Head-to-head comparison of [11C]methionine PET, [11C]choline PET, and 4-dimensional CT as second-line scans for detection of parathyroid adenomas in primary hyperparathyroidism.

PURPOSE: Accurate preoperative localization is imperative to guide surgery in primary hyperparathyroidism (pHPT). It remains unclear which second-line imaging technique is most effective after negative first-line imaging. In this study, we compare the diagnostic effectiveness of [11C]methionine PET/CT, [11C]choline PET/CT, and four dimensional (4D)-CT head-to-head in patients with pHPT, to explore which of these imaging techniques to use as a second-line scan. METHODS: We conducted a powered, prospective, blinded cohort study in patients with biochemically proven pHPT and prior negative or discordant first-line imaging consisting of ultrasonography and 99mTc-sestamibi. All patients underwent [11C]methionine PET/CT, [11C]choline PET/CT, and 4D-CT. At first, all scans were interpreted by a nuclear medicine physician, and a radiologist who were blinded from patient data and all imaging results. Next, a non-blinded scan reading was performed. The scan results were correlated with surgical and histopathological findings. Serum calcium values at least 6 months after surgery were used as gold standard for curation of HPT. RESULTS: A total of 32 patients were included in the study. With blinded evaluation, [11C]choline PET/CT was positive in 28 patients (88%), [11C]methionine PET/CT in 23 (72%), and 4D-CT in 15 patients (47%), respectively. In total, 30 patients have undergone surgery and 32 parathyroid lesions were histologically confirmed as parathyroid adenomas. Based on the blinded evaluation, lesion-based sensitivity of [11C]choline PET/CT, [11C]methionine PET/CT, and 4D-CT was respectively 85%, 67%, and 39%. The sensitivity of [11C]choline PET/CT differed significantly from that of [11C]methionine PET/CT and 4D-CT (p = 0.031 and p < 0.0005, respectively). CONCLUSION: In the setting of pHPT with negative first-line imaging, [11C]choline PET/CT is superior to [11C]methionine PET/CT and 4D-CT in localizing parathyroid adenomas, allowing correct localization in 85% of adenomas. Further studies are needed to determine cost-benefit and efficacy of these scans, including the timing of these scans as first- or second-line imaging techniques.

The Effect of a Temporary Stoma on Long-term Functional Outcomes Following Surgery for Rectal Cancer.

BACKGROUND: Patients with rectal cancer may undergo surgical resection with or without a temporary stoma. OBJECTIVE: This study primarily aimed to compare long-term functional outcomes between patients with and without a temporary stoma after surgery for rectal cancer. The secondary aim was to investigate the effect of time to stoma reversal on functional outcomes. DESIGN: This was a multicenter, cross-sectional study. SETTINGS: This study was conducted at 7 Dutch hospitals. PATIENTS: Included were patients who had undergone rectal cancer surgery (2009-2015). Excluded were deceased patients, who were deceased, had a permanent stoma, or had intellectual disability. MAIN OUTCOME MEASURES: Functional outcomes were measured using the Rome IV criteria for constipation and fecal incontinence and the low anterior resection syndrome score. RESULTS: Of 656 patients, 32% received a temporary ileostomy and 20% a temporary colostomy (86% response). Follow-up was at 56 (interquartile range, 38.5-79) months. Patients who had a temporary ileostomy experienced less constipation, more fecal incontinence, and more major low anterior resection syndrome than those without a temporary stoma. Patients who had a temporary colostomy experienced more major low anterior resection syndrome than those without a temporary stoma. A temporary ileostomy or colostomy was not associated with constipation or fecal incontinence after correction for confounding factors (eg, anastomotic height, anastomotic leakage, radiotherapy). Time to stoma reversal was not associated with constipation, fecal incontinence, or major low anterior resection syndrome. LIMITATIONS: Cross-sectional design. CONCLUSIONS: Although patients with a temporary ileostomy or colostomy have worse functional outcomes in the long term, it seems that the reason for creating a temporary stoma, rather than the stoma itself, underlies this phenomenon. Time to reversal of a temporary stoma does not influence functional outcomes. See Video Abstract . EL EFECTO DEL ESTOMA TEMPORAL SOBRE LOS RESULTADOS FUNCIONALES A LARGO PLAZO DESPUS DE LA CIRUGA POR CNCER DE RECTO: ANTECEDENTES:Los pacientes con cáncer de recto pueden someterse a resección quirúrgica con o sin un estoma temporal.OBJETIVO:El objetivo principal de este estudio fue comparar los resultados funcionales a largo plazo entre pacientes con y sin estoma temporal después de cirugía por cáncer de recto. El objetivo secundario fue investigar el efecto del tiempo transcurrido hasta la reversión del estoma sobre los resultados funcionales.DISEÑO:Este fue un estudio transversal multicéntrico.ESCENARIO:Este estudio se llevó a cabo en siete hospitales holandeses.PACIENTES:Se incluyeron pacientes sometidos a cirugía de cáncer de recto (2009-2015). Se excluyeron pacientes fallecidos, pacientes con estoma permanente o discapacidad intelectual.PRINCIPALES MEDIDAS DE RESULTADO:Los resultados funcionales se midieron utilizando los criterios de Roma IV para el estreñimiento y la incontinencia fecal y la puntuación del síndrome de resección anterior baja (LARS).RESULTADOS:De 656 pacientes, el 32% recibió una ileostomía temporal y el 20% una colostomía temporal (respuesta del 86%). El seguimiento fue de 56.0 (RIQ 38.5-79.0) meses. Los pacientes a los que se les realizó una ileostomía temporal experimentaron menos estreñimiento, más incontinencia fecal y más LARS mayor que los pacientes sin un estoma temporal. Los pacientes que tuvieron una colostomía temporal experimentaron más LARS mayor que los pacientes sin un estoma temporal. Una ileostomía o colostomía temporal no se asoció con estreñimiento o incontinencia fecal después de la corrección de factores de confusión (p. ej., altura anastomótica, fuga anastomótica, radioterapia). El tiempo hasta la reversión del estoma no se asoció con estreñimiento, incontinencia fecal o LARS mayor.LIMITACIONES:El presente estudio está limitado por su diseño transversal.CONCLUSIONES:Aunque los pacientes con una ileostomía o colostomía temporal tienen peores resultados funcionales a largo plazo, parece que la razón para crear un estoma temporal, más que el estoma en sí, se asocia a este fenómeno. El tiempo hasta la reversión de un estoma temporal no influye en los resultados funcionales. (Traducción-Dr. Jorge Silva Velazco ).

