Impact of the COVID-19 pandemic on breast cancer patient pathways and outcomes in the United Kingdom and the Republic of Ireland - a scoping review.

The COVID-19 pandemic brought unplanned service disruption for breast cancer diagnostic, treatment and support services. This scoping review describes these changes and their impact in the UK and the Republic of Ireland based on studies published between January 2020 and August 2023. Thirty-four of 569 papers were included. Data were extracted and results thematically organized. Findings include fewer new cases; stage shift (fewer early- and more late-stage disease); and changes to healthcare organization, breast screening and treatment. Examples are accepting fewer referrals, applying stricter referral criteria and relying more on virtual consultations and multi-disciplinary meetings. Screening service programs paused during the pandemic before enacting risk-based phased restarts with longer appointment times to accommodate reduced staffing numbers and enhanced infection-control regimes. Treatments shifted from predominantly conventional to hypofractionated radiotherapy, fewer surgical procedures and increased use of bridging endocrine therapy. The long-term impact of such changes are unknown so definitive guidelines for future emergencies are not yet available. Cancer registries, with their large sample sizes and population coverage, are well placed to monitor changes to stage and survival despite difficulties obtaining definitive staging during diagnosis because surgery and pathological assessments are delayed. Multisite longitudinal studies can also provide guidance for future disaster preparedness.

Impact of COVID-19 on cancer incidence, presentation, diagnosis, treatment and survival in Northern Ireland.

The COVID-19 pandemic had a major impact on cancer patients and services but has been difficult to quantify. We examined how the entire cancer pathway-from incidence, presentation, diagnosis, stage, treatment and survival-was affected in Northern Ireland during April-December 2020 compared to equivalent 2018-2019 periods using retrospective, observational cancer registry data from the Northern Ireland Cancer Registry (NICR). There were 6748 cancer cases in April-December 2020 and an average 7724 patients in April-December 2018-2019. Incident cases decreased by 13% (almost 1000). Significant differences were found across age cohorts and deprivation quintiles, with reductions greatest for younger people (<55 years; 19% decrease) and less deprived (22% decrease). A higher proportion had emergency admission (16%-to-20%) with lower proportions diagnosed pathologically (85%-to-83%). There was a significant stage shift, with lower proportions of early stage (29%-to-25%) and higher late-stage (21%-to-23%). Lower proportions received surgery (41%-to-38%) and radiotherapy (24%-to-22%) with a higher proportion not receiving treatment (29%-to-33%). One-year observed-survival decreased from 73.7% to 69.8% and 1-year net-survival decreased from 76.1% to 72.9%, with differences driven by five tumours; Lung (40.3%-to-35.0%), Head-and-Neck (77.4%-to-68.4%), Oesophageal (53.5%-to-42.3%), Lymphoma (81.1%-to-75.2%) and Uterine cancer (87.4%-to-80.4%). Our study reveals profound adverse impact of COVID-19 on the entire cancer patient pathway, with 13% fewer cases, greater emergency admissions and significant stage-shift from early to more advanced-stage disease. There was major treatment impact with lower rates of surgery and radiotherapy and higher proportions receiving no treatment. There were significant reductions in 1-year survival. Our study will support service recovery and protect cancer services in future pandemics or disruptions.

Impact of COVID-19 control on lung, breast, and colorectal pathological cancer diagnoses. A comparison between the Netherlands, Aotearoa New Zealand, and Northern Ireland.

