Introduction: Up to 32% of patients with esophageal cancer show a pathological complete response (ypCR) after neoadjuvant therapy. To prevent overtreatment, the indication to perform esophagectomy in these patients should be reconsidered. Implementing an organ-preserving strategy for patients with ypCR requires an accurate assessment of residual disease after neoadjuvant treatment. The aim of this study was to systematically review the effectiveness of imaging techniques used for detection of ypCR after neoadjuvant therapy but before resection in patients with esophageal cancer.

ObjectivesLymph node dissection (LND) is part of the standard operating procedure in patients with resectable oesophageal cancer after neoadjuvant chemoradiotherapy regardless of lymph node (LN) status. The aims of this case vignette survey were to acquire expert opinions on the current practice of LND and to determine potential consequences of non-invasive LN staging on the extent of LND and postoperative morbidity.DesignAn online survey including five short clinical cases (case vignettes) was sent to 272 oesophageal surgeons worldwide.Participants86 oesophageal surgeons (median experience in oesophageal surgery of 15 years) participated in the survey (response rate 32%).Main outcome measuresExtent of standard LND, potential changes in LND based on accurate LN staging and consequences for postoperative morbidity were evaluated.ResultsStandard LND varied considerably between experts; for example, pulmonary ligament, splenic artery, aortopulmonary window and paratracheal LNs are routinely dissected in less than 60%. The omission of (parts of) LND is expected to decrease the number of chyle leakages, pneumonias, and laryngeal nerve pareses and to reduce operating time. In order to guide surgical treatment decisions, a diagnostic test for LN staging after neoadjuvant therapy requires a minimum sensitivity of 92% and a specificity of 90%.ConclusionsThis expert case vignette survey study shows that there is no consensus on the extent of standard LND. Oesophageal surgeons seem more willing to extend LND rather than omit LND, based on accurate LN staging. The majority of surgeons expect that less extensive LND can reduce postoperative morbidity.

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Introduction Tumor-targeted imaging is a promising technique for the detection of lymph node metastases (LNM) and primary tumors. It remains unclear which biomarker is the most suitable target to distinguish malignant from healthy tissue in esophageal adenocarcinoma (EAC).Objective We performed an immunohistochemistry study to identify viable tumor markers for tumor-targeted imaging of EAC. Methods We used samples from 72 patients with EAC to determine the immunohistochemical expression of ten potential tumor biomarkers for EAC (carbonic anhydrase IX [CA-IX], carcinoembryonic antigen [CEA], hepatic growth factor receptor, epidermal growth factor receptor, epithelial membrane antigen [EMA], epithelial cell adhesion molecule [EpCAM], human epidermal growth factor receptor 2 [HER-2], urokinase plasminogen activator receptor, vascular endothelial growth factor-A [VEGF-A], and VEGF receptor 2). Immunohistochemistry was performed on tissue microarrays of LNM (n = 48), primary EACs (n = 62), fibrotic tissues (n = 11), nonmalignant lymph nodes (n = 24), and normal esophageal and gastric tissues (n = 40). Tumor marker staining was scored on intensity and percentage of positive cells. Results EMA and EpCAM showed strong expression in LNM (> 95%) and primary EACs (> 95%). Significant expression was also observed for LNM and EAC using VEGF-A (85 and 92%), CEA (68 and 54%), and CA-IX (4 and 34%). The other tumor biomarkers showed expression of 0-15% for LNM and primary EAC. Except for VEGF-A, nonmalignant lymph node staining was scored as slight or absent. Conclusions High expression rates and correlation between LNM in EAC combined with low expression rates in healthy lymph nodes and esophagus tissues were observed for EpCAM and CEA, meaning these are promising targets for tumortargeted imaging approaches for lymph nodes in patients with EAC. Key PointsThe use of intraoperative targeted imaging to detect lymph node metastases is promising and will be an important step forward in personalizing the surgical treatment of patients with esophageal cancer.The most suitable biomarker for targeted imaging techniques in lymph node metastases of esophageal adenocarcinoma remains unclear.Histological evaluation shows that epithelial cell adhesion molecule and carcinoembryonic antigen are suitable targets for image-guided esophageal surgery, both before and after neoadjuvant chemoradiotherapy.

Background Up to 32% of patients with esophageal cancer show a pathological complete response (ypCR) after neoadjuvant therapy. To prevent overtreatment, the indication to perform esophagectomy in these patients should be reconsidered. Implementing an organ-preserving strategy for patients with ypCR requires an accurate assessment of residual disease after neoadjuvant treatment. The aim of this study was to systematically review the effectiveness of imaging techniques used for detection of ypCR after neoadjuvant therapy but before resection in patients with esophageal cancer. Methods A systematic literature search of the Medline, Embase, and Cochrane Library databases was performed from January 1, 2000, to December 13, 2017. Eligible studies were diagnostic studies that compared results of imaging modalities after neoadjuvant therapy to histopathological findings in the resection specimen after esophagectomy. Methodological quality was assessed by the Cochrane Quality Assessment of Diagnostic Accuracy Studies, version 2, model. Primary outcome measures were true positive, false positive, false negative, and true negative values of imaging techniques predicting ypCR. A meta-analysis was performed by pooling sensitivities and specificities by using a bivariate model. Results A total of 4420 articles were identified. After exclusion of irrelevant titles and abstracts, 360 articles were reviewed in full text. In total, four imaging modalities (computed tomography [CT], positron emission tomography [PET-CT], endoscopic ultrasound [EUS], and magnetic resonance imaging [MRI]) were used for restaging. The meta-analysis was conducted with data from 56 studies involving 3625 patients. The pooled sensitivities of CT, PET-CT, EUS, and MRI for detecting ypCR were 0.35, 0.62, 0.01 and 0.80, respectively, whereas the pooled specificities were 0.83, 0.73, 0.99, and 0.83, respectively. The positive predictive value in detecting ypCR was 0.47 for CT, 0.41 for PET-CT, not applicable for EUS, and 0.61 for MRI. Conclusions Current imaging modalities such as CT, PET-CT, and EUS seem to be insufficiently accurate to identify complete responders. More accurate diagnostic tests are needed to improve restaging accuracy for patients with esophageal cancer.