Human precision-cut cystic duct and gallbladder slices: a novel method for studying cholangiopathies.

Background and aims: Precision-cut tissue slices (PCTS) are widely used as an ex vivo culture tissue culture technique to study pathogeneses of diseases and drug activities in organs in vitro. A novel application of the PCTS model may be in the field of translational research into cholangiopathies such as biliary atresia. Therefore, the aim of this study was to apply the precision-cut slice technique to human bile duct and gallbladder tissue. Methods: Cystic duct and gallbladder tissue derived from patients undergoing a cholecystectomy were collected, preserved and used for preparation of precision-cut cystic duct slices (PCCDS) and precision-cut gallbladder slices (PCGS). The PCCDS and PCGS were prepared using a mechanical tissue slicer and subsequently incubated for 24 and 48 h respectively in William's Medium E (WME) culture medium. Viability was assessed based on ATP/protein content and tissue morphology [hematoxylin and eosin (H&E) staining]. Results: It was shown that viability, assessed by the ATP/protein content and morphology, of the PCCDS (n = 8) and PCGS (n = 8) could be maintained over the 24 and 48 h incubation period respectively. ATP/protein content of the PCCDS increased significantly from 0.58 ± 0.13 pmol/µg at 0 h to 2.4 ± 0.29 pmol/µg after 24 h incubation (P = .0003). A similar significant increase from 0.94 ± 0.22 pmol/µg at 0 h to 3.7 ± 0.41 pmol/µg after 24 h (P = .0005) and 4.2 ± 0.47 pmol/µg after 48 h (P = .0002) was observed in the PCGS. Morphological assessment of the PCCDS and PCGS showed viable tissue at 0 h and after 24 and 48 h incubation respectively. Conclusion: This study is the first to report on the use of the PCTS model for human gallbladder and cystic duct tissue. PCCDS and PCGS remain viable for an incubation period of at least 24 h, which makes them suitable for research purposes in the field of cholangiopathies, including biliary atresia.

Trends in Distal Esophageal and Gastroesophageal Junction Cancer Care: The Dutch Nationwide Ivory Study.

OBJECTIVE: This study evaluated the nationwide trends in care and accompanied postoperative outcomes for patients with distal esophageal and gastro-esophageal junction cancer. SUMMARY OF BACKGROUND DATA: The introduction of transthoracic esophagectomy, minimally invasive surgery, and neo-adjuvant chemo(radio)therapy changed care for patients with esophageal cancer. METHODS: Patients after elective transthoracic and transhiatal esophagectomy for distal esophageal or gastroesophageal junction carcinoma in the Netherlands between 2007-2016 were included. The primary aim was to evaluate trends in both care and postoperative outcomes for the included patients. Additionally, postoperative outcomes after transthoracic and tran-shiatal esophagectomy were compared, stratified by time periods. RESULTS: Among 4712 patients included, 74% had distal esophageal tumors and 87% had adenocarcinomas. Between 2007 and 2016, the proportion of transthoracic esophagectomy increased from 41% to 81%, and neo-adjuvant treatment and minimally invasive esophagectomy increased from 31% to 96%, and from 7% to 80%, respectively. Over this 10-year period, postoperative outcomes improved: postoperative morbidity decreased from 66.6% to 61.8% ( P = 0.001), R0 resection rate increased from 90.0% to 96.5% (P <0.001), median lymph node harvest increased from 15 to 19 ( P <0.001), and median survival increased from 35 to 41 months ( P = 0.027). CONCLUSION: In this nationwide cohort, a transition towards more neo-adju-vant treatment, transthoracic esophagectomy and minimally invasive surgery was observed over a 10-year period, accompanied by decreased postoperative morbidity, improved surgical radicality and lymph node harvest, and improved survival.

