A randomized phase II trial on the addition of dutasteride to combined androgen blockade therapy versus combined androgen blockade therapy alone in patients with advanced or metastatic salivary duct carcinoma - the DUCT study protocol.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients. METHODS: This prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome. DISCUSSION: The DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial's findings could be readily applied into clinical practice. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022. PROTOCOL VERSION: Current protocol version 4.0, February 21, 2024.

[18F]FDG-PET/CT to prevent futile surgery in indeterminate thyroid nodules: a blinded, randomised controlled multicentre trial.

PURPOSE: To assess the impact of an [18F]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology. METHODS: In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [18F]FDG-PET/CT and were randomised to an [18F]FDG-PET/CT-driven or diagnostic surgery group. In the [18F]FDG-PET/CT-driven group, management was based on the [18F]FDG-PET/CT result: when the index nodule was visually [18F]FDG-positive, diagnostic surgery was advised; when [18F]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hürthle cell and Hürthle cell nodules. RESULTS: Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32-53%]) of patients in the [18F]FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68-93%]) in the diagnostic surgery group (p < 0.001). [18F]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28-53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33-63%]) in non-Hürthle cell and 13% (2/15 [95% CI, 2-40%]) in Hürthle cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [18F]FDG-PET/CT were 94.1% (80.3-99.3%), 39.8% (30.0-50.2%), 95.1% (83.5-99.4%), 35.2% (25.4-45.9%), and 31.1% (23.3-39.7%), respectively. CONCLUSION: An [18F]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hürthle cell nodules. TRIAL REGISTRATION NUMBER: This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544 .

Impact of optimizing diagnostic workup and reducing the time to treatment in head and neck cancer.

BACKGROUND: Timely and efficient diagnostic workup of patients with head and neck cancer (HNC) is challenging. This observational study describes the implementation of an optimized multidisciplinary oncological diagnostic workup for patients with HNC and its impact on diagnostic and treatment intervals, survival, costs, and patient satisfaction. METHODS: All patients with newly diagnosed HNC who underwent staging and treatment at the Radboud University Medical Center were included. Conventional workup (CW) in 2009 was compared with the fast-track, multidisciplinary, integrated care program, that is, optimized workup (OW), as implemented in 2014. RESULTS: The study included 486 patients with HNC (218 with CW and 268 with OW). The time-to-treatment interval was significantly lower in the OW cohort than the CW cohort (21 vs 34 days; P < .0001). The 3-year overall survival rate was 12% higher after OW (72% in the CW cohort vs 84% in the OW cohort; P = .002). After correction for confounders, the 3-year risk of death remained significantly lower in the OW cohort (hazard ratio, 1.73; 95% confidence interval, 1.14-2.63; P = .010). Total diagnostic costs were comparable in the 2 cohorts. The general satisfaction score, as measured with the Consumer Quality Index for Oncological Care, was significantly better in a matched OW group than the CW group (9.1 vs 8.5; P = .007). CONCLUSIONS: After the implementation of a fast-track, multidisciplinary, integrated care program, the time-to-treatment interval was significantly reduced. Overall survival and patient satisfaction increased significantly, whereas costs did not change. This demonstrates the impact and improved quality of care achieved by efficiently organizing the diagnostic phase of HNC management.

MRI evaluation of vulvar squamous-cell carcinoma in fresh radical local excision specimens for cancer localization and prediction of surgical tumor-free margins.

