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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.

Intrathyroidal parathyroid adenomas (IPAs) are a rare cause of primary hyperparathyroidism. They are often difficult to localize preoperatively and intraoperatively, making diagnosis and treatment challenging. Current data on IPAs are sparse and fragmented in the literature. This makes it difficult to compare the effectiveness of different imaging and surgical techniques. To address this issue, this scoping review maps the literature on IPAs, focusing on four domains: clinical presentation, current localization methods, different surgical techniques, and histopathological features. A search of MEDLINE, Embase, and the Cochrane Library was conducted, with 19 studies meeting the inclusion criteria. The characteristics of IPAs on ultrasound, fine-needle aspiration, CT, MRI, sestamibi-based techniques, and selective venous sampling are summarized. Emerging imaging modalities, including autofluorescence, are introduced. Surgical methods and intraoperative factors that correlate with high success rates for removal are highlighted. This review also identifies gaps in knowledge to guide further research into this area.

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. In this prospective clinical trial, we examined cell-mediated immune responses to HPV16 E2, E6 and E7 in peripheral blood using IFN-? 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. 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. 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., Proceedings on Cancer-Immuno-Oncology, Vol 1 No 1 (2018)

Main supervisor: Dr. Jane Sterling PhD FRCP Internal examiner: Dr. Lucy Truman PhD FRCS External examiner: Prof. Chris Nutting BSc (Hons) MD PhD FRCP FRCR MedFIPEm Assessor to Regius Professor of Physic: Dr. Chris Allen MA MD FRCP, In head and neck squamous cell carcinoma (HNSCC), the evidence that human papillomavirus (HPV) is associated with a subgroup of tumours has increased over the last thirty years. Prospective randomised controlled clinical trials have now established that detection of HPV in oropharyngeal tumours (~60-70% of cases in North America and Europe) may confer a survival advantage to the patient. Within the oropharynx, HPV16 constitutes ~90-95% of HPV subtypes associated with malignancy. This contrasts with uterine cervix mucosa, where approximately 15 high-risk subtypes cause >99% of disease. Other factors such as differences in genetic background, host immune response, hormonal and environmental influences (e.g. tobacco smoke, alcohol) all play a part in the pathway and susceptibility to oncogenesis. Analogous to uterine cervix disease, HPV-associated cancers involve wild-type TP53 whilst HPV negative tumours often have mutations in this gene. As most patients with HPV associated OPSCC present at an advanced stage, the detection and genetic analysis of a pre-malignant state would be important as it infers the potential for a screening test (similar to the uterine cervix model). To investigate this, whole transcriptome analysis with verification of results by reverse transcription–quantitative polymerase chain reaction (PCR), was performed on OPSCC fresh tissue biopsy samples. Predictable fold changes of RNA expression in HPV-associated disease included multiple transcripts within the p53 oncogenic pathway (e.g. CDKN2A / CCND1). In addition to this, a testis-specific gene not normally expressed in somatic cells, SYCP2, showed a consistently elevated fold change from baseline in pre-malignant and malignant tissue. A subtle immune defect has long been thought to trigger the susceptibility of some individuals to persistent HPV infection with either low or high risk HPV types. Following on from this, we investigated if clinical outcomes in HPV-related head and neck cancer may be affected by host immune response. Peripheral blood from patients with OPSCC treated by chemoradiotherapy underwent IFN-γ enzyme-linked immunosorbent spot assay (ELISPOT) to examine cell-mediated immune responses to HPV16 E2, E6 and E7. T cell responses against E6 or E7 peptides correlated with HPV DNA/RNA status. Within the HPV16+ OPSCC cohort, enhanced immunoreactivity to antigen E7 was linked to improved survival. In addition, an observed increase in regulatory T cell frequencies after treatment would suggest that immunosuppression may contribute to a reduced HPV specific cell mediated response. A further aspect of this study was to determine the role of HPV and Epstein Barr Virus (EBV) in the pathogenesis of squamous cell carcinoma within the temporal bone region. This is an uncommon tumour which is normally preceded by a history of inflammation within the external auditory canal (EAC) or middle ear / mastoid cavity. Although HPV has been implicated in many head and neck malignancies, its role in SCC of the temporal bone has not been established. Treatment strategies could change if a viral aetiology can be found. HPV16 DNA was detected in ~20% of the cases studied, however, no significant difference in disease specific survival was noted for the papillomavirus positive group. Epstein-Barr virus was not detected. The data presented highlight the functional and biological influence of high risk HPV infection on HNSCC. Further studies are likely to focus on developing non-invasive screening tools, therapeutic strategies based on vaccination or immune modulation or indeed de-escalation of current treatment protocols., HPV associated OPSCC immunology analysis Cancer Research UK (London, United Kingdom) 2012-07 to 2013-12|Award GRANT_NUMBER: C45051/A14962 Total funding amount GBP 15,500 H&N cancer HPV analysis Addenbrooke's Charitable Trust, Cambridge University Hospitals (Cambridge, United Kingdom) 2011-07 to 2013-12|Award GRANT_NUMBER: KDD/9478 Total funding amount GBP 15,000