Pan-Asian adaptation of the EHNS-ESMO-ESTRO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with squamous cell carcinoma of the head and neck.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia.

Iron-withdrawing anti-infectives for new host-directed therapies based on iron dependence, the Achilles' heel of antibiotic-resistant microbes.

The iron dependence of antibiotic-resistant microbes represents an Achilles' heel that can be exploited broadly. The growing global problem of antibiotic resistance of microbial pathogens wherein microbes become resistant to the very antibiotics used against them during infection is linked not only to our health uses but also to agribusiness practices and the changing environment. Here we review mechanisms of microbial iron acquisition and host iron withdrawal defense, and the influence of iron withdrawal on the antimicrobial activity of antibiotics. Antibiotic-resistant microbes are unaltered in their iron requirements, but iron withdrawal from microbes enhances the activities of various antibiotics and importantly suppresses outgrowth of antibiotic-exposed resistant microbial survivors. Of the three therapeutic approaches available to exploit microbial iron susceptibility, including (1) use of gallium as a non-functional iron analogue, (2) Trojan horse conjugates of microbial siderophores carrying antibiotics, and (3) new generation iron chelators, purposely designed as anti-microbials, the latter offers various advantages. For instance, these novel anti-microbial chelators overcome the limitations of conventional clinically-used hematological chelators which display host toxicity and are not useful antimicrobials. 3-Hydroxypyridin-4-one-containing polymeric chelators appear to have the highest potential. DIBI (developmental code name) is a well-developed lead candidate, being a low molecular weight, water-soluble copolymer with enhanced iron binding characteristics, strong anti-microbial and anti-inflammatory activities, low toxicity for animals and demonstrated freedom from microbial resistance development. DIBI has been shown to enhance antibiotic efficacy for antibiotic-resistant microbes during infection, and it also prevents recovery growth and resistance development during microbe exposure to various antibiotics. Because DIBI bolsters innate iron withdrawal defenses of the infected host, it has potential to provide a host-directed anti-infective therapy.

Can Paediatric Femoral Fracture Hip Spica Application be Done in the Outpatient Setting?

INTRODUCTION: Hip spica casting is a standard treatment for children with femur fractures. This study compares the outcomes of spica cast application, in terms of quality of fracture reduction and hospital charges when performed in operating theatre versus outpatient clinics at a local institution. MATERIALS AND METHODS: A total of 93 paediatric patients, aged between 2 months to 8 years, who underwent spica casting for an isolated femur fracture between January 2008 and March 2019, were identified retrospectively. They were separated into inpatient or outpatient cohort based on the location of spica cast application. Five patients with metaphyseal fractures and four with un-displaced fractures were excluded. There were 13 and 71 patients in the outpatient and inpatient cohort respectively who underwent spica casting for their diaphyseal and displaced femur fractures. Variables between cohorts were compared. RESULTS: There were no significant differences in gender, fracture pattern, and mechanism of injury between cohorts. Spica casting as inpatients delayed the time from assessment to casting (23.55 ± 29.67h vs. 6.75 ± 4.27h, p<0.05), increased average hospital stay (41.2 ± 31.1h vs. 19.2 ± 15.0h, p<0.05) and average hospital charges (US$1857.14 vs US$775.49, p<0.05). Excluding the un-displaced fractures, there were no significant differences in the period of cast immobilisation and median follow-up length. Both cohorts had a similar proportion of unacceptable reduction and revision casting rate. CONCLUSION: Both cohorts presented similar spica casting outcomes of fracture reduction and follow-up period. With spica cast application in operating theatre reporting higher hospital charges and prolonged hospital stay, the outpatient clinic should always be considered for hip spica application.

Enhanced Fe3+ binding through cooperativity of 3-hydroxypyridin-4-one groups within a linear co-polymer: wrapping effect leading to superior antimicrobial activity.