In the surgical treatment of vulvar squamous-cell carcinoma (VSCC), tumor-free margins of 8 mm or more are considered adequate. However, limited perioperative information on the tumor-free margins other than the surgeon's own estimation is available. The purpose of this study was therefore to investigate the feasibility of ex vivo MRI in localizing VSCC and to assess the surgical tumor-free margins in fresh radical local excision (RLE) specimens to guide the surgeon during resections. Nine patients with biopsy-proven VSCC scheduled for RLE were prospectively included. Intact fresh specimens were scanned using a 7 T preclinical MR-scanner. Whole mount H&E-stained slides were obtained every 3 mm and correlated with ex vivo MRI. A pathologist annotated VSCC and minimal tumor-free margins (3 o'clock, 9 o'clock, basal) on the digitalized histological slides. An observer with knowledge of histology (the non-blinded annotation) and a radiologist blinded to histology (the blinded annotation) separately performed annotation of the same features on ex vivo MRI. Linear correlation and agreement of the ex vivo MRI measurements with histology were assessed. Diagnostic performance for VSCC localization and identification of margins less than 8 mm was expressed as positive and negative predictive values (PPV, NPV). In 153 matched ex vivo MRI slices, the observer correctly identified 79/91 margins as less than 8 mm (PPV 87%) and 110/124 margins as 8 mm or greater (NPV 89%). The radiologist correctly annotated absence of VSCC in 73/81 (NPV 90%) and presence in 65/72 (PPV 90%) slices. Sixty-four of 90 margins were correctly identified as less than 8 mm (PPV 71%) and 83/102 margins as 8 mm or greater (NPV 81%). Both non-blinded and blinded annotations were linearly correlated and demonstrated good agreement with histology. Accurate localization of VSCC and measurements of the surgical tumor-free margins in fresh RLE specimens using ex vivo MRI seems feasible. High diagnostic performance in VSCC localization and identification of margins less than 8 mm suggest ex vivo MRI to be clinically applicable.

NRAS mutations are more prevalent than KIT mutations in melanoma of the female urogenital tract--a study of 24 cases from the Netherlands.

OBJECTIVE: The aim of this study was to evaluate a series of primary melanomas of the female urogenital tract for oncogenic mutations in KIT, NRAS and BRAF in order to identify patients who may be amenable to targeted therapy. METHODS: We reviewed twenty-four cases of female urogenital tract melanomas and used Sanger sequencing analysis for the detection of oncogenic mutations in exons 9, 11, 13, and 17 of KIT; exons 2 and 3 of NRAS; and exon 15 of BRAF. RESULTS: Twenty-four patients were included: fourteen vaginal melanomas, four cervical melanomas, five urethral melanomas and one vulvar melanoma. NRAS mutations (4/24, 21%) were more prevalent than KIT mutations (1/24, 4%), while BRAF mutations were absent. Three of four NRAS mutations were present in vaginal melanomas (21%), mainly affecting codon 61 (3/4). They were mutually exclusive with the KIT mutation. The KIT mutation was present in a vaginal melanoma and affected exon 17. CONCLUSIONS: Melanomas of the female urogenital tract relatively commonly harbor mutations in NRAS; this makes NRAS an interesting therapeutic target for these patients in the advanced setting. KIT mutations were rare in our study in contrast to some previous reports. We cannot exclude that anatomical site-related differences and/or population related differences in KIT mutation frequency exist within urogenital tract melanomas.

Digoxin treatment does not reinduce radioiodine uptake in radioiodine refractory non-medullary thyroid carcinoma.

Objective: Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so-called redifferentiation, are promising but not suitable for all patients. Preclinical studies, in human cell lines just as in a murine model, have shown that the cardiac glycoside digoxin restored RAI uptake. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI-refractory NMTC. Methods: Eight patients with metastasized RAI-refractory NMTC were included between November 2022 and June 2023. Before treatment, a baseline [123I]NaI scintigraphy was performed. Thereafter, patients were treated with digoxin for 3 weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After 1 week, the digoxin plasma concentration was measured, and the digoxin dose was adjusted if necessary. After 3 weeks of digoxin treatment, a second [123I]NaI scintigraphy was performed. RAI uptake was compared between the two scintigraphies. Results: Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial. Conclusion: Contrary to results from preclinical trials, in this trial, 3 weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach toward optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.

Molecular Diagnostics and [18F]FDG-PET/CT in Indeterminate Thyroid Nodules: Complementing Techniques or Waste of Valuable Resources?