Anastomotic Height Is a Valuable Indicator of Long-term Bowel Function Following Surgery for Rectal Cancer.

BACKGROUND: The exact relation between anastomotic height after rectal cancer surgery and postoperative bowel function problems has not been investigated in the long term, resulting in ineffective treatment. OBJECTIVE: The goal of this study was to determine the effect of anastomotic height on long-term bowel function and generic quality of life. DESIGN: This was a multicenter, cross-sectional study. SETTINGS: Seven hospitals in the north of the Netherlands participated. PATIENTS: All patients who underwent rectal cancer surgery between 2009 and 2015 in participating hospitals received the validated Defecation and Fecal Continence and Short-Form 36 questionnaires. Deceased patients, patients with a permanent stoma or an anastomosis >15 cm from the anal verge, patients with intellectual disability, and patients living abroad were excluded. MAIN OUTCOME MEASURES: Primary outcomes were constipation (Rome IV), fecal incontinence (Rome IV), and major low anterior resection syndrome. Secondary outcomes were the generic quality of life scores. RESULTS: The study population ( n = 630) had a median follow-up of 58.0 months. In multivariable analysis, constipation (OR = 1.08; 95% CI, 1.02-1.15; p = 0.011), fecal incontinence (OR = 0.91; 95% CI, 0.84-0.97; p = 0.006), and major low anterior resection syndrome (OR = 0.93; 95% CI, 0.87-0.99; p = 0.027), were significantly associated with anastomotic height. The curves illustrating the probability of constipation and fecal incontinence crossed at an anastomotic height of 7 cm, with 95% CIs overlapping between 4.5 and 9.5 cm. There was no relation between quality-of-life scores and anastomotic height. LIMITATIONS: The study is limited by its cross-sectional design. CONCLUSIONS: This study might serve as a guide for the clinician to effectively screen and treat fecal incontinence and constipation during patient follow-up after rectal cancer surgery. More attention should be paid to fecal incontinence in patients with an anastomosis below 4.5 cm and toward constipation in patients with an anastomosis above 9.5 cm. See Video Abstract at http://links.lww.com/DCR/B858 . LA ALTURA ANASTOMTICA ES UN INDICADOR VALIOSO DE LA FUNCIN INTESTINAL A LARGO PLAZO DESPUS DE LA CIRUGA PARA EL CNCER DE RECTO: ANTECEDENTES:La relación exacta entre la altura anastomótica después de la cirugía de cáncer de recto y los problemas posoperatorios de la función intestinal no se ha investigado a largo plazo, lo que causa un tratamiento ineficaz.OBJETIVO:Determinar el efecto de la altura anastomótica sobre la función intestinal a largo plazo y la calidad de vida genérica.DISEÑO:Estudio multicéntrico transversal.DISEÑO DEL ESTUDIO:Participaron siete hospitales holandeses en el norte de los Países Bajos.PACIENTES:Todos los pacientes que se sometieron a cirugía de cáncer de recto entre 2009 y 2015 en los hospitales participantes recibieron los cuestionarios validados de Defecación y Continencia Fecal y Short-Form 36. Se excluyeron pacientes fallecidos, pacientes con estoma permanente o anastomosis > 15 cm del borde anal, discapacidad intelectual o residentes en el extranjero.PRINCIPALES MEDIDAS DE RESULTADO:Los resultados primarios fueron estreñimiento (Roma IV), incontinencia fecal (Roma IV) y síndrome de resección anterior baja mayor. Los resultados secundarios fueron las puntuaciones genéricas de calidad de vida.RESULTADOS:La población de estudio (N = 630) tuvo una mediana de seguimiento de 58.0 meses. En el análisis multivariable el estreñimiento (OR = 1,08, IC del 95%, 1,02-1,15, p = 0,011), incontinencia fecal (OR = 0,91, IC del 95%, 0,84-0,97, p = 0,006) y síndrome de resección anterior baja mayor (OR = 0,93, IC del 95%, 0,87-0,99, p = 0,027) se asociaron significativamente con la altura anastomótica. Las curvas que ilustran la probabilidad de estreñimiento e incontinencia fecal se cruzaron a una altura anastomótica de 7 cm, con IC del 95% superpuestos entre 4,5 y 9,5 cm. No hubo relación entre las puntuaciones de calidad de vida y la altura anastomótica.LIMITACIONES:El estudio está limitado por su diseño transversal.CONCLUSIONES:Este estudio podría servir como una guía para que el médico evalúe y trate eficazmente la incontinencia fecal y el estreñimiento durante el seguimiento de los pacientes después de la cirugía de cáncer de recto. Se debe prestar más atención a la incontinencia fecal en pacientes con anastomosis por debajo de 4,5 cm y al estreñimiento en pacientes con anastomosis por encima de 9,5 cm. Consulte Video Resumen en http://links.lww.com/DCR/B858 . (Traducción-Dr. Yazmin Berrones-Medina ).

Patient-derived parathyroid organoids as a tracer and drug-screening application model.

