Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice.

Positron emission tomography (PET) radioligands that bind with high-affinity to α4ß2-type nicotinic receptors (α4ß2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and the cerebellum for kinetic analysis of radioligand binding in mice. Two radioligands were explored: 2-[18F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [18F]Nifene, displaying similar pKa and binding affinity to nicotine. Time-activity curves of the left ventricle of the heart displayed similar distribution across wild type mice, mice lacking the ß2-subunit for ligand binding, and acute nicotine-treated mice, whereas reference tissue binding displayed high variation between groups. Binding potential estimated from a two-tissue compartment model fit of the data with the image-derived input function were higher than estimates from reference tissue-based estimations. Rate constants of radioligand dissociation were very slow for 2-FA and very fast for Nifene. We conclude that using an image-derived input function for kinetic modeling of nicotinic PET ligands provides suitable results compared to reference tissue-based methods and that the chemical properties of 2-FA and Nifene are suitable to study receptor response to nicotine addiction and smoking cessation therapies.

Trapping of Nicotinic Acetylcholine Receptor Ligands Assayed by In Vitro Cellular Studies and In Vivo PET Imaging.

A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in brain. Ligands, like varenicline, with high pKa and high affinity for α4ß2-type nicotinic receptors (α4ß2Rs) are trapped in intracellular acidic vesicles containing α4ß2Rs in vitro Nicotine, with lower pKa and α4ß2R affinity, is not trapped. Here, we extend our results by imaging nicotinic PET ligands in vivo in male and female mouse brain and identifying the trapping brain organelle in vitro as Golgi satellites (GSats). Two PET 18F-labeled imaging ligands were chosen: [18F]2-FA85380 (2-FA) with varenicline-like pKa and affinity and [18F]Nifene with nicotine-like pKa and affinity. [18F]2-FA PET-imaging kinetics were very slow consistent with 2-FA trapping in α4ß2R-containing GSats. In contrast, [18F]Nifene kinetics were rapid, consistent with its binding to α4ß2Rs but no trapping. Specific [18F]2-FA and [18F]Nifene signals were eliminated in ß2 subunit knock-out (KO) mice or by acute nicotine (AN) injections demonstrating binding to sites on ß2-containing receptors. Chloroquine (CQ), which dissipates GSat pH gradients, reduced [18F]2-FA distributions while having little effect on [18F]Nifene distributions in vivo consistent with only [18F]2-FA trapping in GSats. These results are further supported by in vitro findings where dissipation of GSat pH gradients blocks 2-FA trapping in GSats without affecting Nifene. By combining in vitro and in vivo imaging, we mapped both the brain-wide and subcellular distributions of weak-base nicotinic receptor ligands. We conclude that ligands, such as varenicline, are trapped in neurons in α4ß2R-containing GSats, which results in very slow release long after nicotine is gone after smoking.SIGNIFICANCE STATEMENT Mechanisms of nicotine addiction remain poorly understood. An earlier study using in vitro methods found that the anti-smoking nicotinic ligand, varenicline (Chantix) was trapped in α4ß2R-containing acidic vesicles. Using a fluorescent-labeled high-affinity nicotinic ligand, this study provided evidence that these intracellular acidic vesicles were α4ß2R-containing Golgi satellites (GSats). In vivo PET imaging with F-18-labeled nicotinic ligands provided additional evidence that differences in PET ligand trapping in acidic vesicles were the cause of differences in PET ligand kinetics and subcellular distributions. These findings combining in vitro and in vivo imaging revealed new mechanistic insights into the kinetics of weak base PET imaging ligands and the subcellular mechanisms underlying nicotine addiction.

Novel Strategies for Managing Retropharyngeal Lymph Node Metastases in Head and Neck and Thyroid Cancer with Transoral Robotic Surgery (TORS).