Background: An accurate preoperative workup of cytologically indeterminate thyroid nodules (ITN) may rule out malignancy and avoid diagnostic surgery for benign nodules. This study assessed the performance of molecular diagnostics (MD) and 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG)-positron emission tomography/computed tomography (PET/CT) in ITN, including their combined use, and explored whether molecular alterations drive the differences in [18F]FDG uptake among benign nodules. Methods: Adult, euthyroid patients with a Bethesda III or IV thyroid nodule were prospectively included in this multicenter study. They all underwent MD and an [18F]FDG-PET/CT scan of the neck. MD was performed using custom next-generation sequencing panels for somatic mutations, gene fusions, and copy number alterations and loss of heterozygosity. Sensitivity, specificity, negative and positive predictive value (NPV, PPV), and benign call rate (BCR) were assessed for MD and [18F]FDG-PET/CT separately and for a combined approach using both techniques. Results: In 115 of the 132 (87%) included patients, MD yielded a diagnostic result on cytology. Sensitivity, specificity, NPV, PPV, and BCR were 80%, 69%, 91%, 48%, and 57% for MD, and 93%, 41%, 95%, 36%, and 32% for [18F]FDG-PET/CT, respectively. When combined, sensitivity and specificity were 95% and 44% for a double-negative test (i.e., negative MD plus negative [18F]FDG-PET/CT) and 68% and 86% for a double-positive test, respectively. Concordance was 63% (82/130) between MD and [18F]FDG-PET/CT. There were more MD-positive nodules among the [18F]FDG-positive benign nodules (25/59, 42%, including 11 (44%) isolated RAS mutations) than among the [18F]FDG-negative benign nodules (7/30, 19%, p = 0.02). In oncocytic ITN, the BCR of [18F]FDG-PET/CT was mere 3% and MD was the superior technique. Conclusions: MD and [18F]FDG-PET/CT are both accurate rule-out tests when unresected nodules that remain unchanged on ultrasound follow-up are considered benign. It may vary worldwide which test is considered most suitable, depending on local availability of diagnostics, expertise, and cost-effectiveness considerations. Although complementary, the benefits of their combined use may be confined when therapeutic consequences are considered, and should therefore not routinely be recommended. In nononcocytic ITN, sequential testing may be considered in case of a first-step MD negative test to confirm that withholding diagnostic surgery is oncologically safe. In oncocytic ITN, after further validation studies, MD might be considered. Clinical Trial Registration: This trial is registered with ClinicalTrials.gov: NCT02208544 (August 5, 2014), https://clinicaltrials.gov/ct2/show/NCT02208544.

Lutetium-177-PSMA therapy for recurrent/metastatic salivary gland cancer: a prospective pilot study.

There is an urgent need for novel systemic therapies for recurrent/systemic salivary gland cancer, as current treatment options are scarce. [68Ga]Ga-PSMA-11 PET/CT revealed relevant uptake of prostate-specific membrane antigen (PSMA) in adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC). Therefore, we assessed the safety, feasibility, efficacy and radiation dosimetry of [177Lu]Lu-PSMA-I&T treatment in AdCC and SDC patients in a prospective pilot study. Methods: This single-center, single-arm study intended to include 10 recurrent/metastatic AdCC patients and five recurrent/metastatic SDC patients. AdCC patients could only participate in case of progressive and/or symptomatic disease. Patients required ≥ 1 lesion ≥ 1.5 cm with an SUVmax on [68Ga]Ga-PSMA-11 PET/CT above liver SUVmean. Patients were planned to receive four cycles ~ 7.4 GBq [177Lu]Lu-PSMA-I&T. In case of progressive disease per RECIST 1.1 at mid-treatment evaluation after two cycles, treatment was discontinued. Safety was the primary endpoint. Secondary endpoints included objective response rate (ORR), tumor- and organ-absorbed radiation doses and progression-free survival. Results: After screening, 10 out of 15 (67%) AdCC and two out of 10 (20%) SDC patients were eligible. Two patients (17%) demonstrated grade 3 treatment-related toxicity: lymphocytopenia (8%) and hyponatremia (8%). No dose-limiting toxicities occurred. In the AdCC cohort, six patients (60%) completed the four treatment cycles. Due to progressive disease, treatment was discontinued after two cycles in three patients (30%) and after one cycle in one patient (10%). No objective responses were observed (ORR: 0%). Three AdCC patients (30%) showed stable disease ≥ 6 months (7, 17 and 23 months). None of the two SDC patients completed the treatment: one patient deteriorated after the first cycle, while the other had progressive disease after two cycles. The high screen failure rate due to insufficient PSMA uptake resulted in premature closure of the SDC cohort. Dosimetry revealed low tumor-absorbed doses (median 0.07 Gy/GBq, range 0.001-0.63 Gy/GBq). Conclusions: [177Lu]Lu-PSMA-I&T in AdCC and SDC patients was safe and generally well-tolerated. However, efficacy was limited, likely due to low tumor-absorbed doses. For SDC, [177Lu]Lu-PSMA-I&T appears unfeasible due to insufficient PSMA uptake.

