Clinicopathological significance of ataxia-telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3 related (ATR) kinase in MYC overexpressed breast cancers

Purpose: MYC 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 and ATR- mediated signalling is critical for MYC induced DNA damage response. Whether ATM and ATR expression influence clinical outcomes in MYC overexpressed breast cancers is unknown.Methods: We 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 expression to clinicopathological features and survival outcomes.Results: In 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 [less than] 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 [less than] 0.05).Conclusions: We conclude that ATR/ATM directed stratification and personalisation of therapy may be feasible in MYC overexpressed breast cancer

Pneumothorax following ERCP: Report of Two Cases with Different Pathophysiology

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

Werner Syndrome Protein Expression in Breast Cancer

IntroductionWerner protein (WRN) plays an important role in DNA repair, replication, transcription, and consequently genomic stability via its DNA-helicase and exonuclease activity. Loss of function of WRN is associated with Werner syndrome (WS), which is characterized by premature aging and cancer predisposition. Malignancies that are commonly linked to WS are thyroid carcinoma, melanoma, breast cancer, meningioma, and soft tissue and bone sarcomas. Currently, the clinicopathologic significance of WRN in breast cancer is largely unknown.Patients and MethodsWe investigated the clinicopathologic and prognostic significance of WRN protein expression in a cohort of clinically annotated series of sporadic (n = 1650) and BRCA-mutated (n = 75) invasive breast cancers. We correlated WRN protein expression to clinicopathologic characteristics, DNA repair protein expression, and survival outcomes.ResultsThere is strong evidence of association between low nuclear and cytoplasmic WRN co-expression and low levels of KU70/KU80, DNA-PK, DNA Pol-B, CKD18, cytoplasmic RECQL4, and nuclear BLM protein expression (adjusted P-values < .05). Tumors with low nuclear or cytoplasmic WRN expression have worse overall breast cancer-specific survival (BCSS) (adjusted P-values < .05). In topoisomerase I overexpressed tumors, low WRN nuclear expression was associated with poor BCSS (P-value < .05). In BRCA-mutated tumors, low WRN cytoplasmic expression conferred shortest BCSS (P < .05).ConclusionsLow WRN protein expression is associated with poor BCSS in patients with breast cancer. This can be used to optimize the risk stratification for personalized treatment

Advances and unmet needs in genetic, basic and clinical science in Alport syndrome::report from the 2015 International Workshop on Alport Syndrome

Alport syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including 'repurposing') therapies on an international basis

The impact of crown-like structures and metabolic intervention on immune responses in patients with primary breast cancer

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. <br/

Pembrolizumab for early triple-negative breast cancer

Pembrolizumab is an immune checkpoint inhibitor (ICPI), a type of immunotherapy that blocks the programmed death 1 (PD1) receptor expressed on T cells. In cancer, PD1 binds to its ligand, programmed death ligand 1 (PDL1), which is expressed by both innate immune cells and tumour cells and prevents T cells from killing cancer cells. Triple-negative breast cancer (TNBC) is characterised by a higher density of immune cell infiltrates, a higher expression of PDL1 and a higher tumour mutational burden than other breast cancer subtypes, making ICPI a promising treatment option in TNBC. 1 Furthermore, the use of anthracyclines, taxanes and platinum-based neoadjuvant chemotherapy is associated not only with improved pathological complete responses (pCRs) but also with increased PDL1 expression in tumour cells in TNBC. 2 The KEYNOTE-522 study investigated whether the combination of chemotherapy and ICPI improves clinical outcomes in this group of patients.</p

Management of immunotherapy related adverse effects

Background: Over the last 5years ever since Ipilimumab received FDA approval for the treatment of metastatic melanoma, immunotherapy as a treatment modality is making its presence felt in oncology clinics across the globe. While initially approved for the treatment of metastatic melanoma alone, the immunotherapy repertoire is ever expanding with its’ utility being assessed for in the metastatic and adjuvant setting. The adverse effect profile from immunotherapy drugs differs from that of conventional chemotherapy that oncological services have trained in managing over the last few decades. This raises the need for educating health care professionals as the scenarios that patients present with at acute admissions or in clinic secondary to immune related adverse effects (iRAEs) can often be misleading.Aims: This review aims to synopsise the common and less common iRAEs and highlight their varied presentations, in addition to stressing the need to institute timely immunosuppression, which forms the cornerstone in the management of iRAEs.Recommendations: iRAEs have been recognised more frequently and in greater severity in dose dense and combination treatment regimens. While dermatological, gastrointestinal, hepatic toxicities in addition to endocrinopathies are the most commonly encountered iRAEs though other organ systems can be involved. The appropriate grading of an iRAEs’ severity, delaying or discontinuing immunotherapy based treatment, supportive care, commencement of immunosuppression (with corticosteroids and/or steroid sparing agents) and a multidisciplinary approach are key constituents in the treatment pathway of iRAEs.Conclusion: Early recognition of iRAEs and timely commencement of appropriate immunosuppression is imperative in order to reduce the risk of significant morbidity and potential mortality. The management of iRAEs warrants a multidisciplinary approach which would be aided by the development of local guidelines and educational activities directed at providing health care professionals with the information and tools required to recognise and appropriately treat iRAE

Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature

ObjectivesOncogenic osteomalacia is a rare paraneoplastic metabolic syndrome that is characterised by severe hypophosphataemia, hyperphosphaturia and osteomalacia secondary to renal loss of phosphate. It is commonly caused by overproduction of fibroblast growth factor-23 (FGF23) from benign tumours of mesenchymal origin. Currently, there is no clear evidence on the management of oncogenic osteomalacia in patients with metastatic solid tumours.MethodsWe report a case of breast cancer-induced oncogenic osteomalacia and discuss its diagnosis and management.ResultsA 71-year-old woman with advanced breast cancer developed symptomatic oncogenic osteomalacia with raised FGF23, severe hypophosphataemia and hypocalcaemia. The electrolytic disturbances were exacerbated after the administration of bisphosphonates in the context of her oncological treatment. Systemic chemotherapy and maintenance endocrine treatment along with phosphate and calcium supplementation reduced the activity of oncogenic osteomalacia and resolved the electrolytic imbalances.ConclusionsTo our knowledge, this is the first reported case of oncogenic osteomalacia in a patient with breast cancer. Oncogenic osteomalacia constitutes a diagnostic and therapeutic challenge. Pre-clinical and clinical evidence suggest that a possible underlying mechanism is the presence of molecular alterations in the FGF/FGFR signalling pathway leading to overexpression of FGF23. In metastatic setting, anticancer treatment can potentially lead to the normalisation of the electrolytic disturbances and reduction of the activity of oncogenic osteomalacia. The use of antiresorptive therapy in patients with bone metastases can potentially trigger FGF23 overexpression. Its use should be guided by the patients’ risk of skeletal-related events and electrolytic disturbances as well as the degree of activity of oncogenic osteomalacia.<br/

Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study: Copson ER, Maishman TC, Tapper WJ, Cutress RI, Greville-Heygate S, Altman DG, et al. Lancet Oncol 19(2):169–180, 2018

Young-onset breast cancer (YOBC) is defined as breast cancer (BC) diagnosed in women under the age of 40 years. 1 YOBC accounts for 5% of all female BCs and is associated with higher stage disease on presentation, higher rates of local recurrence and distant disease and poor survival. 2 A higher number of YOBC patients carry inherited pathogenic BRCA1 or BRCA2 variants (gBRCA1/2) compared to older patients diagnosed with BC. The BRCA genes are tumour suppressor genes involved in DNA repair by homologous recombination. They have an autosomal dominant pattern of inheritance. 3 Pathogenic mutations in the BRCA genes result in ineffective DNA repair, leading to chromosomal instability. They are characterised by high penetrance, with a lifetime BC risk of up to 70%, and are associated with aggressive histopathological characteristics, such as triple-negative breast cancer (TNBC). 4 However, there is no clear evidence on the impact of gBRCA mutations on the prognosis of patients with BC. The Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH) study investigated the association between gBRCA1/2 pathogenic variants and clinical outcomes in patients with YOBC.</p

Advanced concrete optical remote sensors: Structural health monitoring of concrete buildings using polymer sensors

A significant amount of public funds in Cyprus are allocated for civil infrastructure construction and maintenance. As technology progresses, coupled with the need to increase the general safety of structures and citizens, the civil infrastructure is required to become “smart” by incorporating sensing technologies. An essential parameter to assess the health condition in concrete structures is the internal moisture which is linked with the concrete deterioration mechanisms, such as carbonation, frost, corrosion and crack formation and can be measured indirectly by monitoring the relative humidity (RH). This paper is a review of the latest results regarding the project “ACOReS”. During the research project, we developed a novel monitoring system based on polymer optical fibre sensors embedded in concrete structures. The proposed polymer sensors used to measure essential quantities in concretes, such as relative humidity, temperature and strain for estimating the health condition of the building structures