Peritonsillar Abscess Outcomes with and Without Computed Tomography: A Retrospective Cohort Study.

OBJECTIVES: Peritonsillar abscess (PTA) is a common deep space head and neck infection, which can be diagnosed with or without computed tomography (CT). CT poses a risk for false positives, leading to unnecessary abscess drainage attempts without benefit, whereas needle or open aspiration without imaging could potentially lead to missed abscess in need of treatment. This study considered the utility and impact of obtaining CT scans in patients with suspected PTA by comparing outcomes between CT and non-CT usage. METHODS: Retrospective cohort analysis using TriNetX datasets compared the outcomes of two cohorts: PTA without CT and PTA with CT. Measured outcomes included incision and drainage; quinsy adenotonsillectomy; recurrent PTA; airway emergency/obstruction; repeat emergency department (ED) visits; and need for antibiotics, opiates, or steroids. Odds ratios (OR) were calculated using a cohort analysis. RESULTS: The CT usage group had increased odds of receiving antibiotics (OR 3.043, [2.043-4.531]), opiates (OR 1.614, [1.138-1.289]), and steroids (OR 1.373, [1.108-1.702]), as well as a higher likelihood of returning to the ED (OR 5.900, [3.534-9.849]) and developing a recurrent PTA (OR 1.943, [1.410-2.677]). No significant differences were observed in the incidence of incision and drainage, quinsy adenotonsillectomy, or airway emergency/obstruction. CONCLUSION: Our study indicated that CT scans for PTA diagnosis were associated with increased prescription of antibiotics, opioids, steroids, return ED visits, and recurrent PTA. Future prospective trials are needed to determine if the use of CT scans indicates higher patient acuity that explains the potential negative outcomes. LEVEL OF EVIDENCE: Level II Laryngoscope, 2024.

Reversal of MYB-dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML.

The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.

Evidence for reduced BRCA2 functional activity in Homo sapiens after divergence from the chimpanzee-human last common ancestor.

We performed a comparative analysis of human and 12 non-human primates to identify sequence variations in known cancer genes. We identified 395 human-specific fixed non-silent substitutions that emerged during evolution of human. Using bioinformatics analyses for functional consequences, we identified a number of substitutions that are predicted to alter protein function; one of these mutations is located at the most evolutionarily conserved domain of human BRCA2.

Author Correction: High WBP5 expression correlates with elevation of HOX genes levels and is associated with inferior survival in patients with acute myeloid leukaemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

High WBP5 expression correlates with elevation of HOX genes levels and is associated with inferior survival in patients with acute myeloid leukaemia.

WW domain binding protein 5 (WBP5), also known as Transcriptional Elongation Factor A like 9 (TCEAL9) has been proposed as a candidate oncogene for human colorectal cancers with microsatellite instability and as a predictive indicator of small cell lung cancers. Furthermore, several independent studies have proposed WBP5, and its association with Wilms Tumor-1 (WT1) expression, as part of a gene expression-based risk score for predicting survival and clinical outcome in patients with Acute Myeloid Leukaemia (AML). To date, the prognostic significance of the sole WBP5 expression and its impact on the survival outcome in AML patients remains largely understudied. In the present study, we have made use of publicly available patient expression arrays and have developed an unbiased approach to classify AML patients into low versus high WBP5 expressers and to balance them for known mutations and cytogenetic findings. Interestingly, we found that patients characterized by high WBP5 expression displayed inferior overall and event-free survival rates. Notably, gene expression profiling showed that patients with high WBP5 had elevated expression of several HOX cluster genes, such as HOXA5, HOXA7, HOXA9 and HOXA10, and several of their partner proteins, such as MEIS1 and FOXC1, which have been demonstrated to be causative for AML. Taken together, our data suggest that WBP5 expression level could serve as an indicator for prognosis and survival outcome in patients with AML.

Combined neurosurgical and orbital intervention for spheno-orbital meningiomas - the Manchester experience.

