Comparison of Transoral and Transcervical Ultrasonography with MRI for the Diagnostic Work-Up of Oropharynx Tumors: A Protocol for a Multicenter Clinical Trial (SPOTUS).

This study protocol for a prospective, multicenter, diagnostic, clinical trial describes the integration of transoral and transcervical ultrasonography (US) in the initial clinical work-up of patients referred to tertiary head and neck cancer centers with suspected oropharyngeal cancer. The study evaluates the blinded detection rate of oropharyngeal tumors and their US-estimated size and T-stage before histopathology and cross-sectional imaging are available. Magnetic resonance imaging (MRI) scans will be prospectively rated while blinded to T-site histopathology and US. The primary outcome measures of diagnostic accuracy, including sensitivity, specificity, positive and negative predictive values, and overall accuracy, will be reported for both US and MRI. A sub-analysis of prospectively rated 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) scans in patients with clinically suspected unknown primary tumors will also be compared to US and MRI. Secondary outcome measures, including a comparison of tumor size estimation between US, MRI, and CT, will also be reported. This prospective multicenter study will provide clinically impactful information regarding the use of transoral and transcervical US for the diagnostic work-up of oropharyngeal cancer.

Intraoral Ultrasound versus MRI for Depth of Invasion Measurement in Oral Tongue Squamous Cell Carcinoma: A Prospective Diagnostic Accuracy Study.

Oral squamous cell carcinoma (OSCC) of the tongue is the most common type of oral cavity cancer, and tumor depth of invasion (DOI) is an important prognostic factor. In this study, we investigated the accuracy of intraoral ultrasound and magnetic resonance imaging (MRI) for assessing DOI in patients with OSCC. Histopathological measurement of DOI was used as a reference standard. We conducted a prospective study including patients planned for surgical treatment of OSCC in the tongue. The DOI was measured in an outpatient setting by intraoral ultrasound and MRI, and was compared to the histopathological DOI measurements. Bland-Altman analysis compared the mean difference and 95% limits of agreement (LOA) for ultrasound and MRI, and the Wilcoxon signed-rank test was used to test for significance. The correlation was evaluated using Pearson's correlation coefficient. We included 30 patients: 26 with T1 or T2 tumors, and 4 with T3 tumors. The mean difference from histopathology DOI was significantly lower for ultrasound compared to MRI (0.95 mm [95% LOA -4.15 mm to 6.06 mm] vs. 1.90 mm [95% LOA -9.02 mm and 12.81 mm], p = 0.023). Ultrasound also led to significantly more correct T-stage classifications in 86.7% (26) of patients compared to 56.7% (17) for MRI, p = 0.015. The Pearson correlation between MRI and histopathology was 0.57 (p < 0.001) and the correlation between ultrasound and histopathology was 0.86 (p < 0.001). This prospective study found that intraoral ultrasound is more accurate than MRI in assessing DOI and for the T-staging of oral tongue cancers. Clinical practice and guidelines should implement intraoral ultrasound accordingly.

Transoral Ultrasound in the Outpatient Clinic for the Diagnostic Work-Up of Oropharyngeal Cancer: A Feasibility Study.

Magnetic resonance imaging (MRI) is the preferred imaging modality for oropharyngeal cancers (OPCs), but it has difficulties distinguishing between small OPCs and unilateral tonsil hypertrophy. We hypothesized that surgeon-performed transoral ultrasound (US) could be used to accurately detect T-stage OPCs. We performed a single-center prospective diagnostic accuracy study including patients with suspected or biopsy-verified OPCs during outpatient appointments. All patients were offered transoral US and MRI. If transoral US could not be tolerated by the patient, transcervical US was performed. The primary outcome was the diagnostic accuracy of detecting OPCs with US compared to MRI, using histopathology as the reference standard. The secondary outcome was comparing the primary tumor diameters between US and MRI blinded to each other. Out of the 26 patients included in the study, 21 (81%) had OPCs. Transoral US could be performed in 21/21 and 1/5 patients with suspected palatine and lingual tonsil OPCs, respectively. Overall, US diagnostic accuracy was 92%, compared to 81% with MRI (p = 0.37). US and MRI had a high correlation between tumor diameters in the anteroposterior diameter (R = 0.80, p < 0.001), corresponding to the depth axis on US. In conclusion, this small study showed the promise and feasibility of transoral US to improve the initial clinical evaluations of patients with suspected OPCs.

