Airway decision making in major head and neck surgery: Irish multicenter, multidisciplinary recommendations.

Major head and neck surgery poses a threat to perioperative airway patency. Adverse airway events are associated with significant morbidity, potentially leading to hypoxic brain injury and even death. Following a review of the literature, recommendations regarding airway management in head and neck surgery were developed with multicenter, multidisciplinary agreement among all Irish head and neck units. Immediate extubation is appropriate in many cases where there is a low risk of adverse airway events. Where a prolonged definitive airway is required, elective tracheostomy provides increased airway security postoperatively while delayed extubation may be appropriate in select cases to reduce postoperative morbidity. Local institutional protocols should be developed to care for a tracheostomy once inserted. We provide guidance on decision making surrounding airway management at time of head and neck surgery. All decisions should be agreed between the operating, anesthetic, and critical care teams.

Retrospective analysis of radiological investigation of surgically excised head and neck lipomas.

PURPOSE: Differentiating benign lipomas from malignant causes is challenging and preoperative investigative guidelines are not well-defined. The purpose of this study was to retrospectively identify cases of head and neck lipomas that were surgically resected over a 5-year period and to identify the radiological modality chosen and features discussed in the final report. Multidisciplinary outcomes and pathology reports were examined with a view to identifying high risk features of a lipoma to aid in future risk stratification. METHODS: Retrospective chart review of pathology characteristics, radiological features (modality, size, calcifications, septations, globular/nodular foci), multidisciplinary discussion and history of presenting complaint was performed. RESULTS: Two liposarcomas and 138 lipomas were identified. Twenty-two percent of all lipomas received radiological investigation. Twenty-two percent of imaging referrals were possibly inappropriate. Furthermore, radiological features suggestive of malignancy were not present in the final radiology report, X2 = 28.8, p < 0.0001. CONCLUSION: As expected, the incidence of liposarcoma is low. There is limited awareness of radiology referral guidelines superimposed with a tendency to over-investigate lipomas. Furthermore, radiological features suggestive of malignancy were inconsistently reported on and not documented in multidisciplinary discussions. Therefore, we propose a multidisciplinary checklist for referring physicians and radiologists to aid in diagnostic work-up.

Clinical Response With Pembrolizumab for Cutaneous Squamous Cell Carcinoma.

This case report describes an 89-year-old patient with prior cutaneous squamous cell carcinoma who presented with a new isolated metastasis and was subsequently treated with pembrolizumab, which produced a complete clinical response.

CD4-mediated immunity shapes neutrophil-driven tuberculous pathology.

Pulmonary Mycobacterium tuberculosis (Mtb) infection results in highly heterogeneous lesions ranging from granulomas with central necrosis to those primarily comprised of alveolitis. While alveolitis has been associated with prior immunity in human post-mortem studies, the drivers of these distinct pathologic outcomes are poorly understood. Here, we show that these divergent lesion structures can be modeled in C3HeB/FeJ mice and are regulated by prior immunity. Using quantitative imaging, scRNAseq, and flow cytometry, we demonstrate that Mtb infection in the absence of prior immunity elicits dysregulated neutrophil recruitment and necrotic granulomas. In contrast, prior immunity induces rapid recruitment and activation of T cells, local macrophage activation, and diminished late neutrophil responses. Depletion studies at distinct infection stages demonstrated that neutrophils are required for early necrosis initiation and necrosis propagation at chronic stages, whereas early CD4 T cell responses prevent neutrophil feedforward circuits and necrosis. Together, these studies reveal fundamental determinants of tuberculosis lesion structure and pathogenesis, which have important implications for new strategies to prevent or treat tuberculosis.

Ocular lymphoma: overcoming a diagnostic challenge with an endoscopic sinus approach.

BACKGROUND: Ocular lymphomas are rare, indolent tumours that pose a diagnostic challenge. Patients may be asymptomatic or present with symptoms of increased orbital mass. An index of suspicion is required alongside an understanding of the diagnostics and staging required to facilitate expedited multi-disciplinary work-up and management. METHODS: A comprehensive literature review was performed. We present a series of three cases, each presenting their own diagnostic challenge. RESULTS: Although ocular lymphomas are notoriously difficult to diagnose histologically, our case series show procurement of a diagnostic histological sample using an image-guided endoscopic sinus approach. CONCLUSIONS: Although not typically involved in the diagnosis or management, the otolaryngologist may encounter ocular lymphoma masquerading as sinus disease or with disseminated disease at other sites in the head and neck. Endoscopic sinus surgery is considered a safe, effective approach for achieving a histological diagnosis in these cases.