Parathyroid diseases are characterized by dysregulation of calcium homeostasis and alterations in parathyroid hormone (PTH) excretion. The development of parathyroid-targeted treatment and imaging tracers could benefit from in vitro models. Therefore, we aim to establish a patient-derived parathyroid organoid model representing human parathyroid tissue. Hyperplastic parathyroid tissue was dispersed, and parathyroid organoids (PTOs) were cultured and characterized. PTO-derived cells exhibited self-renewal over several passages, indicative of the presence of putative stem cells. Immunofluorescence and RNA sequencing confirmed that PTOs phenocopy hyperplastic parathyroid tissue. Exposure of PTOs to increasing calcium concentrations and PTH-lowering drugs resulted in significantly reduced PTH excretion. PTOs showed specific binding of the imaging tracers 11C-methionine and 99mTc-sestamibi. These data show the functionality of PTOs resembling the parathyroid. This PTO model recapitulates the originating tissue on gene and protein expression and functionality, paving the way for future physiology studies and therapeutic target and tracer discovery.

Diagnostic Accuracy of Radioactive Iodine Seed Placement in the Axilla With Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy in Node-Positive Breast Cancer.

Importance: Several less-invasive staging procedures have been proposed to replace axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC) in patients with initially clinically node-positive (cN+) breast cancer, but these procedures may fail to detect residual disease. Owing to the lack of high-level evidence, it is not yet clear which procedure is most optimal to replace ALND. Objective: To determine the diagnostic accuracy of radioactive iodine seed placement in the axilla with sentinel lymph node biopsy (RISAS), a targeted axillary dissection procedure. Design, Setting, and Participants: This was a prospective, multicenter, noninferiority, diagnostic accuracy trial conducted from March 1, 2017, to December 31, 2019. Patients were included within 14 institutions (general, teaching, and academic) throughout the Netherlands. Patients with breast cancer clinical tumor categories 1 through 4 (cT1-4; tumor diameter <2 cm and up to >5 cm or extension to the chest wall or skin) and pathologically proven positive axillary lymph nodes (ie, clinical node categories cN1, metastases to movable ipsilateral level I and/or level II axillary nodes; cN2, metastases to fixed or matted ipsilateral level I and/or level II axillary nodes; cN3b, metastases to ipsilateral level I and/or level II axillary nodes with metastases to internal mammary nodes) who were treated with NAC were eligible for inclusion. Data were analyzed from July 2020 to December 2021. Intervention: Pre-NAC, the marking of a pathologically confirmed positive axillary lymph node with radioactive iodine seed (MARI) procedure, was performed and after NAC, sentinel lymph node biopsy (SLNB) combined with excision of the marked lymph node (ie, RISAS procedure) was performed, followed by ALND. Main Outcomes and Measures: The identification rate, false-negative rate (FNR), and negative predictive value (NPV) were calculated for all 3 procedures: RISAS, SLNB, and MARI. The noninferiority margin of the observed FNR was 6.25% for the RISAS procedure. Results: A total of 212 patients (median [range] age, 52 [22-77] years) who had cN+ breast cancer underwent the RISAS procedure and ALND. The identification rate of the RISAS procedure was 98.2% (223 of 227). The identification rates of SLNB and MARI were 86.4% (197 of 228) and 94.1% (224 of 238), respectively. FNR of the RISAS procedure was 3.5% (5 of 144; 90% CI, 1.38-7.16), and NPV was 92.8% (64 of 69; 90% CI, 85.37-97.10), compared with an FNR of 17.9% (22 of 123; 90% CI, 12.4%-24.5%) and NPV of 72.8% (59 of 81; 90% CI, 63.5%-80.8%) for SLNB and an FNR of 7.0% (10 of 143; 90% CI, 3.8%-11.6%) and NPV of 86.3% (63 of 73; 90% CI, 77.9%-92.4%) for the MARI procedure. In a subgroup of 174 patients in whom SLNB and the MARI procedure were successful and ALND was performed, FNR of the RISAS procedure was 2.5% (3 of 118; 90% CI, 0.7%-6.4%), compared with 18.6% (22 of 118; 90% CI, 13.0%-25.5%) for SLNB (P < .001) and 6.8% (8 of 118; 90% CI, 3.4%-11.9%) for the MARI procedure (P = .03). Conclusions and Relevance: Results of this diagnostic study suggest that the RISAS procedure was the most feasible and accurate less-invasive procedure for axillary staging after NAC in patients with cN+ breast cancer.

Long-term Bowel Dysfunction and Decline in Quality of Life Following Surgery for Colon Cancer: Call for Personalized Screening and Treatment.

