The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK.

Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.

CompARE: study protocol for a phase III randomised controlled platform trial comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer.

Background: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival.

Methods: CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention.

Developing and Validating a Multivariable Prognostic-Predictive Classifier for Treatment Escalation of Oropharyngeal Squamous Cell Carcinoma: The PREDICTR-OPC Study.

Purpose: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC.

Experimental Design: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012.

Patient preference for commonly-used, head and neck cancer-specific quality of life questionnaires in the follow-up setting (Determin): A multi-centre randomised controlled trial and mixed methods study.

Background: Quality of life (QoL) assessment forms an integral part of modern cancer care and research. The aim of this study is to determine patients' preferences and willingness to complete commonly used head-and-neck cancer (HNC) QoL questionnaires (QLQs) in routine follow-up clinics.

Methods: This is a randomised control trial of 583 subjects from 17 centres during follow-up after treatment for oral, oropharyngeal or laryngeal cancer.

MBTPS2 acts as a regulator of lipogenesis and cholesterol synthesis through SREBP signalling in prostate cancer.

Background: Prostate cancer is the most common cancer in men in the developed world, with most deaths caused by advanced and metastatic disease which has no curative options. Here, we identified Mbtps2 alteration to be associated with metastatic disease in an unbiased in vivo screen and demonstrated its regulation of fatty acid and cholesterol metabolism.

Methods: The Sleeping Beauty transposon system was used to randomly alter gene expression in the Pten murine prostate.

The role of PPARγ in prostate cancer development and progression.

Advanced and metastatic prostate cancer is often incurable, but its dependency on certain molecular alterations may provide the basis for targeted therapies. A growing body of research has demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) is amplified as prostate cancer progresses. PPARγ has been shown to support prostate cancer growth through its roles in fatty acid synthesis, mitochondrial biogenesis, and co-operating with androgen receptor signalling.

Why are There not More Bayesian Clinical Trials? Ability to Interpret Bayesian and Conventional Statistics Among Medical Researchers.

Objective And Background: We assessed current understandings in interpretation of Bayesian and traditional statistical results within the clinical researcher (non-statistician) community.

Methods: Within a 22-question survey, including demographics and experience and comfort levels with Bayesian analyses, we included questions on how to interpret both Bayesian and traditional statistical outputs. We also assessed whether Bayesian or traditional interpretations are considered more useful.

Cryo-EM structure of a monomeric yeast S. cerevisiae complex IV isolated with maltosides: Implications in supercomplex formation.

In mitochondria, complex IV (CIV) can be found as a monomer, a dimer or in association with other respiratory complexes. The atomic structure of the yeast S. cerevisiae CIV in a supercomplex (SC) with complex III (CIII) pointed to a region of significant conformational changes compared to the homologous mammalian CIV structures.

Why are not There More Bayesian Clinical Trials? Perceived Barriers and Educational Preferences Among Medical Researchers Involved in Drug Development.

Objective And Background: The clinical trials community has been hesitant to adopt Bayesian statistical methods, which are often more flexible and efficient with more naturally interpretable results than frequentist methods. We aimed to identify self-reported barriers to implementing Bayesian methods and preferences for becoming comfortable with them.

Methods: We developed a 22-question survey submitted to medical researchers (non-statisticians) from industry, academia, and regulatory agencies.

Safety and Treatment Outcomes of Nivolumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Retrospective Multicenter Cohort Study.

Nivolumab is an anti-PD-1 monoclonal antibody currently used as immunotherapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of disease progression after platinum-based chemotherapy. This study evaluates real-world safety and treatment outcomes of non-trial nivolumab use. A retrospective multicenter cohort study of patients with recurrent/metastatic HNSCC treated with nivolumab between January 2017 and March 2020 was performed.

Hypofractionated chemoradiation for head and cancer: Data from the PET NECK trial.

There has been increased interest in hypofractionated accelerated chemoradiation for head and neck cancer during the recent first peak of the COVID-19 pandemic. Prospective data regarding this approach from randomised trials is lacking. In the PET NECK study, 564 patients with squamous cell carcinoma of the head and neck receiving definitive chemoradiation were randomised to either planned neck dissection or PET CT scan guided surveillance.

Heterogeneous Circles for Liver Allocation.

Background And Aims: In February 2020, the Organ Procurement and Transplantation Network replaced donor service area-based allocation of livers with acuity circles, a system based on three homogeneous circles around each donor hospital. This system has been criticized for neglecting to consider varying population density and proximity to coast and national borders.

Approach And Results: Using Scientific Registry of Transplant Recipients data from July 2013 to June 2017, we designed heterogeneous circles to reduce both circle size and variation in liver supply/demand ratios across transplant centers.

Targeting the BAF complex in advanced prostate cancer.