Liquid biopsies in thyroid cancers: a systematic review and meta-analysis.

Thyroid cancer (TC) represents the most common endocrine malignant tumor. Liquid biopsy has been suggested as a new and accurate biomarker in cancer. This systematic review analyzes the existing literature on circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free DNA integrity index (cfDI), and their potential as biomarkers for TC, including the subtypes: differentiated (papillary and follicular), medullary, and anaplastic. A systematic search was performed in PubMed, Embase, and Cochrane databases for published articles in English between 1 January 1970 and 6 September 2022 (PROSPERO: CRD42022358592). The literature search generated a total of 635 articles. In total, 36 articles were included (patients = 2566). Four studies reported that higher levels of CTCs were associated with metastases and worse prognosis. Nineteen studies found the presence of mutated ctDNA in TC patients. The diagnostic accuracy in detecting BRAFV600E as ctDNA was determined in 11 studies regarding papillary TC. The pooled sensitivity, specificity, and diagnostic odds ratio were estimated at 56% (95% CI 36-74), 91% (95% CI 84-95) and 12 (95% CI 4.09-33.11), respectively. Four studies concluded that the cfDI was higher in patients with TC compared to benign thyroid lesions and healthy controls. The detection of CTCs, ctDNA, and cfDI may have a potential prognostic value in TC in relation to diagnosis, disease progression, and treatment efficacy. Despite the promising potential of CTCs, ctDNA, and cfDI in TC management, limitations hinder direct comparison and generalization of findings. Standardized methodologies, larger patient cohorts, and a consensus on relevant markers are needed to validate their clinical applicability and enhance TC management.

Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A in Denmark 1930­2021: A Nationwide Population-Based Retrospective Study

Studies of primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 2A (MEN 2A) shows divergence in frequency, disease definition, reporting of clinical characteristics and traces of selection bias. This is a nationwide population-based retrospective study of PHPT in MEN 2A, suggesting a representative frequency, with complete reporting and a strict PHPT definition. The Danish MEN 2A cohort 1930-2021 was used. Of 204 MEN 2A cases, 16 had PHPT, resulting in a frequency of 8% (CI, 5-12). Age-related penetrance at 50 years was 8% (CI, 4-15). PHPT was seen in the American Thyroid Association moderate (ATA-MOD) and high (ATA-H) risk groups in 62% and 38% of carriers, respectively. Median age at PHPT diagnosis was 45 years (range, 21-79). A total of 75% were asymptomatic and 25% were symptomatic. Thirteen underwent parathyroid surgery, resulting in a cure of 69%, persistence in 8% and recurrence in 23%. In this first study with a clear PHPT definition and no selection bias, we found a lower frequency of PHPT and age-related penetrance, but a higher age at PHPT diagnosis than often cited. This might be affected by the Danish RET p.Cys611Tyr founder effect. Our study corroborates that PHPT in MEN 2A is often mild, asymptomatic and is associated with both ATA-MOD and ATA-H variants. Likelihood of cure is high, but recurrence is not infrequent and can occur decades after surgery.

Diagnostics and treatment of cysts of the neck.

Different congenital and acquired lesions can present as a cystic mass of the neck. The diagnostics and treatment of these is described in this review. Ultrasound and fine-needle aspiration biopsy are essential in the diagnostic workup of neck cysts, and especially cysts located laterally in the neck in adults over 40 years of age require further examination, due to the risk of malignancy. Treatment of the cysts depends on the type and location and can consist of aspiration, surgery, and sclerotherapy. Especially cystic thyroid nodules and macrocystic lymphatic malformations may be treated with schlerotherapy.

Quality of life in thyroid cancer.