One-day core needle biopsy in a breast clinic: 4 years experience.

Many attempts have been made to combine the high diagnostic accuracy and conclusive rate of core needle biopsy (CNB) with the speed of fine needle aspiration cytology in evaluation of solid breast lesions. Multiple hybrid techniques have been developed to achieve this. We describe a cohort of patients for whom we used a relatively new, accelerated method of CNB processing, allowing for a definitive diagnosis the same day. All patients visiting the Radboud University Nijmegen Medical Centre breast clinic during a 4-year period were reviewed to identify all CNBs in this period performed in a same-day diagnosis track. CNB result was compared to post-operative pathology reports when available, and to follow-up when patients were not surgically treated. 1,060 patients underwent CNB of 1,383 lesions, 898 of which in a same-day diagnosis track with a sensitivity of 96.9 % and a specificity of 99.4 %. The inconclusive rate was 9.2 %. For a same-day diagnosis for solid breast lesions, we could give a conclusive diagnosis with accelerated CNB processing in 65 % of our patients requiring CNB. This technique can be used reliably in a same-day diagnosis breast clinic with a very high sensitivity, specificity, and conclusive rate.

Interobserver variability and the effect of education in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia.

No published data concerning intraobserver and interobserver variability in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia (DVIN) are available, although it is widely accepted to be a subtle and difficult histopathological diagnosis. In this study, the reproducibility of the histopathological diagnosis of DVIN is evaluated. Furthermore, we investigated the possible improvement of the reproducibility after providing guidelines with histological characteristics and tried to identify histological characteristics that are most important in the recognition of DVIN. A total number of 34 hematoxylin and eosin-stained slides were included in this study and were analyzed by six pathologists each with a different level of education. Slides were reviewed before and after studying a guideline with histological characteristics of DVIN. Kappa statistics were used to compare the interobserver variability. Pathologists with a substantial agreement were asked to rank items by usefulness in the recognition of DVIN. The interobserver agreement during the first session varied between 0.08 and 0.54, which slightly increased during the second session toward an agreement between -0.01 and 0.75. Pathologists specialized in gynecopathology reached a substantial agreement (kappa 0.75). The top five of criteria indicated to be the most useful in the diagnosis of DVIN included: atypical mitosis in the basal layer, basal cellular atypia, dyskeratosis, prominent nucleoli and elongation and anastomosis of rete ridges. In conclusion, the histopathological diagnosis of DVIN is difficult, which is expressed by low interobserver agreement. Only in experienced pathologists with training in gynecopathology, kappa values reached a substantial agreement after providing strict guidelines. Therefore, it should be considered that specimens with an unclear diagnosis and/or clinical suspicion for DVIN should be revised by a pathologist specialized in gynecopathology. When adhering to suggested criteria the diagnosis of DVIN can be made easier.

Precision oncology using organoids of a secretory carcinoma of the salivary gland treated with TRK-inhibitors.

The use of anticancer drugs targeting specific molecular tumor characteristics is rapidly increasing in clinical practice, but selecting patients to benefit from these remains a challenge. It has been suggested that organoid cultures would be ideally suited to test drug responses in vitro. Here we describe and characterize in depth a case of ETV6-NTRK3 gene fusion-positive secretory carcinoma of the salivary glands and corresponding organoid cultures that responded and subsequently acquired resistance to TRK targeting therapy with larotrectinib. This case-culture-characterization illustrates the advances made in precision oncology, but also exposes important caveats in using organoids to predict treatment response.

Results of histopathological revisions of major salivary gland neoplasms in routine clinical practice.