PURPOSE: Surgical resection of spheno-orbital meningioma (SOM) is challenging, requiring a multidisciplinary surgical approach. We present our experience of the surgical management of patients with SOM. METHODS: A retrospective analysis of patients with SOM who underwent joint neurosurgical and orbital surgical procedures between January 2000 and June 2017. Pre-operative clinical signs, indication for surgery, surgical complications and post-operative outcomes were recorded. RESULTS: Twenty-four operations were performed. Mean age was 49.5 years. Ninety-two percent of patients were female. Pre-operatively mean Snellen acuity vision was 6/12; 13 (54%) had an RAPD; 12 (50%) had reduced colour vision; 16 (67%) had a visual field defect. The majority (21 patients, 88%) had proptosis (average 4.5 mm ± 2.8 mm). The indication for surgery was evidence of visual dysfunction in 17 (71%), the remaining 7 (29%) had high risk of visual loss clinically or radiologically. Three-months post operatively, vision was stable in 13 (58%), improved in 6 (21%) and worse in 5 (17%). Average long-term follow-up was 82 months (1-220). Fourteen (58%) maintain improved or stable visual function. Four (17%) had reduced vision due to regrowth of the tumour at an average of 24 months. CONCLUSION: SOMs are very challenging to treat surgically. In this cohort the patients were predominantly young females with aggressive disease. Visual function was improved or stabilised in 79% of the patients.

Implantable biosensors and their contribution to the future of precision medicine.

Precision medicine can be defined as the prevention, investigation and treatment of diseases taking individual variability into account. There are multiple ways in which the field of precision medicine may be advanced; however, recent innovations in the fields of electronics and microfabrication techniques have led to an increased interest in the use of implantable biosensors in precision medicine. Implantable biosensors are an important class of biosensors because of their ability to provide continuous data on the levels of a target analyte; this enables trends and changes in analyte levels over time to be monitored without any need for intervention from either the patient or clinician. As such, implantable biosensors have great potential in the diagnosis, monitoring, management and treatment of a variety of disease conditions. In this review, we describe precision medicine and the role implantable biosensors may have in this field, along with challenges in their clinical implementation due to the host immune responses they elicit within the body.

A qualitative synthesis of gastro-oesophageal reflux in bronchiectasis: Current understanding and future risk.

Gastro-oesophageal reflux disease (GORD) is a common comorbidity in bronchiectasis, and is often associated with poorer outcomes. The cause and effect relationship between GORD and bronchiectasis has not yet been fully elucidated and a greater understanding of the pathophysiology of the interaction and potential therapies is required. This review explores the underlying pathophysiology of GORD, its clinical presentation, risk factors, commonly applied diagnostic tools, and a detailed synthesis of original articles evaluating the prevalence of GORD, its influence on disease severity and current management strategies within the context of bronchiectasis. The prevalence of GORD in bronchiectasis ranges from 26% to 75%. Patients with co-existing bronchiectasis and GORD were found to have an increased mortality and increased bronchiectasis severity, manifest by increased symptoms, exacerbations, hospitalisations, radiological extent and chronic infection, with reduced pulmonary function and quality of life. The pathogenic role of Helicobacter pylori infection in bronchiectasis, perhaps via aspiration of gastric contents, also warrants further investigation. Our index of suspicion for GORD should remain high across the spectrum of disease severity in bronchiectasis. Identifying GORD in bronchiectasis patients may have important therapeutic and prognostic implications, although clinical trial evidence that treatment targeted at GORD can improve outcomes in bronchiectasis is currently lacking.

Oral health and dental morbidity in long-term allogeneic blood and marrow transplant survivors in Australia.