To tackle the rise of antibiotic resistant pathogenic microbes, iron withdrawal agents have shown considerable promise as antibiotic alternatives due to the microbes' irreplaceable metabolic need for the essential element iron. DIBI is a water-soluble, linear co-polymer functionalized with 3-hydroxy-pyridin-4-one (HPO) chelators that selectively and strongly bind iron(III) in biological environments. Compared to HPO congeners, DIBI has over 1000 times higher antimicrobial activity against a broad-spectrum of Gram-(+) and Gram-(-) bacteria including highly antibiotic resistant clinical isolates. Herein, we explain the enhanced antimicrobial activity of DIBI by a cooperativity effect of the linear co-polymer wrapping around three iron(III) centres. DIBI's structural and iron(III) binding properties were investigated by comparative experiments against HPO monomer and deferiprone using chemical and physical characterization methods with direct biological implications such as pH stability, reductive off-loading of bound iron(III), trans-membrane permeability, and competition experiments with vertebrate transferrin class iron carrier. The three iron(III) ions bound to DIBI are preferentially incorporated into a tris-bidentate chelates, which forces the linear backbone of the polymer to wrap around the complexes, as the bound iron was much less susceptible to dithionite reduction than the tris iron(III) complexes of HPO monomers and deferiprone. The results suggest a high degree of cooperativity of the polymer-bound HPO groups to effect a wrapping of the polymer backbone around the chelated iron, shielding the iron(III) centres from ready access by microbes. The structural effect of DIBI is compared to polymers containing 3-hydroxy-pyridin-4-one chelators that do not undergo this wrapping effect.

Antibiotic-Resistant Acinetobacter baumannii Is Susceptible to the Novel Iron-Sequestering Anti-infective DIBI In Vitro and in Experimental Pneumonia in Mice.

Acinetobacter baumannii is a major cause of nosocomial infections especially hospital-acquired pneumonia. This bacterium readily acquires antibiotic resistance traits and therefore, new treatment alternatives are urgently needed. The virulence of A. baumannii linked to iron acquisition suggests a potential for new anti-infectives that target its iron acquisition. DIBI, a 3-hydroxypyridin-4-one chelator, is a purpose-designed, iron-sequestering antimicrobial that has shown promise for treating microbial infection. DIBI was investigated for its in vitro and in vivo activities against clinical A. baumannii isolates. DIBI was inhibitory for all isolates tested with very low MICs (2 µg/ml, equivalent to 0.2 µM), i.e., at or below the typical antibiotic MICs reported for antibiotic-sensitive strains. DIBI inhibition is Fe specific, and it caused an iron-restricted bacterial physiology that led to enhanced antibiotic killing by several discrete antibiotics. DIBI also strongly suppressed recovery growth of the surviving population following antibiotic exposure. A low intranasal dose (11 µmol/kg) of DIBI after intranasal challenge with hypervirulent ciprofloxacin (CIP)-resistant A. baumannii LAC-4 significantly reduced bacterial burdens in mice, and DIBI also suppressed the spread of the infection to the spleen. Treatment of infected mice with CIP alone (20 mg/kg, equivalent to 60 µmol/kg) was ineffective given LAC-4's CIP resistance, but if combined with DIBI, the treatment efficacy improved significantly. Our evidence suggests that DIBI restricts host iron availability to A. baumannii growing in the respiratory tract, bolstering the host innate iron restriction mechanisms. DIBI has potential as a sole anti-infective or in combination with conventional antibiotics for the treatment of A. baumannii pneumonia.

DIBI, a 3-hydroxypyridin-4-one chelator iron-binding polymer with enhanced antimicrobial activity.

Depriving microorganisms of bioavailable iron is a promising strategy for new anti-infective agents. The new, highly water-soluble, low molecular weight co-polymer DIBI was developed to selectively bind iron(iii) ions as a tris chelate and acts as a standalone anti-infective. Minimum inhibitory concentration (MIC) studies show DIBI is effective against representative reference strains for Gram-positive and Gram-negative bacteria S. aureus and A. baumannii, and the fungus C. albicans. Compared to the small molecule iron chelators, deferiprone and deferoxamine, DIBI outclassed these by factors of 100 to 1000 for inhibition of initial growth. DIBI and a series of related co-polymers (Mw of 2-9 kDa) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization of a chelating 3-hydroxypyridin-4-one (HPO) methacrylamide monomer and N-vinylpyrrolidone (NVP). Full incorporation of the HPO monomer into the co-polymers from the reaction solution was determined by 1H NMR spectroscopy and ranged from 4.6 to 25.6 mol%. UV-vis spectroscopy showed that all the HPO in DIBI binds readily to iron(iii) in a tris chelate mode to the maximum theoretical iron(iii) binding capacity of the co-polymer. Chemical characterization including single crystal X-ray diffraction analyses of the O-benzyl protected and the functional HPO monomer are discussed. By design, DIBI is highly water soluble; the highest mass fraction in water tested was 70% w/w, without the need of organic co-solvents.