BACKGROUND: The COVID-19 pandemic was managed in Aotearoa New Zealand (NZ) by a COVID-19 elimination policy, involving border closure and an initial national lockdown. This was different to most other countries including Northern Ireland (NI) and the Netherlands (NED). We quantify the effect of these policies on the diagnosis of three major cancers, comparing NZ with these two European countries. METHOD: Data from NED, NZ and NI population-based cancer registries were used to assess trends in all pathologically diagnosed (PD) lung, breast, and colorectal cancers from March to December 2020 (pandemic period) and compared to the similar pre-pandemic period (2017-2019). Trend data were also collated on COVID-19 cases and deaths per 100,000 in each population. RESULTS: Comparing the pre-pandemic period to the pandemic period there were statistically significant reductions in numbers of lung (↓23%) and colorectal (↓15%) PD cancers in NI and numbers of breast (↓18%) and colorectal cancer (↓18.5%) diagnosed in the NED. In NZ there was no significant change in the number of lung (↑10%) or breast cancers (↑0.2%) but a statistically significant increase in numbers of colorectal cancer diagnosed (↑5%). CONCLUSION: The impact of COVID-19 on cancer services was mitigated in NZ as services continued as usual reflecting minimal healthcare disruption and protected cancer services linked with the elimination approach adopted. The reduction in PD cases diagnosed in NED and NI were linked with higher COVID-19 rates and reflect societal restrictions which resulted in delayed patient presentation to primary and secondary care, disruption to screening and healthcare services as a result of COVID-19 infections on staff and the need to shift intensive care to COVID-19 patients. Reductions in PD cancers in NI and the NED and in particularly lung cancers in NI, highlight the need for targeted public health campaigns to identify and treat 'missing' patients. Protecting cancer services should be a priority in any future pandemic or systemic healthcare system disruption.

Impact of the COVID-19 pandemic on emergency hospital cancer admissions in a UK region.

BACKGROUND: The pandemic disrupted society and health services through lockdowns and resource reallocation to care for COVID-19 patients. Reductions in numbers of cancer patients having surgery, being diagnosed pathologically or via 2-week wait, and screening programs pauses have been described. The effect on emergency presentation, which represents an acute episode with poor outcomes, has not been investigated. This study explored the pandemic's impact on emergency hospital admissions for cancer patients in a UK region. METHODS: Hospital discharge data for cancer patients in Northern Ireland, which included route to admission, were analysed for the pandemic era in 2020 compared to averages for March to December 2017-2019, focusing on volume and route of emergency admissions by demography and tumour site. FINDINGS: Compared with the pre-pandemic era, the number of cancer emergency admissions fell by 12·3% in 2020. Emergency admissions for cancer were significantly reduced when COVID-19 levels were highest (- 18·5% in April and - 16.8% in October). Females (- 15·8%), urban residents (- 13·2%), and age groups 0 to 49 and 65-74 years old (- 17%) experienced the largest decreases as did those with haematological (- 14·7%), brain and CNS (- 27·9%), and lung cancers(- 14·3%). Significant reductions in referrals from outpatient departments (- 51%) and primary care (- 43%) (p < 0·001) were counterbalanced by admissions from other routes including confirmed or suspected COVID-19 infection (increase 83·6%). INTERPRETATION: Reductions in emergency admissions, and pathologically diagnosed cancers, as reported by the Northern Ireland Cancer Registry (NICR), indicate undiagnosed patients in the community which has implications for future workloads and survival. Data suggest undiagnosed cases may be higher for haematological, brain and CNS, and lung cancers and among females. Efforts should be made to encourage people with symptoms to present for diagnosis or reassurance. FUNDING: The NICR is funded by the Public Health Agency of Northern Ireland. This work was supported by Macmillan Cancer Support and uses data collected by health services as part of their care and support functions.

Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy.

Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.

The EMT modulator SNAI1 contributes to AML pathogenesis via its interaction with LSD1.

Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML.

Intravenous versus subcutaneous trastuzumab: an economic and patient perspective.

Since 2005, when the first patients outside of a clinical trial were treated with trastuzumab at The Christie NHS Foundation Trust, a nurse-led service has been developed to facilitate and support a safe treatment pathway for patients. There have been significant developments in the number of patients treated, the mode of administration of the drug and patient choice regarding the location of treatment delivery. This article focuses on the change from intravenous to subcutaneous administration, considering patient experience and choice, particularly in light of the advent of biosimilar drugs, which will necessitate a return to the intravenous route. The relative costs of intravenous and subcutaneous administration are illustrated and the results of a patient survey presented, indicating a strong preference for subcutaneous trastuzumab.