To explore the impact of differentiated thyroid cancer (DTC) on quality of life (QoL) a clinical analytical framework was developed. Based on the clinical analytical framework, a systematic literature search was performed to identify studies applying patient-reported outcomes (PRO) instruments among patients with DTC. Subsequently, the scope was narrowed down to studies comparing scores on the Medical Outcomes Study (MOS) Short form 36 (SF-36) to a reference population (clinical interpretability criterion). Further, the currently available thyroid cancer (TC) specific QoL PROs were review in accordance with the standards of the International Society of Quality of Life Research. In the initial search, 213 studies were included. The additional 'clinical interpretability'-criteria, limited the final study sample to 16 studies, 13 cross-sectional and 3 longitudinal. QoL was impacted across all SF-36 scales. The impact was generally modest and the impact was impeded by time since diagnosis and treatment. Four TC specific instruments were identified. Generally, the documentation of their measurement properties, particularly content validity and clinical validity, including substantial quantitative validation, was scarce. As was the cross-cultural applicability of the currently available instruments. This restricted, focused, clinically founded review showed an impact on a broad range of QoL issues. There is a need for large-scale measurement of QoL outcome longitudinally, using well-validated PRO instruments in order to identify with certainty the impact on subgroups.

Spinal versus conventional fine needle for ultrasound-guided thyroid nodule biopsy: a protocol for a randomised clinical trial.

INTRODUCTION: Thyroid nodules are very common and constitute an increasing clinical challenge since improved imaging capabilities and utilisation have led to a higher number of incidental findings. Ultrasound-guided fine-needle aspiration biopsy (FNAB) is the standard diagnostic tool in the work-up of thyroid nodules suspected of malignancy. Non-diagnostic results remain common and require repeated FNAB, leading to increased costs and delayed treatment of thyroid diseases, including treatment of thyroid cancer. If cytological diagnoses cannot be achieved, surgery may be warranted, which may potentially lead to overtreatment. Optimisation of the FNAB procedure is therefore essential. Spinal needles with a stylet have been found to lead to fewer non-diagnostic results, but studies on the subject are few. METHODS: This is a multicentre, two-arm, randomised clinical trial. Adults with thyroid nodules suspected of malignancy will be included consecutively. A total of 350 patients will be assigned randomly 1:1 to have a FNAB with either a spinal (25G) or a conventional (25G) needle. The primary outcome is the rate of diagnostic cytological samples according to the Bethesda system. Secondary outcomes are patient-experienced pain, complication rate and sensitivity and specificity. CONCLUSIONS: This trial will explore whether FNAB from thyroid nodules employing spinal needles compared with conventional fine needles improves diagnostic results, thereby providing evidence-based recommendations for a future choice of the FNAB needle. Secondary outcomes are patient-experienced pain, complication rate and sensitivity and specificity. FUNDING: This trial received funding from Erik and Susanna Olesens Fond. The funding source had no influence on trial design, data collection, analysis or publication. CLINICALTRIALS: gov Identifier: NCT04879355. Registration date: 07032021; version: 29062022.

Locating hyperfunctioning parathyroid glands using 11C-Choline PET/CT: an inter- and intra-observer variation study.