Introduction: The BRG1/BRM associated factors (BAF) complex is a chromatin remodeling SWI/SNF which is mutated in 20% of cancers. This complex has many interchangeable subunits which may have oncogenic or tumor suppressor activity in a context-dependent manner. The BAF complex is mutated in 35-50% of metastatic prostate cancer (PC); however, its role in advanced disease is unclear.

Quantitative Imaging of B1 Cyclin Expression Across the Cell Cycle Using Green Fluorescent Protein Tagging and Epifluorescence.

In this article, we report the number of cyclin B1 proteins tagged with enhanced green fluorescent protein (eGFP) in fixed U-2 OS cells across the cell cycle. We use a quantitative analysis of epifluorescence to determine the number of eGFP molecules in a nondestructive way, and integrated over the cell we find 10 to 10 molecules. Based on the measured number of eGFP tagged cyclin B1 proteins, knowledge of cyclin B1 dynamics through the cell cycle, and the cell morphology, we identify the stages of cells in the cell cycle.

A common coupling mechanism for A-type heme-copper oxidases from bacteria to mitochondria.

Mitochondria metabolize almost all the oxygen that we consume, reducing it to water by cytochrome oxidase (CO). CO maximizes energy capture into the protonmotive force by pumping protons across the mitochondrial inner membrane. Forty years after the H/e stoichiometry was established, a consensus has yet to be reached on the route taken by pumped protons to traverse CO's hydrophobic core and on whether bacterial and mitochondrial COs operate via the same coupling mechanism.

Rcf2 revealed in cryo-EM structures of hypoxic isoforms of mature mitochondrial III-IV supercomplexes.

The organization of the mitochondrial electron transport chain proteins into supercomplexes (SCs) is now undisputed; however, their assembly process, or the role of differential expression isoforms, remain to be determined. In , cytochrome oxidase (CIV) forms SCs of varying stoichiometry with cytochrome (CIII). Recent studies have revealed, in normoxic growth conditions, an interface made exclusively by Cox5A, the only yeast respiratory protein that exists as one of two isoforms depending on oxygen levels.

Proton-transfer pathways in the mitochondrial S. cerevisiae cytochrome c oxidase.

In cytochrome c oxidase (CytcO) reduction of O to water is linked to uptake of eight protons from the negative side of the membrane: four are substrate protons used to form water and four are pumped across the membrane. In bacterial oxidases, the substrate protons are taken up through the K and the D proton pathways, while the pumped protons are transferred through the D pathway. On the basis of studies with CytcO isolated from bovine heart mitochondria, it was suggested that in mitochondrial CytcOs the pumped protons are transferred though a third proton pathway, the H pathway, rather than through the D pathway.

Promotion of protocell self-assembly from mixed amphiphiles at the origin of life.

Vesicles formed from single-chain amphiphiles (SCAs) such as fatty acids probably played an important role in the origin of life. A major criticism of the hypothesis that life arose in an early ocean hydrothermal environment is that hot temperatures, large pH gradients, high salinity and abundant divalent cations should preclude vesicle formation. However, these arguments are based on model vesicles using 1-3 SCAs, even though Fischer-Tropsch-type synthesis under hydrothermal conditions produces a wide array of fatty acids and 1-alkanols, including abundant C-C compounds.

Evidence for the approach to the diagnostic evaluation of squamous cell carcinoma occult primary tumors of the head and neck.

Metastases to the cervical lymph nodes from a occult primary (CUP) of head and neck squamous carcinomas has been increasing in presentation (HNSCC). Modern diagnostic workup, including clinical evaluation, conventional imaging, FDG-PET/CT and panendoscopy/tonsillectomy enables detection of the primary site in over half of all cases, and is associated with significantly improved survival rates. Recent studies have demonstrated the utility of novel molecular pathology and transoral surgical techniques in improving diagnosis and treatment.

Structure of yeast cytochrome c oxidase in a supercomplex with cytochrome bc.

Cytochrome c oxidase (complex IV, CIV) is known in mammals to exist independently or in association with other respiratory proteins to form supercomplexes (SCs). In Saccharomyces cerevisiae, CIV is found solely in an SC with cytochrome bc (complex III, CIII). Here, we present the cryogenic electron microscopy (cryo-EM) structure of S.

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 Expanding Role of Radiosurgery for Brain Metastases.

Stereotactic radiosurgery (SRS) has become increasingly important in the management of brain metastases due to improving systemic disease control and rising incidence. Initial trials demonstrated SRS with whole-brain radiotherapy (WBRT) improved local control rates compared with WBRT alone. Concerns with WBRT associated neurocognitive toxicity have contributed to a greater use of SRS alone, including for patients with multiple metastases and following surgical resection.

Assessing Novel Drugs and Radiation Technology in the Chemoradiation of Oropharyngeal Cancer.

Integrating immunotherapy, proton therapy and biological dose escalation into the definitive chemoradiation of oropharyngeal cancer poses several challenges. Reliable and reproducible data must be obtained in a timely fashion. However, despite recent international radiotherapy contouring guidelines, controversy persists as to the applicability of such guidelines to all cases.