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BACKGROUND: This study evaluated the proportion of patients with residual neoplasia after endoscopic resection (ER) for Barrett's neoplasia with confirmed tumor-positive vertical resection margin (R1v). METHODS: This retrospective cohort study included patients undergoing ER for Barrett's neoplasia with histologically documented R1v since 2008 in the Dutch Barrett Expert Centers. We defined R1v as cancer cells touching vertical resection margins and Rx as nonassessable margins. Reassessment of R1v specimens was performed by experienced pathologists until consensus was reached regarding vertical margins. RESULTS: 101/110 included patients had macroscopically complete resections (17 T1a, 84 T1b), and 99/101 (98%) ER specimens were histologically reassessed, with R1v confirmed in 74 patients (75%), Rx in 16%, and R0 in 9%. Presence/absence of residual neoplasia could be assessed in 66/74 patients during endoscopic reassessment (52) and/or in the surgical resection specimen (14), and 33/66 (50%) had residual neoplasia. Residual neoplasia detected during endoscopy was always endoscopically visible and biopsies from a normal-appearing ER scar did not detect additional neoplasia. Of 25 patients who underwent endoscopic follow-up (median 37 months [interquartile range 12-50]), 4 developed local recurrence (16.0%), all detected as visible abnormalities. CONCLUSIONS: After ER with R1v, 50% of patients had no residual neoplasia. Histological evaluation of ER margins appears challenging, as in this study 75% of documented R1v cases were confirmed during reassessment. Endoscopic reassessment 8-12 weeks after ER seems to accurately detect residual neoplasia and can help to determine the most appropriate strategy for patients with R1v.

Background Lymph node metastases in papillary thyroid cancer (PTC) increase the risk for persistent and recurrent disease. Data on the predictive value of histopathological features of lymph node metastases, however, are inconsistent. The aim of this study was to evaluate the prognostic significance of known and new histopathological features of lymph node metastases in a well-defined cohort of PTC patients with clinically evident lymph node metastases. Methods A total of 1042 lymph node metastases, derived from 129 PTC patients, were reexamined according to a predefined protocol and evaluated for diameter, extranodal extension, cystic changes, necrosis, calcifications, and the proportion of the lymph node taken up by tumor cells. Predictors for a failure to achieve a complete biochemical and structural response to treatment were determined. Results The presence of more than 5 lymph node metastases was the only independent predictor for a failure to achieve a complete response to treatment (odds ratio [OR] 3.39 [95% CI, 1.57-7.33], P < .05). Diameter nor any of the other evaluated lymph node features were significantly associated with the response to treatment. Conclusions Detailed reexamination of lymph nodes revealed that only the presence of more than 5 lymph node metastases was an independent predictor of failure to achieve a complete response to treatment. No predictive value was found for other histopathological features, including the diameter of the lymph node metastases. These findings have the potential to improve risk stratification in patients with PTC and clinically evident lymph node metastases.

CONTEXTS:Risk factors for radioactive iodine (RAI)-refractory disease in follicular (FTC) and oncocytic thyroid carcinoma (OTC) are unknown. Therefore, the aim of this study is to identify clinical and histopathological risk factors for RAI-refractory disease in FTC and OTC patients, facilitated by an extensive histopathological revision.METHODS: All adult FTC and OTC patients treated at Erasmus MC (the Netherlands) between 2000 and 2016 were retrospectively included. 2015 ATA Guidelines were used to define RAI-refractory disease. An extensive histopathological revision was performed applying the 2022 WHO Classification using Palga: Dutch Pathology Databank. Logistic regression was used to identify risk factors for RAI-refractory disease, stratified for histological subtype.RESULTS: Ninety FTC and 52 OTC patients were included, of which 14 FTC (15.6%) and 22 OTC (42.3%) developed RAI-refractory disease over a follow-up time of 8.5 years. RAI-refractory disease occurred in OTC after fewer cycles than in FTC (2.0 [IQR: 1.0-2.0] vs 2.5 [IQR: 2.0-3.75]), and it substantially decreased the 10-year disease specific survival, especially in OTC (46.4%; FTC 85.7%). In FTC, risk factors were higher age at diagnosis, pT3/pT4-stage, N1-stage, widely invasive tumors and extra-thyroidal extension. N1-stage and M1-stage were the strongest risk factors in OTC, rather than histopathological characteristics of the primary tumor.CONCLUSION: To our knowledge, this is the first study that correlates clinical and histopathological risk factors with RAI-refractory disease in FTC and OTC, facilitated by a histopathological revision. In FTC, risk factors for RAI-refractory disease were foremost histopathological characteristics of the primary tumor, whereas in OTC presentation with lymph node and distant metastasis was associated with RAI-refractory disease. Our data can help clinical decision making, particular