T-SPOT.TB Reactivity in Southern African Children With and Without in Utero Human Immunodeficiency Virus Exposure.

Infants who are human immunodeficiency virus (HIV)-exposed uninfected (iHEU) experience higher risk of infectious morbidity than infants HIV-unexposed uninfected (iHUU). We compared tuberculosis (TB) infection prevalence in 418 Bacillus Calmette-Guérin vaccinated sub-Saharan African iHEU and iHUU aged 9-18 months using T-SPOT.TB. Prevalence of TB infection was low and did not differ by HIV exposure status.

Distinct immune responses associated with vaccination status and protection outcomes after malaria challenge.

Understanding immune mechanisms that mediate malaria protection is critical for improving vaccine development. Vaccination with radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) induces high level of sterilizing immunity against malaria and serves as a valuable tool for the study of protective mechanisms. To identify vaccine-induced and protection-associated responses during malarial infection, we performed transcriptome profiling of whole blood and in-depth cellular profiling of PBMCs from volunteers who received either PfRAS or noninfectious mosquito bites, followed by controlled human malaria infection (CHMI) challenge. In-depth single-cell profiling of cell subsets that respond to CHMI in mock-vaccinated individuals showed a predominantly inflammatory transcriptome response. Whole blood transcriptome analysis revealed that gene sets associated with type I and II interferon and NK cell responses were increased in prior to CHMI while T and B cell signatures were decreased as early as one day following CHMI in protected vaccinees. In contrast, non-protected vaccinees and mock-vaccinated individuals exhibited shared transcriptome changes after CHMI characterized by decreased innate cell signatures and inflammatory responses. Additionally, immunophenotyping data showed different induction profiles of vδ2+ γδ T cells, CD56+ CD8+ T effector memory (Tem) cells, and non-classical monocytes between protected vaccinees and individuals developing blood-stage parasitemia, following treatment and resolution of infection. Our data provide key insights in understanding immune mechanistic pathways of PfRAS-induced protection and infective CHMI. We demonstrate that vaccine-induced immune response is heterogenous between protected and non-protected vaccinees and that inducted-malaria protection by PfRAS is associated with early and rapid changes in interferon, NK cell and adaptive immune responses. Trial Registration: ClinicalTrials.gov NCT01994525.

Parathyroid carcinoma: Current management and outcomes - A systematic review.

OBJECTIVE: Parathyroid carcinoma is rarely encountered in clinical practice. When faced with this clinical challenge, there is currently a paucity of evidence available for the optimal management of patients with parathyroid carcinoma. This systematic review synthesizes the available literature to evaluate the optimal management approach, thus providing guidance for future management. METHODS: A systematic review was conducted according to PRISMA guidelines using Ovid MEDLINE, EMBASE, and PubMed databases for studies, published in English, reporting on parathyroid carcinoma. Full text of potentially eligible articles were reviewed by two authors independently and eligible studies selected. Treatment options and associated outcomes were evaluated. Descriptive statistics were used to describe pooled patient cohorts. RESULTS: 3203 articles were initially identified using the search criteria with 59 full-text articles then screened for eligibility. Seven articles, all retrospective studies, concerning 2307 patients (median 224/study). Parathyroidectomy alone was the most frequently utilised surgical approach across all studies, followed by en-bloc resection (with adjacent thyroid and/or nodal tissue). There was no difference in post-operative morbidity, mortality or survival between surgical approaches (p < 0.005). Patients who underwent either form of surgery had longer overall survival than those managed non-operatively (p < 0.005). CONCLUSION: Surgical resection is the optimal treatment of parathyroid carcinoma. However there remains no consensus on the optimal extent of surgery, and as such future randomised prospective studies are necessary to evaluate the effects of different surgical approaches on morbidity, mortality and oncologic outcomes. Following resection, long-term surveillance with PTH is advised.