Porphyromonas gulae Has Virulence and Immunological Characteristics Similar to Those of the Human Periodontal Pathogen Porphyromonas gingivalis.

Periodontitis is a significant problem in companion animals, and yet little is known about the disease-associated microbiota. A major virulence factor for the human periodontal pathogen Porphyromonas gingivalis is the lysyl- and arginyl-specific proteolytic activity of the gingipains. We screened several Porphyromonas species isolated from companion animals-P. asaccharolytica, P. circumdentaria, P. endodontalis, P. levii, P. gulae, P. macacae, P. catoniae, and P. salivosa-for Lys- and Arg-specific proteolytic activity and compared the epithelial and macrophage responses and induction of alveolar bone resorption of the protease active species to that of Porphyromonas gingivalis Only P. gulae exhibited Lys-and Arg-specific proteolytic activity. The genes encoding the gingipains (RgpA/B and Kgp) were identified in the P. gulae strain ATCC 51700 and all publicly available 12 draft genomes of P. gulae strains. P. gulae ATCC 51700 induced levels of alveolar bone resorption in an animal model of periodontitis similar to those in P. gingivalis W50 and exhibited a higher capacity for autoaggregation and binding to oral epithelial cells with induction of apoptosis. Macrophages (RAW 264.7) were found to phagocytose P. gulae ATCC 51700 and the fimbriated P. gingivalis ATCC 33277 at similar levels. In response to P. gulae ATCC 51700, macrophages secreted higher levels of cytokines than those induced by P. gingivalis ATCC 33277 but lower than those induced by P. gingivalis W50, except for the interleukin-6 response. Our results indicate that P. gulae exhibits virulence characteristics similar to those of the human periodontal pathogen P. gingivalis and therefore may play a key role in the development of periodontitis in companion animals.

Defining the palliative care patient: its challenges and implications for service delivery.

BACKGROUND: Within the UK, general practitioners (GPs) are required to maintain a register of palliative patients under their care. The term 'palliative' when applied to patients encompasses a highly heterogeneous population with varying meanings amongst health professionals. We explored GPs views of what defines a palliative care patient in the context of identifying clinical service needs. METHODS: Audiotaped semi-structured interviews were conducted with GPs to explore how they identify patients requiring inclusion on a palliative care register. Thematic analysis was undertaken and emerging themes identified. RESULTS: Major themes suggested GPs found it difficult to define the palliative care patient. The decision to include a patient on the palliative care register was made as a multidisciplinary team. Patients not identified as 'palliative' were often discussed unofficially if care requirements were significant or prognosis uncertain. The needs of patients with non-malignant disease were considered equal to those with cancer but the challenges of identifying such patients greater. More emphasis was placed on intensity of care required than prognosis. Inclusion on a register triggered greater professional input and was considered beneficial to patient care. CONCLUSIONS: No definition of the palliative care patient exists in working practice and without one there is a risk that some patients with palliative needs will not receive the necessary support, while others may access valuable resources before time. Achieving health policy targets which require identification of palliative patients will continue to be a challenge until a workable and reliable definition of the term 'palliative' is agreed upon.

The Porphyromonas gingivalis ferric uptake regulator orthologue does not regulate iron homeostasis.

Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that has an absolute requirement for iron which it transports from the host as heme and/or Fe(2 +). Iron transport must be regulated to prevent toxic effects from excess metal in the cell. P. gingivalis has one ferric uptake regulator (Fur) orthologue encoded in its genome called Har, which would be expected to regulate the transport and usage of iron within this bacterium. As a gene regulator, inactivation of Har should result in changes in gene expression of several genes compared to the wild-type. This dataset (GEO accession number GSE37099) provides information on expression levels of genes in P. gingivalis in the absence of Har. Surprisingly, these genes do not relate to iron homeostasis.