Retropharyngeal metastases are encountered in a variety of head and neck malignancies, imposing significant surgical challenges owing to their distinct location and proximity to neurovascular structures. Radiotherapy is the recommended treatment in most cases owing to its oncological efficacy. However, retropharyngeal irradiation affects the superior pharyngeal constrictor muscles and parotid glands, with the potential for long-term dysphagia and xerostomia. A younger oropharyngeal and thyroid cancer patient demographic is trending, fueling interest in treatment de-escalation strategies. Consequently, reducing radiotoxicity and its long-term effects is of special relevance in modern head and neck oncology practice. Through its unique ability to safely extirpate these traditionally difficult-to-access retropharyngeal lymph nodes via a natural orifice, TransOral Robotic Surgery (TORS) can considerably lower the surgical morbidity of retropharyngeal lymph node dissection (RPLND), compared with current existing approaches. This review summarizes the latest developments in the field, exposing current research gaps and discusses specific clinical settings where TORS could enable treatment de-escalation. In early-stage node-negative oropharyngeal cancer, single-modality surgical treatment with TORS RPLND may improve risk stratification of metastasis and recurrence in this region. TORS RPLND is also a potentially viable treatment option in salvage of an isolated retropharyngeal node recurrence or in the primary setting of a thyroid malignancy with a single positive retropharyngeal node. In time, TORS RPLND may provide an alternative de-escalation strategy in these three scenarios. However, with the reported morbidities, further prospective trials with long-term follow-up data are required to prove oncological safety and functional benefits over existing strategies.

Challenging NICE guidelines on parathyroid surgery.

BACKGROUND: National Institute of Clinical Excellence (NICE) recommend against routinely using Intra-Operative Parathyroid Hormone (IOPTH) for first-time parathyroid surgery due to its cost and minimal surgical benefit. The European Society of Endocrine Surgeons differ from this and recommends IOPTH with conflicting pre-operative or single imaging. NICE guidance acknowledged that this may change practice in larger centres. We devised a retrospective single-centre cohort study to analyse the impact of IOPTH on decision-making and cost-effectiveness. METHODOLOGY: First-time parathyroidectomy procedures for primary hyperparathyroidism were assessed between 2017 and 2019. Ultrasound (US) and Sestamibi with parathyroid single-photon emission with computed tomography (SPECT-CT) were compared with IOPTH. The contribution of IOPTH to cure and cost effectiveness ratio was calculated. RESULTS: 114 cases were included, with IOPTH performed in all cases, SPECT-CT in 112 and US in 108 cases. A cure rate of 99.1% (113/114) was achieved. 11.4% (13/114) of the cure rate was influenced by IOPTH (P 0.01), instigating further exploration when its levels didn't decrease. This included 7.1% (4/56) in the concordant-imaging cohort. IOPTH accuracy (96.5%) was significantly superior (P = 0.03) to both US (80%) and SPECT-CT (81%). Comparing the total costs for IOPTH testing over 2 years (£39,721) with 13 potential re-operative procedures in its absence (£63,536), a positive cost-effectiveness ratio of £1832 per re-operative procedure averted was achieved. CONCLUSION: Abandoning IOPTH in first-time parathyroid surgery is too ambitious when weighing the cost of re-operative surgery against cost savings obtained by using routine IOPTH to achieve an improved cure rate, even in concordant imaging.

The prevalence of oropharyngeal squamous cell carcinoma in patients admitted with symptoms of peritonsillar abscess or cellulitis: A retrospective multicentre study.

OBJECTIVES: Anecdotal evidence suggests that oropharyngeal squamous cell carcinoma (OPSCC) should be suspected in patients presenting with symptoms of peritonsillar abscess (PTA) or cellulitis (PTC). The aim of this study was to estimate the prevalence of OPSCC in patients presenting with symptoms of PTA/PTC. METHOD, SETTING AND PARTICIPANTS: We retrospectively identified all adults with a coded diagnosis of PTA or PTC who presented between 2012 and 2016 inclusive, across six ENT units in Merseyside. Records were compared to that of the centralised regional head and neck cancer database. The clinical records of a subset of patients were reviewed for the purposes of data validation. RESULTS: A total of 1975 patients with PTA/PTC were identified. Three patients were subsequently diagnosed with OPSCC. None of the three actually had an objective underlying diagnosis of PTA/PTC on the same side. The prevalence of OPSCC in patients admitted with symptoms of PTA/PTC was 0.15% or approximately 1:650 admissions. The records of 510 patients who presented over a one-year period (2016) were reviewed in even greater detail. There were 298 patients with PTA (59.4%) and 151 with PTC (29.1%) and 61 had an alternative diagnosis (11.9%). High-risk features (age ≥40, tonsillar asymmetry or tonsillar lesion) were present in 106 patients (24%). Urgent follow-up was expedited for 77 patients (73%). CONCLUSION: This study estimates the risk of OPSCC in patients with peritonsillar symptoms. The prevalence is low, even in a region with a relatively heavy disease burden. Clinicians should, however, retain a high level of suspicion in patients with persistent symptoms.

Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in down syndrome.

INTRODUCTION: Adults with Down syndrome are genetically predisposed to develop Alzheimer's disease and accumulate beta-amyloid plaques (Aß) early in life. While Aß has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aß burden. METHODS: A total of 161 adults with Down syndrome (mean age = 39.2 (8.50) years) and 40 healthy, non-Down syndrome sibling controls (43.2 (12.6) years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans. PET images were converted to units of standardized uptake value ratios (SUVrs). Aß burden was calculated using the amyloid load metric (AßL); a measure of global Aß burden that improves quantification from SUVrs by suppressing the nonspecific binding signal component and computing the specific Aß signal from all Aß-carrying voxels from the image. Regional tau was assessed using control-standardized AV-1451 SUVr. Control-standardized SUVrs were compared across Down syndrome groups of Aß-negative (A-) (AßL < 13.3), subthreshold A+ (13.3 ≤ AßL < 20) and conventionally A+ (AßL ≥ 20) individuals. The subthreshold A + group was identified as having significantly higher Aß burden compared to the A- group, but not high enough to satisfy a conventional A + classification. RESULTS: A large-sized association that survived adjustment for chronological age, mental age (assessed using the Peabody Picture Vocabulary Test), and imaging site was observed between AßL and AV-1451 within each Braak region (p < .05). The A + group showed significantly higher AV-1451 retention across all Braak regions compared to the A- and subthreshold A + groups (p < .05). The subthreshold A + group showed significantly higher AV-1451 retention in Braak regions I-III compared to an age-matched sample from the A- group (p < .05). DISCUSSION: These results show that even the earliest detectable Aß accumulation in Down syndrome is accompanied by elevated tau in the early Braak stage regions. This early detection of tau can help characterize the tau accumulation phase during preclinical Alzheimer's disease progression in Down syndrome and suggests that there may be a relatively narrow window after Aß accumulation begins to prevent the downstream cascade of events that leads to Alzheimer's disease.

Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys.

Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD1. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues1,2. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.

Importance of serum calcium in spontaneous neck haematoma.

We present an unusual case of spontaneous cervical haemorrhage secondary to extra-capsular bleeding from a parathyroid adenoma. Signs and symptoms on presentation included sore throat, dysphagia and anterior chest ecchymosis. While CT confirmed active cervical haemorrhage, elevated serum calcium and parathyroid hormone raised suspicion of possible parathyroid pathology. This case report and literature review highlight the diagnostic value of serum calcium in presentations of acute spontaneous neck haematoma. This should be considered especially in the acute phase, where imaging may not identify the source of haemorrhage. Initial observation and deferred surgery is the treatment of choice, with emergency operative management reserved for respiratory distress and worsening compressive symptoms.

Beckwith-Wiedemann Syndrome Review: A Guide for the Neonatal Nurse.

Beckwith-Wiedemann syndrome (BWS) is the most common pediatric overgrowth syndrome. Features characteristic of the BWS phenotype include both physical attributes, such as macroglossia, abdominal wall defects, gigantism, nevus flammeus, visceromegaly, and mid-face hypoplasia, as well as biochemical abnormalities such as hypoglycemia. It is essential for the neonatal nurse to be able to recognize BWS in the patient's early years of life because of the increased frequency of medical complications, malformations, and the increased risk of embryonic malignancies. This article focuses on the presentation of BWS as an aid to early detection.