Diagnostic utility of 11 C-methionine PET/CT in primary hyperparathyroidism in a UK cohort: A single-centre experience and literature review.

OBJECTIVE: Primary hyperparathyroidism is a common endocrine disorder, with 80% of all cases usually caused by one single hyperfunctioning parathyroid adenoma. Conventional imaging modalities for the diagnostic work-up of primary hyperparathyroidism (PHPT) include ultrasound of the neck, 99mTc-sestamibi scintigraphy, and four-dimensional computed tomography (4D-CT). However, the role of other imaging modalities, such as 11C-methionine PET/CT, in the care pathway for PHPT is currently unclear. Here, we report our experience of the diagnostic utility of 11C-methionine PET/CT in a single-center patient cohort (n = 45). DESIGN: Retrospective single-center cohort study. PATIENTS AND MEASUREMENTS: The data of eligible patients that underwent 11C-methionine PET/CT between 2014 and 2022 at Addenbrooke's Hospital (Cambridge, UK) were collected and analyzed. The clinical utility of imaging modalities was determined by comparing the imaging result with histopathological and biochemical outcomes following surgery. RESULTS: In patients with persistent primary hyperparathyroidism following previous surgery, 11C-methionine PET/CT identified a candidate lesion in 6 of 10 patients (60.0%), and histologically confirmed in 5 (50.0%). 11C-methionine PET/CT also correctly identified a parathyroid adenoma in 9 out of 12 patients (75.0%) that failed to be localized on other imaging modalities. 11C-methionine PET/CT had a sensitivity of 70.0% (95% CI 55.8 - 84.2%) for the detection of parathyroid adenomas. CONCLUSIONS: This study highlights a diagnostic role for 11C-methionine PET/CT in patients that have undergone unsuccessful prior surgery or have equivocal or negative prior imaging results, aiding localization and a targeted surgical approach.

An Approach to a Patient With Primary Hyperparathyroidism and a Suspected Ectopic Parathyroid Adenoma.

Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia driven by excess parathyroid hormone (PTH) secretion. PHPT is a common endocrine condition with a prevalence of 1 to 7 cases per 1000 adults. PHPT typically presents in the fifth or sixth decade and shows significant female preponderance. Solitary hyperfunctioning parathyroid adenomas account for 85% to 90% of PHPT cases. The remaining 10% to 15% include cases of multiglandular disease (multiple adenomas or hyperplasia) and, rarely, parathyroid carcinoma (1%). Ectopic parathyroid adenomas may arise due to abnormal embryological migration of the parathyroid glands and can be difficult to localize preoperatively, making surgical cure challenging on the first attempt. The potential existence of multiglandular disease should be considered in all patients in whom preoperative localization fails to identify a target adenoma or following unsuccessful parathyroidectomy. Risk factors for multiglandular disease include underlying genetic syndromes (eg, MEN1/2A), lithium therapy, or previous radiotherapy. In addition to multifocal disease, the possibility of an ectopic parathyroid gland should also be considered in patients requiring repeat parathyroid surgery. In this article, we use illustrative clinical vignettes to discuss the approach to a patient with primary hyperparathyroidism (PHPT) and a suspected ectopic parathyroid adenoma.

Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort.

BACKGROUND: Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism-jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost-effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR > 0.02 presenting (i) <35 years of age, or (ii) <45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR < 0.02. AIMS AND METHODS: A retrospective review of patients referred for genetic testing over a 4 year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next-generation sequencing of the following genes; MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1 in NHS-accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort. RESULTS: A total of 121 patients were included in this study (92 female) with a mean age of 41 years (SD 17). A pathogenic germline variant was identified in 16% (n = 19). A pathogenic variant was identified in the PHPTH genes CDC73 in a single patient and MEN1 in six patients (6% of total), in the FHH genes, CASR in 11 patients and AP2S1 in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re-classification of four of the variants, with two VUS's in the CASR gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (P = .0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified CASR pathogenic variant versus those without (P = .0001) was demonstrated in this study. Thirty-three patients were aged over 50 years and the diagnostic rate of a pathogenic variant was 15.1% in those patients >50 years of age compared to 15.9% in those <50 years. Five patients >50 years and with a CCCR of <0.01, were diagnosed with a pathogenic variant in CASR. CONCLUSION: Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re-evaluating VUS's in order to inform patient management and enable appropriate genetic counselling. Finally, this study has demonstrated the need to consider genetic testing for PHPTH in patients of any age, particularly those with additional risk factors.

