12 LARC patients, three (25

In patients with resectable pancreatic and periampullary neoplasm, MIPD was noninferior to OPD for 90-day overall complications (Funded by Intuitive Surgical and Fondazione Poliambulanza Istituto Ospedaliero; International Standard Randomised Controlled Trial Number Registry, ISRCTN27483786.).

The development of fluorescent probes that target the tumor stroma to help surgeons detect and remove malignant lesions using near-infrared fluorescence (NIRF)-guided surgery is advancing rapidly. Such advancements show promise for a range of malignancies, expanding the eligibility of patients for surgical intervention and offering improved surgical outcomes. Fibroblast activation protein (FAP), expressed by cancer-associated fibroblasts (CAFs), is highly upregulated within the tumor stroma of nearly all solid tumors. It is a promising tumor target for NIRF-guided surgery, especially in solid tumors with dense tumor stroma, such as pancreatic cancer. In this study, we aimed to develop FAP-targeting fluorescent probes with enhanced pharmacokinetics for the NIRF-guided surgery of pancreatic cancer. Three novel FAP-targeted probes (eFAPs) based on a (4-quinolinoyl)-glycyl-2-cyanopyrrolidine (QCP) structure equipped with the NIRF dye IRDye800CW were designed and synthesized. All of the probes displayed excellent inhibition potency and selectivity to FAP. The probes consistently exhibited strong inhibition and specific uptake in FAP-expressing U87 glioblastoma cells. In in vivo optical imaging studies, eFAP-24 showed a tumor-to-background ratio (TBR) of 3.1 ± 0.6 at 24 h postinjection, enabling the clear delineation of tumors using the clinical Quest Spectrum NIRF imaging system. A strong fluorescence signal in the tumor and a negligible uptake in nontarget tissues were confirmed by biodistribution analyses. The successful development and validation of FAP-targeting fluorescent probes, especially eFAP-24, offers promising prospects for enhancing the visualization of FAP-rich stromal compartments improving surgical outcomes through NIRF-guided surgery, particularly in solid tumors with dense stroma such as pancreatic cancer.

Near-infrared fluorescence (NIRF) imaging assists surgeons intraoperatively to achieve radical resection of malignant tissue with one centimeter depth and can be supplemented with photoacoustic imaging to increase depth-of-view. Tumor-associated carbohydrate antigens are promising targets for tumor imaging with potential advantages over protein targeting. This study preclinically evaluates the anti-glycan tracers CH88.2-800CW (anti-Lea/c/x) and CH129-800CW (anti-sdi-Lea) for bimodal NIRF/PA imaging of gastrointestinal cancers. Using immunohistochemistry, we found that Lea/c/x and sdi-Lea were highly expressed in gastric and colorectal cancer tissue, with limited expression in healthy surrounding tissue, except for strong Lea/c/x expression in healthy colorectal epithelium. Bimodal NIRF/PA imaging using CH88.2-800CW and CH129-800CW was performed on subcutaneous and orthotopic HT-29_luc2 (colon cancer) and BxPC-3_luc2 (pancreatic cancer) tumor-bearing mice, using rituximab-800CW as a negative control tracer. At 96 h post-injection, all orthotopic tumors were delineated using the clinical Artemis NIRF imager with mean CH88.2-800CW and CH129-800CW tumor-to-background ratios of 4.8 ± 1.4 and 4.9 ± 0.5 for the HT-29_luc2 model, and 2.5 ± 0.3 and 2.9 ± 0.4 for the BxPC-3_luc2 model, respectively. Similarly specific photoacoustic signal was observed within all tumors for both CH88.2-800CW and CH129-800CW. Biodistribution analyses showed high tumor fluorescence with minimal signal in healthy organs, including the liver and kidneys. Bimodal NIRF/PA imaging employing CH88.2-800CW and CH129-800CW facilitates real-time, high-contrast gastrointestinal tumor visualization. Given their strong and mostly tumor-specific expression, both tracers hold promise as effective imaging agents for gastrointestinal cancers, and are compelling candidates for further clinical evaluation.

Near-infrared fluorescence imaging using intravenously administered indocyanine green (ICG) improves colorectal liver metastases (CRLM) surgery by enhancing lesion detection and real-time tumor margin assessment. However, ICG accumulates in hepatocytes around CRLM with high variance between patients. This study evaluates the effects of tumor and patient characteristics on ICG accumulation using a standardized imaging and analysis workflow. This single-center study included patients with CRLM who received 10 mg of ICG intravenously 24 h before surgery. Resected lesions were sliced in 5–10-mm-thick sections and immediately imaged for standardized fluorescence analysis. Fluorescence parameters were compared based on chemotherapy treatment, tumor response, tumor size and superficiality, and degree of steatosis. Associations between the patient and tumor characteristics and fluorescence parameters were determined while correcting for confounders. Thirty-two lesions from 32 patients were analyzed. Lesions from chemotherapy-pretreated patients exhibited a lower mean signal fluorescence intensity (MSFI, 0.23 vs. 0.65 a.u.; p = 0.002) and signal-to-background ratio (SBR, 2.28 vs. 6.08; p < 0.001) than lesions from patients without pretreatment. Tumor size correlated positively with MSFI (p = 0.003), SBR (p = 0.02), and maximum intensity (p < 0.001). After correcting for the other characteristics, chemotherapy showed statistically significant association with the fluorescence parameters. The tumor superficiality, degree of steatosis, and response to chemotherapy had no statistically significant associations with the fluorescence parameters. Neoadjuvant chemotherapy significantly lowers ICG accumulation around CRLM resulting in suboptimal contrast. To optimize fluorescence-guided surgery protocols for chemotherapy-pretreated patients, future research should focus on adjusting ICG dose and timing and exploring specific fluorescence tumor-targeting imaging agents.