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is a standard treatment for potentially curable esophageal cancer. Active surveillance in patients with a clinically complete response (cCR) 12 weeks after nCRT is regarded as possible alternative to standard surgery. The aim of this study is to monitor the safety, adherence and effectiveness of active surveillance in patients outside a randomized trial. METHODS: This nationwide prospective cohort study aims to accrue operable patients with non-metastatic histologically proven adenocarcinoma or squamous cell carcinoma of the esophagus or esophagogastric junction. Patients receive nCRT and response evaluation consists of upper endoscopy with bite-on-bite biopsies, endoscopic ultrasonography plus fine-needle aspiration of suspicious lymph nodes and 18F-fluorodeoxyglucose positron emission tomography/computed tomography scan. When residue or regrowth of tumor in the absence of distant metastases is detected, surgical resection is advised. Patients with cCR after nCRT are suitable to undergo active surveillance. Patients can consult an independent physician or psychologist to support decision-making. Primary endpoint is the number and severity of adverse events in patients with cCR undergoing active surveillance, defined as complications from response evaluations, delayed surgery and the development of distant metastases. Secondary endpoints include timing and quality of diagnostic modalities, overall survival, progression-free survival, fear of cancer recurrence and decisional regret. DISCUSSION: Active surveillance after nCRT may be an alternative to standard surgery in patients with esophageal cancer. Similar to organ-sparing approaches applied in other cancer types, the safety and efficacy of active surveillance needs monitoring before data from randomized trials are available. TRIAL REGISTRATION: The SANO-2 study has been registered at ClinicalTrials.gov as NCT04886635 (May 14, 2021) - Re

Oesophageal adenocarcinomas may show different histopathological patterns, including excessive acellular mucin pools, signet-ring cells (SRCs), and poorly cohesive cells (PCCs). These components have been suggested to correlate with poor outcomes after neoadjuvant chemoradiotherapy (nCRT), which might influence patient management. However, these factors have not been studied independently of each other with adjustment for tumour differentiation grade (i.e. the presence of well-formed glands), which is a possible confounder. We studied the pre- and post-treatment presence of extracellular mucin, SRCs, and/or PCCs in relation to pathological response and prognosis after nCRT in patients with oesophageal or oesophagogastric junction adenocarcinoma. A total of 325 patients were retrospectively identified from institutional databases of two university hospitals. All patients were scheduled for ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) nCRT and oesophagectomy between 2001 and 2019. Percentages of well-formed glands, extracellular mucin, SRCs, and PCCs were scored in pre-treatment biopsies and post-treatment resection specimens. The association between histopathological factors (≥1 and >10%) and tumour regression grade 3-4 (i.e. >10% residual tumour), overall survival, and disease-free survival (DFS) was evaluated, adjusted for tumour differentiation grade amongst other clinicopathological variables. In pre-treatment biopsies, ≥1% extracellular mucin was present in 66 of 325 patients (20%); ≥1% SRCs in 43 of 325 (13%), and ≥1% PCCs in 126 of 325 (39%). We show that pre-treatment histopathological factors were unrelated to tumour regression grade. Pre-treatment presence of >10% PCCs was associated with lower DFS (hazard ratio [HR] 1.73, 95% CI 1.19-2.53). Patients with post-treatment presence of ≥1% SRCs had higher risk of death (HR 1.81, 95% CI 1.10-2.99). In conclusion, pre-treatment presence of extracellular mucin, SRCs, and/o