Thyroidectomy in octogenarians is not associated with poorer postoperative outcomes.

BACKGROUND: The elderly represents one of the most rapidly growing subsets of the population. This population experiences a higher incidence of thyroid pathology. However, there are concerns that the elderly also experiences increased perioperative complications and are poor candidates for thyroidectomy. METHODS: Patients who underwent thyroidectomy over the age of 80 years at three tertiary head and neck units were included. Data regarding age, sex, presenting symptoms, comorbidities, preoperative investigations, type of surgery, postoperative complications, and final thyroid pathology were retrieved from hospital records. RESULTS: Of a total of 39 patients (69% women, mean age 83.1), the majority (40.1%) presented with a combination of symptoms: shortness of breath, feeling of pressure in the neck, dysphagia, or tiredness. Two (5.1%) were asymptomatic. Low rates of postoperative complications were encountered and were minor (n = 5). No intensive care unit admissions or mortality was experienced. CONCLUSION: Thyroid surgery in octogenarians carries an acceptable complication profile.

A multifaceted approach to improving the quality of ENT Emergency Clinic referrals.

It is imperative that primary care referrals are directed to the appropriate secondary care service. Patients presenting to a primary care physician with ENT conditions may require review in an Emergency Clinic. The latter clinics provide patients with rapid access to secondary care, for urgent, yet non-life-threatening conditions. In our department, we noticed that patients with conditions inappropriate to the capabilities of the Clinic were being booked in or reviewed too late; thus causing wasted journeys for the patient. We conducted a Quality Improvement Project to improve the efficiency of the referral process. A prospective evaluation of referrals was collected continuously over a two-month period. Overall, 5 domains were deemed crucial to enable timely and accurate booking of patients to clinic: booking date, urgency, legibility, patient identification and appropriateness. Our proposed standard set for this project was 100% compliance over the 5 domains. Three separate interventions were instigated following the first cycle. The main components of the intervention were the phased development of an electronic referral system and an educational initiative for junior doctors. 20 referral forms were analysed during the initial 3-week period. No referrals met the recommended overall compliance standard of 100% (mean number of domains achieved: 3.38; standard deviation (SD): 0.637). Legibility and patient information were included in 21% and 30% of referrals, respectively. There was a trend of improvement following initiation of interventions. The mean number of domains achieved was 4.27 (SD 0.647; n=13) in the second data collection period, 4.53 (SD 0.514; n=16) in the third, and 4.75 (SD 0.452; n=24) in the fourth. Using linear regression, this change demonstrates a statistically significant improvement (p<0.001). An e-Proforma referral system represents a safe and efficient communication technology. When implementing policy change, it is crucial to acquire managerial and consultant support.

Minimally invasive surgery versus radiotherapy/chemoradiotherapy for small-volume primary oropharyngeal carcinoma.

