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Obesity can initiate, promote, and maintain systemic inflammation via metabolic reprogramming of macrophages that encircle adipocytes, termed crown-like structures (CLS). In breast cancer the presence of CLS has been correlated to high body mass index (BMI), larger mammary adipocyte size and postmenopausal status. However, the prognostic significance of CLS in HER2 + breast cancer is still unknown. We investigated the prognostic significance of CLS in a cohort of 69 trastuzumab-naïve and 117 adjuvant trastuzumab-treated patients with primary HER2 + breast cancer. Immunohistochemistry of tumour blocks was performed for CLS and correlated to clinical outcomes. CLS were more commonly found at the adipose-tumour border (B-CLS) (64.8% of patients). The presence of multiple B-CLS was associated with reduced time to metastatic disease (TMD) in trastuzumab treated patients with BMI ≥ 25 kg/m 2 but not those with BMI < 25 kg/m 2 . Phenotypic analysis showed the presence of CD32B + B-CLS was strongly correlated to BMI ≥ 25 kg/m 2 and reduced TMD in trastuzumab treated patients. Multivariable analysis suggested that CD32B + B-CLS positive tumours are associated with shorter TMD in trastuzumab-treated patients (HR 4.2 [95%CI, (1.01–17.4). This study indicates adipose-tumour border crown-like structures that are CD32B + potentially represent a biomarker for improved personalisation of treatment in HER2-overexpressed breast cancer patients.

This Review presents a comprehensive analysis of the amounts and distribution of public and philanthropic global cancer research funding between 2016 and 2023, including patterns of international collaboration and downstream research output, with an emphasis on the Commonwealth. We show that annual investment decreased globally each year, apart from a rise in 2021. Network analysis revealed that grant and publication collaborations between the Commonwealth, the USA, and the EU are facilitated by linkages through a core group of Commonwealth countries, including the UK, Australia, and Canada. There are inequities in research investment and low funding for treatment modalities for many cancers. These inequities also manifest in the central positioning of high-income Commonwealth countries in research collaborations, but also point to opportunities for high-income Commonwealth countries to facilitate linkages with low-income countries and support active cancer research in the USA and the EU. There is an urgent need to review research investment priorities, both within the Commonwealth and globally, to align with population needs and promote collaborative strategies that can build research skills and infrastructure in low-income settings to impact global cancer control. Finite resources should be invested wisely to achieve maximum improvements in mortality and alleviate the cancer burden.

Obesity is associated with worse breast cancer outcomes and decreased therapeutic efficacy. However, the mechanisms driving obesity-associated therapy resistance remain unclear; in part due to a lack of suitable models that recapitulate the obese tumour microenvironment. To address this, we developed a 3D in vitro model of obesity-associated breast cancer, to investigate biological mechanisms and to use as a drug testing tool. A penta-culture system was developed by co-culturing adipocyte spheroids with breast tumour cells, myoepithelial cells, macrophages, and fibroblasts in a collagen matrix. Tumour cells and macrophages infiltrated adipocyte spheroids, replicating the inflamed-adipose border typical of obese patients. This model was then assessed as a drug testing platform. Obese cultures exhibited increased sensitivity to metformin and, conversely, resistance to paclitaxel, compared to non-obese cultures. This 3D organotypic model effectively recapitulates key features of the obese adipose tumour microenvironment, providing a useful tool to interrogate mechanisms underpinning obesity-related therapy resistance.

We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45–6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99–3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07–2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28–0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25–2.21]) and Asian (1.51 [1.28–1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34–3.15]).