Porphyromonas gingivalis Type IX Secretion Substrates Are Cleaved and Modified by a Sortase-Like Mechanism.

The type IX secretion system (T9SS) of Porphyromonas gingivalis secretes proteins possessing a conserved C-terminal domain (CTD) to the cell surface. The C-terminal signal is essential for these proteins to translocate across the outer membrane via the T9SS. On the surface the CTD of these proteins is cleaved prior to extensive glycosylation. It is believed that the modification on these CTD proteins is anionic lipopolysaccharide (A-LPS), which enables the attachment of CTD proteins to the cell surface. However, the exact site of modification and the mechanism of attachment of CTD proteins to the cell surface are unknown. In this study we characterized two wbaP (PG1964) mutants that did not synthesise A-LPS and accumulated CTD proteins in the clarified culture fluid (CCF). The CTDs of the CTD proteins in the CCF were cleaved suggesting normal secretion, however, the CTD proteins were not glycosylated. Mass spectrometric analysis of CTD proteins purified from the CCF of the wbaP mutants revealed the presence of various peptide/amino acid modifications from the growth medium at the C-terminus of the mature CTD proteins. This suggested that modification occurs at the C-terminus of T9SS substrates in the wild type P. gingivalis. This was confirmed by analysis of CTD proteins from wild type, where a 648 Da linker was identified to be attached at the C-terminus of mature CTD proteins. Importantly, treatment with proteinase K released the 648 Da linker from the CTD proteins demonstrating a peptide bond between the C-terminus and the modification. Together, this is suggestive of a mechanism similar to sortase A for the cleavage and modification/attachment of CTD proteins in P. gingivalis. PG0026 has been recognized as the CTD signal peptidase and is now proposed to be the sortase-like protein in P. gingivalis. To our knowledge, this is the first biochemical evidence suggesting a sortase-like mechanism in Gram-negative bacteria.

Management of menopausal symptoms for breast cancer patients.

BACKGROUND: Menopausal symptoms are commonly experienced in women treated for breast cancer. This project aimed to identify the types and prevalence of menopausal symptoms women experience and assess how well such symptoms are managed by means of a clinical audit. The authors also wanted to identify whether patients and health professionals require further education in this area to enhance patients' quality of life. METHOD: A pilot audit was initially undertaken. Twenty women were recruited from medical and clinical oncology clinics spanning a 2-week period. The main audit was conducted over a 3-week period (19 March 2012 to 6 April 2012). A total of 215 patients were surveyed from 11 consultant-led and 1 nurse-led clinic per week. A menopause rating scale (MRS) developed by Heinemann et al (2003) was used to assess the types and severity of symptoms. RESULTS: Findings from the main audit provided preliminary evidence that certain breast cancer treatments can cause either the early onset of menopausal symptoms in pre-menopausal women or the return or aggravation of menopausal symptoms in peri-menopausal or post-menopausal women. This indicated that, for many women, symptoms are inadequately managed and supported. DISCUSSION: A more detailed exploratory study of the management of menopausal symptoms is needed. Health professionals should consider discussing such symptoms when patients start treatment and assess these symptoms at follow-up appointments to identify potential interventions.

The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator.