Donor-Derived Candida dubliniensis Resulting in Perigraft Abscesses in a Liver Transplant Recipient Proven by Whole Genome Sequencing: A Case Report.

BACKGROUND: The transmission of fungi via transplant, although well-known, has not often been molecularly proven. We describe a case of donor-derived candidiasis verified by whole genome sequencing. CASE DESCRIPTION: The multiorgan donor was a 42-year-old woman with subdural hemorrhage. Procurement of the thoracic organs was performed followed by the abdominal organs. Tissue from the left bronchus grew Candida dubliniensis. The liver recipient was a 63-year-old woman with cryptogenic liver cirrhosis. She was noted to have worsening leukocytosis on postoperative day (POD) 9. Computed tomography of the abdomen and pelvis showed multiple rim-enhancing collections around the graft. Percutaneous drainage was performed. Fluid cultures grew C dubliniensis. C dubliniensis isolated from the donor's left bronchus and the liver recipient's abscesses were verified to be related by whole genome sequencing. We postulate that C dubliniensis colonizing the donor's transected trachea could have contaminated the inferior vena cava when the former was left open after explant of the donor's lungs. A portion of the donor's contaminated inferior vena cava was transplanted along with the liver graft, resulting in the infected collections in the recipient. CONCLUSIONS: Our case report highlights the importance of maintaining a sterile field during organ procurement, especially in a multiorgan donor whose organs are explanted in succession.

An overview of the clinical applications of optical coherence tomography angiography.

Optical coherence tomography angiography (OCTA) has emerged as a novel, non-invasive imaging modality that allows the detailed study of flow within the vascular structures of the eye. Compared to conventional dye angiography, OCTA can produce more detailed, higher resolution images of the vasculature without the added risk of dye injection. In our review, we discuss the advantages and disadvantages of this new technology in comparison to conventional dye angiography. We provide an overview of the current OCTA technology available, compare the various commercial OCTA machines technical specifications and discuss some future software improvements. An approach to the interpretation of OCTA images by correlating images to other multimodal imaging with attention to identifying potential artefacts will be outlined and may be useful to ophthalmologists, particularly those who are currently still unfamiliar with this new technology. This review is based on a search of peer-reviewed published papers relevant to OCTA according to our current knowledge, up to January 2017, available on the PubMed database. Currently, many of the published studies have focused on OCTA imaging of the retina, in particular, the use of OCTA in the diagnosis and management of common retinal diseases such as age-related macular degeneration and retinal vascular diseases. In addition, we describe clinical applications for OCTA imaging in inflammatory diseases, optic nerve diseases and anterior segment diseases. This review is based on both the current literature and the clinical experience of our individual authors, with an emphasis on the clinical applications of this imaging technology.

Penetrating foreign body in the masticator space with injury to the internal maxillary artery: a surgical challenge.

INTRODUCTION Foreign bodies (FBs) in the masticator space (MS) are a unique problem because of the difficulty of accessing this deep compartment within the head and neck. In addition, MS contents include critical structures such as the internal maxillary artery (IMA) and mandibular nerve. CASE HISTORY A 39-year-old tradesman was involved in a construction accident whereby a metallic projectile from a machinery drill penetrated his left cheek. Computed tomography revealed a metallic object of dimension 1.9 ×1.2 cm within the MS, with concomitant fracture of left maxillary anterior and lateral walls. Surgery was indicated in view of constant pain and swelling. The FB was removed through the cheek laceration with the aid of an X-ray image intensifier. Persistent significant bleeding was observed within the wound cavity after FB removal that could not be arrested despite attempts at haemostasis with adrenaline packing and oxidised cellulose polymers. Urgent selective left external carotid angiography showed breach of a distal branch of the left internal maxillary artery with contrast extravasation. Embolisation of this branch was undertaken successfully with a liquid agent. CONCLUSIONS This is the first time a FB within the MS with injury to the internal maxillary artery has been described.

Structure and spectroscopic properties of N,S-coordinating 2-methyl-sulfanyl-N-[(1H-pyrrol-2-yl)methyl-idene]aniline methanol monosolvate.

The reaction of pyrrole-2-carboxaldehyde and 2-(methyl-sulfan-yl)aniline in refluxing methanol gave an olive-green residue in which yellow crystals of the title compound, C12H12N2S·CH3OH, were grown from slow evaporation of methanol at 263 K. In the crystal, hydrogen-bonding inter-actions link the aniline mol-ecule and a nearby methanol solvent mol-ecule. These units are linked by a pair of weak C-H⋯Omethanol interactions, forming inversion dimers consisting of two main molecules and two solvent molecules.

