Intraoperative Molecular Fluorescence Imaging of Pancreatic Cancer by Targeting Vascular Endothelial Growth Factor: A Multicenter Feasibility Dose-Escalation Study.

Tumor visualization with near-infrared fluorescence (NIRF) imaging might aid exploration and resection of pancreatic cancer by visualizing the tumor in real time. Conjugation of the near-infrared fluorophore IRDye800CW to the monoclonal antibody bevacizumab enables targeting of vascular endothelial growth factor A. The aim of this study was to determine whether intraoperative tumor-specific imaging of pancreatic cancer with the fluorescent tracer bevacizumab-800CW is feasible and safe. Methods: In this multicenter dose-escalation phase I trial, patients in whom pancreatic ductal adenocarcinoma (PDAC) was suspected were administered bevacizumab-800CW (4.5, 10, or 25 mg) 3 d before surgery. Safety monitoring encompassed allergic or anaphylactic reactions and serious adverse events attributed to bevacizumab-800CW. Intraoperative NIRF imaging was performed immediately after laparotomy, just before and after resection of the specimen. Postoperatively, fluorescence signals on the axial slices and formalin-fixed paraffin-embedded tissue blocks from the resected specimens were correlated with histology. Subsequently, tumor-to-background ratios (TBR) were calculated. Results: Ten patients with clinically suspected PDAC were enrolled in the study. Four of the resected specimens were confirmed PDACs; other malignancies were distal cholangiocarcinoma, ampullary carcinoma, and neuroendocrine tumors. No serious adverse events were related to bevacizumab-800CW. In vivo tumor visualization with NIRF imaging differed per tumor type and was nonconclusive. Ex vivo TBRs were 1.3, 1.5, and 2.5 for the 4.5-, 10-, and 25-mg groups, respectively. Conclusion: NIRF-guided surgery in patients with suspected PDAC using bevacizumab-IRDye800CW is feasible and safe. However, suboptimal TBRs were obtained because no clear distinction between pancreatic cancer from normal or inflamed pancreatic tissue was achieved. Therefore, a more tumor-specific tracer than bevacizumab-IRDye800CW for PDAC is preferred.

Somatostatin analogues for the prevention of pancreatic fistula after open pancreatoduodenectomy: A nationwide analysis.

BACKGROUND: Somatostatin analogues (SA) are currently used to prevent postoperative pancreatic fistula (POPF) development. However, its use is controversial. This study investigated the effect of different SA protocols on the incidence of POPF after pancreatoduodenectomy in a nationwide population. METHODS: All patients undergoing elective open pancreatoduodenectomy were included from the Dutch Pancreatic Cancer Audit (2014-2017). Patients were divided into six groups: no SA, octreotide, lanreotide, pasireotide, octreotide only in high-risk (HR) patients and lanreotide only in HR patients. Primary endpoint was POPF grade B/C. The updated alternative Fistula Risk Score was used to compare POPF rates across various risk scenarios. RESULTS: 1992 patients were included. Overall POPF rate was 13.1%. Lanreotide (10.0%), octreotide-HR (9.4%) and no protocol (12.7%) POPF rates were lower compared to the other protocols (varying from 15.1 to 19.1%, p = 0.001) in crude analysis. Sub-analysis in patients with HR of POPF showed a significantly lower rate of POPF when treated with lanreotide (10.0%) compared to no protocol, octreotide and pasireotide protocol (21.6-26.9%, p = 0.006). Octreotide-HR and lanreotide-HR protocol POPF rates were comparable to lanreotide protocol, however not significantly different from the other protocols. Multivariable regression analysis demonstrated lanreotide protocol to be positively associated with a low odds-ratio (OR) for POPF (OR 0.387, 95% CI 0.180-0.834, p = 0.015). In-hospital mortality rates were not affected. CONCLUSION: Use of lanreotide in all patients undergoing pancreatoduodenectomy has a potential protective effect on POPF development. Protocols for HR patients only might be favorable too. However, future studies are warranted to confirm these findings.

Detection, Treatment, and Survival of Pancreatic Cancer Recurrence in the Netherlands: A Nationwide Analysis.

OBJECTIVE: To evaluate whether detection of recurrent pancreatic ductal adenocarcinoma (PDAC) in an early, asymptomatic stage increases the number of patients receiving additional treatment, subsequently improving survival. SUMMARY OF BACKGROUND DATA: International guidelines disagree on the value of standardized postoperative surveillance for early detection and treatment of PDAC recurrence. METHODS: A nationwide, observational cohort study was performed including all patients who underwent PDAC resection (2014-2016). Prospective baseline and perioperative data were retrieved from the Dutch Pancreatic Cancer Audit. Data on follow-up, treatment, and survival were collected retrospectively. Overall survival (OS) was evaluated using multivariable Cox regression analysis, before and after propensity-score matching, stratified for patients with symptomatic and asymptomatic recurrence. RESULTS: Eight hundred thirty-six patients with a median follow-up of 37 months (interquartile range 30-48) were analyzed. Of those, 670 patients (80%) developed PDAC recurrence after a median follow-up of 10 months (interquartile range 5-17). Additional treatment was performed in 159/511 patients (31%) with symptomatic recurrence versus 77/159 (48%) asymptomatic patients (P < 0.001). After propensity-score matching on lymph node ratio, adjuvant therapy, disease-free survival, and recurrence site, additional treatment was independently associated with improved OS for both symptomatic patients [hazard ratio 0.53 (95% confidence interval 0.42-0.67); P < 0.001] and asymptomatic patients [hazard ratio 0.45 (95% confidence interval 0.29-0.70); P < 0.001]. CONCLUSIONS: Additional treatment of PDAC recurrence was independently associated with improved OS, with asymptomatic patients having a higher probability to receive recurrence treatment. Therefore, standardized postoperative surveillance aiming to detect PDAC recurrence before the onset of symptoms has the potential to improve survival. This provides a rationale for prospective studies on standardized surveillance after PDAC resection.