Glucocorticoids are used widely in the treatment of inflammatory diseases, but use is accompanied by a significant burden of adverse effects. It has been hypothesized that gene- and cell-specific regulation of the glucocorticoid receptor by small molecule ligands could be translated into a therapeutic with an improved risk-benefit profile. MK-5932 is a highly selective glucocorticoid receptor modulator that is anti-inflammatory in vivo with an improved profile on glucose metabolism: Bungard et al. (2011). Bioorg. Med. Chem. 19, 7374-7386. Here we describe the full biological profile of MK-5932. Cytokine production following lipopolysaccharide (LPS) challenge was blocked by MK-5932 in both rat and human whole blood. Oral administration reduced inflammatory cytokine levels in the serum of rats challenged with LPS. MK-5932 was anti-inflammatory in a rat contact dermatitis model, but was differentiated from 6-methylprednisolone by a lack of elevation of fasting insulin or glucose levels after 7 days of dosing, even at high exposure levels. In fact, animals in the vehicle group were consistently hyperglycemic at the end of the study, and MK-5932 normalized glucose levels in a dose-dependent manner. MK-5932 was also anti-inflammatory in the rat collagen-induced arthritis and adjuvant-induced arthritis models. In healthy dogs, oral administration of MK-5932 exerted acute pharmacodynamic effects with potency comparable to prednisone, but with important differences on neutrophil counts, again suggestive of a dissociated profile. Important gaps in our understanding of mechanism of action remain, but MK-5932 will be a useful tool in dissecting the mechanisms of glucose dysregulation by therapeutic glucocortiocids.

The study protocol of: 'Initiating end of life care in stroke: clinical decision-making around prognosis'.

BACKGROUND: The initiation of end of life care in an acute stroke context should be focused on those patients and families with greatest need. This requires clinicians to synthesise information on prognosis, patterns (trajectories) of dying and patient and family preferences. Within acute stroke, prognostic models are available to identify risks of dying, but variability in dying trajectories makes it difficult for clinicians to know when to commence palliative interventions. This study aims to investigate clinicians' use of different types of evidence in decisions to initiate end of life care within trajectories typical of the acute stroke population. METHODS/DESIGN: This two-phase, mixed methods study comprises investigation of dying trajectories in acute stroke (Phase 1), and the use of clinical scenarios to investigate clinical decision-making in the initiation of palliative care (Phase 2). It will be conducted in four acute stroke services in North Wales and North West England. Patient and public involvement is integral to this research, with service users involved at each stage. DISCUSSION: This study will be the first to examine whether patterns of dying reported in other diagnostic groups are transferable to acute stroke care. The strengths and limitations of the study will be considered. This research will produce comprehensive understanding of the nature of clinical decision-making around end of life care in an acute stroke context, which in turn will inform the development of interventions to further build staff knowledge, skills and confidence in this challenging aspect of acute stroke care.

Defining the palliative care patient: its challenges and implications for service delivery.

BACKGROUND: Within the UK, general practitioners (GPs) are required to maintain a register of palliative patients under their care. The term 'palliative' when applied to patients encompasses a highly heterogeneous population with varying meanings amongst health professionals. We explored GPs views of what defines a palliative care patient in the context of identifying clinical service needs. METHODS: Audiotaped semi-structured interviews were conducted with GPs to explore how they identify patients requiring inclusion on a palliative care register. Thematic analysis was undertaken and emerging themes identified. RESULTS: Major themes suggested GPs found it difficult to define the palliative care patient. The decision to include a patient on the palliative care register was made as a multidisciplinary team. Patients not identified as 'palliative' were often discussed unofficially if care requirements were significant or prognosis uncertain. The needs of patients with non-malignant disease were considered equal to those with cancer but the challenges of identifying such patients greater. More emphasis was placed on intensity of care required than prognosis. Inclusion on a register triggered greater professional input and was considered beneficial to patient care. CONCLUSIONS: No definition of the palliative care patient exists in working practice and without one there is a risk that some patients with palliative needs will not receive the necessary support, while others may access valuable resources before time. Achieving health policy targets which require identification of palliative patients will continue to be a challenge until a workable and reliable definition of the term 'palliative' is agreed upon.

Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology.

Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.

Design, synthesis, and biological evaluation of 16-substituted 4-azasteroids as tissue-selective androgen receptor modulators (SARMs).

A novel series of 16-substituted-4-azasteroids has been identified as potential tissue-selective androgen receptor modulators. These ligands display potent hAR binding and agonist activity, low virilizing potential, and good pharmacokinetic profiles in dogs. On the basis of its in vitro profile, 21 was evaluated in the OVX and ORX rat models and exhibited an osteoanabolic, tissue-selective profile.