BACKGROUND: More than 400,000 cases of oropharyngeal squamous cell carcinoma (OPSCC) are diagnosed each year worldwide and the incidence is rising, partly as a result of human papillomavirus. Human papillomavirus-associated OPSCC affects younger patients and often presents at a higher stage; however, it is associated with a better prognosis.Until recently, first-line management of OPSCC involved chemoradiotherapy, as research had demonstrated comparable survival outcomes when compared with open surgery, with significantly decreased morbidity. However, interventions have now evolved with computerised planning and intensity-modulated radiotherapy, and the advent of endoscopic head and neck surgery, which provide the potential for decreased treatment-associated morbidity.The oropharynx plays an essential role in swallowing, speech and protecting the airway as it is situated at the bifurcation of the respiratory and digestive tracts. Treatment modality recommendations are based on survival outcomes. Given the younger patient demographic, establishing the safety of modalities that potentially have better functional outcome is becoming increasingly important. OBJECTIVES: To assess the efficacy of endoscopic head and neck surgery (transoral robotic surgery or transoral laser microsurgery) for small-volume, primary (T1-2, N0-2) oropharyngeal squamous cell carcinoma (OPSCC) in comparison to radiotherapy/chemoradiotherapy. SEARCH METHODS: The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2016, Issue 10); PubMed; EMBASE; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 8 November 2016. SELECTION CRITERIA: Randomised controlled trials in patients with carcinoma in the oropharynx subsite (as defined by the World Health Organization classification C09, C10). Cancers included were primary squamous cell carcinomas arising from the oropharyngeal mucosa. The tumours were classified as T1-T2 with or without nodal disease and with no evidence of distant metastatic spread. The intervention was transoral, minimally invasive surgery with or without adjuvant radiotherapy or adjuvant chemoradiotherapy. The comparator was primary radiotherapy with or without induction or concurrent chemotherapy for the tumour. The treatments received and compared were of curative intent and patients had not undergone prior intervention, other than diagnostic biopsy. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival (disease-related mortality was to be studied where possible), locoregional control, disease-free survival and progression-free survival or time to recurrence. All outcomes were to be measured at two, three and five years after diagnosis. Our secondary outcomes included quality of life, harms associated with treatment, patient satisfaction and xerostomia score. MAIN RESULTS: No completed studies met the inclusion criteria for the review. Two ongoing trials fulfilled the selection criteria, however neither are complete.'Early-stage squamous cell carcinoma of the oropharynx: radiotherapy versus trans-oral robotic surgery (ORATOR)' is a phase II randomised controlled trial comparing primary radiation therapy with primary transoral robotic surgery for small-volume primary (T1-2, N0-2) OPSCC. It is currently in progress with an estimated completion date of June 2021.'European Organisation for Research and Treatment of Cancer 1420 (EORTC 1420-HNCG-ROG)' is a phase III, randomised study assessing the "best of" radiotherapy compared to transoral robotic surgery/transoral laser microsurgery in patients with T1-T2, N0 squamous cell carcinoma of the oropharynx and base of tongue. It was due to start accrual mid-2016. AUTHORS' CONCLUSIONS: The role of endoscopic head and neck surgery in the management of OPSCC is clearly expanding as evidenced by its more overt incorporation into the current National Comprehensive Cancer Network guidelines. Data are mounting regarding its outcomes both in terms of survival and lower morbidity. As confidence increases, it is being used in the management of more advanced OPSCC.Based on this review, there is currently no high-quality evidence from randomised controlled trials regarding clinical outcomes for patients with oropharyngeal cancer receiving endoscopic head and neck surgery compared with primary chemoradiotherapy.

CD8+ T cell response to human papillomavirus 16 E7 is able to predict survival outcome in oropharyngeal cancer.

INTRODUCTION: Immunological response to human papillomavirus (HPV) in the development and progression of HPV16+ oropharyngeal squamous cell carcinoma (OPSCC) (accounting for the majority of viral associated cases) is largely unknown and may provide important insights for new therapeutic strategies. METHODS: In this prospective clinical trial (UKCRN11945), we examined cell-mediated immune responses to HPV16 E2, E6 and E7 in peripheral blood using IFN-γ enzyme-linked immunosorbent spot assay. CD56+, CD4+, CD8+ and regulatory T cell frequencies were also discerned by flow cytometry. Fifty-one study participants with oropharyngeal carcinoma were recruited. Control subjects were those undergoing tonsillectomy for benign disease. All patients were treated with curative intent by radiotherapy ± chemotherapy. Disease-specific survival was investigated by multivariate analysis. RESULTS: HPV16 DNA was detected in 41/51 of the OPSCC participants. T cell responses against HPV16 E6 or E7 peptides were detected in 33/51 evaluable patients, respectively and correlated with HPV status. Matched pre- and post-treatment T cell responses were available for 39/51 OPSCC cases. Within the whole cohort, elevated post-treatment CD8+ response to HPV16 E7 correlated with longer disease free survival (multivariate DFS p < 0.03). Within the HPV + OPSCC cohort, a significant increase in regulatory T cells (p < 0.02) was noted after treatment. CONCLUSIONS: This is the first study to provide survival data in OPSCC stratified by cell-mediated immune response to HPV16 peptides. Within the HPV16+ OPSCC cohort, enhanced immunoreactivity to antigen E7 was linked to improved survival. An increase in regulatory T cell frequencies after treatment may suggest that immunosuppression can contribute to a reduced HPV-specific cell-mediated response.

