Granular cell tumor of the breast: Molecular pathology and clinical management.

Granular cell tumor is a rare condition that occasionally affects breast parenchyma: approximately, 5%-15% of all granular cell tumors represent 1:1000 of breast tumors. In this study, we reported a consecutive series of 12 patients with primary granular cell tumor of the breast observed at our institute, focusing attention on preoperative management, surgical approach, and long-term follow-up. Eight cases (8/12; 66.78%) presented with left-breast tumors; in the majority of patients (11/12; 91.7%), the lesion was identified in one of the upper quadrants. Specifically, upper intern quadrants (10 cases) were more affected. Surgical excision was performed in all patients. Mean diameter at pathologic section was 11.4 mm (range: 5-22). Tumor relapse was reported only in one case (8.3%). Mean follow-up was 98.1 months (range: 1-192). We proposed a model to explain the molecular mechanism of granular cell tumorigenesis associating to the high level of S100 protein. Management of primary granular cell tumor of the breast requires a correct initial diagnosis using breast imaging associated with core biopsy. Surgical procedure with wide resection or quadrantectomy requires a careful evaluation of breast margins.

Ataxia-Telangiectasia patients get a rare chance to meet the experts at a dedicated workshop in IFOM (the FIRC Institute of Molecular Oncology).

Ataxia telangiectasia (A-T) is a genetic syndrome characterized by cerebellar degeneration, telangiectasia, immunodeficiency and cancer predisposition. A-T occurs in between 1 in 40,000 and 1 in 100,000 live births. The first symptoms normally occur in early childhood when the infant begins to walk. Affected children have immunodeficiency and an increased predisposition for cancers. A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name.

Highlights from the ecancer Future Horizons in Lung Cancer conference, 1-2 September 2016: Focusing on the future of treatment for NSCLC and SCLC.

The 'Future Horizons in Lung Cancer' meeting was designed to bring leading scientists together alongside clinicians to discuss the most recent advances in lung cancer pathophysiology and treatment. The aim was to take those attending the event on a journey through decades of lung cancer research and understanding, with topics spanning from screening and surgical care to "omics" approaches for drug target and biomarker discovery. There were also several talks describing the role of radiotherapy in lung cancer and advancements in imaging techniques, aiding surgeons in their attempts to resect early lesions. Current standards of care were both challenged and celebrated, while new and innovative immunotherapies also came into the spotlight. The meeting, held over two days, attracted a high calibre of speakers and delegates from across the globe. There were 10 sessions in total focusing on the latest therapeutic advances and predictions for the future of lung cancer treatment. Highlights included a key note lecture from Dr Frances Shepherd packing 40 years of lung cancer research into a 40-minute presentation. Heated debates were had regarding the validity of maintenance therapy and immune checkpoint inhibitors that have taken the research community by storm. The latest developments in imaging, surgery, systemic and radiotherapy were presented over 10 sessions of exciting, innovative and stimulating presentations, leaving the audience lively yet pensive.

Highlights of the twelfth annual meeting of the National Cancer Research Institute (NCRI), 6-9 November 2016, Liverpool, UK.

The annual meeting of the National Cancer Research Institute (NCRI), held in Liverpool, UK, is a multidisciplinary conference. The meeting generally outlines research trends for the coming year and is aimed at cancer professionals at every level. The most important themes discussed for this conference was that of cancer stem cells. Alongside once again prominence was given to topics of cancer evolution and the role of social prevention programmes like previous years.

Cancer immunotherapy: from the lab to clinical applications-Potential impact on cancer centres' organisation.

This report covers the Immunotherapy sessions of the 2016 Organisation of European Cancer Institutes (OECI) Oncology Days meeting, which was held on 15th-17th June 2016 in Brussels, Belgium. Immunotherapy is a potential cancer treatment that uses an individual's immune system to fight the tumour. In recent years significant advances have been made in this field in the treatment of several advanced cancers. Cancer immunotherapies include monoclonal antibodies that are designed to attack a very specific part of the cancer cell and immune checkpoint inhibitors which are molecules that stimulate or block the inhibition of the immune system. Other cancer immunotherapies include vaccines and T cell infusions. This report will summarise some of the research that is going on in this field and will give us an update on where we are at present.

Highlights from the 38th SABCS annual meeting, 8th - 12th December 2015, San Antonio, USA.

The 2015 San Antonio Breast Cancer Symposium (SABCS) annual meeting highlighted the latest discoveries in breast cancer research and as ever provided a unique opportunity for investigators from all over the world to meet and network. With the rapidly increasing pace of discoveries in the basic, translational, and clinical sciences, mainly because of the advent of new technologies, cancer researchers are making rapid progress that is having significant patient benefit. This year's meeting featured studies on targeted therapy plus endocrine therapy for metastatic disease with a mutation of PIK3CA, chemotherapy combinations for HER-2-positive disease, long-term outcomes of different surgeries for early-stage cancers, and the first-ever trial of a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor as an adjuvant treatment for breast cancer in postmenopausal women. In the educational session, there was significant emphasis on the role of metabolic syndrome and lifestyle on breast cancer outcome.

Conference report from the 2015 OECI Oncology Days, Portugal, 22-24 June-tumour heterogeneity and next generation sequencing: morphology and technology.

Tumour heterogeneity was the topic of the 'Oncology Days' series held at the 2015 OECI conference in which experts within the field provided an update on tumour heterogeneity and its relevance in the clinical setting. Here we present a summary of the presentations from the two major sessions of the meeting: clonal heterogeneity and phenotypic heterogeneity.

Eurocan Platform meeting: European recommendations for biomarker-based chemoprevention trials.

