A Thpok-Directed Transcriptional Circuitry Promotes Bcl6 and Maf Expression to Orchestrate T Follicular Helper Differentiation.

The generation of high-affinity neutralizing antibodies, the objective of most vaccine strategies, occurs in B cells within germinal centers (GCs) and requires rate-limiting "help" from follicular helper CD4 T (Tfh) cells. Although Tfh differentiation is an attribute of MHC II-restricted CD4 T cells, the transcription factors driving Tfh differentiation, notably Bcl6, are not restricted to CD4 T cells. Here, we identified a requirement for the CD4-specific transcription factor Thpok during Tfh cell differentiation, GC formation, and antibody maturation.

Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.

Background: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy.

Methods: We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years).

The impact of institutional clinical trial recruitment versus hospital volume on survival outcomes of patients with head and neck cancer: An analysis of the PET-NECK trial outcomes, UKCRN portfolio, and Hospital Episode Statistics (HES) in England.

Objectives: High institutional clinical trial recruitment and high hospital volume are reported to be independent indicators of better patient outcomes following cancer treatment. However, their relationship in head and neck cancers (HNC) remains less clear.

Methods: We aimed to assess the relationship between institutional clinical trial recruitment, hospital throughput of HNC cases, and survival of patients with advanced HNC treated with primary chemoradiotherapy at hospitals which recruited to the PET-NECK trial (2008-2012).

Cost-effectiveness analysis of PET-CT-guided management for locally advanced head and neck cancer.

Background: A recent large United Kingdom (UK) clinical trial demonstrated that positron-emission tomography-computed tomography (PET-CT)-guided administration of neck dissection (ND) in patients with advanced head and neck cancer after primary chemo-radiotherapy treatment produces similar survival outcomes to planned ND (standard care) and is cost-effective over a short-term horizon. Further assessment of long-term outcomes is required to inform a robust adoption decision. Here we present results of a lifetime cost-effectiveness analysis of PET-CT-guided management from a UK secondary care perspective.

PET-NECK: a multicentre randomised Phase III non-inferiority trial comparing a positron emission tomography-computerised tomography-guided watch-and-wait policy with planned neck dissection in the management of locally advanced (N2/N3) nodal metastases in patients with squamous cell head and neck cancer.

Background: Planned neck dissection (ND) after radical chemoradiotherapy (CRT) for locally advanced nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) remains controversial. Thirty per cent of ND specimens show histological evidence of tumour. Consequently, a significant proportion of clinicians still practise planned ND.

Hand exercises for patients with rheumatoid arthritis: an extended follow-up of the SARAH randomised controlled trial.

Objectives: The Stretching And strengthening for Rheumatoid Arthritis of the Hand (SARAH) randomised controlled trial evaluated the effectiveness of a hand exercise programme and demonstrated it was clinically effective and cost-effective at 12 months. The aim of this extended follow-up was to evaluate the effects of the SARAH programme beyond 12 months.

Methods: Using postal questionnaires, we collected the Michigan Hand Questionnaire hand function (primary outcome), activities of daily living and work subscales, pain troublesomeness, self-efficacy and health-related quality of life.

Outrunning the Red Queen: bystander activation as a means of outpacing innate immune subversion by intracellular pathogens.

Originally described by the late evolutionary biologist Leigh Van Valen, the Red Queen hypothesis posits that the evolutionary arms race between hosts and their pathogens selects for discrete, genetically encoded events that lead to competitive advantages over the other species. Examples of immune evasion strategies are seen throughout the co-evolution of the mammalian immune system and pathogens, such as the enzymatic inactivation of nuclear factor-κB signaling or host translation by pathogen-encoded virulence factors. Such immunoevasive maneuvers would be expected to select for the evolution of innate immune counterstrategies.

PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer.

Background: The role of image-guided surveillance as compared with planned neck dissection in the treatment of patients with squamous-cell carcinoma of the head and neck who have advanced nodal disease (stage N2 or N3) and who have received chemoradiotherapy for primary treatment is a matter of debate.