AIMS: Salivary gland neoplasms are rare and are characterised by overlapping histopathological aspects. Therefore, the assessment of the correct histopathological diagnosis can be challenging. This study evaluated the frequency of pathology consultations and revisions for salivary gland neoplasms during routine clinical practice in the Netherlands. Furthermore, the concordance and discordance rates of these revisions are presented. METHODS: The Dutch Pathology Registry (PALGA) was searched for patients that underwent a resection of a major salivary gland neoplasm between 2006 and 2016. Frequencies of pathology consultations and revisions are presented and, in order to calculate the rates of concordance and discordance, the results of the initial histopathological review were compared with the results of the revision. RESULTS: Between 2006 and 2016, 13 441 major salivary gland neoplasms were resected in the Netherlands. 90% (n=12 082) of these tumours were diagnosed as benign and 10% (n=1359) as malignant. The initial pathologist requested a consultation in 3.3% of resections (n=439). Revision of the histopathological specimen was performed in 2.6% (n=350) of cases. Revisions were discordant in 8.3%; including 5.8% of the initially benign diagnosed lesions reclassified as malignant by the second expert pathologist and 8% of the revised malignant tumours that underwent a subtype change. CONCLUSIONS: The number of discordant histopathological revisions (8.3%) emphasises the complexity of the histopathological diagnosis of salivary gland neoplasms. An increase in consultations may improve the accuracy of the initial diagnosis and thus treatment in salivary gland tumours while lowering the need for revisions and the number of discordant revisions.

[18F]FDG Uptake and Expression of Immunohistochemical Markers Related to Glycolysis, Hypoxia, and Proliferation in Indeterminate Thyroid Nodules.

PURPOSE: The current study explored the association between 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) uptake and the quantitative expression of immunohistochemical markers related to glucose metabolism, hypoxia, and cell proliferation in benign and malignant thyroid nodules of indeterminate cytology. PROCEDURES: Using a case-control design, 24 patients were selected from participants of a randomized controlled multicenter trial (NCT02208544) in which [18F]FDG-PET/CT and thyroid surgery were performed for Bethesda III and IV nodules. Three equally sized groups of [18F]FDG-positive malignant, [18F]FDG-positive benign, and [18F]FDG-negative benign nodules were included. Immunohistochemical staining was performed for glucose transporters (GLUT) 1, 3, and 4; hexokinases (HK) 1 and 2; hypoxia-inducible factor-1 alpha (HIF1α; monocarboxylate transporter 4 (MCT4); carbonic anhydrase IX (CA-IX); vascular endothelial growth factor (VEGF); sodium-iodide symporter (NIS); and Ki-67. Marker expression was scored using an immunoreactive score. Unsupervised cluster analysis was performed. The immunoreactive score was correlated to the maximum and peak standardized uptake values (SUVmax, SUVpeak) and SUVmax ratio (SUVmax of nodule/background SUVmax of contralateral, normal thyroid) of the [18F]FDG-PET/CT using the Spearman's rank correlation coefficient and compared between the three groups using Kruskal-Wallis tests. RESULTS: The expression of GLUT1, GLUT3, HK2, and MCT4 was strongly positively correlated with the SUVmax, SUVpeak, and SUVmax ratio. The expression of GLUT1 (p = 0.009), HK2 (p = 0.02), MCT4 (p = 0.01), and VEGF (p = 0.007) was statistically significantly different between [18F]FDG-positive benign nodules, [18F]FDG-positive thyroid carcinomas, and [18F]FDG-negative benign nodules. In both [18F]FDG-positive benign nodules and [18F]FDG-positive thyroid carcinomas, the expression of GLUT1, HK2, and MCT4 was increased as compared to [18F]FDG-negative benign nodules. VEGF expression was higher in [18F]FDG-positive thyroid carcinomas as compared to [18F]FDG-negative and [18F]FDG-positive benign nodules. CONCLUSIONS: Our results suggest that [18F]FDG-positive benign thyroid nodules undergo changes in protein expression similar to those in thyroid carcinomas. To expand the understanding of the metabolic changes in benign and malignant thyroid nodules, further research is required, including correlation with underlying genetic alterations.

European experience with the Afirma Gene Expression Classifier for indeterminate thyroid nodules: A clinical utility study in the Netherlands.