Longitudinal immune profiling after radiation-attenuated sporozoite vaccination reveals coordinated immune processes correlated with malaria protection.

Background: Identifying immune processes required for liver-stage sterilizing immunity to malaria remains an open problem. The IMRAS trial comprised 5x immunizations with radiation-attenuated sporozoites resulting in 55% protection from subsequent challenge. Methods: To identify correlates of vaccination and protection, we performed detailed systems immunology longitudinal profiling of the entire trial time course including whole blood transcriptomics, detailed PBMC cell phenotyping and serum antigen array profiling of 11 IMRAS radiation-attenuated sporozoite (RAS) vaccinees at up to 21 timepoints each. Results: RAS vaccination induced serum antibody responses to CSP, TRAP, and AMA1 in all vaccinees. We observed large numbers of differentially expressed genes associated with vaccination response and protection, with distinctly differing transcriptome responses elicited after each immunization. These included inflammatory and proliferative responses, as well as increased abundance of monocyte and DC subsets after each immunization. Increases in Vδ2 γδ; T cells and MAIT cells were observed in response to immunization over the course of study, and CD1c+ CD40+ DC abundance was significantly associated with protection. Interferon responses strongly differed between protected and non-protected individuals with high interferon responses after the 1st immunization, but not the 2nd-5th. Blood transcriptional interferon responses were correlated with abundances of different circulating classical and non-classical monocyte populations. Conclusions: This study has revealed multiple coordinated immunological processes induced by vaccination and associated with protection. Our work represents the most detailed immunological profiling of a RAS vaccine trial performed to date and will guide the design and interpretation of future malaria vaccine trials.

Transoral robotic surgery in Ireland: the beginning.

BACKGROUND: Transoral robotic surgery (TORS) has shown promising results in the treatment of myriad head and neck pathologies but is now most commonly used in the investigation and management of oropharyngeal squamous cell carcinoma. AIMS: The aim of this study was to report our cases of the newly introduced TORS, particularly its role in identifying primary of unknown origin and the potential implications for patients. A literature review and our early experience should begin to debunk some of the criticisms of TORS including setup times and cost. METHODS: Prospective data was collected from all patients undergoing transoral robotic surgery including demographics, indication, histology results in primary of unknown origin and complications. RESULTS: We have performed 36 TORS procedures in total ranging from intermediate to major complex. Our complication rate is low, and this has improved with the passage of time. Haemorrhage rates remain at 5.6% (n = 2), and the average length of stay is 1 day. Successful identification of a primary tumour in cancer of unknown primary was 80% (n = 8). CONCLUSIONS: We anticipate the integration of TORS into routine practice in the investigation and management of a number of ENT pathologies following robust clinical trials.

Supporting the use of adjuvant radiotherapy in recurrent pleomorphic adenoma of the parotid.

BACKGROUND: The use of adjuvant radiotherapy remains controversial in the treatment of recurrent pleomorphic adenomas. AIMS/OBJECTIVES: The aim of this study was to provide the highest level of evidence possible by performing a systematic review and meta-analysis of the literature. MATERIAL AND METHODS: We searched the English-language literature between 1985 and 2019.Inclusion criteria included any study on the treatment and outcome of recurrent pleomorphic adenomas. Exclusion criteria included the use of radiotherapy for residual tumors, case reports, and pleomorphic adenomas not arising from the parotid. RESULTS: A total of 522 abstracts were studied, data analyzed from 14 studies, on a total of 697 patients. When the data werepooled, the overall risk of further recurrence was 21%. In studies where surgery alone was undertaken this increased to 26% and decreased to 10% in those receiving adjuvant radiotherapy (p = .000). There were 21 recurrences in 159 patients in the radiotherapy group, and 151 recurrences out of 538 patients in the surgery group (p < .0001). CONCLUSIONS: These data support the use of radiotherapy to decrease the risk of re-recurrence in recurrent pleomorphic adenoma. SIGNIFICANCE: This study is the highest level of evidence currently available in guiding management of recurrent pleomorphic adenoma.

Early whole blood transcriptional responses to radiation-attenuated Plasmodium falciparum sporozoite vaccination in malaria naïve and malaria pre-exposed adult volunteers.