Methods: In this prospective, randomized, controlled trial, we assessed the noninferiority of positron-emission tomography-computed tomography (PET-CT)-guided surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck dissection performed only if PET-CT showed an incomplete or equivocal response) to planned neck dissection in patients with stage N2 or N3 disease. The primary end point was overall survival.

A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance.

In eutherians, the placenta acts as a barrier and conduit at the maternal-fetal interface. Syncytiotrophoblasts, the multinucleated cells that cover the placental villous tree surfaces of the human placenta, are directly bathed in maternal blood and are formed by the fusion of progenitor cytotrophoblasts that underlie them. Despite their crucial role in fetal protection, many of the events that govern trophoblast fusion and protection from microbial infection are unknown.

Predicting Anthracycline Benefit: TOP2A and CEP17-Not Only but Also.

Purpose: Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient-level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer.

Patients And Methods: Fluorescent in situ hybridization for CEP17, HER2, and TOP2A was performed in three laboratories on samples from 3,846 of 4,864 eligible patients from five trials evaluating anthracycline-containing chemotherapy versus CMF.

Strengthening And stretching for Rheumatoid Arthritis of the Hand (SARAH). A randomised controlled trial and economic evaluation.

Background: The effectiveness of exercise for improving hand and wrist function in people with rheumatoid arthritis (RA) is uncertain.

Objectives: The study aims were (1) to estimate the clinical effectiveness and cost-effectiveness of adding an optimised exercise programme for hands and upper limbs to standard care for patients with RA; and (2) to qualitatively describe the experience of participants in the trial with a particular emphasis on acceptability of the intervention, exercise behaviours and reasons for adherence/non-adherence.

Design: A pragmatic, multicentred, individually randomised controlled trial with an embedded qualitative study.

Exercises to improve function of the rheumatoid hand (SARAH): a randomised controlled trial.

Background: Disease-modifying biological agents and other drug regimens have substantially improved control of disease activity and joint damage in people with rheumatoid arthritis of the hand. However, commensurate changes in function and quality of life are not always noted. Tailored hand exercises might provide additional improvements, but evidence is lacking.

Linking genetic variation in human Toll-like receptor 5 genes to the gut microbiome's potential to cause inflammation.

Immunodeficiencies can lead to alterations of the gut microbiome that render it pathogenic and capable of transmitting disease to naïve hosts. Here, we review the role of Toll-like receptor (TLR) 5, the innate receptor for bacterial flagellin, in immune responses to the normal gut microbiota with a focus its role on adaptive immunity. Loss of TLR5 has profound effects on the microbiota that include greater temporal instability of major lineages and upregulation of flagellar motility genes that may be linked to the reduced levels of anti-flagellin antibodies in the TLR5(-/-) host.

Investigation of p16(INK4a) as a prognostic biomarker in oral epithelial dysplasia.

Background: Human papilloma virus is a risk factor for oropharyngeal cancer. Evidence for a similar aetiological role in the development of oral dysplasia or its transformation to oral cancer is not as clear. Meta-analyses estimate the prevalence of high-risk human papilloma virus (HPV) serotypes to be three times higher in pre-malignant lesions and cancer than in normal oral mucosa.

Revised radiobiological modelling of the contribution of synchronous chemotherapy to the rate of grades 3-4 mucositis in head and neck cancer.

Introduction: Biological effective dose (BED) calculations modelled on reduced accelerated repopulation when synchronous chemotherapy is delivered significantly correlate with observed differences in local control in randomised trials of platinum-based chemoradiation. The purpose of this study was to examine whether a similar relationship existed in the context of grades 3-4 mucositis.

Methods: Biological effective dose from radiotherapy and synchronous chemotherapy was calculated using three different models: AB using the additional BED attributable to chemotherapy and standard repopulation parameters; zero repopulation (ZRP) using zero correction for repopulation; and variable t(p) (Vt(p)) using a variable doubling time for mucosal stem cell repopulation.

Tetraspanins CD9 and CD151, epidermal growth factor receptor and cyclooxygenase-2 expression predict malignant progression in oral epithelial dysplasia.