Inhibition of Staphylococcus aureus by crude and fractionated extract from lactic acid bacteria.

Increasing levels of antibiotic resistance by Staphylococcus aureus have posed a need to search for non-antibiotic alternatives. This study aimed to assess the inhibitory effects of crude and fractionated cell-free supernatants (CFS) of locally isolated lactic acid bacteria (LAB) against a clinical strain of S. aureus. A total of 42 LAB strains were isolated and identified from fresh vegetables, fresh fruits and fermented products prior to evaluation of inhibitory activities. CFS of LAB strains exhibiting a stronger inhibitive effect against S. aureus were fractionated into crude protein, polysaccharide and lipid fractions. Crude protein fractions showed greater inhibition against S. aureus compared to polysaccharide and lipid fractions, with a more prevalent effect from Lactobacillus plantarum 8513 and L. plantarum BT8513. Crude protein, polysaccharide and lipid fractions were also characterised with glycine, mannose and oleic acid being detected as the major component of each fraction, respectively. Scanning electron microscopy revealed roughed and wrinkled membrane morphology of S. aureus upon treatment with crude protein fractions of LAB, suggesting an inhibitory effect via the destruction of cellular membrane. This research illustrated the potential application of fractionated extracts from LAB to inhibit S. aureus for use in the food and health industry.

Preoperative evaluation of oral tongue squamous cell carcinoma with intraoral ultrasound and magnetic resonance imaging-comparison with histopathological tumour thickness and accuracy in guiding patient management.

The aim of this study was to investigate the correlation between tumour thickness (TT) on intraoral ultrasound (US) and magnetic resonance imaging (MRI) with the histologically determined TT of tongue cancers. Secondary objectives included evaluation of potential confounders that affect this association and the predictive value for simultaneous neck dissection. Eighty-eight consecutive patients referred to the study institution between January 2007 and August 2012 with the presumptive diagnosis of invasive squamous cell carcinoma (SCC) of the tongue were analyzed. Seventy-nine patients had preoperative US and 81 had MRI. Correlation between image-determined TT and histological TT was assessed by Bland-Altman plot and Pearson's correlation coefficient. Potential confounders were assessed by subgroup analysis. Preoperative TT as determined by US demonstrated high correlation and MRI moderate correlation with histological TT. With subgroup analysis, negative associations were biopsy prior to imaging and resection diagnosis other than invasive SCC. Our experience suggests that US could be considered the initial modality of choice for preoperative assessment of TT.

IgE-mediated food allergy--diagnosis and management in New Zealand children.

AIM: To summarise the diagnosis and management of IgE-mediated food allergy (FA) in New Zealand children. METHOD: A review of the scientific literature and subsequent consensus development. RESULTS: FA is a common problem in New Zealand children with management necessitating accurate diagnosis, appropriate risk management, and reassessment over time. CONCLUSION: This paper highlights the importance of a structured approach to diagnosis and management of FA in New Zealand children, guided by appropriately skilled health professionals.

A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma.

BACKGROUND & AIMS: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma. METHODS: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume. RESULTS: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume. CONCLUSIONS: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity.

Different cellular p16(INK4a) localisation may signal different survival outcomes in head and neck cancer.

