Hydroxychloroquine in combination with platinum doublet chemotherapy as first-line treatment for extensive-stage small cell lung cancer (Study 15): A randomised phase II multicentre trial.

Background: Most patients with small-cell lung cancer (SCLC) present with extensive-stage (ES) disease and have a poor prognosis despite achieving high initial response rates to platinum-based doublet chemotherapy. This study evaluated whether adding hydroxychloroquine (HCQ) to chemotherapy could improve outcomes.

Methods: This was a randomised multicentre phase II trial.

Maintenance durvalumab after first-line chemotherapy in patients with HER2-negative advanced oesophago-gastric adenocarcinoma: results from the randomised PLATFORM study.

Background: PLAnning Treatment For Oesophago-gastric Cancer: a Randomised Maintenance Therapy Trial (PLATFORM) is an adaptive phase II study assessing the role of maintenance therapies in advanced oesophago-gastric (OG) adenocarcinoma. We evaluated the role of the anti-programmed death-ligand 1 (PD-L1) inhibitor durvalumab in these patients.

Patients And Methods: Patients with human epidermal growth factor receptor 2-negative locally advanced or metastatic OG adenocarcinoma with disease control or response to 18 weeks of platinum-based first-line chemotherapy were randomised to active surveillance or maintenance durvalumab.

Virtually the same? Examining the impact of the COVID-19 related shift to virtual lung cancer multidisciplinary team meetings in the UK National Health Service: a mixed methods study.

Objectives: To evaluate the impact of the shift to virtual lung cancer multidisciplinary team meetings (MDTMs) in response to the COVID-19 pandemic, specifically in relation to the magnitude of information technology (IT) issues and distractions and MDT members'/managers' perceptions and experiences of this shift.

Design: A mixed methods study comprising real-time observations of IT issues/distractions within virtual MDTM case discussions held between April and July 2021 and qualitative data from interviews/surveys.

Setting: Eight hospital organisations in Southern England.

The evolution of lung cancer and impact of subclonal selection in TRACERx.

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome.

Investigating the efficiency of lung multi-disciplinary team meetings-A mixed methods study of eight lung multi-disciplinary teams.

Background: Multidisciplinary team meetings (MDTMs), where treatment recommendations are discussed and agreed, are fundamental to effective cancer care. The increasing volume and complexity of caseloads has led to the need to transform MDTM pathways to improve efficiency and allow sufficient time for discussion of complex cases. Understanding of current functioning and inefficiencies is required to inform such transformation.

Healthcare Professional and Patient Perceptions of Changes in Colorectal Cancer Care Delivery During the COVID-19 Pandemic and Impact on Health Inequalities.

Background: The COVID-19 pandemic changed the way in which people were diagnosed and treated for cancer. We explored healthcare professional and patient perceptions of the main changes to colorectal cancer delivery during the COVID-19 pandemic and how they impacted on socioeconomic inequalities in care.

Methods: In 2020, using a qualitative approach, we interviewed patients (n = 15) who accessed primary care with colorectal cancer symptoms and were referred for further investigations.

Socioeconomic differences in help seeking for colorectal cancer symptoms during COVID-19: a UK-wide qualitative interview study.

Background: COVID-19 has led to rapid changes in healthcare delivery, raising concern that these changes may exacerbate existing inequalities in patient outcomes.

Aim: To understand how patients' help-seeking experiences in primary care for colorectal cancer symptoms during COVID-19 were affected by their socioeconomic status (SES).

Design And Setting: Qualitative semi-structured interviews with males and females across the UK, recruited using purposive sampling by SES.

Sarcomatoid Carcinoma Arising in a Gastric Duplication Cyst.

Malignancy arising within a gastric duplication cyst (GDC) is extremely rare; only 15 cases have been reported in the literature. We present a 70-year-old woman who was referred with a history of vague postprandial abdominal discomfort. Subsequent imaging identified a gastric cystic mass.

Nutritional status and symptom burden in advanced non-small cell lung cancer: results of the dietetic assessment and intervention in lung cancer (DAIL) trial.

Introduction: European Society for Clinical Nutrition and Metabolism guidelines recommend that patients with cancer should be screened for malnutrition at diagnosis. The dietetic assessment and intervention in lung cancer study investigated the nutritional status of patients with non-small cell lung cancer (NSCLC) and the need for dietetic intervention.

Methods: In this observational cohort pilot study, patients with stage 3b and 4 NSCLC were assessed prior to starting first line systemic anticancer therapy (SACT) with a range of measurements and questionnaires.

Mismatch Repair Deficiency, Microsatellite Instability, and Survival: An Exploratory Analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial.

Importance: Mismatch repair (MMR) deficiency (MMRD) and microsatellite instability (MSI) are prognostic for survival in many cancers and for resistance to fluoropyrimidines in early colon cancer. However, the effect of MMRD and MSI in curatively resected gastric cancer treated with perioperative chemotherapy is unknown.

Objective: To examine the association among MMRD, MSI, and survival in patients with resectable gastroesophageal cancer randomized to surgery alone or perioperative epirubicin, cisplatin, and fluorouracil chemotherapy in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial.

Cytosine-based nucleoside analogs are selectively lethal to DNA mismatch repair-deficient tumour cells by enhancing levels of intracellular oxidative stress.

Background: DNA mismatch repair deficiency is present in a significant proportion of a number of solid tumours and is associated with distinct clinical behaviour.

Methods: To identify the therapeutic agents that might show selectivity for mismatch repair-deficient tumour cells, we screened a pair of isogenic MLH1-deficient and MLH1-proficient tumour cell lines with a library of clinically used drugs. To test the generality of hits in the screen, selective agents were retested in cells deficient in the MSH2 mismatch repair gene.