BACKGROUND: Ustekinumab (UST), which targets p40/interleukin (IL)-23 and IL-12, is an effective treatment for Crohn's disease (CD). Therapeutic drug monitoring may optimize UST posology. The aim of this study was to investigate UST and IL-23 serum and tissue concentrations in relation to mucosal inflammation and treatment response at an early time point. METHODS: CD patients starting UST between December 2016 and November 2018 were prospectively enrolled. Endoscopies were performed at baseline and week 16. UST and IL-23 serum and tissue concentrations were measured at week 16. Clinical and biochemical response were defined as decline of ≥3 points in Harvey-Bradshaw Index and reduction of ≥50% in fecal calprotectin levels. Endoscopic response was defined as a ≥50% decline in Simple Endoscopic Score or a decline of ≥1 points in Rutgeerts score. Histological remission was defined as Global Histologic Disease Activity Score ≤4. RESULTS: Of 56 included patients, 17 (30%) of 56 showed clinical response, 16 (30%) of 53 showed biochemical response, and 20 (36%) of 56 showed endoscopic response. UST, but not IL-23, concentration in biopsies was correlated to levels in corresponding sera (P < .0001). No correlation was found between UST tissue levels and treatment response. Patients achieving biochemical response showed significantly higher UST serum levels (3.12 µg/mL vs 1.41 µg/mL; P = .01). Tissue IL-23-to-UST ratio correlated with mucosal inflammation (P = .01). CONCLUSIONS: This is the first study to demonstrate a correlation between serum and tissue UST levels. While tissue IL-23-to-UST ratio correlated with mucosal inflammation, UST serum levels were more indicative for biochemical response. The role of UST levels for therapeutic drug monitoring in inflammatory bowel disease needs further research.

BACKGROUND: Active surveillance after neoadjuvant treatment is increasingly implemented. The success of this strategy relies on the accurate detection of residual cancer. This study aimed to assess the diagnostic value of a second (bite-on-bite) biopsy for the detection of residual esophageal cancer and to correlate outcomes to the distribution of residual cancer found in the resection specimen.METHODS: A multicenter prospective study of esophageal cancer patients undergoing active surveillance after neoadjuvant chemoradiotherapy was performed. At clinical response evaluations, an upper gastrointestinal (GI) endoscopy was performed with at least four bite-on-bite biopsies of the primary tumor site. First and second biopsies were analyzed separately. Patients with histopathological evidence of residual cancer were included in the primary analysis. Two pathologists blinded for biopsy outcome examined all resection specimens.RESULTS: Between October 2017 and July 2020, 626 upper GI endoscopies were performed in 367 patients. Of 138 patients with residual cancer, 112 patients (81 %) had at least one positive biopsy. In 14 patients (10 %) only the first biopsy was positive and in 25 patients (18 %) only the second biopsy (P = 0.11). Remarkably, the rates of patients with tumor-free mucosa and deeper located tumors were higher in patients detected by the first biopsy. The second biopsy increased the false-positive rate by 3 percentage points. No adverse events occurred.CONCLUSIONS: A second (bite-on-bite) biopsy improves the detection of residual esophageal cancer by almost 20 percentage points, at the expense of increasing the false-positive rate by 3 percentage points. The higher detection rate is explained by the higher number of biopsies obtained rather than by the penetration depth.