BACKGROUND: Recently, the management of head and neck squamous cell carcinoma (HNSCC) has focused considerable attention on biomarkers, which may influence outcomes. Tests for human papilloma infection, including direct assessment of the virus as well as an associated tumour suppressor gene p16, are considered reproducible. Tumours from familial melanoma syndromes have suggested that nuclear localisation of p16 might have a further role in risk stratification. We hypothesised p16 staining that considered nuclear localisation might be informative for predicting outcomes in a broader set of HNSCC tumours not limited to the oropharynx, human papilloma virus (HPV) status or by smoking status. METHODS: Patients treated for HNSCC from 2002 to 2006 at UNC (University of North Carolina at Chapel Hill) hospitals that had banked tissue available were eligible for this study. Tissue microarrays (TMA) were generated in triplicate. Immunohistochemical (IHC) staining for p16 was performed and scored separately for nuclear and cytoplasmic staining. Human papilloma virus staining was also carried out using monoclonal antibody E6H4. p16 expression, HPV status and other clinical features were correlated with progression-free (PFS) and overall survival (OS). RESULTS: A total of 135 patients had sufficient sample for this analysis. Median age at diagnosis was 57 years (range 20-82), with 68.9% males, 8.9% never smokers and 32.6% never drinkers. Three-year OS rate and PFS rate was 63.0% and 54.1%, respectively. Based on the p16 staining score, patients were divided into three groups: high nuclear, high cytoplasmic staining group (HN), low nuclear, low cytoplasmic staining group (LS) and high cytoplasmic, low nuclear staining group (HC). The HN and the LS groups had significantly better OS than the HC group with hazard ratios of 0.10 and 0.37, respectively, after controlling for other factors, including HPV status. These two groups also had significantly better PFS than the HC staining group. This finding was consistent for sites outside the oropharynx and did not require adjustment for smoking status. CONCLUSION: Different p16 protein localisation suggested different survival outcomes in a manner that does not require limiting the biomarker to the oropharynx and does not require assessment of smoking status.

Interferon-gamma release assay as a diagnostic test for tuberculosis-associated uveitis.

BACKGROUND: To study the use of interferon-gamma release assay (IFN-γ) (IGRAs) as a diagnostic test for tuberculosis (TB)-associated uveitis (TAU). DESIGN: Prospective cohort study. PARTICIPANTS: Consecutive new patients (n=162) with clinical ocular signs suggestive of TAU, seen >1 year period at a single tertiary center. METHODS: All subjects underwent investigations to rule out underlying disease, including T-SPOT.TB and tuberculin skin test (TST). Twenty-one subjects with underlying disease and three with interdeterminate T-SPOT.TB results were excluded. Those with T-SPOT.TB- or TST-positive results were referred to infectious diseases physician for evaluation. Anti-TB therapy (ATT) was prescribed if required. Patients' treatment response and recurrence were monitored for six months after completion of ATT, if given; or 1 year if no ATT was given. MAIN OUTCOME MEASURE: Diagnosis of TAU. RESULTS: Mean age of study cohort (n=138) was 46.8 ± 15.3 years. Majority were Chinese (n=80, 58.0%) and female (n=75, 54.3%). TST was more sensitive than T-SPOT.TB (72.0% vs 36.0%); but T-SPOT.TB was more specific (75.0% vs 51.1%) for diagnosing TAU. Patients with either a T-SPOT.TB (1.44; 95% confidence intervals (CI), 0.86-2.42) or TST (1.47; 95% CI, 1.12-1.94)-positive result are more likely to have TAU. The accuracy of diagnosing TAU increases when both tests are used in combination (area under the receiver operator curve=0.665; 95% CI, 0.533-0.795). Patients with both tests positive are 2.16 (95% CI, 1.23-3.80) times more likely to have TAU. Negative T-SPOT.TB or TST results do not exclude TAU (negative likelihood ratios <1.0). CONCLUSIONS: We recommend using a combination of clinical signs, IGRA, and TST to diagnose TAU.

Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers.

BACKGROUND: Gefitinib was demonstrated to be synergistic with cisplatin and radiotherapy (RT) in in vitro studies. Biomarkers predictive of response to gefitinib in squamous cell head and neck cancer is still lacking. METHODS: Thirty-one patients with locally advanced and easily accessible primary tumor sites for biopsies were recruited. Gefitinib was started 3 weeks before the start of cisplatin/concurrent radiotherapy (CTRT) and continued during the CTRT phase and thereafter for 4 months as consolidation phase. Two baselines and a repeat tumor sample were taken after 2 weeks of gefitinib alone to study its impact on tumor gene expression. Epidermal growth factor receptor (EGFR) protein expression, FISH and mutational status, and matrix metallopeptidase 11 (MMP11) protein expression were correlated with response and survival outcome. RESULTS: The overall response rate to gefitinib alone was 9.7%. The survival outcome is as follows: median disease free 1.3 years, median survival time 2.4 years, 3-year disease free 42.9%, and 3-year overall survival 48.4%. EGFR FISH, protein expression, and mutational status did not predict for response nor survival outcome of patients. Although MMP11 overexpression did not predict for response, it predicted significantly for a poorer survival outcome. CONCLUSIONS: Gefitinib can be combined safely with cisplatin/RT. More studies are needed to uncover predictive biomarkers of benefit to gefitinib.