Obesity can initiate, promote, and maintain systemic low-grade inflammation partly via metabolic reprogramming of macrophages that encircle adipocytes termed crown-like structures (CLS). The tumour microenvironment can also exert metabolic stress on both innate and adaptive immunity, leading to local immunosuppression. Metformin has demonstrated antitumorigenic properties both in pre-clinical and clinical studies. Nevertheless, its immunomodulating properties in patients with breast cancer are largely unknown. Tumour-associated macrophages (TAM) and CLS are a diverse and heterogenous population of cells. The prognostic significance of CLS and their association with the spatial distribution of TAM and T-cells in breast cancer are still not clear. First, the effect of metformin on tumour infiltrating immune cells was investigated in two independent cohorts of 31 and 47 patients each using immunohistochemistry. Metformin administration was associated with higher densities of tumour-infiltrating CD68+ macrophages, tumour-infiltrating CD8+ T-cells and lower density of regulatory T-cells suggesting that metformin may enhance antitumour immune responses. Then, to assess the effect of systemic inflammation on metformin-related immune responses, patients were stratified by circulatory levels of serum leptin. Elevated levels of leptin were associated with inactivated T-cell populations which were restored with the administration of metformin. These changes were confined to the tumour islands suggesting that there is an interplay between tumour and immune cells which may be partly mediated via metabolic competition. Then, the prognostic significance of CLS in a cohort of 69 trastuzumab-naïve and 117 adjuvant trastuzumab-treated patients with primary HER2+ breast cancer was evaluated. This showed that CD32B+ CLS at the adipose-tumour border were strongly correlated to BMI≥25 kg/m2 and were an independent prognostic factor for reduced time to metastatic disease in trastuzumab treated patients suggesting that adiposity potentially plays an important role in therapeutic responses. To elucidate the immune mechanisms involved, multiplexed immunohistochemistry for various immune markers on CLS, TAM and T-cells was performed using the BEGIN cohort (Investigating outcomes from breast cancer: Correlating genetic, immunological, and nutritional predictors) (n=134). Analysis of the BEGIN cohort showed that CLS were associated with a differential effect on the densities and spatial distribution stromal immune cells and fibroblasts that is tumour subtype specific. These results imply that the interplay between CLS and tumour biology may be associated with an adaptation in the tumour microenvironment that promotes polarization of macrophages towards immunosuppressive phenotypes and T-cell inhibition in high histological grade breast tumours. Whilst CLS were associated with activated macrophage and T-cell phenotypes in low histological grade tumours. To further understand the effect of CLS on the tumour-immune microenvironment, targeted RNA sequencing of 36 samples with matched multiplexed immunohistochemistry data using the Precision Immuno-Oncology Panel in HTG EdgeSeq platform was done. Targeted RNA sequencing showed that gene sets that are associated with cell cycle progression were upregulated, whereas gene sets involved in the regulation of anticancer immune responses were downregulated in patients with high CLS that is consistent with immunohistochemistry findings. In summary, the presence of CLS may be associated with inflammatory signatures at the tumour border and an aggressive molecular phenotype in the core that may promote tumour growth and immune suppression. Metabolic interventions such as metformin may play a role in the metabolic reprogramming of T-cell and macrophages populations that are dysregulated by systemic inflammation.

PurposeMYC transcription factor has critical roles in cell growth, proliferation, metabolism, differentiation, transformation and angiogenesis. MYC overexpression is seen in about 15% of breast cancers and linked to aggressive phenotypes. MYC overexpression also induces oxidative stress and replication stress in cells. ATM signalling and ATR-mediated signalling are critical for MYC-induced DNA damage response. Whether ATM and ATR expressions influence clinical outcomes in MYC overexpressed breast cancers is unknown.MethodsWe investigated ATM, ATR and MYC at the transcriptional level [Molecular Taxonomy of Breast Cancer International Consortium cohort (n = 1950)] and at the protein level in the Nottingham series comprising 1650 breast tumours. We correlated ATM, ATR and MYC expressions to clinicopathological features and survival outcomes.ResultsIn MYC over expressed tumours, high ATR or low ATM levels were associated with aggressive breast cancer features such as higher tumour grade, de-differentiation, pleomorphism, high mitotic index, high-risk Nottingham Prognostic Index, triple negative and basal-like breast cancers (all adjusted p values < 0.05). Tumours with low ATM or high ATR levels in conjunction with MYC overexpression also have worse overall breast cancer-specific survival (BCSS) (p value < 0.05).ConclusionsWe conclude that ATR/ATM-directed stratification and personalisation of therapy may be feasible in MYC overexpressed breast cancer.