BACKGROUND: Differences in long-term outcomes regarding types of colon resections are inconclusive, precluding patient counseling, effective screening, and personalized treatment. OBJECTIVE: This study aimed to compare long-term bowel function and quality of life in patients who underwent right or left hemicolectomy or sigmoid colon resection. DESIGN: This was a multicenter cross-sectional study. SETTINGS: Seven Dutch hospitals participated in this study. PATIENTS: This study included patients who underwent right or left hemicolectomy or sigmoid colon resection without construction of a permanent stoma between 2009 and 2015. Patients who were deceased, mentally impaired, or living abroad were excluded. Eligible patients were sent the validated Defecation and Fecal Continence and Short-Form 36 questionnaires. MAIN OUTCOME MEASURES: Constipation, fecal incontinence (both Rome IV criteria), separate bowel symptoms, and generic quality of life were the main outcomes assessed. RESULTS: This study included 673 patients who underwent right hemicolectomy, 167 who underwent left hemicolectomy, and 284 who underwent sigmoid colon resection. The median follow-up was 56 months. Sigmoid colon resection increased the likelihood of constipation compared to right and left hemicolectomy (OR, 2.92; 95% CI, 1.80-4.75; p < 0.001 and OR, 1.93; 95% CI, 1.12-3.35; p = 0.019). Liquid incontinence and fecal urgency increased after right hemicolectomy compared to sigmoid colon resection (OR, 2.15; 95% CI, 1.47-3.16; p < 0.001 and OR, 2.01; 95% CI, 1.47-2.74; p < 0.001). Scores on quality-of-life domains were found to be significantly lower after right hemicolectomy. LIMITATIONS: Because of the cross-sectional design, longitudinal data are still lacking. CONCLUSIONS: Different long-term bowel function problems occur after right or left hemicolectomy or sigmoid colon resection. The latter seems to be associated with more constipation than right or left hemicolectomy. Liquid incontinence and fecal urgency seem to be associated with right hemicolectomy, which may explain the decline in physical and mental generic quality of life of these patients. See Video Abstract at http://links.lww.com/DCR/C13 . DISFUNCIN INTESTINAL A LARGO PLAZO Y DISMINUCIN DE LA CALIDAD DE VIDA DESPUS DE LA CIRUGA DE CNCER DE COLON SOLICITUD DE DETECCIN Y TRATAMIENTO PERSONALIZADOS: ANTECEDENTES:Las diferencias en los resultados a largo plazo con respecto a los tipos de resecciones de colon no son concluyentes, lo que impide el asesoramiento preoperatorio del paciente y la detección eficaz y el tratamiento personalizado de la disfunción intestinal postoperatoria durante el seguimiento.OBJETIVO:Comparar la función intestinal a largo plazo y la calidad de vida en pacientes sometidos a hemicolectomía derecha o izquierda, o resección de colon sigmoide.DISEÑO:Estudio transversal multicéntrico.AJUSTES:Participaron siete hospitales holandeses.PACIENTES:Se incluyeron pacientes sometidos a hemicolectomía derecha o izquierda, o resección de colon sigmoide sin construcción de estoma permanente entre 2009 y 2015. Se excluyeron pacientes fallecidos, con discapacidad mental o residentes en el extranjero. A los pacientes elegibles se les enviaron los cuestionarios validados de Defecación y Continencia Fecal y Short-Form 36.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron el estreñimiento, la incontinencia fecal (ambos criterios de Roma IV), los síntomas intestinales separados y la calidad de vida genérica.RESULTADOS:Se incluyeron 673 pacientes con hemicolectomía derecha, 167 con hemicolectomía izquierda y 284 con resección de colon sigmoide. La mediana de seguimiento fue de 56 meses (RIC 41-80). La resección del colon sigmoide aumentó la probabilidad de estreñimiento en comparación con la hemicolectomía derecha e izquierda (OR, 2,92, IC 95%, 1,80-4,75, p < 0,001 y OR 1,93, IC 95%, 1,12-3,35, p = 0,019). La incontinencia de líquidos y la urgencia fecal aumentaron después de la hemicolectomía derecha en comparación con la resección del colon sigmoide (OR, 2,15, IC 95%, 1,47-3,16, p < 0,001 y OR 2,01, IC 95%, 1,47-2,74, p < 0,001). Las puntuaciones en los dominios de calidad de vida fueron significativamente más bajas después de la hemicolectomía derecha.LIMITACIONES:Debido al diseño transversal, aún faltan datos longitudinales.CONCLUSIONES:Se producen diferentes problemas de función intestinal a largo plazo después de la hemicolectomía derecha o izquierda, o la resección del colon sigmoide. Este último parece estar asociado con más estreñimiento que la hemicolectomía derecha o izquierda. La incontinencia de líquidos y la urgencia fecal parecen estar asociadas a la hemicolectomía derecha, lo que puede explicar el deterioro de la calidad de vida física y mental en general de estos pacientes. Consulte Video Resumen en http://links.lww.com/DCR/C13 . (Traducción-Dr. Yolanda Colorado ).

Recurrent Disease After Esophageal Cancer Surgery: A Substudy of The Dutch Nationwide Ivory Study.