ObjectivesTwo-thirds of patients do not harbor lymph node (LN) metastases after neoadjuvant chemoradiotherapy (nCRT). Our aim was to explore under which circumstances a selective lymph node dissection (LND) strategy, which selects patients for LND based on the restaging results after nCRT, has added value compared with standard LND in esophageal cancer.DesignA decision tree with state-transition model was developed. Input data on short-term and long-term consequences were derived from literature. Sensitivity analyses were conducted to assess promising scenarios and uncertainty.SettingDutch healthcare system.ParticipantsHypothetical cohort of esophageal cancer patients who have already received nCRT and are scheduled for esophagectomy.InterventionsA standard LND cohort was compared with a cohort of patients that received selective LND based on the restaging results after nCRT.Main outcome measuresQuality-adjusted life years (QALYs), residual LN metastases and LND-related complications.ResultsSelective LND could have short-term benefits, that is, a decrease in the number of performed LNDs and LND-related complications. However, this may not outweigh a slight increase in residual LN metastases which negatively impacts QALYs in the long-term. To accomplish equal QALYs as with standard LND, a new surgical strategy should have the same or higher treatment success rate as standard LND, that is, should show equal or less recurrences due to residual LN metastases.ConclusionsThe reduction in LND-related complications that is accomplished by selecting patients for LND based on restaging results after nCRT seems not to outweigh a QALY loss in the long-term due to residual LN metastases. Despite the short-term advantages of selective LND, this strategy can only match long-term QALYs of standard LND when its success rate equals the success rate of standard LND.

Background: In various cancer types, the first step towards extended metastatic disease is the presence of lymph node metastases. Imaging methods with sufficient diagnostic accuracy are required to personalize treatment. Lymph node metastases can be detected with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI), but this method needs validation. Here, a workflow is presented, which is designed to compare MRI-visible lymph nodes on a node-to-node basis with histopathology. Methods: In patients with prostate, rectal, periampullary, esophageal, and head-and-neck cancer, in vivo USPIO-enhanced MRI was performed to detect lymph nodes suspicious of harboring metastases. After lymphadenectomy, but before histopathological assessment, a 7 Tesla preclinical ex vivo MRI of the surgical specimen was performed, and in vivo MR images were radiologically matched to ex vivo MR images. Lymph nodes were annotated on the ex vivo MRI for an MR-guided pathological examination of the specimens. Results: Matching lymph nodes of ex vivo MRI to pathology was feasible in all cancer types. The annotated ex vivo MR images enabled a comparison between USPIO-enhanced in vivo MRI and histopathology, which allowed for analyses on a nodal, or at least on a nodal station, basis. Conclusions: A workflow was developed to validate in vivo USPIO-enhanced MRI with histopathology. Guiding the pathologist towards lymph nodes in the resection specimens during histopathological work-up allowed for the analysis at a nodal basis, or at least nodal station basis, of in vivo suspicious lymph nodes with corresponding histopathology, providing direct information for validation of in vivo USPIO-enhanced, MRI-detected lymph nodes.

BackgroundIn various cancer types, the first step towards extended metastatic disease is the presence of lymph node metastases. Imaging methods with sufficient diagnostic accuracy are required to personalize treatment. Lymph node metastases can be detected with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI), but this method needs validation. Here, a workflow is presented which is designed to compare MRI-visible lymph nodes on a node-to-node basis with histopathology. MethodsIn patients with prostate, rectal, periampullary, esophageal, and head-and-neck cancer, in vivo USPIO-enhanced MRI was performed to detect lymph nodes suspicious for harboring metastases. After lymphadenectomy, but before histopathological assessment, a 7 Tesla (T) preclinical ex vivo MRI of the surgical specimen was performed, and in vivo MR-images were radiologically matched to ex vivo MR images. Lymph nodes were annotated on the ex vivo MRI for an MR-guided pathological examination of the specimens. ResultsMatching lymph nodes of ex vivo MRI to pathology was feasible in all cancer types. The annotated ex vivo MR images enabled a comparison between USPIO-enhanced in vivo MRI and histopathology which allowed for analyses on nodal, or at least on nodal station level.ConclusionsA workflow was developed to validate in vivo USPIO-enhanced MRI with histopathology. Guiding the pathologist towards lymph nodes in the resection specimens during histopathological work-up allowed analysis at nodal level, or at least nodal station level of in vivo suspicious lymph nodes with corresponding histopathology, providing direct information for validation of in vivo USPIO-enhanced MRI detected lymph nodes. Trial registrationVALINODE data is collected from patients undergoing USPIO-enhanced MRI in the clinical setting. Therefore, the trial has not been registered in an online trial register. 7TNANO1 is registered at Clinicaltrials.gov: NCT02751606, April 26 2016 (https://clinicaltrials.gov/ct2/show/NCT02751606). NANO-PANC is registered at Clinicaltrials.gov: NCT04311047, March 17 2020 (https://www.clinicaltrials.gov/ct2/show/NCT04311047). PRECIES is registered in the Dutch Trial Register: NTR6072, August 5 2016 (https://www.trialregister.nl/trial/5797). USPIO-NECK is registered at Clinicaltrials.gov: NCT03817307, January 25 2019 (https://clinicaltrials.gov/ct2/show/NCT03817307).