Chromosome 17 centromere amplification and chromosomal instability (CIN) in breast cancer: Pathogenic and therapeutic implications.

Chromosomal instability (CIN) is present in variable degrees in a significant percentage (up to 90%) of cancers and often portends adverse outcomes. However, it has not been incorporated in clinical practice as a prognostic marker due to the lack of standardization and proof of clinical utility of assays to measure it, as well as uncertainties regarding optimal cut-offs. Amplification of the centromeric region of chromosome 17 as measured by In Situ Hybridization (ISH) of the CEP17 probe is used clinically as part of the ISH assay for HER2 status determination in breast cancer in cases with intermediate (2+) result of HER2 protein expression by immunohistochemistry. CEP17 amplification concerns the centromeric area and rarely extends beyond it to involve polysomy of the whole chromosome. The association of CEP17 amplification with generalized CIN remains uncertain. Such association, if confirmed, could be an opportunity for a practical and clinically validated test of CIN in breast cancer. This paper explores the association of CIN with centromere 17 amplification and with centromere function in general, as well as the pathophysiology of centromeres/kinetochore function during mitosis that underlies their relationship with CIN in cancer and in breast cancer in particular.

HER2 in stemness and epithelial-mesenchymal plasticity of breast cancer.

Breast cancer had been the first non-hematologic malignancy where sub-types based on molecular characterization had entered clinical practice. HER2 over-expression, due to either gene amplification or protein up-regulation, defines one of these sub-types and is clinically exploited by addition of HER2-targeted treatments to the regimens of treatment. Nevertheless, in many occasions HER2-positive cancers are resistant or become refractory to these therapies. Several mechanisms, such as activation of alternative pathways or loss of expression of the receptor in cancer cells, have been proposed as the cause of these therapeutic failures. Cancer stem cells (CSCs, alternatively called tumor-initiating cells) comprise a small percentage of the tumor cells, but are capable of reconstituting and propagating tumors due to their superior intrinsic capacity for regeneration, survival and resistance to therapies. CSCs possess circuits enabling epigenetic plasticity which endow them with the ability to alternate between epithelial and mesenchymal states. This paper will discuss the expression and regulation of HER2 in CSCs of the different sub-types of breast cancer and relationships of the receptor with both the circuits of stemness and epithelial-mesenchymal plasticity. Therapeutic repercussions of the relationship of HER2-initiated signaling with stemness networks will also be proposed.

Statin use and peripheral blood progenitor cells mobilization in patients with multiple myeloma.

PURPOSE: Statins have beneficial effects in patients after myocardial infarction and at least part of the benefit results from mobilization of marrow endothelial progenitors to repopulate damaged myocardial tissues. This study examines if statins may have the same effect in mobilizing marrow progenitors to be harvested and subsequently used in high-dose chemotherapy with progenitor cell rescue in multiple myeloma. METHODS: From 2006 to 2012, 86 patients with multiple myeloma were mobilized with the use of G-CSF and were retrospectively analyzed. Patients with other malignancies or mobilized with the use of chemotherapy or with plerixafor were excluded. RESULTS: The median age of the patients was 60 years. 72 patients had received one line of chemotherapy and 14 patients two or more lines of chemotherapy. Twenty patients were taking statins at the time of the harvest while 66 patients were not. In the group of patients taking statins the success rate of first leukapheresis (obtaining the target number of 4 × 10(6) CD34+ cells/kg) was 85 % while in the group not taking statins this rate was 63.6 %. Despite the comparatively small number of patients this difference approached statistical significance (χ (2) = 0.07). CONCLUSION: This retrospective analysis of 86 patients shows for the first time a possible benefit of statins for peripheral blood progenitor cells mobilization in patients with multiple myeloma. Larger studies would be required to clarify the issue. If their effectiveness is confirmed, statins could be a safe and cheaper addition to chemotherapy and plerixafor for peripheral hematopoietic stem cell mobilization.

Epithelial to mesenchymal transition in the pathogenesis of uterine malignant mixed Müllerian tumours: the role of ubiquitin proteasome system and therapeutic opportunities.