OBJECTIVE: This study investigated the patterns, predictors, and survival of recurrent disease following esophageal cancer surgery. BACKGROUND: Survival of recurrent esophageal cancer is usually poor, with limited prospects of remission. METHODS: This nationwide cohort study included patients with distal esophageal and gastroesophageal junction adenocarcinoma and squamous cell carcinoma after curatively intended esophagectomy in 2007 to 2016 (follow-up until January 2020). Patients with distant metastases detected during surgery were excluded. Univariable and multivariable logistic regression were used to identify predictors of recurrent disease. Multivariable Cox regression was used to determine the association of recurrence site and treatment intent with postrecurrence survival. RESULTS: Among 4626 patients, 45.1% developed recurrent disease a median of 11 months postoperative, of whom most had solely distant metastases (59.8%). Disease recurrences were most frequently hepatic (26.2%) or pulmonary (25.1%). Factors significantly associated with disease recurrence included young age (≤65 y), male sex, adenocarcinoma, open surgery, transthoracic esophagectomy, nonradical resection, higher T-stage, and tumor positive lymph nodes. Overall, median postrecurrence survival was 4 months [95% confidence interval (95% CI): 3.6-4.4]. After curatively intended recurrence treatment, median survival was 20 months (95% CI: 16.4-23.7). Survival was more favorable after locoregional compared with distant recurrence (hazard ratio: 0.74, 95% CI: 0.65-0.84). CONCLUSIONS: This study provides important prognostic information assisting in the surveillance and counseling of patients after curatively intended esophageal cancer surgery. Nearly half the patients developed recurrent disease, with limited prospects of survival. The risk of recurrence was higher in patients with a higher tumor stage, nonradical resection and positive lymph node harvest.

Heterogeneity in Utilization of Optical Imaging Guided Surgery for Identifying or Preserving the Parathyroid Glands-A Meta-Narrative Review.

BACKGROUND: Postoperative hypoparathyroidism is the most common complication after total thyroidectomy. Over the past years, optical imaging techniques, such as parathyroid autofluorescence, indocyanine green (ICG) angiography, and laser speckle contrast imaging (LSCI) have been employed to save parathyroid glands during thyroid surgery. This study provides an overview of the utilized methods of the optical imaging techniques during total thyroidectomy for parathyroid gland identification and preservation. METHODS: PUBMED, EMBASE and Web of Science were searched for studies written in the English language utilizing parathyroid autofluorescence, ICG-angiography, or LSCI during total thyroidectomy to support parathyroid gland identification or preservation. Case reports, reviews, meta-analyses, animal studies, and post-mortem studies were excluded after the title and abstract screening. The data of the studies were analyzed qualitatively, with a focus on the methodologies employed. RESULTS: In total, 59 articles were included with a total of 6190 patients. Overall, 38 studies reported using parathyroid autofluorescence, 24 using ICG-angiography, and 2 using LSCI. The heterogeneity between the utilized methodology in the studies was large, and in particular, regarding study protocols, imaging techniques, and the standardization of the imaging protocol. CONCLUSION: The diverse application of optical imaging techniques and a lack of standardization and quantification leads to heterogeneous conclusions regarding their clinical value. Worldwide consensus on imaging protocols is needed to establish the clinical utility of these techniques for parathyroid gland identification and preservation.

A Standardized Framework for Fluorescence-Guided Margin Assessment for Head and Neck Cancer Using a Tumor Acidosis Sensitive Optical Imaging Agent.

PURPOSE: Intra-operative management of the surgical margin in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) remains challenging as surgeons still have to rely on visual and tactile information. Fluorescence-guided surgery using tumor-specific imaging agents can assist in clinical decision-making. However, a standardized imaging methodology is lacking. In this study, we determined whether a standardized, specimen-driven, fluorescence imaging framework using ONM-100 could assist in clinical decision-making during surgery. PROCEDURES: Thirteen patients with histologically proven HNSCC were included in this clinical study and received ONM-100 24 ± 8 h before surgery. Fluorescence images of the excised surgical specimen and of the surgical cavity were analyzed. A fluorescent lesion with a tumor-to-background ratio (TBR) > 1.5 was considered fluorescence-positive and correlated to standard of care (SOC) histopathology. RESULTS: All six tumor-positive surgical margins were detected immediately after excision using fluorescence-guided intra-operative imaging. Postoperative analysis showed a median TBR (±IQR) of the fluorescent lesions on the resection margin of 3.36 ± 1.62. Three fluorescence-positive lesions in the surgical cavity were biopsied and showed occult carcinoma and severe dysplasia, and a false-positive fluorescence lesion. CONCLUSION: Our specimen-driven fluorescence framework using a novel, pH-activatable, fluorescent imaging agent could assist in reliable and real-time adequate clinical decision-making showing that a fluorescent lesion on the surgical specimen with a TBR of 1.5 is correlated to a tumor-positive resection margin. The binary mechanism of ONM-100 allows for a sharp tumor delineation in all patients, giving the surgeon a clinical tool for real-time margin assessment, with a high sensitivity.

Non-adherence to consensus guidelines on preoperative imaging in surgery for primary hyperparathyroidism.

OBJECTIVE: The aim of this study was to determine the adherence to consensus guidelines on preoperative imaging of patients with primary hyperparathyroidism (pHPT) in real local practice. METHODS: This was a retrospective multicenter cohort study of 411 patients undergoing parathyroidectomy for pHPT from 2007 to 2017 in three referral centers. RESULTS: In 286/411 patients (69%) the preoperative imaging workup adhered to guidelines (utilizing ultrasound and parathyroid scintigraphy). In patients in whom guidelines were followed 63% were discharged within one day versus 37% in whom guidelines were not followed (P < .0005). The use of a bimodality imaging workup, starting with ultrasound and parathyroid scintigraphy followed by imaging upscaling aiming for anatomical and functional concordance, was a predictor for the performance of a minimally invasive parathyroidectomy (OR 4.098, 95% CI 2.296-7.315, P < .0005). CONCLUSION: The level of compliance to preoperative imaging guidelines is suboptimal in this population. Patients in whom adherence was achieved showed a shorter length of stay. More education of physicians is required regarding the appropriate preoperative imaging workup in pHPT. LEVEL OF EVIDENCE: 2b (individual cohort study).