The Role of CT in Assessment of Extraregional Lymph Node Involvement in Pancreatic and Periampullary Cancer: A Diagnostic Accuracy Study.

Purpose: To investigate the diagnostic accuracy of CT in assessing extraregional lymph node metastases in pancreatic head and periampullary cancer. Materials and Methods: This prospective observational cohort study was performed at two tertiary hepatopancreatobiliary (HPB) referral centers between March 2013 and December 2014. Patients undergoing pancreatoduodenectomy or bypass surgery with or without palliative radiofrequency ablation were included. Extraregional lymph node involvement was defined as positive lymph nodes in the aortocaval window. Two expert HPB radiologists assessed aortocaval lymph nodes at preoperative CT according to a standardized protocol. All tissue from the aortocaval window was collected intraoperatively. Positive histopathologic finding was the reference standard. Analysis of predictive values and diagnostic accuracy was performed. Results: A total of 198 consecutive patients (mean age, 66 years; range, 39-86 years; 105 men) with pancreatic head or periampullary carcinoma were included. In 70% of patients, a pancreatoduodenectomy was performed, 4% underwent total pancreatectomy, 4% underwent radiofrequency ablation, and 22% underwent bypass surgery. Forty-four patients (22%) had histologically positive aortocaval lymph nodes. Negative predictive value of CT in assessing aortocaval lymph nodes was 80% for both observers, and positive predictive value was 31%-33%. Overall diagnostic accuracy was 69%-70%. Conclusion: CT has a low diagnostic accuracy in assessing extraregional lymph node metastases in patients suspected of having pancreatic or periampullary cancer.Keywords: CT, Abdomen/GI, Pancreas, Oncology© RSNA, 2021.

Pancreatic resection in the pediatric, adolescent and young adult population: nationwide analysis on complications.

BACKGROUND: The aim of this study was to determine pancreatic surgery specific short- and long-term complications of pediatric, adolescent and young adult (PAYA) patients who underwent pancreatic resection, as compared to a comparator cohort of adults. METHODS: A nationwide retrospective cohort study was performed in PAYA patients who underwent pancreatic resection between 2007 and 2016. PAYA was defined as all patients <40 years at time of surgery. Pancreatic surgery-specific complications were assessed according to international definitions and textbook outcome was determined. RESULTS: A total of 230 patients were included in the PAYA cohort (112 distal pancreatectomies, 99 pancreatoduodenectomies), and 2526 patients in the comparator cohort. For pancreatoduodenectomy, severe morbidity (29.3% vs. 28.6%; P = 0.881), in-hospital mortality (1% vs. 4%; P = 0.179) and textbook outcome (62% vs. 58%; P = 0.572) were comparable between the PAYA and the comparator cohort. These outcomes were also similar for distal pancreatectomy. After pancreatoduodenectomy, new-onset diabetes mellitus (8% vs. 16%) and exocrine pancreatic insufficiency (27% vs. 73%) were lower in the PAYA cohort when compared to adult literature. CONCLUSION: Pancreatic surgery-specific complications were comparable with patients ≥40 years. Development of endocrine and exocrine insufficiency in PAYA patients who underwent pancreatoduodenectomy, however, was substantially lower compared to adult literature.

Fluorescence-Guided Visualization of Soft-Tissue Sarcomas by Targeting Vascular Endothelial Growth Factor A: A Phase 1 Single-Center Clinical Trial.

Resection of soft-tissue sarcoma (STS) is accompanied by a high rate of tumor-positive surgical margins (14%-34%), which potentially lead to decreased disease-free survival. Vascular endothelial growth factor A is overexpressed in malignant tumors, including STS, and can be targeted with bevacizumab-800CW during fluorescence-guided surgery for real-time tumor detection. In this phase 1 clinical trial, we determined the feasibility, safety, and optimal dose of bevacizumab-800CW for fluorescence-guided surgery in STS for in vivo and ex vivo tumor detection. Methods: Patients with a histopathologic diagnosis of STS were included. In the dose-escalation phase, patients received bevacizumab-800CW intravenously 3 d before surgery (10, 25, and 50 mg; n = 8). In the subsequent dose-expansion phase, 7 additional patients received bevacizumab-800CW at the optimal dose. Fluorescence images were obtained in vivo and ex vivo during all stages of standard care. The optimal dose was determined by calculating in vivo and ex vivo tumor-to-background ratios (TBR) and correlating these results with histopathology. Results: Fifteen patients with STS completed this study. All tumors could be visualized during in vivo and ex vivo imaging. The optimal bevacizumab-800CW dose proved to be 10 mg, with a median in vivo TBR of 2.0 (±0.58) and a median ex vivo TBR of 2.67 (±1.6). All 7 tumor-positive margins could be observed in real time after surgical resection. Conclusion: GS using 10 mg of bevacizumab-800CW is feasible and safe for intraoperative imaging of STS, potentially allowing tumor detection and margin assessment during surgery. An additional follow-up phase 2 study is needed to confirm the diagnostic accuracy.