Langerhans cell sarcoma of the head and neck.

Head and neck Langerhans cell sarcoma (HNLCS) is a rare malignant tumor carrying a poor prognosis. The aim of this work was to perform a systematic review of HNLCS cases, examine outcomes, and develop an evidence-based management algorithm. We performed a systematic literature search yielding 16 studies with 17 cases of HNLCS; 33 studies with 55 Non-HNLCS were used as a comparison. Mean disease-specific survival was 20.5 months (SE ± 5.1) for HNLCS versus 26.2 months (SE±4.2) for non-HNLCS. There was no significant difference in disease-specific (p = 0.768) or disease-free survival (p = 0.880) between the two cohorts. There was a significant difference in both disease-specific (p = 0.044) and disease-free survival (p = 0.001) between local, locoregional and disseminated disease favoring more limited disease. HNLCS appears to present later, with more disseminated disease. Surgery remains the mainstay of treatment of local disease, however clear margins do not guarantee clearance.

Multi-institutional validation of a novel textural analysis tool for preoperative stratification of suspected thyroid tumors on diffusion-weighted MRI.

PURPOSE: Ultrasound-guided fine needle aspirate cytology fails to diagnose many malignant thyroid nodules; consequently, patients may undergo diagnostic lobectomy. This study assessed whether textural analysis (TA) could noninvasively stratify thyroid nodules accurately using diffusion-weighted MRI (DW-MRI). METHODS: This multi-institutional study examined 3T DW-MRI images obtained with spin echo echo planar imaging sequences. The training data set included 26 patients from Cambridge, United Kingdom, and the test data set included 18 thyroid cancer patients from Memorial Sloan Kettering Cancer Center (New York, New York, USA). Apparent diffusion coefficients (ADCs) were compared over regions of interest (ROIs) defined on thyroid nodules. TA, linear discriminant analysis (LDA), and feature reduction were performed using the 21 MaZda-generated texture parameters that best distinguished benign and malignant ROIs. RESULTS: Training data set mean ADC values were significantly different for benign and malignant nodules (P = 0.02) with a sensitivity and specificity of 70% and 63%, respectively, and a receiver operator characteristic (ROC) area under the curve (AUC) of 0.73. The LDA model of the top 21 textural features correctly classified 89/94 DW-MRI ROIs with 92% sensitivity, 96% specificity, and an AUC of 0.97. This algorithm correctly classified 16/18 (89%) patients in the independently obtained test set of thyroid DW-MRI scans. CONCLUSION: TA classifies thyroid nodules with high sensitivity and specificity on multi-institutional DW-MRI data sets. This method requires further validation in a larger prospective study. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance.

Thyroid surgery for Graves' disease and Graves' ophthalmopathy.