BACKGROUND: Oral and dental disease is a major cause of long-term morbidity following allogeneic blood and marrow transplantation (Allo-BMT). This study aimed to describe the extent and range of oral and dental complications in BMT recipients and to identify gaps in service provision provided to this high-risk group. METHODS: Participants were Allo-BMT recipients, aged >18 years, and received transplants between 2000 and 2012 in NSW. They completed seven surveys, the purpose-designed Sydney Post-BMT Study survey and six other validated instruments. RESULTS: Of 441 respondents, many reported dry mouth (45.1%), dental caries (36.7%), mouth ulcers (35.3%), oral GVHD (35.1%), gingivitis (16.2%), tooth abscess (6.1%) and oral cancer (1.5%). Regular dental visits were reported by 66.2% of survivors. Middle-high income, older age and geographic location showed a positive association with regular dental visits. Of those who did not visit the dentist regularly, 37% stated they did not feel it necessary, 36% reported cost and 20% stated it was not advised by the treating team. CONCLUSION: Despite oral complications commonly occurring after Allo-BMT, many survivors receive inadequate dental care. These results emphasize the need for improved oral health education, the importance of regular dental checks and improvement in the delivery of dental health services for BMT survivors.

Spinal ependymomas in NF2: a surgical disease?

The management of spinal cord ependymomas in Neurofibromatosis Type 2 (NF2) has traditionally been conservative, in contrast to the management of sporadic cases; the assumption being that, in the context of NF2, they did not cause morbidity. With modern management and improved outcome of other NF2 tumours, this assumption, and therefore the lack of role for surgery, has been questioned. To compare the outcome of conservative treatment of spinal ependymomas in NF2 with surgical intervention in selected patients. Retrospective review at two NF2 centers, Manchester, UK and Paris/Lille, France. In Manchester patients were managed conservatively. In France surgery was a treatment option. Inclusion in the study was based on tumor length of greater than 1.5 cm. The primary parameter assessed was acquired neurological deficit measured by the Modified McCormick Outcome Score. 24 patients from Manchester and 46 patients from France were analyzed. From Manchester, 27% of these patients deteriorated during the course of follow-up. This effectively represents the natural history of ependymomas in NF2. Of the surgical cases, 23% deteriorated postoperatively, but only 2/18 (11%) of those operated on in the NF2 specialist centers. Comparison of the two specialist centers Manchester/France showed a significantly improved outcome (P = 0.012, χ2 test) in the actively surgical center. Spinal ependymomas produce morbidity. Surgery can prevent or improve this in selected cases but can itself can produce morbidity. Surgery should be considered in growing/symptomatic ependymomas, particularly in the absence of overwhelming tumor load where bevacizumab is the preferred option.

Mean platelet diameter measurements to classify inherited thrombocytopenias.

INTRODUCTION: Mean platelet volume (MPV) assists the differential diagnosis of inherited thrombocytopenia (IT) but lacks standardisation and varies between automated analysers. Classification of IT based on mean platelet diameter (MPD) has been proposed by an international collaborative study but has not been validated. METHODS: To assess the applicability of MPD to classify forms of IT, digital images of blood films from patients with established genetic causes for IT were generated, and the MPD measured (ZEISS Axio-scanner and Image J software) by a blinded reviewer. Comparison was made to the proposed classification system. RESULTS: Mean platelet volume was measured in thrombocytopenia with different genetic aetiologies, bilallelic BSS (bBSS) (n = 1), monoallelic BSS (mBSS) (n = 2), MYH9-related disorders (MYH9-RD) (n = 11), GFI1B-related thrombocytopenia (RT) (n = 15), FLI1-RT (n = 2), TUBB1-RT (n = 3), ITGA2B/ITGB3-RT (n = 1), RUNX1-RT (n = 2) and controls (n = 54). bBSS and 82% of MYH9-RD samples had MPD >4 µm which correlated with "IT with giant platelets." Only 55% of samples expected in the "large platelet group" had MPD meeting the classification cut-off (MPD >3.2 µm). FLI1-RT MPD were significantly larger than expected whilst ITGA2B/ITGB3-RT MPD were smaller than proposed. MPD in FPD/AML were "normal." CONCLUSION: Platelet MPD measurements are a useful guide to classify IT, but the time taken to record measurements may limit clinical applicability.