Patient-Derived Papillary Thyroid Cancer Organoids for Radioactive Iodine Refractory Screening.

Patients with well-differentiated thyroid cancer, especially papillary thyroid cancer (PTC), are treated with surgical resection of the thyroid gland. This is followed by post-operative radioactive iodine (I131), resulting in total thyroid ablation. Unfortunately, about 15-33% of PTC patients are unable to take up I131, limiting further treatment options. The aim of our study was to develop a cancer organoid model with the potential for pre-treatment diagnosis of these I131-resistant patients. PTC tissue from thirteen patients was used to establish a long-term organoid model. These organoids showed a self-renewal potential for at least five passages, suggesting the presence of cancer stem cells. We demonstrated that thyroid specific markers, a PTC marker, and transporters/receptors necessary for iodine uptake and thyroid hormone production were expressed on a gene and protein level. Additionally, we cultured organoids from I131-resistant PTC material from three patients. When comparing PTC organoids to radioactive iodine (RAI)-refractory disease (RAIRD) organoids, a substantial discordance on both a protein and gene expression level was observed, indicating a treatment prediction potential. We showed that patient-derived PTC organoids recapitulate PTC tissue and a RAIRD phenotype. Patient-specific PTC organoids may enable the early identification of I131-resistant patients, in order to reduce RAI overtreatment and its many side effects for thyroid cancer patients.

Angiosarcomatous transdifferentiation of metastatic melanoma.

Melanoma is known to show considerable variation in its histopathological presentation. In exceptional cases, heterologous or divergent differentiation (metaplastic melanoma) can be observed. We report a case of a 69-year-old man who was diagnosed with nodular melanoma on the right upper leg. One year later, the patient presented with an inguinal lymph node metastasis and a lymph node dissection was carried out. In two out of five positive lymph nodes, an angiosarcomatous component was found next to a conventional melanoma component. Shortly after, the patient developed two in-transit metastases in which again an angiosarcomatous component was seen. The vascular component stained positive for ERG and CD31 and negative for melanocytic markers (Mart-1, S100, SOX-10), while the conventional melanoma had an opposite staining pattern. Molecular analysis on both components showed an identical mutation in the NRAS gene, which in our opinion proves the divergent differentiation. To the best of our knowledge, this is the first case report describing angiosarcomatous transdifferentiation of melanoma.

Implementation and benchmarking of a novel analytical framework to clinically evaluate tumor-specific fluorescent tracers.

During the last decade, the emerging field of molecular fluorescence imaging has led to the development of tumor-specific fluorescent tracers and an increase in early-phase clinical trials without having consensus on a standard methodology for evaluating an optical tracer. By combining multiple complementary state-of-the-art clinical optical imaging techniques, we propose a novel analytical framework for the clinical translation and evaluation of tumor-targeted fluorescent tracers for molecular fluorescence imaging which can be used for a range of tumor types and with different optical tracers. Here we report the implementation of this analytical framework and demonstrate the tumor-specific targeting of escalating doses of the near-infrared fluorescent tracer bevacizumab-800CW on a macroscopic and microscopic level. We subsequently demonstrate an 88% increase in the intraoperative detection rate of tumor-involved margins in primary breast cancer patients, indicating the clinical feasibility and support of future studies to evaluate the definitive clinical impact of fluorescence-guided surgery.

Validation and update of a lymph node metastasis prediction model for breast cancer.

PURPOSE: This study aimed to validate and update a model for predicting the risk of axillary lymph node (ALN) metastasis for assisting clinical decision-making. METHODS: We included breast cancer patients diagnosed at six Dutch hospitals between 2011 and 2015 to validate the original model which includes six variables: clinical tumor size, tumor grade, estrogen receptor status, lymph node longest axis, cortical thickness and hilum status as detected by ultrasonography. Subsequently, we updated the original model using generalized linear model (GLM) tree analysis and by adjusting its intercept and slope. The area under the receiver operator characteristic curve (AUC) and calibration curve were used to assess the original and updated models. Clinical usefulness of the model was evaluated by false-negative rates (FNRs) at different cut-off points for the predictive probability. RESULTS: Data from 1416 patients were analyzed. The AUC for the original model was 0.774. Patients were classified into four risk groups by GLM analysis, for which four updated models were created. The AUC for the updated models was 0.812. The calibration curves showed that the updated model predictions were better in agreement with actual observations than the original model predictions. FNRs of the updated models were lower than the preset 10% at all cut-off points when the predictive probability was less than 12.0%. CONCLUSIONS: The original model showed good performance in the Dutch validation population. The updated models resulted in more accurate ALN metastasis prediction and could be useful preoperative tools in selecting low-risk patients for omission of axillary surgery.