Chemoprevention or the now more preferred 'cancer prevention' is the long-term administration of a biological or chemical agent to reduce the risk of cancer. This approach has long been active in individuals at high risk of developing breast or colon cancer. The aim of this expert meeting was to review the current status of the field of cancer prevention and potential, emerging biomarkers specifically focusing on breast, colon, and lung cancer but also with sessions on ovary and prostate.

Empowering young people with long-term illness.

In response to recommendations in the National Service Framework for children with long-term conditions, a programme was developed based on the Expert Patient Programme for adults. Children who were heavy users of primary care, hospital care or both were invited to attend one of two programmes: the first for young people aged between 12 and 18; the second for children aged between five and 11. Evaluation feedback was obtained using questionnaires. Findings included benefits to young people of social contact, increased social confidence, improved family communications and relationships, and acquisition of new skills. Preliminary data indicates some reduced use of health services by these children and young people following the programme. Although the findings should be treated with caution, they suggest that the programmes achieved their aim of helping participants to acknowledge their illness and feel more in control of their lives.

Stem cell-mediated muscle regeneration is enhanced by local isoform of insulin-like growth factor 1.

We investigated the mechanism whereby expression of a transgene encoding a locally acting isoform of insulin-like growth factor 1 (mIGF-1) enhances repair of skeletal muscle damage. Increased recruitment of proliferating bone marrow cells to injured MLC/mIgf-1 transgenic muscles was accompanied by elevated bone marrow stem cell production in response to distal trauma. Regenerating MLC/mIgf-1 transgenic muscles contained increased cell populations expressing stem cell markers, exhibited accelerated myogenic differentiation, expressed markers of regeneration and readily converted cocultured bone marrow to muscle. These data implicate mIGF-1 as a powerful enhancer of the regeneration response, mediating the recruitment of bone marrow cells to sites of tissue damage and augmenting local repair mechanisms.

Deletion of a negatively acting sequence in a chimeric GATA-1 enhancer-long terminal repeat greatly increases retrovirally mediated erythroid expression.

The locus control region of the beta-globin gene cluster has been used previously to direct erythroid expression of globin genes from retroviral vectors for the purpose of gene therapy. Short erythroid regulatory elements represent a potentially valuable alternative to the locus control region. Among them, the GATA-1 enhancer HS2 was used to replace the retroviral enhancer within the 3'-long terminal repeat (LTR) of the retroviral vector SFCM, converting it into an erythroid-specific regulatory element. In this work, we have functionally studied an additional GATA-1 enhancer, HS1. HS1 participates in the transcriptional autoregulation of GATA-1 through an essential GATA-binding site that is footprinted in vivo. In this work we identified within HS1 a new in vivo footprinted region, and we showed that this sequence indeed binds a nuclear protein in vitro. Addition of HS1 to HS2 within the LTR of SFCM significantly improves the expression of a reporter gene. The deletion of the newly identified footprinted sequence in the retroviral construct further increases expression up to a level almost equal to that of the wild type retroviral LTR, without loss of erythroid specificity, suggesting that this sequence may act as a negative regulatory element. An improved vector backbone, MDeltaN, allows even better expression from the new GATA cassette. These results suggest that substantial improvement of overall expression can be achieved by the combination of multiple changes in both regulatory elements and vectors.

Kit regulatory elements required for expression in developing hematopoietic and germ cell lineages.

The Kit (White) gene encodes the transmembrane receptor of stem cell factor/Kit ligand (KL) and is essential for the normal development/maintenance of pluripotent primordial germ cells (PGCs), hematopoietic stem cells (HSCs), melanoblasts, and some of their descendants. The molecular basis for the transcriptional regulation of Kit during development of these important cell types is unknown. We investigated Kit regulation in hematopoietic cells and PGCs. We identified 6 DNase I hypersensitive sites (HS1-HS6) within the promoter and first intron of the mouse Kit gene and developed mouse lines expressing transgenic green fluorescent protein (GFP) under the control of these regulatory elements. A construct driven by the Kit promoter and including all 6 HS sites is highly expressed during mouse development in Kit+ cells including PGCs and hematopoietic progenitors (erythroid blast-forming units and mixed colony-forming units). In contrast, the Kit promoter alone (comprising HS1) is sufficient to drive low-level GFP expression in PGCs, but unable to function in hematopoietic cells. Hematopoietic expression further requires the addition of the intronproximal HS2 fragment; HS2 also greatly potentiates the activity in PGCs. Thus, HS2 acts as an enhancer integrating transcriptional signals common to 2 developmentally unrelated stem cell/progenitor lineages. Optimal hematopoietic expression further requires HS3-HS6.

Induction of globin mRNA expression by interleukin-3 in a stem cell factor-dependent SV-40 T-antigen-immortalized multipotent hematopoietic cell line.

Erythropoiesis requires the stepwise action on immature progenitors of several growth factors, including stem cell factor (SCF), interleukin 3 (IL-3), and erythropoietin (Epo). Epo is required to sustain proliferation and survival of committed progenitors and might further modulate the level of expression of several erythroid genes, including globin genes. Here we report a new SCF-dependent immortalized mouse progenitor cell line (GATA-1 ts SCF) that can also grow in either Epo or IL-3 as the sole growth factor. When grown in SCF, these cells show an "open" chromatin structure of the beta-globin LCR, but do not significantly express globin. However, Epo or IL-3 induce globin expression and are required for its maintainance. This effect of IL-3 is unexpected as IL-3 was previously reported either to be unable to induce hemoglobinization, or even to antagonize it. This suggests that GATA-1 ts SCF cells may have progressed to a stage in which globin genes are already poised for expression and only require signal(s) that can be elicited by either Epo or IL-3. Through the use of inhibitors, we suggest that p38 may be one of the molecules modulating induction and maintenance of globin expression.