Thrombocytopenia and CD34 expression is decoupled from α-granule deficiency with mutation of the first growth factor-independent 1B zinc finger.

Essentials The phenotypes of different growth factor-independent 1B (GFI1B) variants are not established. GFI1B variants produce heterogeneous clinical phenotypes dependent on the site of mutation. Mutation of the first non-DNA-binding zinc-finger causes a mild platelet and clinical phenotype. GFI1B regulates the CD34 promoter; platelet CD34 expression is an indicator of GFI1B mutation. SUMMARY: Background Mutation of the growth factor-independent 1B (GFI1B) fifth DNA-binding zinc-finger domain causes macrothrombocytopenia and α-granule deficiency leading to clinical bleeding. The phenotypes associated with GFI1B variants disrupting non-DNA-binding zinc-fingers remain uncharacterized. Objectives To determine the functional and phenotypic consequences of GFI1B variants disrupting non-DNA-binding zinc-finger domains. Methods The GFI1B C168F variant and a novel GFI1B c.2520 + 1_2520 + 8delGTGGGCAC splice variant were identified in four unrelated families. Phenotypic features, DNA-binding properties and transcriptional effects were determined and compared with those in individuals with a GFI1B H294 fs mutation of the fifth DNA-binding zinc-finger. Patient-specific induced pluripotent stem cell (iPSC)-derived megakaryocytes were generated to facilitate disease modeling. Results The DNA-binding GFI1B variant C168F, which is predicted to disrupt the first non-DNA-binding zinc-finger domain, is associated with macrothrombocytopenia without α-granule deficiency or bleeding symptoms. A GFI1B splice variant, c.2520 + 1_2520 + 8delGTGGGCAC, which generates a short GFI1B isoform that lacks non-DNA-binding zinc-fingers 1 and 2, is associated with increased platelet CD34 expression only, without quantitative or morphologic platelet abnormalities. GFI1B represses the CD34 promoter, and this repression is attenuated by different GFI1B zinc-finger mutations, suggesting that deregulation of CD34 expression occurs at a direct transcriptional level. Patient-specific iPSC-derived megakaryocytes phenocopy these observations. Conclusions Disruption of GFI1B non-DNA-binding zinc-finger 1 is associated with mild to moderate thrombocytopenia without α-granule deficiency or bleeding symptomatology, indicating that the site of GFI1B mutation has important phenotypic implications. Platelet CD34 expression appears to be a common feature of perturbed GFI1B function, and may have diagnostic utility.

Hearing optimisation in neurofibromatosis type 2: A systematic review.

BACKGROUND: It is common for patients with neurofibromatosis type 2 to develop bilateral profound hearing loss hearing loss, and this is one of the main determinants of quality of life in this patient group. OBJECTIVES: The aim of this systematic review was to review the current literature regarding hearing outcomes of treatments for vestibular schwannomas in neurofibromatosis type 2 including conservative and medical management, radiotherapy, hearing preservation surgery and auditory implantation in order to determine the most effective way of preserving or rehabilitating hearing. SEARCH STRATEGY: A MESH search in PubMed using search terms (('Neurofibromatosis 2' [Mesh]) AND 'Neuroma, Acoustic'[Mesh]) AND 'Hearing Loss' [Mesh] was performed. A search using keywords was also performed. Studies with adequate hearing outcome data were included. With the exception of the cochlear implant studies (cohort size was very small), case studies were excluded. EVALUATION METHOD: The GRADE system was used to assess quality of publication. Formal statistical analysis of data was not performed because of very heterogenous data reporting. RESULTS: Conservative management offers the best chance of hearing preservation in stable tumours. The use of bevacizumab probably improves the likelihood of hearing preservation in growing tumours in the short term and is probably more effective than hearing preservation surgery and radiotherapy in preserving hearing. Of the hearing preservation interventions, hearing preservation surgery probably offers better hearing preservation rates than radiotherapy for small tumours but recurrence rates for hearing preservation surgery were high. For patients with profound hearing loss, cochlear implantation provides significantly better auditory outcomes than auditory brainstem implantation. Patients with untreated stable tumours are likely to achieve the best outcomes from cochlear implantation. Those who have had their tumours treated with surgery or radiotherapy do not gain as much benefit from cochlear implantation than those with untreated tumours. CONCLUSIONS: This review summarises the current literature related to hearing preservation/rehabilitation in patients with NF2. Whilst it provides indicative data, the quality of the data was low and should be interpreted with care. It is also important to consider that the management of vestibular schwannomas in NF2 is complex and decision-making is determined by many factors, not just the need to preserve hearing.

