John Conibear

St. Bartholomews Hospital · Radiotherapy Department

Murine tissues harbor signature γδ T cell compartments with profound yet differential impacts on carcinogenesis. Conversely, human tissue-resident γδ cells are less well defined. In the present study, we show that human lung tissues harbor a resident Vδ1 γδ T cell population. Moreover, we demonstrate that Vδ1 T cells with resident memory and effect...

The use of stereotactic ablative radiotherapy (SABR) in the UK has expanded over the past decade, in part as the result of several UK clinical trials and a recent NHS England Commissioning through Evaluation programme. A UK SABR Consortium consensus for normal tissue constraints for SABR was published in 2017, based on the existing literature at th...

Introduction: NUT(Nuclear Protein in Testis) carcinoma(NC), formerly NUT Midline Carcinoma, comprises rare, poorly differentiated carcinoma genetically defined by the presence of NUTM1 gene rearrangement. Chromosomal translocation t(15;19)(q14;p13.1) resulting in NUTM1 to BRD4 fusion prevails in > 75% cases. Usually metastatic at presentation, thei...

Introduction: Paraneoplastic Opsoclonus Myoclonus Syndrome (OMS) is a rare paraneoplastic neurological disorder, with an incidence of 0.18/million/year in the UK. It involves rapid, involuntary, multidirectional eye movements, myoclonus and cerebellar ataxia. Two-thirds of cases precede the diagnosis of cancer, with Small Cell Lung Cancer (SCLC) be...

Introduction We evaluated the arginine-depleting enzyme pegargiminase (ADI-PEG20; ADI) with pemetrexed (Pem) and cisplatin (Cis) (ADIPemCis) in ASS1-deficient non-squamous non-small cell lung cancer (NSCLC) via a phase 1 dose-expansion trial with exploratory biomarker analysis. Methods Sixty-seven chemonaïve patients with advanced non-squamous NSC...

Background The treatment landscape for advanced non-small cell lung cancer (aNSCLC) has evolved rapidly since immuno-oncology (IO) therapies were introduced. This study used recent data to assess real-world treatment patterns and clinical outcomes in aNSCLC in the United Kingdom. Methods Electronic prescribing records of treatment-naive patients s...

Clinical features and natural history of MET mutant Lung Adenocarcinoma in UK. First report from multiple centres.

When treating patients with unresectable stage III non-small-cell lung cancer (NSCLC), those with a good performance status and disease measured within a radical treatment volume should be considered for definitive concurrent chemoradiotherapy (cCRT). This guidance is based on key scientific rationale from two large Phase 3 randomised studies and m...

Background: The treatment landscape for advanced non-small cell lung cancer (aNSCLC) has evolved rapidly since immuno-oncology (IO) therapies were introduced. This study used recent data to assess real-world treatment patterns and clinical outcomes in aNSCLC in the United Kingdom. Methods: Electronic prescribing records of treatment-naive patients...

Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape1–5. However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-se...

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

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

PURPOSE The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivasertib has shown preclinical activity in TNBC models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN. The PAKT trial was designed to evaluat...

Background The humanised PD1 antibody, Pembrolizumab, is used as monotherapy in the 1st and 2nd line setting for patients with advanced non-small cell lung cancer (NSCLC). There is a lack of data about the delayed onset of IRAEs which is important as patients can be on prolonged treatment. Methods This is a retrospective study of NSCLC patients tr...

Aims: Accurate delineation of organs at risk (OAR) is vital to the radiotherapy planning process. Inaccuracies in OAR delineation arising from imprecise anatomical definitions may affect plan optimisation and risk inappropriate dose delivery to normal tissues. The aim of this study was to review the provision of OAR contouring guidance in National...

Delayed Onset Immune Related Adverse Effects (IRAEs) of Pembrolizumab in Non Small Cell Lung Cancer

Importance Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad...