BACKGROUND: Use of 11C-Choline PET/CT is gaining ground in detecting hyperfunctioning parathyroid glands in primary hyperparathyroidism. The purpose of this study was to evaluate the robustness of 11C-Choline PET/CT by assessing intra- and inter-observer agreement to determine whether the method was reader sensitive and therefore should only be performed at highly specialised sites with a high number of cases. PET/CT images of 40 patients diagnosed with primary hyperparathyroidism were anonymised and evaluated three times by three readers: an expert reader and two non-experts (non-experts were experienced in PET/CT imaging, but not in 11C-Choline PET/CT in the setting of primary hyperparathyroidism). Number of hyperfunctioning parathyroid glands, location relative to the thyroid gland and confidence of each assessment (low, moderate or high) were noted, and intra- and inter-observer agreement calculated using Fleiss' kappa method. Sensitivities and specificities of the non-experts were calculated using the expert reader as gold standard. RESULTS: Intra-observer agreement was 'good' to 'near perfect' for all readers. Inter-observer agreement was good between non-experts and the expert, with kappa values ≥ 0.74. Sensitivities between non-experts and the expert were high, > 81%, when assessing which side and 75% when assessing thyroid quadrant. All specificities were > 94%. Reader certainties were 'high' in > 80% of cases for the expert and > 70% and > 65%, respectively for the two non-experts. CONCLUSION: 11C-Choline PET/CT is not reader sensitive for the localisation of hyperfunctioning parathyroid glands and may therefore be safely implemented at sites that have a moderate number of cases. Access to a cyclotron laboratory is, however, a necessity for the production of 11C-Choline. The study was conducted in accordance with the Helsinki 2 declaration and The International Council for Harmonisation Guideline for Good Clinical Practice (ICH_GCP) clinical trial, approved by the Research Ethics Committee of the Capital Region of Denmark (Journal-nr.:H-18012490, date of approval: 18 June 2018) and the Danish Medicines Agency (EudraCT no. 2018-000726-63, date of approval: 6 June 2018). The GCP unit in Eastern Denmark has carried out regular monitoring of the trial according to GCP (ID: 2018-1050).

Risk Factors for Recurrence of Follicular Thyroid Cancer: A Systematic Review.

Background: In risk assessment of recurrence, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are often grouped together as differentiated thyroid cancer (DTC). However, while risk factors affecting recurrence of PTC are well established, risk factors for recurrence of FTC are not. This systematic review examines risk factors for recurrence of FTC and evaluates their significance. Methods: A systematic search on PubMed and Embase was performed in September 2020, including studies evaluating risk factors for recurrence of FTC. A quality assessment of the enrolled studies was performed. Results: Nine studies (n = 1544 patients) from eight countries were included. The average recurrence rate was 13.6%, and distant metastasis (DM) constituted 64.8% of the recurrent cases. The risk factors examined were sex, age at diagnosis, primary tumor size, degree of invasiveness, focality, positive resection margin, lymph node (LN) metastasis, and DM at diagnosis. Risk factors correlated with recurrence of FTC were age older than 45 years, primary tumor size above 40 mm, widespread invasion, multifocality, positive resection margin, LN metastasis, and DM at diagnosis. Sex was not a statistically significant risk factor. Conclusions: We identified seven risk factors associated with recurrence of FTC. Age and multifocality were found to be of greater impact regarding recurrence risk of FTC compared with PTC. Future research needs to address the impact of different risk factors for recurrence of FTC particularly including age, primary tumor size, angioinvasion, and mutational status.

Protocol for a randomised clinical trial of transoral ultrasound versus standard of care in the diagnosis of peritonsillar abscess.

INTRODUCTION: Peritonsillar infection is a common complication to acute tonsillitis in younger adults. If peritonsillar cellulitis progresses to a peritonsillar abscess (PTA), the primary treatment is surgical drainage. But distinguishing cellulitis from PTA on a standard clinical examination is difficult. This trial aims to explore whether point-of-care transoral ultrasound can improve diagnostic accuracy and guide successful needle aspiration in patients referred with PTA. METHODS: A randomised, controlled multicentre trial will be conducted at the departments of otorhinolaryngology, head and neck surgery at Rigshospitalet and Odense University Hospital. Patients referred with PTA will be randomised to either standard clinical examination (control) or standard clinical examination with supplemental transoral ultrasound (intervention). The diagnostic accuracy, the total number of performed needle aspirations and the proportion of successful needle aspirations will be compared between the two groups. The difference will be evaluated using binary logistic regression and a generalised estimating equation to adjust for clustering of data within each physician and each hospital. A total of 88 patients are necessary to measure the clinical effect of adding transoral ultrasound. CONCLUSIONS: This study will explore the clinical benefits of adding transoral ultrasound to the diagnostic work-up of patients with peritonsillar infections. FUNDING: The Rigshospitalet and Odense University Hospital Foundation. TRIAL REGISTRATION: Clinicaltrials NCT03824288.