BACKGROUND: Graves' disease is an autoimmune disease caused by the production of auto-antibodies against the thyroid-stimulating hormone receptor, which stimulates follicular cell production of thyroid hormone. It is the commonest cause of hyperthyroidism and may cause considerable morbidity with increased risk of cardiovascular and respiratory adverse events. Five per cent of people with Graves' disease develop moderate to severe Graves' ophthalmopathy. Thyroid surgery for Graves' disease commonly falls into one of three categories: 1) total thyroidectomy, which aims to achieve complete macroscopic removal of thyroid tissue; 2) bilateral subtotal thyroidectomy, in which bilateral thyroid remnants are left; and 3) unilateral total and contralateral subtotal thyroidectomy, or the Dunhill procedure. Recent American Thyroid Association guidelines on treatment of Graves' hyperthyroidism emphasised the role of surgery as one of the first-line treatments. Total thyroidectomy removes target tissue for the thyroid-stimulating hormone receptor antibody. It controls hyperthyroidism at the cost of lifelong thyroxine replacement. Subtotal thyroidectomy leaves a thyroid remnant and may be less likely to lead to complications, however a higher rate of recurrent hyperthyroidism is expected and revision surgery would be challenging. The choice of the thyroidectomy technique is currently largely a matter of surgeon preference, and a systematic review of the evidence base is required to determine which option offers the best outcomes for patients. OBJECTIVES: To assess the optimal surgical technique for Graves' disease and Graves' ophthalmopathy. SEARCH METHODS: We searched the Cochrane Library, MEDLINE and PubMed, EMBASE, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The date of the last search was June 2015 for all databases. We did not apply any language restrictions. SELECTION CRITERIA: Only randomised controlled trials (RCTs) involving participants with a diagnosis of Graves' disease based on clinical features and biochemical findings of hyperthyroidism were eligible for inclusion. Trials had to directly compare at least two surgical techniques of thyroidectomy. There was no age limit to study inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and cross-checked the data for analysis, evaluation of risk of bias and establishment of 'Summary of findings' tables using the GRADE instrument. The senior review authors reviewed the data and reconciled disagreements. MAIN RESULTS: We included five RCTs with a total of 886 participants; 172 were randomised to total thyroidectomy, 383 were randomised to bilateral subtotal thyroidectomy, 309 were randomised to the Dunhill procedure and 22 were randomised to either bilateral subtotal thyroidectomy or the Dunhill procedure. Follow-up ranged between six months and six years. One trial had three comparison arms. All five trials were conducted in university hospitals or tertiary referral centres for thyroid disease. All thyroidectomies were performed by experienced surgeons. The overall quality of the evidence ranged from low to moderate. In all trials, blinding procedures were insufficiently described. Outcome assessment for objective outcomes was blinded in one trial. Surgeons were not blinded in any of the trials. One trial blinded participants. Attrition bias was a substantial problem in one trial, with 35% losses to follow-up. In one trial the analysis was not carried out on an intention-to-treat basis.Total thyroidectomy was more effective than subtotal thyroidectomy techniques (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in 0/150 versus 11/200 participants (OR 0.14 (95% CI 0.04 to 0.46); P = 0.001; 2 trials; moderate quality evidence). Total thyroidectomy was also more effective than bilateral subtotal thyroidectomy at preventing recurrent hyperthyroidism in 0/150 versus 10/150 participants (odds ratio (OR) 0.13 (95% confidence interval (CI) 0.04 to 0.44); P = 0.001; 2 trials; moderate quality evidence). Compared to bilateral subtotal thyroidectomy, the Dunhill procedure was more likely to prevent recurrent hyperthyroidism in 20/283 versus 8/309 participants (OR 2.73 (95% CI 1.28 to 5.85); P = 0.01; 3 trials; low quality evidence). Total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism in 8/172 versus 3/221 participants (OR 4.79 (95% CI 1.36 to 16.83); P = 0.01; 3 trials; low quality evidence). Effects of the various surgical techniques on permanent recurrent laryngeal nerve palsy and regression of Graves' ophthalmopathy were neutral. One death was reported in one study in year three of follow-up. No study investigated health-related quality of life or socioeconomic effects. AUTHORS' CONCLUSIONS: Total thyroidectomy is more effective than subtotal thyroidectomy (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in Graves' disease. The type of surgery performed does not affect regression of Graves' ophthalmopathy. There was some evidence that total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism, which however, was not seen in comparison with bilateral subtotal thyroidectomy. Permanent recurrent laryngeal nerve palsy did not seem to be affected by type of thyroidectomy. Health-related quality of life as a patient-important outcome measure should form a core determinant of any future trial on the effects of thyroid surgery for Graves' disease.