Malignant mixed Müllerian tumours (malignant mixed mesodermal tumours, MMMT) of the uterus are metaplastic carcinomas with a sarcomatous component and thus they are also called carcinosarcomas. It has now been accepted that the sarcomatous component is derived from epithelial elements that have undergone metaplasia. The process that produces this metaplasia is epithelial to mesenchymal transition (EMT), which has recently been described as a neoplasia-associated programme shared with embryonic development and enabling neoplastic cells to move and metastasise. The ubiquitin proteasome system (UPS) regulates the turnover and functions of hundreds of cellular proteins. It plays important roles in EMT by being involved in the regulation of several pathways participating in the execution of this metastasis-associated programme. In this review the specifi c role of UPS in EMT of MMMT is discussed and therapeutic opportunities from UPS manipulations are proposed.

Fludarabine-induced eosinophilia: case report.

Eosinophilia induced by nucleoside analogs has been described in a handful of case reports and during the treatment of both chronic lymphocytic leukemia (CLL) and follicular non-Hodgkin's lymphoma (NHL). This paper reports an additional case of fludarabine-induced eosinophilia during the treatment of CLL. The patient, a 58-year-old man, developed peripheral eosinophilia with a peak value of 1.7x10(9)/l 5 months after the beginning of treatment with fludarabine. A thorough investigation for other causes of eosinophilia was negative and the eosinophilia subsided after the completion of the treatment.

Interferon-alpha and the pathogenesis of myeloproliferative disorders.

Interferon-alpha (IFN-alpha), a molecule with multiple biological actions, is widely used in the treatment of chronic myelogenous leukemia (CML) and the other myeloproliferative disorders. This glycoprotein belonging to the type I subfamily of interferons has been recombinantly manufactured and has been approved for the biotherapy of CML, now becoming the first line of treatment for CML patients in chronic phase who are not candidates for allogeneic hematopoietic stem cell or bone marrowtransplantation. Interferon-alpha action involves binding to its cell membrane receptor and initiation of an intracellular signal transduction cascade. Two major pathways mediate the biologic actions of IFN-alpha. The JAK-STAT pathway leads to phosphorylation and activation of STAT 1 and STAT 2 molecules and transcription of genes like p21 and caspase-1 resulting in cycle arrest and apoptosis. The PKR (protein kinase dsRNA-induced) kinase phosphorylates and inhibits the eukaryotic initiator of translation eIF-2alpha leading again to apoptosis. The PKR kinase cascade also leads to activation of the transcription factor NF-kappaB. The relevance of this activation is unclearand it is possiblethat NF-kappaB has not had the opportunity to transcribe its target genes as it is a substrate of effector caspases and is maybe cleaved by them before exerting any transcription activity. Through the JAK-STAT and the PKR kinase pathways IFN-alpha is able to modify the proliferative and antiapoptotic actions of the constitutively activated kinase bcr-abl, the product of the t(9;22) translocation present in CML, and has therapeutic effects in this disease.

Eccrine sweat gland carcinoma: a case report and review of diagnosis and treatment.

Carcinomas of the skin appendices are rare neoplasms but for prognostic reasons it is important to differentiate them from the indolent squamous and basal cell carcinomas, as their behavior is more aggressive. We report on a case of eccrine sweat gland carcinoma that displayed all the typical features of those neoplasms. The patient sought medical attention after a lesion in his foot, already present for four years, began to enlarge and developed satellite lesions. The pathological diagnosis was made only after the lesion was initially misdiagnosed as basal cell carcinoma of the skin. Multiple chemotherapeutic regimens and radiation therapy were administered with only temporary benefit. The patient developed distant metastatic disease but survived with metastases for three years. He died nine years after the initial lesion developed in his foot and five years after the diagnosis. The diagnosis of sweat gland carcinomas can be facilitated by histochemical stains. In contrast to squamous and basal cell carcinomas of the skin, these are generally positive for the carcinoembryonic antigen (CEA). Once metastatic, these neoplasms are only infrequently, and usually briefly, responsive to either chemotherapy or radiotherapy and new treatments are urgently needed. Early recognition of the entity may allow more timely treatment.

Apoptosis and the pathogenesis of lymphoma.

The pathogenesis of follicular lymphoma and chronic lymphocytic leukemia (CLL) involves the dysregulation of the bcl-2 protein. This protein is a critical regulator of apoptosis and interferes with the caspase cascade, which is the backbone of the apoptotic machinery. The multiple interactions of caspases with bcl-2 and its related proteins which comprise the bcl-2 family of proteins have become more clear over the past few years and its importance in carcinogenesis is increasingly appreciated. The network of proteins of both the apoptotic pathway and the cell cycle regulators and their interactions and mutual regulations are in the process of being elucidated. It is hoped that this will soon be translated to clinical benefit for patients with lymphomas.