Aims: This study aimed to examine whether any significant differences existed in trial protocol compliance in target volumes (TV) and organs at risk (OARs) contouring amongst clinical oncologists specialised in lung cancer radiotherapy. Materials/methods: Two lung radiotherapy trials that require all prospective investigators to submit pre-trial...

9097 Background: Pegylated arginine deiminase (ADI-PEG20) targets ASS1-ve tumors, including non–small-cell lung cancer (NSCLC), by potentiating pemetrexed cytotoxicity via arginine depletion. In Beddowes et al (JCO 2017) we showed a 100% disease control rate in thoracic cancers treated with ADI-PEG20, cisplatin and pemetrexed (ADIPemCis). Thus, we...

Aims: The National Mastectomy and Breast Reconstruction Audit report (NMBRA, 2011)¹ revealed that immediate implant-based breast reconstruction (IIBR) was the most common type of primary reconstruction performed in the UK (37%). The main reason given by clinicians for not offering immediate breast reconstruction was the need for adjuvant radiothera...

Background: Loss of the metabolic tumor suppressor argininosuccinate synthetase 1 (ASS1) sensitizes non-squamous non-small cell lung cancer (NSCLC) cells to arginine deprivation with pegylated arginine deiminase (ADI-PEG20), which also disrupts thymidine pools and potentiates pemetrexed (Pem) cytotoxicity. In the phase I dose-escalation TRAP study...

Introduction: Following growing evidence to support the safety, local control (LC) and potential improvement in overall survival (OS) in patients with oligometastatic non-small cell lung cancer (NSCLC) that have been treated with local ablative therapy such as stereotactic ablative radiotherapy (SABR) and stereotactic radiosurgery (SRS), we initia...

AIMS: Radiotherapy quality assurance (RTQA) is now a requirement of radiotherapy trials since poor target volume and organ at risk (OAR) contouring has been shown to impact on patient outcomes within the context of clinical trials. The first hypothesis for this research is that statistically significant inter-observer variation exists amongst clini...

Background: Resistance to endocrine therapy remains a major clinical challenge with aberrant PI3K/ mTOR pathway activation being one of the main drivers. Randomised clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Vistusertib (AZD2014), a dual inhibitor of mTORC1 and mTORC2, has shown a broader rang...

Background: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis an...

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to...

The early detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. He...

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-C...

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-C...

Purpose of review: Cancer cachexia is common and reduces function, treatment tolerability and quality of life. Given its multifaceted pathophysiology a multimodal approach to cachexia management is advocated for, but can be difficult to realise in practice. We use a case-based approach to highlight practical approaches to the multimodal management...

Radiation is one of the principal treatment options for prostate cancer and has been used to treat all stages of the disease since the early twentieth century. This chapter gives a broad overview of both external beam radiotherapy and brachytherapy in relation to treating prostate cancer. It describes the technical and scientific developments that...

As the complexity of radiotherapy (RT) trials increases, issues surrounding target volume delineation will become more important. Some form of outlining assessment prior to trial entry is increasingly being mandated in UK RT trials. This document produced by the Outlining and Imaging Subgroup (OISG) of the National Cancer Research Institute will ad...

Over the past 20 years advances in radiological technology have led to dramatic changes in cervical cancer management. External beam radiotherapy has evolved radically as a result of these changes. More recently, though, three-dimensional (3D) image guidance and volume-based prescribing has been adopted into cervical cancer brachytherapy. This over...

Vestibular schwannomas are the hallmark of neurofibromatosis type two. They are difficult to treat, due to their bilateral presentation and the quest for hearing preservation. Our report describes a new treatment approach in this clinical scenario. We report two cases which confirm that bevacizumab, a monoclonal antibody targeting vascular endothel...

A woman with known adenocarcinoma of the right parotid gland presented with bony metastasis in her left proximal femur. This was histologically confirmed and the patient underwent prophylactic intramedullary nail and hip screw fixation of her left proximal femur. This represents the first report of adenocarcinoma of parotid origin metastasising to...