BACKGROUND: The Gene Expression Classifier (GEC) and Genomic Sequencing Classifier (GSC) were developed to improve risk stratification of indeterminate nodules. Our aim was to assess the clinical utility in a European population with restrictive diagnostic workup. METHODS: Clinical utility of the GEC was assessed in a prospective multicenter cohort of 68 indeterminate nodules. Diagnostic surgical rates for Bethesda III and IV nodules were compared to a historical cohort of 171 indeterminate nodules. Samples were post hoc tested with the GSC. RESULTS: The GEC classified 26% as benign. Surgical rates between the prospective and historical cohort did not differ (72.1% vs. 76.6%). The GSC classified 59% as benign, but misclassified six malignant lesions as benign. CONCLUSION: Implementation of GEC in management of indeterminate nodules in a European country with restrictive diagnostic workup is currently not supported, especially in oncocytic nodules. Prospective studies with the GSC in European countries are needed to determine the clinical utility.

Validation of the Milan System for Reporting Salivary Gland Cytopathology and the diagnostic accuracy of FNA cytology for submandibular gland lesions.

BACKGROUND: The Milan System for Salivary Gland Cytopathology (MSRSGC) is a categorical system for salivary gland fine-needle aspiration cytopathology (FNAC) developed to aid clinicians in the management of salivary gland lesions. This classification is widely studied and validated, especially in cohorts that consist of mostly parotid gland lesions. However, only sparse literature describes the use of this classification for submandibular gland lesions in particular. METHODS: All patients in the Netherlands that underwent a submandibular gland resection between January 1, 2006, and January 1, 2017, with a FNAC before resection were identified with the use of the Dutch Pathology Registry database (PALGA). All FNAC results were retrospectively classified according to the MSRSGC. The risk of malignancy was calculated for all the MSRSGC categories. The sensitivity and specificity of the MSRSGC classification were calculated for submandibular gland FNAC. RESULTS: A total of 837 patients who underwent 975 FNAC aspirates from the submandibular glands were included in the analysis. Risks of malignancy for each of the MSRSGC categories were 14.4% in nondiagnostic, 4.4% in nonneoplastic, 37.0% in atypia of unknown significance, 3.9% in benign neoplasms, 40.7% in salivary gland neoplasms of unknown malignant potential, 76.2% in suspected malignant, and 91.3% in malignant cytology results. The sensitivity for diagnosing malignant submandibular gland tumors was 71.6% and specificity was 98.4%. CONCLUSIONS: The results of the present study validate the use of this classification for submandibular gland lesions. Risks of malignancy vary according to the anatomical subsites of the salivary gland lesions. LAY SUMMARY: The risks of malignancy of the various Milan System for Salivary Gland Cytopathology (MSRSGC) categories vary according to the anatomical subsite of the salivary gland lesion. The proposed management techniques of the MSRSGC are valid for use with submandibular gland lesions.

Development and characterization of patient-derived salivary gland cancer organoid cultures.

OBJECTIVE: Three-dimensional organoid cell cultures have been established for a variety of human cancers. For most rare cancers, including salivary gland cancer (SGC), these models are lacking, despite the great unmet need to study cancer biology in these diseases. Therefore, we aimed to develop patient-derived organoid (PDO) models for different subtypes of SGC. METHODS: Tumor samples of SGC patients were processed and embedded in Matrigel. Successful PDOs (expandable > 1*106 cells) were phenotypically characterized using immunohistochemistry (IHC) and genotypically by gene fusion analysis and by targeted and whole-exome sequencing. Successfully established PDOs were subjected to small-scale drug screening. RESULTS: Out of 37 attempts, 7 viable short-term PDOs were established (19 % success rate; 3 salivary duct carcinoma, 3 adenoid cystic carcinoma and 1 mucoepidermoid carcinoma). Each PDO showed close phenotypical mimicry to parental tissue. Genotypic characterization revealed that in each PDO > 97.6 % of all COSMIC annotated variants and all MYB, MYBL1 and NFIB gene rearrangements were retained. Drug screening was proven feasible in all PDOs. CONCLUSION: We present the first comprehensively characterized short-term SGC PDO models for three subtypes of SGC with close phenotypic and genotypic resemblance to parental tissue, which can be used for drug screening applications.

High-Accuracy Nodal Staging of Head and Neck Cancer With USPIO-Enhanced MRI: A New Reading Algorithm Based on Node-to-Node Matched Histopathology.