Background: Prognostic biomarkers aim to improve on the current inadequate method of histological assessment to identify patients with oral epithelial dysplasia at greatest risk of malignant transformation. We aimed to assess the prognostic ability of six protein biomarkers linked to the epidermal growth factor receptor (EGFR) pathway, including three tetraspanins, in a large multicentre oral dysplasia cohort.

Methods: One hundred and forty-eight cases with varying degrees of epithelial dysplasia underwent immunohistochemical assessment for CD9, CD151, CD82, EGFR, Her-2, and COX-2.

LIHNCS - Lugol's iodine in head and neck cancer surgery: a multicentre, randomised controlled trial assessing the effectiveness of Lugol's iodine to assist excision of moderate dysplasia, severe dysplasia and carcinoma in situ at mucosal resection margins of oral and oropharyngeal squamous cell carcinoma: study protocol for a randomised controlled trial.

Background: Oral cavity and oropharynx cancer are increasing in incidence worldwide but survival outcomes have not significantly improved over the last three decades. The presence of dysplasia or carcinoma in situ at surgical margins following resection of squamous carcinoma of the mucosal surfaces of the head and neck has been shown to be associated with a higher incidence of local recurrence and reduced survival. While invasive carcinoma in mucosal surfaces can usually be distinguished from adjacent normal mucous membrane, pre-malignant disease is much less readily distinguished at operation.

Revising the radiobiological model of synchronous chemotherapy in head-and-neck cancer: a new analysis examining reduced weighting of accelerated repopulation.

Purpose: Previous studies of synchronous chemoradiation therapy have modeled the additional effect of chemotherapy as additional radiation therapy biologically effective dose (BED). Recent trials of accelerated versus conventional fractionation chemoradiation have cast doubt on such modeling. The purpose of this study was to identify alternative models.

The binary oral dysplasia grading system: validity testing and suggested improvement.

Objectives: A binary system is reputed to be superior to the World Health Organization (WHO) system in grading oral dysplasia. We aimed to validate its reproducibility and prognostic ability and examine whether it could be improved.

Study Design: Three pathologists graded 141 oral epithelial dysplasia biopsies with the use of both systems.

Strengthening and stretching for rheumatoid arthritis of the hand (SARAH): design of a randomised controlled trial of a hand and upper limb exercise intervention--ISRCTN89936343.

Background: Rheumatoid Arthritis (RA) commonly affects the hands and wrists with inflammation, deformity, pain, weakness and restricted mobility leading to reduced function. The effectiveness of exercise for RA hands is uncertain, although evidence from small scale studies is promising. The Strengthening And Stretching for Rheumatoid Arthritis of the Hand (SARAH) trial is a pragmatic, multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of adding an optimised exercise programme for hands and upper limbs to best practice usual care for patients with RA.

The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients: validation in the VICTOR trial.

Background: The intra-tumor stroma percentage in colon cancer (CC) patients has previously been reported by our group as a strong independent prognostic parameter. Patients with a high stroma percentage within the primary tumor have a poor prognosis.

Patients And Methods: Tissue samples from the most invasive part of the primary tumor of 710 patients (52% Stage II, 48% Stage III) participating in the VICTOR trial were analyzed for their tumor-stroma percentage.

Catheter-induced pulmonary artery rupture: haemodynamic compromise necessitates surgical repair.

Pulmonary artery haemorrhage is thankfully a very rare complication following pulmonary artery catheter insertion. It carries a significant mortality of 50%, and most cases are managed conservatively or with embolization therapy. We present an occult case, in which a patient presented with haemodynamic compromise without haemoptysis or significant haemothorax, who required surgical intervention.

Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer--systematic review and meta-analysis of trends by time and region.

Background: Little information has been reported on regional and time trends of human papillomavirus (HPV) prevalence rates of oropharyngeal cancer (OPC) and non-OPC.

Methods: The study consisted of a systematic review and meta-analysis using random effects logistic regression models.

Results: Overall HPV prevalence in OPC (47.

Biomarkers in laryngeal dysplasia: a systematic review.

Background: Prediction of which laryngeal dysplasia cases will progress to cancer is poorly achieved. The differential expression of biomarkers in dysplastic and cancerous lesions may help to improve this.

Methods: We carried out a systematic review of laryngeal dysplasia biomarkers.