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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.Results:We identified cytarabine and other related cytosine-based nucleoside analogues as being selectively toxic to MLH1 and MSH2-deficient tumour cells. The selective cytotoxicity we observed was likely caused by increased levels of cellular oxidative stress, as it could be abrogated by antioxidants.Conclusion:We propose that cytarabine-based chemotherapy regimens may represent a tumour-selective treatment strategy for mismatch repair-deficient cancers. [ABSTRACT FROM AUTHOR]

Abstract Introduction Docetaxel is a semisynthetic taxane commonly used in solid tumour oncology. Its pharmacokinetics has been widely studied, and it is well established that it is metabolized to pharmacologically inactive products by the cytochrome P450 3A iso-enzymes. However, there have been few reports of the consequences of drug interactions between taxanes and other drugs metabolized by the cytochrome P450 pathway. To the best of our knowledge, this is the first case report of the potentially life-threatening interaction that can occur between docetaxel and the protease inhibitors lopinavir and ritonavir. Case presentation A 30-year-old Caucasian woman presented with symptoms suggestive of severe docetaxel toxicity, that is, prolonged myelosuppression, grade 4 mucositis and desquamating rash, following the commencement of post-exposure prophylaxis for a needlestick injury. She had previously received docetaxel chemotherapy with minimal side effects. Conclusion This case report highlights a probable and novel drug interaction between docetaxel and lopinavir and/or ritonavir, which is largely unreported in the medical literature. Even though these interactions may be more relevant in the field of HIV medicine, knowledge of these interactions is also beneficial to oncologists and dermatologists, as well as those providing acute medical care.

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. We report the outcomes related to the Patient Generated Subjective Global Assessment tool (PG-SGA), RESULTS: 96 patients were consented between April 2017 and August 2019. The PG-SGA identified that 78% of patients required specialist nutritional advice; with 52% patients having a critical need for dietetic input and symptom management. Results were dominated by symptom scores. As a screening test, one or more symptoms or recent weight loss history had a sensitivity of 88% (95% CI 78.44% to 94.36%) and specificity of 95.24% (95% CI 76.18% to 99.88%) for need for dietetic intervention., Conclusion: A large proportion of patients with NSCLC have a high symptom burden and are at risk of malnutrition prior to starting SACT and would benefit from dietetic review. It is imperative that oncologists and healthcare professionals discuss weight loss history and symptoms with lung cancer patients to correct nutritional deficiencies and resolve symptoms prior to starting treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Participants: Team members (respiratory physicians, surgeons, oncologists, radiologists, pathologists, palliative care professionals, nurses and MDT coordinators) and managers (n=190) across 8 local MDTs., Results: MDTM observations (n=1664) highlighted significant variation between teams regarding IT functionality. IT issues and other distractions relating to the virtual MDTM format were observed 465 times affecting 20.6% of case discussions, most of which were audio issues (18.1%). Case discussions that had audio issues were, on average, 26 s longer (t(1652)=-2.77, p<0.01). A total of 73 MDT members and managers participated in the survey and 41 participated in interviews, with all 8 teams being represented. Increased flexibility, reduced travel time and easier real-time access to patient information were seen as the main advantages of virtual MDTMs. Views regarding the impact on relational aspects and communication differed. In line with observational findings, concerns were raised in relation to IT, including having inappropriate equipment, insufficient bandwidth (impairing image sharing and video communication) and an overarching theme that virtual meeting platforms provided were not fit for purpose., Conclusions: Despite the potential benefits of virtual MDTMs, IT issues can waste valuable MDTM time. If hospital organisations plan to continue virtual MDTMs, a functioning infrastructure is required, necessitating appropriate resource and investment., Competing Interests: Competing interests: MH is co-chair for lung cancer within the regional cancer alliance through which this research was funded. No competing interests declared for any of the other authors., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Methods: A mixed-methods observational study of all lung cancer MDTMs in one UK cancer network over 12 weeks (n = 8 MDTs, 96 MDT meetings). Data were collected on meeting attendance and on each discussed case using a validated MDT tool. Semi-structured interviews were conducted with a range of MDT members and cancer service managers to gain understanding of perceived influences on the efficiency of MDTMs., Results: In total, 1671 case discussions were observed. Models of MDT working, including referral and diagnostic pathway management, varied within the network. Attendance was quorate in only 21% of the observed MDTMs, most often lacking palliative care specialists. Over a third (37%) of observed cases were repeat discussions pre-diagnosis. Treatment recommendations were agreed in 48% of case discussions but deferred for a quarter (24%) of discussed cases, most commonly due to awaiting results. Information about patients' fitness for treatment and/or performance status score was available for 60% of cases discussed overall (30%-75% by MDT). Interviews (n = 56) identified addressing clinical and administrative workforce shortages, less reliance on the MDTM for pre-diagnostic decision-making and better availability of key clinical information about patients discussed in the MDTM as factors critical to improved MDT function., Conclusions: Inefficiencies were prevalent in all MDTMs; improvements would require an individualised approach due to the variation in ways of working. Local, regional and national support is needed for lung MDTs to develop their diagnostic workforce and facilities, and clinical and administrative resource., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Lung cancer is the leading cause of cancer-associated mortality worldwide 1 . 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. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource., (© 2023. The Author(s).)