Induced pluripotent stem cell (iPSC)-derived kidney organoids are a potential tool for the regeneration of kidney tissue. They represent an early stage of nephrogenesis and have been shown to successfsully vascularize and mature further in vivo. However, there are concerns regarding the long-term safety and stability of iPSC derivatives. Specifically, the potential for tumorigenesis may impede the road to clinical application. To study safety and stability of kidney organoids, we analyzed their potential for malignant transformation in a teratoma assay and following long-term subcutaneous implantation in an immune-deficient mouse model. We did not detect fully functional residual iPSCs in the kidney organoids as analyzed by gene expression analysis, single-cell sequencing and immunohistochemistry. Accordingly, kidney organoids failed to form teratoma. Upon long-term subcutaneous implantation of whole organoids in immunodeficient IL2Ry-/-RAG2-/- mice, we observed tumor formation in 5 out of 103 implanted kidney organoids. These tumors were composed of WT1+CD56+ immature blastemal cells and showed histological resemblance with Wilms tumor. No genetic changes were identified that contributed to the occurrence of tumorigenic cells within the kidney organoids. However, assessment of epigenetic changes revealed a unique cluster of differentially methylated genes that were also present in undifferentiated iPSCs. We discovered that kidney organoids have the capacity to form tumors upon long-term implantation. The presence of epigenetic modifications combined with the lack of environmental cues may have caused an arrest in terminal differentiation. Our results indicate that the safe implementation of kidney organoids should exclude the presence of pro-tumorigenic methylation in kidney organoids.

Background: The association between vedolizumab (VDZ) exposure and treatment response is unclear and seems insufficiently explained by serum levels. The aim of this study was to assess the correlation between VDZ concentrations in serum and intestinal tissue and their association with mucosal inflammation and response to VDZ. Methods: This prospective study included 37 adult patients with inflammatory bowel disease with endoscopic inflammation at baseline who started VDZ. At week 16, serum and biopsies were collected for VDZ measurement by enzyme-linked immunosorbent assay. Nonlinear mixed-effects modeling was used to calculate serum trough concentrations and to assess intestinal tissue concentrations. Validated clinical and endoscopic scores were used to define clinical and endoscopic response and remission, and fecal calprotectin levels were used to assess biochemical response. Histologic remission was determined by the Nancy score. Results: A positive correlation was observed between VDZ concentrations in serum and tissue (r2 = 0.83; P < 0.0001). High mucosal rather than serum VDZ levels correlated with a reduced endoscopic (P = 0.06) grade of mucosal inflammation. Furthermore, patients with a positive biochemical and endoscopic outcome had higher tissue levels of VDZ than patients without biochemical and endoscopic response (P < 0.01 and P = 0.04, respectively). Conclusions: Tissue levels of VDZ may provide a better marker than serum levels for mucosal inflammation and objective treatment outcome at week 16. The potential of VDZ tissue levels for therapeutic drug monitoring in inflammatory bowel disease warrants further exploration.

Context: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine, usually benign, tumors. Currently, the only reliable criterion of malignancy is the presence of metastases. Objective: The aim of this study was to identify genes associated with malignancy in PPGLs. Design: Transcriptomic profiling was performed on 40 benign and 11 malignant PPGLs. Genes showing a significantly different expression between benign and malignant PPGLs with a ratio ≥4 were confirmed and tested in an independent series by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed for the validated genes on 109 benign and 32 malignant PPGLs. Functional assays were performed with hPheo1 cells. Setting: This study was conducted at the Department of Pathology of the Erasmus MC University Medical Center Rotterdam Human Molecular Genetics laboratory of the de Duve Institute, University of Louvain. Patients: PPGL samples from 179 patients, diagnosed between 1972 and 2015, were included. Main outcome measures: Associations between gene expression and malignancy were tested using supervised clustering approaches. Results: Ten differentially expressed genes were selected based on messenger RNA (mRNA) expression array data. Contactin 4 (CNTN4) was overexpressed in malignant vs benign tumors [4.62-fold; false discovery rate (FDR), 0.001]. Overexpression at the mRNA level was confirmed using qRT-PCR (2.90-fold, P = 0.02; validation set: 4.26-fold, P = 0.005). Consistent findings were obtained in The Cancer Genome Atlas cohort (2.7-fold; FDR, 0.02). CNTN4 protein was more frequently expressed in malignant than in benign PPGLs by immunohistochemistry (58% vs 17%; P = 0.002). Survival after 7 days of culture under starvation conditions was significantly enhanced in hPheo1 cells transfected with CNTN4 complementary DNA. Conclusion: CNTN4 expression is consistently associated with malignant behavior in PPGLs.