Catecholamine-secreting paraganglioma: the challenges of perioperative management.

An asymptomatic 48-year-old man presented with a right-sided neck mass. A CT scan demonstrated a lesion at the carotid bifurcation and an angiogram showed splaying of the carotid arteries. His plasma metanephrines were raised confirming a catecholamine-secreting paraganglioma. Metaiodobenzylguanidine single-photon emission CT showed focal high tracer uptake in the right of the neck. Histology revealed a tumour, arising within a nerve, composed of oval-shaped cells arranged in nested (zellballen) as well as in trabecular patterns. Immunohistochemistry was positive for neuroendocrine markers chromogranin A, synaptophysin and CD56. Preoperative management included an endocrinologist initiating α-adrenergic and ß-adrenergic blockers. Intraoperatively, acute hypertension occurred whenever the tumour was manipulated. Close communication between the surgeons and the anaesthetist allowed for these episodes to be predicted and treated with fast-acting antihypertensives such as sodium nitroprusside. Postoperatively, the patient recovered well and his antihypertensives were discontinued.

Deregulation of SYCP2 predicts early stage human papillomavirus-positive oropharyngeal carcinoma: A prospective whole transcriptome analysis.

This study was designed to identify significant differences in gene expression profiles of human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OPSCC) and to better understand the functional and biological effects of HPV infection in the premalignant pathway. Twenty-four consecutive patients with locally advanced primary OPSCC were included in a prospective clinical trial. Fresh tissue samples (tumor vs. matched normal epithelium) were subjected to whole transcriptome analysis and the results validated on the same cohort with RT-quantitative real-time PCR. In a separate retrospective cohort of 27 OPSCC patients, laser capture microdissection of formalin-fixed, paraffin-embedded tissue allowed RNA extraction from adjacent regions of normal epithelium, carcinoma in situ (premalignant) and invasive SCC tissue. The majority of patients showed evidence of high-risk HPV16 positivity (80.4%). Predictable fold changes of RNA expression in HPV-associated disease included multiple transcripts within the p53 oncogenic pathway (e.g. CDKN2A/CCND1). Other candidate transcripts found to have altered levels of expression in this study have not previously been established (SFRP1, CRCT1, DLG2, SYCP2, and CRNN). Of these, SYCP2 showed the most consistent fold change from baseline in premalignant tissue; aberrant expression of this protein may contribute to genetic instability during HPV-associated cancer development. If further corroborated, this data may contribute to the development of a non-invasive screening tool. This study is registered with the UK Clinical Research Network (ref.: 11945).

Conservative or radical surgery for pediatric papillary thyroid carcinoma: A systematic review of the literature.

BACKGROUND: Pediatric papillary thyroid carcinoma (PTC) is characterized by an aggressive clinical course. Early diagnosis is a challenge and treatment consists principally of partial or total thyroidectomy±neck dissection and radioactive iodine therapy. Due to the rarity of PTC in children, there is no consensus on optimal surgical treatment. METHODS AND RESULTS: A literature search was carried out using PubMed, Embase, Medline, Cochrane and Web of Science. Seven studies (489 patients) investigating the outcome of surgically managed pediatric PTC were identified. No clear advantage in survival or recurrence rate was found for total thyroidectomy compared to other surgical approaches. CONCLUSION: Despite the aggressive behavior of PTC, prognosis is good, with low mortality. After removal of disease and prevention of recurrence, reduction of iatrogenic complications are a priority in this age group. Due to the paucity of available evidence, this review cannot recommend conservative or radical surgery for pediatric papillary thyroid carcinoma. To answer this question, we recommend the establishment of a randomized controlled trial with adequately matched baseline variables.

Inverted papilloma of lacrimal sac invading into the orbit: case report and review of literature.

