PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases.

Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs) and pharmacologically (mainly with the pan-PIM inhibitor (PIMi) ETP-39010) in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL) cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.

Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas.

Peripheral T-cell lymphomas are very aggressive hematologic malignancies for which there is no targeted therapy. New, rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol-3-kinase is one of the most important pathways in cell survival and proliferation. We hypothesized that phosphatidylinositol-3-kinase inhibitors could be rationally selected drugs for treating peripheral T-cell lymphomas. Several phosphatidylinositol-3-kinase isoforms were inhibited genetically (using small interfering RNA) and pharmacologically (with CAL-101 and GDC-0941 compounds) in a panel of six peripheral and cutaneous T-cell lymphoma cell lines. Cell viability was measured by intracellular ATP content; apoptosis and cell cycle changes were checked by flow cytometry. Pharmacodynamic biomarkers were assessed by western blot. The PIK3CD gene, which encodes the δ isoform of phosphatidylinositol-3-kinase, was overexpressed in cell lines and primary samples, and correlated with survival pathways. However, neither genetic nor specific pharmacological inhibition of phosphatidylinositol-3-kinase δ affected cell survival. In contrast, the pan-phosphatidylinositol-3-kinase inhibitor GDC-0941 arrested all T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them. We identified phospho-GSK3ß and phospho-p70S6K as potential biomarkers of phosphatidylinositol-3-kinase inhibitors. Interestingly, an increase in ERK phosphorylation was observed in some GDC -0941-treated T-cell lymphoma cell lines, suggesting the presence of a combination of phosphatidylinositol-3-kinase and MEK inhibitors. A highly synergistic effect was found between the two inhibitors, with the combination enhancing cell cycle arrest at G0/G1 in all T-cell lymphoma cell lines, and reducing cell viability in primary tumor T cells ex vivo. These results suggest that the combined treatment of pan-phosphatidylinositol-3-kinase + MEK inhibitors could be more effective than single phosphatidylinositol-3-kinase inhibitor treatment, and therefore, that this combination could be of therapeutic value for treating peripheral and cutaneous T-cell lymphomas.

Sentinel lymph node biopsy in selected cases of ductal carcinoma in situ.

INTRODUCTION: Axillary lymphadenectomy is nowadays not recommended to treat ductal carcinoma in situ (DCIS), but there is controversy surrounding the indication for sentinel lymph node biopsy (SLNB). MATERIALS AND METHODS: A prospective study of a selected group of patients diagnosed preoperatively with DCIS was performed between 2004 and 2009. Indications for SLNB were histologically determined high-grade tumours, tumour size >2 cm and patients scheduled to undergo a mastectomy. RESULTS: Sixty-five patients were analysed. Surgical technique was mastectomy in 39 patients (60%) and conservative breast surgery in 26 (40%). Definitive histological study of the resected breast tumour revealed 43 cases (66.2%) of DCIS, 15 (23.1%) of ductal invasive carcinoma and seven (10.7%) microinvasive tumours. In confirmed DCIS, only 6.9% of sentinel lymph nodes were positive, in microinvasive carcinoma 28.5% and in invasive carcinoma 40% were positive. Total number of patients with positive sentinel lymph nodes was 11 (16.9%). Of 39 mastectomies, 12 corresponded to microinvasive or invasive carcinoma and six (50%) showed a positive SLNB. CONCLUSIONS: Performing SLNB avoids an unnecessary second surgery to study axillary lymph nodes in invasive carcinoma diagnosed after definitive histological study. In patients undergoing a mastectomy, this study requires an axillary lymphadenectomy that is not useful in up to 50% of cases. We think that in a selected group of patients with DCIS, SLNB improves tumour staging, adapts the treatment and avoids second surgery in this group of patients.

Neoplasias mucinosas papilares intraductales de páncreas: presentación de dos casos / Intraductal papillary mucinous neoplasm of the pancreas: a report of two cases

Las neoplasias mucinosas papilares intraductales de páncreas (NMPI) constituyen una entidad bien reconocida, relativamente rara, entre las neoplasias pancreáticas. La OMS las define como neoplasias papilares productoras de mucina que se desarrollan en el conducto de Wirsung o en sus ramas principales. Presentamos 2 casos de NMPI. El primero corresponde a un varón de 69 años que presenta una tumoración única de 7,5cm en cabeza de páncreas con dilatación del conducto de Wirsung que se diagnosticó como NMPI de tipo intestinal. El segundo se trataba de una mujer de 60 años con una tumoración quística multifocal en cabeza de páncreas de 2cm y afectación del borde de resección del cuerpo y la cola del páncreas que se diagnosticó como NMPI de tipo foveolar. En el estudio inmunohistoquímico, las tumoraciones presentaron una expresión diferente para citoqueratinas, siendo la NMPI de tipo intestinal positivo para CK-7 y CK-20 y negativo para CK34βE12; y el foveolar, positivo para CK-7 y CK34βE12 y negativo para CK-20. Estas neoplasias tienen un pronóstico excelente tras la cirugía en ausencia de componente invasor. La diferente expresión de citoqueratinas encontradas en nuestro estudio puede ser útil para determinar el tipo de neoplasia en biopsias de pequeño tamaño(AU)