Nontuberculous mycobacteria in gastrostomy fed patients with cystic fibrosis.

Multi-drug resistant Mycobacterium abscessus complex (MABSC) is a form of Nontuberculous mycobacteria (NTM) of special, international concern in Cystic Fibrosis (CF). We hypothesised that gastric juice and percutaneous endoscopic gastrostomy (PEG) feeding devices might yield MABSC isolates. Gastric juice and sputa from sixteen adult PEG fed CF patients and five replaced PEG tubes were studied. Bacterial and fungal isolates were cultured. Mycobacterium were identified by rpoB, sodA and hsp65 gene sequencing and strain typed using variable number tandem repeat. Bacteria and/or fungi grew from all gastric juice, sputa and PEG samples. MABSC were detected in 7 patients. Five had MABSC in their sputum. Two had an identical MABSC strain in their sputum and gastric juice and one had the same strain isolated from their PEG tube and sputum. Two patients who were sputum sample negative had MABSC isolated in their gastric juice or PEG tube. MABSC were therefore identified for the first time from a gastric sample in a minority of patients. We conclude that gastric juice and PEG-tubes may be a potential source of MABSC isolates in CF patients, and these findings warrant further study.

The albumin-bilirubin grade improves hepatic reserve estimation post-sorafenib failure: implications for drug development.

BACKGROUND: Drug development in hepatocellular carcinoma (HCC) is limited by disease heterogeneity, with hepatic reserve being a major source of variation in survival outcomes. The albumin-bilirubin (ALBI) grade is a validated index of liver function in patients with HCC. AIM: To test the accuracy of the ALBI grade in predicting post-sorafenib overall survival (PSOS) in patients who permanently discontinued treatment. METHODS: From a prospectively maintained international database of 447 consecutive referrals, we derived 386 eligible patients treated with sorafenib within Barcelona Clinic Liver Cancer C stage (62%), 75% of whom were of Child class A at initiation. Clinical variables at sorafenib discontinuation were analysed for their impact on post-sorafenib overall survival using uni- and multivariable analyses. RESULTS: Median post-sorafenib overall survival of the 386 eligible patients was 3.4 months and median sorafenib duration was 2.9 months, with commonest causes of cessation being disease progression (68%) and toxicity (24%). At discontinuation, 92 patients (24%) progressed to terminal stage, due to worsening Child class to C in 40 (10%). Median post-sorafenib overall survival in patients eligible for second-line therapies (n = 294) was 17.5, 7.5 and 1.9 months according respectively to ALBI grade 1, 2 and 3 (P < 0.001). CONCLUSIONS: The ALBI grade at sorafenib discontinuation identifies a subset of patients with prolonged stability of hepatic reserve and superior survival. This may allow improved patient selection for second-line therapies in advanced HCC.

Evaluation of hepatitis C testing in men who have sex with men, and associated risk behaviours, in Manchester, UK.