Inverted papilloma (IP) is a sinonasal tumor of benign etiology with local invasion and malignant potential. IP arising in lacrimal sac invading the orbit is extremely rare with only one case reported so far. The presented case appears to be the second such case reported in the literature. A 60-year-old Caucasian male presented with a medial canthal mass and epiphora. Incisional biopsy confirmed a transitional neoplasm. The lesion was completely excised enbloc with clear margins by using a Weber-Ferguson incision; orbital clearance and nasolacrimalfossa clearance was achieved via a medial maxillectomy. Enbloc resection of orbital and nasolacrimal parts of the tumor with clear margins is recommended.

Langerhans cell sarcoma: a systematic review.

Langerhans cell sarcoma (LCS) is a rare malignant tumour of Langerhans cells with a poor outcome. Given its rarity, there is a lack of evidence regarding the most appropriate treatment for this condition. Therefore the aim of this work was to review, compile, analyse and present clinical details and to determine the optimal treatment regimen. A search of PubMed, CINAHL, EMBASE, Cochrane, CENTRAL, clinicaltrials.gov and Google Scholar was supplemented by hand searching. Data extracted included demographics, treatment, type of LCS and clinical outcome. Of 510 citations identified by a systematic literature search, 46 case series including 66 subjects with LCS met criteria for analysis. The most common treatment modality was chemotherapy, used alone or in combination in 47 cases (71%) followed by surgery in 31 cases (47%). Overall mean (S.E.) disease specific survival and disease free survival were 27.2 (3.9) and 18.3 (3.8) months respectively. There was a significant difference in both disease specific and disease free survival between the local, loco-regional and disseminated disease cohorts (DSS p=0.014; DFS p<0.001). More localised disease confers a survival advantage. Multi-modality therapy appears to be most effective, with the addition of radiotherapy to chemotherapy appearing beneficial. Complete surgical excision with clear margins being most effective for local disease control. Any adjuvant therapy should not be delayed. Bone marrow transplant appears to be the most reliable treatment in terms of outcome especially in disseminated disease however has well known patient selection and toxicity/tolerance issues. The role of cell surface markers for prognostication remains unclear.

Management of tumors arising from the parapharyngeal space: A systematic review of 1,293 cases reported over 25 years.

OBJECTIVES: We present a systematic review of 1,252 lesions published in the past 25 years, the largest to date. We also include our own experience of 41 cases. DATA SOURCES: Our data sources were MEDLINE and Embase databases. REVIEW METHODS: A systematic review of the literature (1988-2014) was performed and data on histological diagnosis, presentation, surgical approach, and postoperative complications were reviewed. RESULTS: In total, 22 studies (including our own institution) revealed 82% of lesions were benign. The most common presentation was an intraoral mass (52%) followed by a cervical mass (48%), and the most common primary lesion was a pleomorphic adenoma (29%). Ninety-six percent of patients underwent surgery. The cervical approach was most frequently used (46%), and the most common complication was vagus nerve injury (13%). Within our institution, 5-year progression-free survival for benign and malignant disease was 93% and 61%, respectively (P = .196). CONCLUSIONS: A parapharyngeal space mass is an uncommon tumor and requires careful preoperative assessment. Definitive treatment is usually surgery, and these patients should be counseled appropriately about the potential for permanent cranial nerve deficits. LEVEL OF EVIDENCE: NA.

Ruxolitinib Associated Tuberculosis Presenting as a Neck Lump.

Tuberculosis is an opportunistic infection with protean clinical manifestations. We describe a case of Ruxolitinib induced miliary tuberculosis presenting as a neck lump. A 78-year-old female presented with a two-month history of right-sided neck lump associated with fever, night sweats, and significant weight loss. She had a past medical history that included myelofibrosis, being treated with Ruxolitinib. Examination demonstrated 4 × 4 cm right-sided cervical lymphadenopathy. A chest radiograph showed extensive shadowing in both lungs. CT scan demonstrated perilymphatic nodes in addition to the cervical mass. An ultrasound-guided biopsy of a cervical lymph node demonstrated confirmed Mycobacterium tuberculosis infection. It was hypothesized that use of Ruxolitinib through its selective inhibition of Janus-activated kinases 1 and 2 resulted in immunosuppression and miliary tuberculosis in this patient. The medication was stopped and a 12-month regime of antituberculosis therapy commenced. She remained well at one-year follow-up with resolution of lung involvement. Clinicians should consider tuberculosis as a differential diagnosis for patients presenting with a neck lump, particularly in those taking immunosuppressant medication such as Ruxolitinib. A multidisciplinary approach is needed to promptly treat the tuberculosis and consider discontinuation of Ruxolitinib.