Routine Chest Computed Tomography for Staging of Pancreatic Head Carcinoma.

OBJECTIVES: The diagnostic value of routine chest computed tomography (CT) in addition to abdominal CT in workup for pancreatic head carcinoma is unclear. The aim of this study was to determine if routine chest CT revealed significant lesions that altered the management of patients with suspected pancreatic head carcinoma. METHODS: All Dutch pancreatic cancer centers were surveyed on the use of chest CT in preoperative staging. In addition, a single-center retrospective cohort study was performed including all patients referred with suspected pancreatic head malignancy without chest CT between 2005 and 2016. The primary end point was the proportion of patients in which chest CT revealed clinically significant lesions, leading to a change in management. RESULTS: In 7 of 18 Dutch pancreatic cancer centers (39%), a preoperative chest CT is not routinely performed. In the study cohort, 170 of 848 patients (20%) were referred without chest CT and underwent one by local protocol. Chest CT revealed new suspicious lesions in 17 patients (10%), of whom 6 had metastatic disease (3.5%). CONCLUSIONS: Routine use of chest CT in diagnostic workup for pancreatic head carcinoma reveals clinically significant lesions in 10% of patients, being metastases in up to 4%.

How to Approach Para-Aortic Lymph Node Metastases During Exploration for Suspected Periampullary Carcinoma: Resection or Bypass?

BACKGROUND: Intraoperative para-aortic lymph node (PALN) sampling during surgical exploration in patients with suspected pancreatic head cancer remains controversial. OBJECTIVE: The aim of this study was to assess the value of routine PALN sampling and the consequences of different treatment strategies on overall patient survival. METHODS: A retrospective, multicenter cohort study was performed in patients who underwent surgical exploration for suspected pancreatic head cancer. In cohort A, the treatment strategy was to avoid pancreatoduodenectomy and to perform a double bypass procedure when PALN metastases were found during exploration. In cohort B, routinely harvested PALNs were not examined intraoperatively and pancreatoduodenectomy was performed regardless. PALNs were examined with the final resection specimen. Clinicopathological data, survival data and complication data were compared between study groups. RESULTS: Median overall survival for patients with PALN metastases who underwent a double bypass procedure was 7.0 months (95% confidence interval [CI] 5.5-8.5), versus 11 months (95% CI 8.8-13) in the pancreatoduodenectomy group (p = 0.049). Patients with PALN metastases who underwent pancreatoduodenectomy had significantly increased postoperative morbidity compared with patients who underwent a double bypass procedure (p < 0.001). In multivariable analysis, severe comorbidity (ASA grade 2 or higher) was an independent predictor for decreased survival in patients with PALN involvement (hazard ratio 3.607, 95% CI 1.678-7.751; p = 0.001). CONCLUSION: In patients with PALN metastases, pancreatoduodenectomy was associated with significant survival benefit compared with a double bypass procedure, but with increased risk of complications. It is important to weigh the advantages of resection versus bypass against factors such as comorbidities and clinical performance when positive intraoperative PALNs are found.

The Additional Value of Laparoscopic Ultrasound to Staging Laparoscopy in Patients with Suspected Pancreatic Head Cancer.

BACKGROUND: This study aimed to evaluate the additional value of laparoscopic ultrasound (LUS) to staging laparoscopy (SL) for detecting occult liver metastases in patients with potentially resectable pancreatic head cancer. METHODS: A retrospective cohort study was performed including all patients who underwent SL and LUS between 2005 and 2016. LUS was performed during SL to detect liver metastases not found by preoperative imaging or visual inspection of the liver. RESULTS: Out of 197 patients, visual inspection during SL detected distant metastases in 29 (14.7%) patients. LUS was performed in 127 patients, revealing 3 additional liver metastases. The proportion of patients with unresectable disease after SL and negative LUS was 32.3%, which was similar to 36.6% of patients with unresectable disease after SL without LUS (difference 4.3%; 95% CI - 13-23%; P = 0.61). Sensitivity, specificity, and positive and negative predictive values of LUS to detect liver metastases were 30, 100, 100, and 94%, respectively. The proportion of patients with distant metastases diagnosed at SL significantly increased over time (P = 0.031). CONCLUSION: The routine use of LUS during SL for patients with potentially resectable pancreatic head cancer cannot be recommended. Imaging should be repeated when significant delay occurs between index CT and the scheduled surgery.