OBJECTIVES: Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) is a potential diagnostic tool for lymph node assessment in patients with head and neck cancer. Validation by radiologic-pathologic correlation is essential before the method is evaluated in clinical studies. In this study, MRI signal intensity patterns of lymph nodes are correlated to their histopathology to develop a new USPIO-enhanced MRI reading algorithm that can be used for nodal assessment in head and neck cancer patients. MATERIALS AND METHODS: Ten head and neck cancer patients underwent in vivo USPIO-enhanced MRI before neck dissection. An ex vivo MRI of the neck dissection specimen was performed for precise coregistration of in vivo MRI with histopathology. Normal clinical histopathological workup was extended with meticulous matching of all lymph nodes regarded as potentially metastatic based on their in vivo MRI signal intensity pattern. On the basis of histopathology of resected nodes, in vivo MRI signal characteristics were defined separating benign from malignant lymph nodes. RESULTS: Fifteen of 34 node-to-node correlated lymph nodes with remaining signal intensity on T2*-weighted MRI were histopathologically metastatic and 19 were benign. Radiological analysis revealed that metastatic lymph nodes showed equal or higher MRI signal intensity when compared with lipid tissue on T2*-weighted MGRE sequence (15/16 lymph nodes; 94%), whereas healthy lymph nodes showed lower (17/19 lymph nodes; 89%) or complete attenuation of signal intensity (273/279; 98%) when compared with lipid tissue on T2*-weighted MGRE. Histopathology of all resected specimens identified 392 lymph nodes. Six lymph nodes with (micro)metastases were missed with in vivo MRI. Whether these 6 lymph nodes were correlated to a nonmalignant lymph node on in vivo MRI or could not be detected at all is unclear. CONCLUSIONS: We developed a new reading algorithm to differentiate benign from malignant lymph nodes in head and neck cancer patients on the basis of their appearance on high-resolution T2*-weighted USPIO-enhanced MRI. Next steps involve validation of our reading algorithm to further improve the accuracy of neck lymph node staging with USPIO-enhanced MRI in prospective clinical studies with larger number of patients.

Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer.

AIM: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC. PATIENTS AND METHODS: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included. RESULTS: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively. CONCLUSION: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT03729297.

Thermal Effects of CO2, KTP, and Blue Lasers with a Flexible Fiber Delivery System on Vocal Folds.

OBJECTIVE: To determine the differences in thermal effects on vocal folds between four fiber-routed lasers. METHODS: In this experimental laboratory study the thermal effects of an AcuPulse Duo CO2 (CO2 AP), UltraPulse Duo CO2 (CO2 UP), KTP, and Blue laser were analyzed using a Schlieren technique on a human tissue mimicking gel model. Power, laser duration, laser fiber distance to tissue and mode (continuous wave [CW] vs pulsed [P] modes) were evaluated in varying combinations in order to compare the effects of the tested lasers and to explore the individual effect on thermal expansion and incision depth of each setting. The model was validated by comparing the results from the Schlieren model with histology of ex vivo fresh human vocal folds after laser irradiation using a selection of the same laser settings, and calculating the intraclass correlation coefficient (ICC). RESULTS: One thousand ninety-eight Schlieren experiments and 56 vocal cord experiments were conducted. In comparison with CW mode, less thermal expansion occurred in P mode in all lasers, while incisions were deeper in the CO2 and more superficial in the KTP and Blue lasers. The mean thermal expansion was found to be minimally smaller, whereas incision depth was pronouncedly smaller in the KTP and Blue compared to the CO2 lasers. Duration of laser irradiation was the most important factor of influence on thermal expansion and incision depth for all lasers in both CW and P modes. The ICC for consistency between the results of the Schlieren model and the vocal cord histology was classified from fair to excellent, except for the thermal expansion of the Blue laser, which was classified as poor. CONCLUSION: This study demonstrates important differences in thermal effects between CO2, KTP, and Blue lasers which can be explained by the different physical characteristics of the P modes and divergence of the fiber delivery system. The Schlieren imaging model is a good predictor of the relative thermal effects in vocal fold tissue. Our results can be used as a guidance for ENT surgeons using fiber-routed lasers, in order to achieve effective treatment of vocal fold lesions and prevention of functional impairment of vocal folds.