Long-term outcome of airway stenosis in granulomatosis with polyangiitis (Wegener granulomatosis): an observational study.

IMPORTANCE: Airway stenosis occurs in patients with granulomatosis with polyangiitis (GPA or Wegener granulomatosis). It produces significant morbidity and contributes to mortality. OBJECTIVE: To investigate the frequency and distribution of airway stenoses in GPA and evaluate the efficacy of local interventions in maintaining airway patency. DESIGN, SETTING, AND PARTICIPANTS: A retrospective single-center study of 44 patients with GPA and airway stenosis assessed and treated as needed by a multidisciplinary team at a university medical center between 1997 and 2012. The median duration of observation for each patient from the time of diagnosis was 146 months. INTERVENTIONS: Patients who had critical stenoses underwent either dilatation or laser radial cuts to the lesion. In some cases, intralesional administration of steroids or topical mitomycin C was used. MAIN OUTCOMES AND MEASURES: The main outcome measure was airway patency for at least 12 months and the number of interventions required to achieve this end point. Details of patients and interventions were recorded at baseline and at each treatment. RESULTS: The median age at diagnosis was 37.6 years; 73% of patients were women (n = 34). The median follow-up after the initial intervention was 62.5 months. Subglottic stenosis was found in 36 patients, lower airway stenosis in 30. There were 213 interventions in 39 patients, including balloon and bougie dilatation and laser treatment. Adjuvant local treatment was used in 71 interventions. A 12-month period of airway stability was achieved in 34 of 36 cases (97%) (5 had no procedures and 3 had follow-up shorter than 12 months). The median interval between procedures was 4.9 months, and after the last intervention recorded, patients had at least 27 months of airway stability. Fourteen adverse events were recorded (6.6%). CONCLUSIONS AND RELEVANCE: The frequency and distribution of airway stenoses in 44 patients with GPA has been described. In the 39 patients who required intervention, multiple procedures were required, but 97% then achieved a prolonged period of airway patency. The procedures and adjuvant treatments were found to be safe. Our experience with a variety of techniques in this rare presentation has permitted design of a structured approach and an algorithm to manage and evaluate airway stenosis in GPA.

De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials.

Iatrogenic complications associated with current treatment protocols for oropharyngeal squamous cell carcinoma are noted to cause high rates of acute and chronic morbidity. The aims of this study are to provide an overview of the current de-escalation trials for human papillomavirus positive (HPV+) oropharyngeal carcinoma and to evaluate the evidence supporting improved response to treatment of patients within this viral cohort. This study reviewed all completed or in progress randomised controlled trials (RCTs) assessing clinical interventions for human papillomavirus-associated locally advanced oropharyngeal squamous cell carcinoma. We utilised a validated 'risk of bias' tool to assess study quality. We identified nine RCTs that met the full inclusion criteria for this review (all of which are currently on-going and will report from 2015 onwards). Five RCTs performed a post hoc analysis by HPV status, which allowed meta-analysis of 1130 patients. The data reveal a significant difference in overall survival (hazard ratio (HR) 0.49 [95% confidence interval (CI) 0.35-0.69]), loco-regional failure (HR 0.43 [95% CI 0.17-1.11]) and disease specific survival (0.41 [95% 0.3-0.56]) in favour of the HPV+ category. In considering de-escalation treatment protocols, nine studies are currently ongoing. Our meta-analysis provides strong evidence for an improved prognosis in the viral associated cohort when treated by platinum based chemotherapy in combination with radiotherapy or primary radiotherapy. So far, one trial (with moderate to high risk of bias) suggests a reduced survival outcome for the HPV+ population when using the epidermal growth factor receptor (EGFR) inhibitor cetuximab.