White adipose tissue (WAT) represents an endocrinologically and immunologically active tissue whose primary role is energy storage and homeostasis. Breast WAT is involved in the secretion of hormones and proinflammatory molecules that are associated with breast cancer development and progression. The role of adiposity and systemic inflammation in immune responses and resistance to anti-cancer treatment in breast cancer (BC) patients is still not clear. Metformin has demonstrated antitumorigenic properties both in pre-clinical and clinical studies. Nevertheless, its immunomodulating properties in BC are largely unknown. This review aims to evaluate the emerging evidence on the crosstalk between adiposity and the immune-tumour microenvironment in BC, its progression and treatment resistance, and the immunometabolic role of metformin in BC. Adiposity, and by extension subclinical inflammation, are associated with metabolic dysfunction and changes in the immune-tumour microenvironment in BC. In oestrogen receptor positive (ER+) breast tumours, it is proposed that these changes are mediated via a paracrine interaction between macrophages and preadipocytes, leading to elevated aromatase expression and secretion of pro-inflammatory cytokines and adipokines in the breast tissue in patients who are obese or overweight. In HER2+ breast tumours, WAT inflammation has been shown to be associated with resistance to trastuzumab mediated via MAPK or PI3K pathways. Furthermore, adipose tissue in patients with obesity is associated with upregulation of immune checkpoints on T-cells that is partially mediated via immunomodulatory effects of leptin and has been paradoxically associated with improved responses to immunotherapy in several cancers. Metformin may play a role in the metabolic reprogramming of tumour-infiltrating immune cells that are dysregulated by systemic inflammation. In conclusion, evidence suggests that body composition and metabolic status are associated with patient outcomes. To optimise patient stratification and personalisation of treatment, prospective studies are required to evaluate the role of body composition and metabolic parameters in metabolic immune reprogramming with and without immunotherapy in patients with BC.

In the last thirty years, the widespread use of endoscopic retrograde cholangiopancreatography (ERCP) has radically changed the management of patients with diseases of the extrahepatic biliary tract and pancreas. Pneumothorax is a rare complication of ERCP. We report two cases of pneumothorax following elective ERCP for ductal stone clearance. The first patient was a 45-year-old female, who developed respiratory distress, abdominal pain, and profoundly abdominal distention immediately after the procedure. Imaging studies revealed the presence of a right-side pneumothorax, pneumomediastinum, pneumoperitoneum, and pneumoretroperitoneum. The second patient was a 94-year-old female, who developed tension pneumothorax with clinical signs of shock during the procedure. Imaging studies revealed the presence of a right-side pneumothorax without free air in the mediastinum and retroperitoneal space. The imaging findings suggest that the occurrence of this rare complication in our patients was caused by entirely different pathophysiological mechanisms. Both patients were successfully treated with chest tube insertion, and no further intervention was required. Clinicians should be aware of this serious complication because delayed diagnosis may involve significant morbidity and mortality risks.

Introduction/BackgroundMalignant ovarian germ cell tumours (MOGCTs) are rare and aggressive malignancies mainly affecting young women. Unlike testicular GCTs, prognostic factors are poorly understood, but small series have most consistently suggested that advanced stage best predicts worse outcomes. Here, we examine a large, international patient series to identify new adverse prognostic factors.MethodologyWe evaluated 254 patients treated in Charing Cross Hospital and Mount Vernon Cancer Centre, UK and in Multi-centre Italian Trials in Ovarian Cancer (MITO) group between 1971 and 2018. Descriptive statistical, survival and Cox regression techniques were performed using STATA (StataCorp, v.16, Texas, USA).ResultsMedian age was 26 years (IQR, 20–32). There were 22.4% dysgerminomas, 18.5% immature teratomas, 33.5% yolk sac, 17.7% mixed, 1.2% embryonal, 2.4% choriocarcinoma and 4.3% unclassified. FIGO stage distribution was 31.5% (IC/M), 12.6% (II), 40.5% (III) and 15.4% (IV). First line chemotherapy consisted of BEP, POMB/ACE or other regimens for 48.0%, 42.5% and 9.5% of patients, respectively. Recurrences received high dose chemotherapy (HDCT), conventional chemotherapy ± surgery, and surgery alone in 24.4%, 65.9% and 7.3% of cases.At multivariable analysis, age ≥35 at presentation [HR 2.3, 95%CI (1.0–5.0), p=0.04], stage [HR 1.5, 95%CI (1.0–2.1), p=0.032], and non-dysgerminoma versus dysgerminoma [HR 12.7, 95%CI (1.7–94.0), p=0.013] were significantly associated with worse cancer-specific survival (CSS). Twenty-year CSS for stage IC/M, II, III, and IV were 94.8%, 82.3%, 83.2% and 84.3%, respectively. In patients relapsing or failing to achieve a complete response, HDCT showed a trend for improved 5-year CSS compared to conventional treatments [HR 0.5, 95%CI (0.2–1.5), p=0.241].ConclusionThis study demonstrated that in addition to advanced stage, age ≥35 years, and non-dysgerminoma, but not immature teratomas, are independent adverse prognostic factors for CSS. Strikingly, stage IV disease can still achieve >80% long-term survival rates. HDCT may improve outcomes for relapsing/incomplete responding patients.