Risk of Thyroid Cancer in 1,504 Patients Referred for Thyroid Surgery with Assumed Benign Histology.

OBJECTIVES: The aims of this study were to report the risk of thyroid malignancy in cases of either benign fine-needle aspiration (FNA) or without FNA performed, and to investigate possible predictive factors for thyroid malignancy in a population with recent moderately low iodine intake. METHODS: All patients referred for thyroid surgery in a tertiary cancer centre between 2000 and 2016 were included (n = 3,703). After excluding cases indicating malignant histology, we included group 1: patients with benign FNA (n = 764), and group 2: patients without FNA (n = 740), leaving 1,504 eligible for further investigation. Information on age, gender, tracheal compression or dislocation, thyroid specimen weight, scintigraphy, ultrasound, medically treated thyrotoxicosis, serum stimulating thyroid hormone, indication for surgery, TNM classification, stage, and outcome were retrieved. RESULTS: The malignancy risk was 7.6% (58/764) in group 1 and 6.8% (50/740) in group 2. Patients with T2-4 tumours constituted 2.2% (33/1,504). In the combined groups, ultrasound verified that solitary solid tumour was predictive for malignancy (p = 0.01 by χ2, and OR = 1.69, p = 0.02 in multiple logistic regression). For group 1 patients, thyrotoxicosis (which in this case was medically treated) was a significant predictive factor for malignancy (p = 0.04). CONCLUSIONS: The risk of malignancy of 7.6% and 6.8% was high, considering that patients with malignant FNA, suspicious FNA, or clinical findings indicating malignancy were excluded, and 2.2% of these malignancies were stages T2-4. In cases with solitary solid tumour on ultrasound, the risk of malignancy should not be ignored, even with benign FNA.

Incidental and Non-incidental Papillary Thyroid Microcarcinoma in Denmark 1996-2015: A national study on incidence, outcome and thoughts on active surveillance.

BACKGROUND: Incidental and non-incidental papillary microcarcinomas (PMC) are associated with different outcomes and treatment options may vary. The least favourable outcome is typically seen when carcinoma is suspected prior to surgery. Only a few studies have addressed the prognosis based on the way of detection for PMC, and they have been limited to retrospective single-center studies. We hypothesize that the "way of detection" may predict prognosis. The aim was to calculate the incidence and outcome of PMC based on the way of detection and to identify patients that may be suitable for active surveillance. METHOD: This national cohort study consists of 803 patients diagnosed with PMC in Denmark from 1996 to 2015. Patients were identified from the DATHYRCA database and allocated into groups according to the way of detection leading to surgery: Incidental at surgery (n = 527), non-incidental with symptoms suspected from the index tumor (n = 134) and non-incidental with symptoms suspected from a metastasis (n = 142). RESULTS: Age-standardized incidence rates increased from 0.35 per 100,000 per year in 1996 to 1.19 per 100,000 per year in 2015. A significant rise in incidence was found for both the incidental group and non-incidental group with symptoms suspected from a metastasis. Recurrence free survival was significantly worse for patients with suspicion of metastasis prior to surgery than patient groups without. No difference in mortality was found between groups. CONCLUSION: PMC patients without suspicion of metastasis have the same low risk of recurrence as incidental cases and may be candidates for active surveillance.

Completeness of RET testing in patients with medullary thyroid carcinoma in Denmark 1997-2013: a nationwide study.

BACKGROUND: The completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested. METHODS: The study included 200 patients identified from the nationwide Danish MTC cohort 1997-2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994-2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested. RESULTS: Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81-0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76-0.88; 131/158). Completeness was 88% (95% CI: 0.75-0.95; 42/48) and 81% (95% CI: 0.72-0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested. CONCLUSION: The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test.

Survival and Long-Term Biochemical Cure in Medullary Thyroid Carcinoma in Denmark 1997-2014: A Nationwide Study.

