Expert consensus to optimize the treatment of elderly patients with luminal metastatic breast cancer.

Most patients diagnosed with luminal metastatic breast cancer (MBC) who are seen in oncology consultations are elderly. MBC in elderly patients is characterized by a higher percentage of hormone receptor (HR) expression and a lower expression of human epidermal growth factor receptor 2 (HER2). The decision regarding which treatment to administer to these patients is complex due to the lack of solid evidence to support the decision-making process. The objective of this paper is to review the scientific evidence on the treatment of elderly patients with luminal MBC. For this purpose, the Oncogeriatrics Section of the Spanish Society of Medical Oncology (SEOM), the Spanish Breast Cancer Research Group (GEICAM) and the SOLTI Group appointed a group of experts who have worked together to establish consensus recommendations to optimize the treatment of this population. It was concluded that the chronological age of the patient alone should not guide therapeutic decisions and that a Comprehensive Geriatric Assessment (CGA) should be performed whenever possible before establishing treatment. Treatment selection for the elderly population should consider the patient's baseline status, the expected benefit and toxicity of each treatment, and the impact of treatment toxicity on the patient's quality of life and functionality.

Interfacial coupling effect of Cr2O3 on the magnetic properties of Fe72Ga28 thin films.

Here it is investigated the effect of the antiferromagnet Cr2O3 on the magnetic properties of ferromagnetic Fe72Ga28 thin films. Sputtered Fe72Ga28 layers have their magnetization in the sample plane with a magnetic fluctuation that gives rise to magnetic ripple. In order to turn its magnetization into the out of plane (OOP) direction, it has been magnetically coupled with Cr2O3 that has magnetic moments along the c-axis, that is the perpendicular direction when properly aligned. Cr2O3 has been obtained from Cr oxidation, whereas Fe72Ga28 has been deposited on top of it by sputtering in the ballistic regime. Although a uniaxial in-plane magnetic anisotropy is expected for Fe72Ga28 thickness above 100 nm, the interfacial coupling with Cr2O3 prevents this anisotropy. The formation of stripe domains in Fe72Ga28 above a critical thickness reveals the enhancement of the out of plane component of the Fe72Ga28 magnetization with respect to uncoupled layers. Due to the interface coupling, the Fe72Ga28 magnetization turns into the out-of-plane direction as its thickness is gradually reduced, and a perpendicular magnetic anisotropy of 3·106 erg·cm-3 is inferred from experimental results. Eventually, the coupling between Cr2O3 and Fe72Ga28 promotes an exchange-bias effect that has been well fitted by means of the random field model.

Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition.

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.

Functional characterization of the promoter region of the human EVI1 gene in acute myeloid leukemia: RUNX1 and ELK1 directly regulate its transcription.

The EVI1 gene (3q26) codes for a transcription factor with important roles in normal hematopoiesis and leukemogenesis. High expression of EVI1 is a negative prognostic indicator of survival in acute myeloid leukemia (AML) irrespective of the presence of 3q26 rearrangements. However, the only known mechanisms that lead to EVI1 overexpression are 3q aberrations, and the MLL-ENL oncoprotein, which activates the transcription of EVI1 in hematopoietic stem cells. Our aim was to characterize the functional promoter region of EVI1, and to identify transcription factors involved in the regulation of this gene. Generation of seven truncated constructs and luciferase reporter assays allowed us to determine a 318-bp region as the minimal promoter region of EVI1. Site-directed mutagenesis and chromatin immunoprecipitation (ChIP) assays identified RUNX1 and ELK1 as putative transcription factors of EVI1. Furthermore, knockdown of RUNX1 and ELK1 led to EVI1 downregulation, and their overexpression to upregulation of EVI1. Interestingly, in a series of patient samples with AML at diagnosis, we found a significant positive correlation between EVI1 and RUNX1 at protein level. Moreover, we identified one of the roles of RUNX1 in the activation of EVI1 during megakaryocytic differentiation. EVI1 knockdown significantly inhibited the expression of megakaryocytic markers after treating K562 cells with TPA, as happens when knocking down RUNX1. In conclusion, we define the minimal promoter region of EVI1 and demonstrate that RUNX1 and ELK1, two proteins with essential functions in hematopoiesis, regulate EVI1 in AML. Furthermore, our results show that one of the mechanisms by which RUNX1 regulates the transcription of EVI1 is by acetylation of the histone H3 on its promoter region. This study opens new directions to further understand the mechanisms of EVI1 overexpressing leukemias.

EVI1 controls proliferation in acute myeloid leukaemia through modulation of miR-1-2.