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., Method: Interviews were carried out with 39 participants (20 higher SES; 19 lower SES) who contacted primary care about possible symptoms of colorectal cancer during COVID-19. Data were analysed using framework analysis followed by comparative thematic analysis to explore differences between groups., Results: Three themes were identified with differences between SES groups: 1) how people decided to seek medical help through appraisal of symptoms; 2) how people navigated services; and 3) impact of COVID-19 on how patients interacted with healthcare professionals. The lower SES group expressed uncertainty appraising symptoms and navigating services (in terms of new processes resulting from COVID-19 and worries about infection). There was also potential for increased disparity in diagnosis and management, with other methods of getting in touch (for example, email or 111) taken up more readily by higher SES patients., Conclusion: The findings suggest that COVID-19 exacerbated disparities between higher and lower SES participants. This study raises awareness around challenges in help seeking in the context of the pandemic, which are likely to persist (post-COVID-19) as healthcare systems settle on new models of care (for example, digital). Recommendations are provided to reduce inequalities of care., (© The Authors.)

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. In 2021, we interviewed a wide range of healthcare professionals (n = 30) across the cancer care pathway and gathered national and local documents/guidelines regarding changes in colorectal cancer care., Results: Changes with the potential to exacerbate inequalities in care, included: the move to remote consultations; changes in symptomatic triage, new COVID testing procedures/ways to access healthcare, changes in visitor policies and treatment (e.g., shorter course radiotherapy). Changes that improved patient access/convenience or the diagnostic process have the potential to reduce inequalities in care., Discussion: Changes in healthcare delivery during the COVID-19 pandemic have the ongoing potential to exacerbate existing health inequalities due to changes in how patients are triaged, changes to diagnostic and disease management processes, reduced social support available to patients and potential over-reliance on digital first approaches. We provide several recommendations to help mitigate these harms, whilst harnessing the gains.

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., Design, Setting, and Participants: This secondary post hoc analysis of the MAGIC trial included participants who were treated with surgery alone or perioperative chemotherapy plus surgery for operable gastroesophageal cancer from July 1, 1994, through April 30, 2002. Tumor sections were assessed for expression of the MMR proteins mutL homologue 1, mutS homologue 2, mutS homologue 6, and PMS1 homologue 2. The association among MSI, MMRD, and survival was assessed., Main Outcomes and Measures: Interaction between MMRD and MSI status and overall survival (OS)., Results: Of the 503 study participants, MSI results were available for 303 patients (283 with microsatellite stability or low MSI [median age, 62 years; 219 males (77.4%)] and 20 with high MSI [median age, 66 years; 14 males (70.0%)]). A total of 254 patients had MSI and MMR results available. Patients treated with surgery alone who had high MSI or MMRD had a median OS that was not reached (95% CI, 11.5 months to not reached) compared with a median OS among those who had neither high MSI nor MMRD of 20.5 months (95% CI, 16.7-27.8 months; hazard ratio, 0.42; 95% CI, 0.15-1.15; P = .09). In contrast, patients treated with chemotherapy plus surgery who had either high MSI or MMRD had a median OS of 9.6 months (95% CI, 0.1-22.5 months) compared with a median OS among those who were neither high MSI nor MMRD of 19.5 months (95% CI, 15.4-35.2 months; hazard ratio, 2.18; 95% CI, 1.08-4.42; P = .03)., Conclusions and Relevance: In the MAGIC trial, MMRD and high MSI were associated with a positive prognostic effect in patients treated with surgery alone and a differentially negative prognostic effect in patients treated with chemotherapy. If independently validated, MSI or MMRD determined by preoperative biopsies could be used to select patients for perioperative chemotherapy.