BACKGROUND: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure. METHODS: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used. RESULTS: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure. CONCLUSIONS: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.

Replication of newly proposed TNM staging system for medullary thyroid carcinoma: a nationwide study.

A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38-4.57) vs 3.04 (95% CI: 1.38-6.67) for stage II, 2.06 (95% CI: 0.45-9.39) vs 3.59 (95% CI: 1.61-8.03) for stage III and 5.87 (95% CI: 2.02-17.01) vs 59.26 (20.53-171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.

Incidence and prevalence of multiple endocrine neoplasia 2A in Denmark 1901-2014: a nationwide study.

BACKGROUND: The incidence and prevalence of multiple endocrine neoplasia 2A (MEN2A) have only been reported once in a nationwide setting. However, it is unclear whether the figures are representative of other populations, as the major component of the syndrome, hereditary medullary thyroid carcinoma (MTC), has been reported as rare in the same country. We conducted a nationwide retrospective cohort study of MEN2A in Denmark from 1901 to 2014, aiming to describe the incidence and prevalence. METHODS: This study included 250 unique MEN2A patients born or resident in Denmark before December 31, 2014. Patients were identified through the Danish REarranged during Transfection (RET) cohort, linkage of MEN2A pedigrees, the Danish MTC cohort, a nationwide collaboration of MEN2 centers, cross-checking of other relevant cohorts, and a systematic literature search. RESULTS: The incidence from 1971 to 2000 was 28 (95% CI: 21-37) per million live births per year. Incidence for the specific mutations or for the overall MEN2A group did not change significantly from 1901 to 2014 (P>0.05). Point prevalence at January 1, 2015, was 24 per million (95% CI: 20-28). CONCLUSION: The incidence and prevalence of MEN2A in Denmark seem higher than those reported in other countries. This is likely explained by the Danish C611Y founder effect. Also, our data indicate no significant change in MEN2A incidence during the last century.

Therapeutic human papillomavirus vaccines in head and neck cancer: A systematic review of current clinical trials.

OBJECTIVES: This systematic review provides an overview of the current clinical trials investigating therapeutic vaccines for HPV+ head and neck cancer and discusses the future directions of therapeutic vaccine therapy. MATERIALS AND METHODS: A systematic search was conducted in PubMed, EMBASE, Cochrane and clinicaltrials.gov for clinical trials involving therapeutic vaccines. We included studies initiated between 2000 and 2018 with patients diagnosed with HPV+ head and neck cancer and extracted data concerning type of vaccine therapy, adverse events, immunogenicity and clinical outcome measures (e.g. tumour response, progression-free survival and overall survival). RESULTS: We identified 11 studies (n = 376 patients) initiated between year 2005 and 2017. Four studies (n = 34) presented preliminary results in patients with incurable, recurrent loco-regional or distant metastatic disease indicating a positive immune response with 74% (n = 25/34 patients) having elevated antibody levels, IFN-γ and/or T-cell response. Five studies presented data on the vaccines' safety profile, demonstrating predominantly grade 1 and 2 toxicity. Three studies evaluated the clinical outcome - one study showed no complete or partial response, one study demonstrated stable disease as the best tumour response in 64% (n = 9/14 patients) and one study showed a 33% overall response rate: one patient with a complete response and seven patients with a partial response. CONCLUSIONS: Treatment with therapeutic vaccines is a promising and seemingly safe strategy for patients with HPV+ head and neck cancer. However, there are not enough data to draw any further conclusions and clinical outcome measures and tumour responses to the vaccines are still missing.

[Transorbital penetrating injury without sequlae].

A 33-year-old man was admitted to hospital with a butter knife stuck in his head after having attempted to commit suicide by forcing the knife through his skull. Physical examination revealed a stable patient with only minimal associated haemorrhage. A CT scan revealed, that the penetrating knife had passed through the sphenoid bone, the posterior orbit and the ethmoid cells and ended in the contralateral nasal cavity. The knife was removed by its own trajectory. After surgery, the patient was neurologically intact with normal sight and well-functioning eye movements, and he made a full recovery.