BACKGROUND: Vaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity. However, the mechanisms underlying this protection remain unclear. In this work, two recent radiation-attenuated sporozoite vaccination studies were used to identify potential transcriptional correlates of vaccination-induced protection. METHODS: Longitudinal whole blood RNAseq transcriptome responses to immunization with radiation-attenuated P. falciparum sporozoites were analysed and compared across malaria-naïve adult participants (IMRAS) and malaria-experienced adult participants (BSPZV1). Parasite dose and method of delivery differed between trials, and immunization regimens were designed to achieve incomplete protective efficacy. Observed protective efficacy was 55% in IMRAS and 20% in BSPZV1. Study vaccine dosings were chosen to elicit both protected and non-protected subjects, so that protection-associated responses could be identified. RESULTS: Analysis of comparable time points up to 1 week after the first vaccination revealed a shared cross-study transcriptional response programme, despite large differences in number and magnitude of differentially expressed genes between trials. A time-dependent regulatory programme of coherent blood transcriptional modular responses was observed, involving induction of inflammatory responses 1-3 days post-vaccination, with cell cycle responses apparent by day 7 in protected individuals from both trials. Additionally, strongly increased induction of inflammation and interferon-associated responses was seen in non-protected IMRAS participants. All individuals, except for non-protected BSPZV1 participants, showed robust upregulation of cell-cycle associated transcriptional responses post vaccination. CONCLUSIONS: In summary, despite stark differences between the two studies, including route of vaccination and status of malaria exposure, responses were identified that were associated with protection after PfRAS vaccination. These comprised a moderate early interferon response peaking 2 days post vaccination, followed by a later proliferative cell cycle response steadily increasing over the first 7 days post vaccination. Non-protection is associated with deviations from this model, observed in this study with over-induction of early interferon responses in IMRAS and failure to mount a cell cycle response in BSPZV1.

Salvage transoral robotic surgery in early-stage oropharyngeal recurrence.

OBJECTIVES: Limited data are currently available regarding outcomes following transoral robotic surgery (TORS) in the salvage setting. This study aims to investigate the functional and oncological outcomes following TORS in salvage oropharyngeal tumors. STUDY DESIGN: All patients undergoing salvage TORS for a residual, recurrent, or new primary oropharyngeal squamous cell carcinoma within a previously radiated field between March 2014 and October 2018 were included. Patients undergoing salvage TORS for other subsites were excluded. Margin status, complication rates, long-term tracheostomy, and gastrostomy requirements and overall and disease-free survival outcomes were recorded. RESULTS: A total of 26 patients were included. Three patients (11%) experienced a TORS-specific major complication. A gastrostomy tube was required in 42% of patients on discharge (n = 11), and in 28% of patients on long-term follow-up (n = 7) at a median of 34 (interquartile range, 11.8-47.8) months. A tracheostomy was placed in 5 patients and all were removed before discharge. The 3-year overall survival and disease-free survival were 74% and 70%, respectively. CONCLUSION: Salvage TORS is a viable and effective option in the management of selected tumors within a previously radiated field.

Ultra-low Dose Aerosol Infection of Mice with Mycobacterium tuberculosis More Closely Models Human Tuberculosis.

Tuberculosis (TB) is a heterogeneous disease manifesting in a subset of individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). Unlike human TB, murine infection results in uniformly high lung bacterial burdens and poorly organized granulomas. To develop a TB model that more closely resembles human disease, we infected mice with an ultra-low dose (ULD) of between 1-3 founding bacteria, reflecting a physiologic inoculum. ULD-infected mice exhibited highly heterogeneous bacterial burdens, well-circumscribed granulomas that shared features with human granulomas, and prolonged Mtb containment with unilateral pulmonary infection in some mice. We identified blood RNA signatures in mice infected with an ULD or a conventional Mtb dose (50-100 CFU) that correlated with lung bacterial burdens and predicted Mtb infection outcomes across species, including risk of progression to active TB in humans. Overall, these findings highlight the potential of the murine TB model and show that ULD infection recapitulates key features of human TB.