OBJECTIVE: To determine the prevalence of newly diagnosed hepatitis C virus (HCV) and associated risk behaviours among men who have sex with men (MSM) in Manchester. METHOD: A survey among MSM attending four genitourinary medicine clinics in Manchester was carried out over 9 months in 2013. Participants were asked about recent sexual behaviour, recreational drug use and HIV status. All men were offered an HCV test. RESULTS: Overall, 2030 MSM completed a questionnaire and accepted an HCV test. Of whom, 0.9% (18) were newly diagnosed with HCV, including 1.8% (13/735) of HIV-positive MSM, 0.7% (3/440) of MSM of unknown HIV status and 0.2% (2/855) of HIV-negative MSM. HCV positivity was significantly associated with HIV status (p<0.001). When compared with HIV-negative MSM, HIV-positive MSM had higher rates of sharing snorting drug equipment, injecting drugs/'slamming' and using recreational drugs (all p<0.05) but lower rates of five or more sexual partners and insertive unprotected anal intercourse (p<0.05). MSM newly diagnosed with HCV had significantly higher prevalence of unprotected sex, sex with someone HCV positive, fisting, group sex, ever injecting drugs/'slamming' and recreational drug use (p<0.002). CONCLUSIONS: In this survey, HIV-positive MSM had significantly different drug use behaviour which may explain the higher HCV burden. However, HCV was also associated with HIV-negative MSM engaging in high-risk sexual practices. All MSM attending sexual health clinics must have a risk assessment and HCV screening should be offered based on the risk. Further studies are warranted to explore the interplay between HCV and HIV risk associated with drug use versus sexual practices.

Transcriptional regulation of SPROUTY2 by MYB influences myeloid cell proliferation and stem cell properties by enhancing responsiveness to IL-3.

Myeloproliferative neoplasms (MPN), which overproduce blood cells in the bone marrow, have recently been linked with a genetically determined decrease in expression of the MYB transcription factor. Here, we use a mouse MYB knockdown model with an MPN-like phenotype to show how lower levels of MYB lead to stem cell characteristics in myeloid progenitors. The altered progenitor properties feature elevated cytokine responsiveness, especially to interleukin-3, which results from increased receptor expression and increased MAPK activity leading to enhanced phosphorylation of a key regulator of protein synthesis, ribosomal protein S6. MYB acts on MAPK signaling by directly regulating transcription of the gene encoding the negative modulator SPRY2. This mechanistic insight points to pathways that might be targeted therapeutically in MPN.

Bile acids: a potential role in the pathogenesis of pharyngeal malignancy.

OBJECTIVE: Gastro-oesophageal reflux disease is thought to be a risk factor for head and neck malignancies. Bile acids are one of the principle components of gastric refluxate and have previously been implicated in the development of oesophageal and bowel malignancies. There is clear evidence that bile acids reflux into the laryngopharynx. Despite this, the carcinogenic properties of bile acids in this area are yet to be fully identified. We therefore investigated the potential role of bile acids in pharyngeal malignancy, through the highly conserved process of epithelial-mesenchymal transition (EMT). EMT occurs in invasion and metastasis and is a central process in the development of epithelial carcinoma. DESIGN: Translational research study. METHODS: Human hypopharyngeal squamous carcinoma FaDu cells were challenged with primary (cholic or chenodeoxycholic) and secondary (deoxycholic or lithocholic) bile acids. EMT-relevant proteins TGF-ß1 and MMP-9 were measured in the cell culture supernates at 48 h via ELISA. Cell viability was confirmed >95% via CellTiter-Blue assay. RESULTS: Significantly greater concentrations of TGF-ß1 were measured in the culture supernates of cells treated with cholic acid, deoxycholic acid and chenodeoxycholic acid. MMP-9 levels were increased in deoxycholic acid and lithocolic acid stimulations when compared to control (P < 0.05). CONCLUSION: This is the first demonstration that bile acids induce TGF-ß1 and MMP-9 in pharyngeal cells. TGF-ß1 is considered a master switch for EMT, while MMP-9 is a part of the EMT proteome which degrades basement membranes. This implies a potential role for bile acids in pharyngeal carcinogenesis through the mechanism of EMT and suggests potential novel therapeutic targets.