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. Inhibition of PINK1 in an MMR-deficient background results in an elevation of reactive oxygen species and the accumulation of both nuclear and mitochondrial oxidative DNA lesions, which likely limit cell viability. Therefore, PINK1 represents a potential therapeutic target for the treatment of cancers characterized by MMR deficiency caused by a range of different gene deficiencies., (©2011 AACR.)

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. MMR deficiency not only contributes to the pathogenesis of a large proportion of CRC, but also determines the response to many of the drugs that are frequently used to treat this disease. In this Review we describe the MMR deficient phenotype and discuss how a deficiency in this DNA repair process may impact on the management of CRC, including surgery, adjuvant chemotherapy and the choice of systemic agents for the palliation of advanced disease. We also discuss how the DNA repair defect in MMR deficient CRC could be exploited in the development of novel therapeutic strategies.

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. Similarly, epigenetic silencing of genes associated with the maintenance of genomic stability have also been implicated in the pathogenesis of cancer. Here, we discuss how different tumours may be classified not only by tumour site but also by the type of underlying genetic instability. This type of classification may assist in the optimization of existing treatment regimens as well as informing the development of new therapeutic approaches.

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. A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples: growth hormone releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH-717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417, NVP-AEW541, NVP-ADW742, AG1024, potent quinolinyl-derived imidazo (1,5-a)pyrazine PQIP, picropodophyllin PPP, Nordihydroguaiaretic acid Insm-18/NDGA). The following tumour types are specifically discussed: lung, breast, colorectal, pancreatic, NETs, sarcoma, prostate, leukaemia, multiple myeloma. Other tumour types are mentioned briefly: squamous cell carcinoma of the head and neck, melanoma, glioblastoma, ovary, gastric and mesothelioma. Results of early stage clinical trials, involving recently patented drugs. are included where appropriate. We then outline the current understanding of toxicity related to IGF-1R targeted therapy, and finally outline areas for further research.

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. Enhanced phagocytic efficiency resulting from IFN-gamma therapy was associated with increased surface expression of MHC II (HLA-DR), a phagocytic receptor (CD16), and the activation marker (CD69), although the levels of activation markers were dissimilar at baseline in the two participants. These results imply that IFN-gamma may be useful in restoring antimycobacterial function in immunosuppressed patients.

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. Five (9%) bandicoot were classified as seropositive using a modified agglutination test. Nineteen additional bandicoot (33%) were classified as serosuspect using a direct agglutination test. No bandicoot showed signs of clinical disease. Seropositive titers were IgG associated, suggesting that infections were chronic and latent. Serostatus was not associated with either sex or being wild-caught, although each seropositive bandicoot was wild-caught. Seropositive animals ranged from 1.25- to 2.5-yr-old. Computer simulations using Vortex 5.1, based on the proportion of seropositive and seronegative bandicoot in this study, indicate that mortalities from T. gondii should have little impact upon captive populations. However, the potential impact of toxoplasmosis on recovery efforts for wild, mainland bandicoot populations is not clear.