The Peripheral Blood Transcriptome Is Correlated With PET Measures of Lung Inflammation During Successful Tuberculosis Treatment.

Pulmonary tuberculosis (PTB) is characterized by lung granulomas, inflammation and tissue destruction. Here we used within-subject peripheral blood gene expression over time to correlate with the within-subject lung metabolic activity, as measured by positron emission tomography (PET) to identify biological processes and pathways underlying overall resolution of lung inflammation. We used next-generation RNA sequencing and [18F]FDG PET-CT data, collected at diagnosis, week 4, and week 24, from 75 successfully cured PTB patients, with the [18F]FDG activity as a surrogate for lung inflammation. Our linear mixed-effects models required that for each individual the slope of the line of [18F]FDG data in the outcome and the slope of the peripheral blood transcript expression data correlate, i.e., the slopes of the outcome and explanatory variables had to be similar. Of 10,295 genes that changed as a function of time, we identified 639 genes whose expression profiles correlated with decreasing [18F]FDG uptake levels in the lungs. Gene enrichment over-representation analysis revealed that numerous biological processes were significantly enriched in the 639 genes, including several well known in TB transcriptomics such as platelet degranulation and response to interferon gamma, thus validating our novel approach. Others not previously associated with TB pathobiology included smooth muscle contraction, a set of pathways related to mitochondrial function and cell death, as well as a set of pathways connecting transcription, translation and vesicle formation. We observed up-regulation in genes associated with B cells, and down-regulation in genes associated with platelet activation. We found 254 transcription factor binding sites to be enriched among the 639 gene promoters. In conclusion, we demonstrated that of the 10,295 gene expression changes in peripheral blood, only a subset of 639 genes correlated with inflammation in the lungs, and the enriched pathways provide a description of the biology of resolution of lung inflammation as detectable in peripheral blood. Surprisingly, resolution of PTB inflammation is positively correlated with smooth muscle contraction and, extending our previous observation on mitochondrial genes, shows the presence of mitochondrial stress. We focused on pathway analysis which can enable therapeutic target discovery and potential modulation of the host response to TB.

High-grade chondrosarcoma of the larynx: a case report and literature review.

A 64-year-old male presented with a 2-month history of sudden onset dysphonia. Endoscopic evaluation of the larynx revealed a complete right vocal cord palsy. Computed tomography of the neck revealed a mass medial to the right thyroid associated with the cricoid cartilage. Histologic examination confirmed high-grade chondrosarcoma. The patient underwent right-sided hemicricoidectomy with tracheal flap reconstruction, right thyroid lobectomy and partial oesophagectomy with primary anastomosis followed by adjuvant radiation therapy. He is currently being followed as an outpatient with no evidence of disease. High-grade chondrosarcoma of the larynx is an exceedingly rare tumour, associated with a poor prognosis. Current best evidence suggests primary surgical resection with negative margins. There is a lack of evidence to guide post-operative management of high-grade chondrosarcoma. They have a poor prognosis following surgical resection and a 10-year survival rate of 29%.

Plasma N-glycans in colorectal cancer risk.

Aberrant glycosylation has been associated with a number of diseases including cancer. Our aim was to elucidate changes in whole plasma N-glycosylation between colorectal cancer (CRC) cases and controls in one of the largest cohorts of its kind. A set of 633 CRC patients and 478 age and gender matched controls was analysed. Additionally, patients were stratified into four CRC stages. Moreover, N-glycan analysis was carried out in plasma of 40 patients collected prior to the initial diagnosis of CRC. Statistically significant differences were observed in the plasma N-glycome at all stages of CRC, this included a highly significant decrease in relation to the core fucosylated bi-antennary glycans F(6)A2G2 and F(6)A2G2S(6)1 (P < 0.0009). Stage 1 showed a unique biomarker signature compared to stages 2, 3 and 4. There were indications that at risk groups could be identified from the glycome (retrospective AUC = 0.77 and prospective AUC = 0.65). N-glycome biomarkers related to the pathogenic progress of the disease would be a considerable asset in a clinical setting and it could enable novel therapeutics to be developed to target the disease in patients at risk of progression.

Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria.

Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRα1.7 domains. Furthermore, a recombinant CIDRα1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRα1 domains in brain swelling.