BACKGROUND: The EVI1(ecotropic virus integration site 1) gene codes for a zinc-finger transcription factor, whose transcriptional activation leads to a particularly aggressive form of acute myeloid leukaemia (AML). Although, EVI1 interactions with key proteins in hematopoiesis have been previously described, the precise role of this transcription factor in promoting leukaemic transformation is not completely understood. Recent works have identified specific microRNA (miRNA) signatures in different AML subgroups. However, there is no analysis of miRNAs profiles associated with EVI1 overexpression in humans. METHODS: We performed QT-RT-PCR to assess the expression of 250 miRNAs in cell lines with or without EVI1 overexpression and in patient samples. We used ChIP assays to evaluated the possible binding of EVI1 binding to the putative miRNA promoter. Proliferation of the different cell lines transfected with the anti- or pre-miRs was quantified by MTT. RESULTS: Our data showed that EVI1 expression was significantly correlated with the expression of miR-1-2 and miR-133-a-1 in established cell lines and in patient samples. ChIP assays confirmed that EVI1 binds directly to the promoter of these two miRNAs. However, only miR-1-2 was involved in abnormal proliferation in EVI1 expressing cell lines. CONCLUSIONS: Our data showed that EVI1 controls proliferation in AML through modulation of miR-1-2. This study contributes to further understand the transcriptional networks involving transcription factors and miRNAs in AML.

[Paratesticular fibrosarcoma. A rare malign neoplasm]. / Fibrosarcoma paratesticular: una neoplasia maligna muy infrecuente.

Hereby we wish to present the clinical and pathological results of a rare paratesticular sarcome of the spermatic cord. This tumor was a fibrosarcoma in a 55 year old male that started in a most unusual way and developed very quickly. We practised a radical orquitectomy with inguinal ligation of the pedicule without post-operatory therapy. After a 5 year follow up, there is no trace of clinical or radiological recurrence in the region or metastasis. We consider radical surgery to be the only therapeutic alternative, even for cases of fast developing, being in our case a good pronostic.

[Burn out bilateral testicular tumor]. / Tumor testicular bilateral "quemado" ("burn out").

UNLABELLED: Differentiating a primary retroperitoneal seminoma from a metastatic testicular tumor with an occult testicular primary or a burned out testicular cancer remains difficult. We present a case of a burned out tumor. The patient had a retroperitoneal seminoma with ultrasonically and pathologically demonstrated abnormalities in both testes, but without evidence of tumor. The patient received chemotherapy and underwent surgery of the residual retroperitoneal mass and bilateral orchiectomy. All surgical specimens were negative for testis cancer. CONCLUSION: Primary extragonadal germ cell tumors in the retroperitoneum are a rare entity. The presence of a retroperitoneal tumor with ultrasonographical abnormalities in testicular evaluation should be considered as a metastases of a burned out testicular cancer, and biopsy is mandatory. Surgical evaluation and orchiectomy should be evaluated in a individual setting.

[Hepatic granulocytic sarcoma: an unusual presentation]. / Sarcoma granulocítico hepático: una presentación inusual.

A case of granulocytic sarcoma (chloroma) of hepatic localization is presented. It is a extramedullary strange tumour, composed of immature precursors of myeloid cells. Clinically it can show, before, during or after a acute myeloid leukemia, chronic myeloproliferative disorders or myelodysplastic syndromes. Our patient, 81 year-old male, presented a process of important acute jaundice, with negative image technics, what indicated us the intrahepatic origin, negative tumorals markers, negative serology and hepatic biopsy (the piece of greenish coloration is described) what showed a hepatic sinusoides diffuse infiltration by indifferentiation cellularity, with study immuno-histochemical that was positive for the myeloperoxydase, giving a diagnose compatible with hepatic infiltration for acute myeloid leukemia. The patient doesn't present affectation of peripheral blood, and he died for acute hepatic and renal failure after 8 days of entrance.

[Bilateral primary adrenal lymphoma: an unusual presentation]. / Linfoma suprarrenal primario bilateral: una presentación inusual.

A case of primary adrenal bilateral non-Hodgking lymphoma, with depressed adrenal reserve is presented. This rare neoplasm causes rapid evolution and fatal outcome in most cases. In our patient, lethal outcome was associated with severe hypercalcemia and refractary hypotension. Many other complications are due to tumoral lysis syndrome associated with high steroid doses in adrenal insufficiency. This rare entity must be included in the differencial diagnosis of adrenal masses, uni or bilateral, because early diagnostic is important for preventing complications, potentially lethals and for improving survival. Image thecnics and ultrasound-guided or computed-tomography-guided FNA, are best diagnostic methods, but in many cases, definitive diagnostic is obtained by necropsy.