Most mammalian rotaviruses contain tripeptide amino acid sequences in outer capsid proteins VP4 and VP7 which have been shown to act as ligands for integrins alpha2beta1 and alpha4beta1. Peptides containing these sequences and monoclonal antibodies directed to these integrins block rotavirus infection of cells. Here we report that SA11 rotavirus binding to and infection of K562 cells expressing alpha2beta1 or alpha4beta1 integrins via transfection is increased over virus binding to and infection of cells transfected with alpha3 integrin or parent cells. The increased binding and growth were specifically blocked by a monoclonal antibody to the transfected integrin subunit but not by irrelevant antibodies. In our experiments, integrin activation with phorbol ester did not affect virus binding to cells. However, phorbol ester treatment of K562 parent and transfected cells induced endogenous gene expression of alpha2beta1 integrin, which was detectable by flow cytometry 16 h after treatment and quantitatively correlated with the increased level of SA11 virus growth observed after this time. Virus binding to K562 cells treated with phorbol ester 24 h previously and expressing alpha2beta1 was elevated over binding to control cells and was specifically blocked by the anti-alpha2 monoclonal antibody AK7. Virus growth in alpha4-transfected K562 cells which had also been induced to express alpha2beta1 integrin with phorbol ester occurred at a level approaching that in the permissive MA104 cell line. We therefore have demonstrated that two integrins, alpha2beta1 and alpha4beta1, are capable of acting as cellular receptors for SA11 rotavirus.

The susceptibility of patients with AIDS to certain opportunistic infections is due to defective cell-mediated immunity. The contribution of direct infection of macrophages with HIV-1 to this defect is unknown. To address this issue, we infected normal human monocyte-derived macrophages with a monocytotropic strain of HIV-1 and examined their ability to phagocytose and kill the opportunistic pathogen, Toxoplasma gondii. Phagocytosis of heat-killed T. gondii was reduced in HIV-infected macrophages compared with mock-infected controls. Opsonization of heat-killed T. gondii increased phagocytosis by both mock- and HIV-infected macrophages, but phagocytosis in HIV-infected cultures remained lower than in controls. Internalization of live T. gondii by macrophages was unaffected by HIV infection. Intracellular replication of live T. gondii was enhanced by HIV infection, as shown in four experiments, each using monocyte-derived macrophages from a different donor. Treatment of HIV-infected macrophages with IFN-gamma decreased parasite replication but not to control levels. These findings suggest that infection of macrophages by HIV may be a contributing factor to the reactivation of T. gondii infection in patients with AIDS.

HIV-1 infection of peripheral blood monocyte-derived macrophages (MDMs) is unrelated to the level of CD4 expression on the surface of the cell, is associated with considerable donor variability, causes minimal cytopathology, and results in peak viral antigen production after 2 weeks of infection. Phagocytosis of opsonized Candida albicans by MDMs infected in vitro with several strains of HIV was compared with that of uninfected cells from the same donors; the proportion of MDMs containing the fluorescein isothiocyanate-labeled yeast was determined by flow cytometry and phase contrast microscopy. The intracellular localization of C. albicans was confirmed by confocal microscopy. Using paired MDMs from nine donors, 81% of uninfected and 53% of HIV-infected MDMs phagocytosed C. albicans. In addition, the number of yeast per cell was significantly higher in uninfected MDMs than in HIV-infected cells (mean 6.1 versus 2.5). These findings may partially explain the high incidence of mucocutaneous candidiasis in HIV-infected patients with advanced disease.

Ureaplasma urealyticum cultures from 124 patients with urinary tract disease were serotyped by indirect immunofluorescence, using antisera to serotypes I to VIII. A similar range of serotypes was recovered from first-voided, midstream, and bladder-aspiration (SPA) urine, upper urinary tract samples, and vaginal swabs. Serotype VI was predominant (44/124) among the samples, whereas serotypes V (1/124 samples) and VII (0/124 samples) were uncommon. Twenty of 124 cultures contained more than one serotype, and three cultures were untypeable. Serotypes cultured from bladder urine were also present in vaginal and urethral samples, although these samples often carried additional serotypes. Consecutive SPA samples from the same patient invariably contained the same serotype, whereas some consecutive midstream urine samples showed a loss or gain of serotypes with time. One patient carried the same serotype in SPA urine over a period of 13 months. The pattern of serotypes recovered from the urinary tract was similar irrespective of the sampling site, the site of infection, the clinical diagnosis and renal function of the patient, and the presence or absence of other microorganisms. Colonization above the urethra and association with urinary tract disease appeared to be serotype independent.