Prospective study of sentinel node biopsy for high-risk cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Nodal metastasis from cutaneous squamous cell carcinoma (SCC) is poorly predicted clinically and is associated with a high mortality rate. METHODS: From 2010 to 2013, patients with high-risk cutaneous SCC were assessed with sentinel node biopsy (SNB) either at the time of primary cutaneous tumor resection or at secondary wide local excision. RESULTS: Of 57 patients, 8 (14%) had nodal metastasis. Significant predictors of metastasis are the number of high-risk factors (p = .008), perineural invasion (PNI; p = .05), and lymphovascular invasion (LVI; p = .05). During a mean of 19.4 months, 9 patients developed recurrence and 6 died of cutaneous SCC, indicating that over 1300 patients would be required for a randomized controlled trial with 80% power to detect a significant difference in disease-free survival. CONCLUSION: Lymph node metastasis occurs in 14% of patients with high-risk cutaneous SCC. Larger studies will be required to identify which "high-risk" factors should be considered as an indication for surgical assessment of the nodal basin. © 2015 Wiley Periodicals, Inc. Head Neck 38: E884-E889, 2016.

Cutaneous head and neck squamous cell carcinoma with regional metastases: the prognostic importance of soft tissue metastases and extranodal spread.

BACKGROUND: Extranodal spread (ENS) is an established adverse prognostic factor in metastatic cutaneous squamous cell carcinoma (cSCC); however, the clinical significance of soft tissue metastases (STM) is unknown. The aim of this study was to evaluate the prognosis of patients with STM from head and neck cSCC, and to compare this with that of node metastases with and without ENS. METHODS: Patients with cSCC metastatic to the parotid and/or neck treated by primary surgical resection between 1987 and 2007 were included. Metastatic nodes >3 cm in size were an exclusion criterion. A Cox proportional hazard model was used to determine the effect of STM adjusting for other relevant prognostic factors. RESULTS: The population included 164 patients with a median follow-up of 26 months. There were 8 distant and 37 regional recurrences. There were 22 were cancer-specific deaths, and 29 patients died. STM was a significant predictor of reduced overall (hazard ratio 3.3; 95% confidence interval 1.6-6.4; P = 0.001) and disease-free survival (hazard ratio 2.4; 95% confidence interval 1.4-4.1; P = 0.001) when compared to patients with node disease with or without ENS. After adjusting for covariates, STM and number of involved nodes were significant independent predictors of overall and disease-free survival. CONCLUSIONS: In metastatic cSCC of the head and neck, the presence of STM is an independent predictor of reduced survival and is associated with a greater adverse effect than ENS alone.

Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results.

The prognosis in advanced-stage ovarian cancer remains poor. Tumor-specific intraoperative fluorescence imaging may improve staging and debulking efforts in cytoreductive surgery and thereby improve prognosis. The overexpression of folate receptor-α (FR-α) in 90-95% of epithelial ovarian cancers prompted the investigation of intraoperative tumor-specific fluorescence imaging in ovarian cancer surgery using an FR-α-targeted fluorescent agent. In patients with ovarian cancer, intraoperative tumor-specific fluorescence imaging with an FR-α-targeted fluorescent agent showcased the potential applications in patients with ovarian cancer for improved intraoperative staging and more radical cytoreductive surgery.

Enhancing surgical vision by using real-time imaging of αvß3-integrin targeted near-infrared fluorescent agent.

BACKGROUND: This study was designed to improve the surgical procedure and outcome of cancer surgery by means of real-time molecular imaging feedback of tumor spread and margin delineation using targeted near-infrared fluorescent probes with specificity to tumor biomarkers. Surgical excision of cancer often is confronted with difficulties in the identification of cancer spread and the accurate delineation of tumor margins. Currently, the assessment of tumor borders is afforded by postoperative pathology or, less reliably, intraoperative frozen sectioning. Fluorescence imaging is a natural modality for intraoperative use by directly relating to the surgeon's vision and offers highly attractive characteristics, such as high-resolution, sensitivity, and portability. Via the use of targeted probes it also becomes highly tumor-specific and can lead to significant improvements in surgical procedures and outcome. METHODS: Mice bearing xenograft human tumors were injected with αvß3-integrin receptor-targeted fluorescent probe and in vivo visualized by using a novel, real-time, multispectral fluorescence imaging system. Confirmatory ex vivo imaging, bioluminescence imaging, and histopathology were used to validate the in vivo findings. RESULTS: Fluorescence images were all in good correspondence with the confirming bioluminescence images in respect to signal colocalization. Fluorescence imaging detected all tumors and successfully guided total tumor excision by effectively detecting small tumor residuals, which occasionally were missed by the surgeon. Tumor tissue exhibited target-to-background ratio of ~4.0, which was significantly higher compared with white-light images representing the visual contrast. Histopathology confirmed the capability of the method to identify tumor negative margins with high specificity and better prediction rate compared with visual inspection. CONCLUSIONS: Real-time multispectral fluorescence imaging using tumor specific molecular probes is a promising modality for tumor excision by offering real time feedback to the surgeon in the operating room.