Parallel high-throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers.

Synthetic lethal approaches to cancer treatment have the potential to deliver relatively large therapeutic windows and therefore significant patient benefit. To identify potential therapeutic approaches for cancers deficient in DNA mismatch repair (MMR), we have carried out parallel high-throughput RNA interference screens using tumor cell models of MSH2- and MLH1-related MMR deficiency. We show that silencing of the PTEN-induced putative kinase 1 (PINK1), is synthetically lethal with MMR deficiency in cells with MSH2, MLH1, or MSH6 dysfunction.

Mismatch repair deficient colorectal cancer in the era of personalized treatment.

The molecular and genetic subtyping of cancer has allowed the emergence of individualized therapies. This approach could potentially deliver treatments that have both increased efficacy as well as reduced toxicity. A well-defined subtype of colorectal cancer (CRC) is characterized by a deficiency in the mismatch repair (MMR) pathway.

Genomic instability and the selection of treatments for cancer.

A critical link exists between DNA mutation and chromosomal rearrangements (genomic instability) and cancer development. This genomic instability can manifest itself as small changes at the nucleotide level or as gross chromosomal alterations. Mutations in the genes that encode DNA damage response proteins are responsible for a variety of genomic instability syndromes including hereditary non-polyposis colorectal carcinoma, Bloom's syndrome, ataxia-telangiectasia, BRCA-associated breast and ovarian cancers and Fanconi anaemia.

Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine.

The insulin-like growth factor 1 receptor (IGF-1R) and its associated signalling system has provoked considerable interest over recent years as a novel therapeutic target in cancer. A brief outline of the IGF-1R signalling system and the rationale for its use in cancer medicine is given. This is followed by a discussion of the different possible targets within the IGF-1R system, and drugs developed to interact at each target.

Rotaviruses interact with alpha4beta7 and alpha4beta1 integrins by binding the same integrin domains as natural ligands.

Group A rotaviruses are major intestinal pathogens that express potential alpha4beta1 and alpha4beta7 integrin ligand sequences Leu-Asp-Val and Leu-Asp-Ile in their outer capsid protein VP7, and Ile-Asp-Ala in their spike protein VP4. Monkey rotavirus SA11 can use recombinant alpha4beta1 as a cellular receptor. In this study a new potential alpha4beta1, alpha4beta7 and alpha9beta1 integrin ligand sequence, Tyr-Gly-Leu, was identified in VP4.

Interferon-gamma therapy activates human monocytes for enhanced phagocytosis of Mycobacterium avium complex in HIV-infected individuals.

Defective immunological function of cells of the macrophage lineage contributes to the pathogenesis of HIV-1 infection. Because monocyte/macrophage function is enhanced by cytokines such as interferon-gamma (IFN-gamma), the use of this immunomodulator is of potential clinical interest as adjunctive immunotherapy in immunosuppressed individuals. In this study, we show that adjunctive IFN-gamma treatment in an HIV-infected individual with Mycobacterium avium complex (MAC) infection increased phagocytosis of MAC by blood monocytes when compared to cells from an HIV-infected patient who was receiving standard chemotherapy alone.

Integrin-using rotaviruses bind alpha2beta1 integrin alpha2 I domain via VP4 DGE sequence and recognize alphaXbeta2 and alphaVbeta3 by using VP7 during cell entry.

Integrins alpha2beta1, alphaXbeta2, and alphaVbeta3 have been implicated in rotavirus cell attachment and entry. The virus spike protein VP4 contains the alpha2beta1 ligand sequence DGE at amino acid positions 308 to 310, and the outer capsid protein VP7 contains the alphaXbeta2 ligand sequence GPR. To determine the viral proteins and sequences involved and to define the roles of alpha2beta1, alphaXbeta2, and alphaVbeta3, we analyzed the ability of rotaviruses and their reassortants to use these integrins for cell binding and infection and the effect of peptides DGEA and GPRP on these events.

Growth of rotaviruses in primary pancreatic cells.

Rotavirus infection in children at risk of developing type 1 diabetes has been temporally associated with development of pancreatic islet autoantibodies. In this study, nonobese diabetic mice were shown to be susceptible to rhesus rotavirus infection and pancreatic islets from nonobese diabetic mice, nonobese diabetes-resistant mice, fetal pigs, and macaque monkeys supported various degrees of rotavirus growth. Human rotaviruses replicated in monkey islets only.

Phorbol dibutyrate-induced megakaryocytic differentiation increases susceptibility of K562 cells to SA11 rotavirus infection.

The role of integrins previously implicated as rotavirus receptors in determining cellular susceptibility to SA11 rotavirus was studied, using phorbol dibutyrate (PDB) treatment of K562 cells to induce megakaryocytic differentiation. Expression of alpha2beta1 integrin was detected after 2 days in PDB, and peaked after PDB treatment for 4-7 days. SA11 titres were increased by 1.

Growth of rotaviruses in continuous human and monkey cell lines that vary in their expression of integrins.

Rotavirus replication occurs in vivo in intestinal epithelial cells. Cell lines fully permissive to rotavirus include kidney epithelial (MA104), colonic (Caco-2) and hepatic (HepG2) types. Previously, it has been shown that cellular integrins alpha 2 beta 1, alpha 4 beta 1 and alpha X beta 2 are involved in rotavirus cell entry.

Agglutinating antibodies to Toxoplasma gondii in sera from captive eastern barred bandicoots in Australia.

Toxoplasmosis is considered a severe health risk for many marsupial species. The mainland Australian population of bandicoot is endangered. Therefore, a preliminary serosurvey was conducted to evaluate exposure to Toxoplasma gondii in 57 captive eastern barred bandicoot and to estimate the possible impact of Toxoplasma on recovering populations.