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a well known but relatively infrequent entity. The World Heath Organization defines it as a papillary mucin producing neoplasm developing in the duct of Wirsung or in its principal branches. We present two cases of IPMN of the pancreas. The first was diagnosed as an intestinal type IPMN occurring in a 69 year old male who presented with a single, 7.5cm tumour in the head of the pancreas with a dilated duct of Wirsung. The second case was a foveolar type IPMN found in a 60 year old woman with a 2cm, multifocal, cystic tumour in the head of the pancreas involving the resection margins in the body and tail of the pancreas. The immunohistochemistry revealed a different expression of cytokeratins in each case; the intestinal type IPMN was positive for CK7 and CK20 and negative for CK34βE12, whilst the foveolar type tumour was positive for CK7 and CK34βE12 but negative for CK20. The post operative prognosis is excellent when no invasion has occurred. The difference in cytokeratin expression found in the reported cases could prove useful in the diagnosis of small biopsy samples(AU)

Prognostic and predictive factors and genetic analysis of early breast cancer.

The great heterogeneity of breast cancer makes it impossible to firmly predict which patients with early-stage tumours will or will not need systemic treatments according to the conventional prognostic factors currently employed. In fact, a substantial percentage of patients receive medical treatment for a disease that will not relapse, while another proportion of patients regarded as having good prognostic factors according to the classic criteria do not receive treatment and suffer disease relapse. Considering that most oncological treatments have short- and long-term toxic effects, new methods capable of offering a more precise prognosis need to be developed. The individualisation of the diagnosis of patients with breast cancer based on molecular and gene expression studies is bringing about a veritable revolution in our understanding of the biology of the disease. The new molecular classification of breast cancer, based on these profiles, allows us to establish a prognosis according to the genetic characteristics of each tumour. Such individualisation of the diagnosis of patients with breast cancer will lead to the application of more specific treatments, thereby improving patient survival with lesser toxicity and increased economic savings. Of the different genetic analytical tests available, MammaPrint has been shown to be the option offering the most information on the behaviour of early breast cancer; as a result, it is the most useful technique in deciding the need for oncological treatment as a complement to surgery.

Infiltrating ductal carcinoma and ductal carcinoma in situ associated with mammary hamartoma.

Mammary hamartoma is a rare nonmalignant lesion. Only 11 cases of carcinoma associated with hamartoma have been previously described in the literature. We describe a case of infiltrating ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS) associated with hamartoma in a 35-year-old woman. Mammography showed the features of a typical hamartoma with suspicious microcalcifications arising in it. The patient underwent a radical modified mastectomy. It is likely that hamartoma is a coincidental finding. The identification of suspicious microcalcifications in a typical mammographic image of a hamartoma should prompt continued examination to exclude an underlying tumor.

[Mammary hamartoma]. / Hamartoma mamario.

For many years, mammary hamartoma was considered to be an under-diagnosed disease. However, with the increasing use of diagnostic procedures in breast tumors (mammography, ultrasound, fine needle aspiration cytology and core needle biopsy), diagnosis of this entity has increased. Mammary hamartomas normally manifest as painless, mobile, palpable lumps without adherence to skin or muscle. Mammography shows well-circumscribed tumors, separated from adjacent normal breast tissue. Macroscopically they are well-defined tumors, consisting of benign mammary glandular tissue, fibrous stroma and fat in variable proportions, sometimes with a pseudoencapulation. Because of the lack of cytological and architectural specificity of hamartomas, correlation between clinical manifestations, imaging techniques and histology is essential. This report describes a case of an 11-cm mammary hamartoma in a 46-year-old woman.

Hamartoma mamario / Mammary hamartoma

El hamartoma mamario se ha considerado durante mucho tiempo como una enfermedad infradiagnosticada, pero con el aumento progresivo en la utilización de procedimientos diagnósticos en las tumoraciones mamarias (mamografía, ecografía, punción aspiración con aguja fina y biopsia con aguja gruesa) el número de casos diagnosticados ha aumentado. Los hamartomas mamarios suelen manifestarse como masas indoloras, móviles y no adheridas a piel ni a músculo. En la mamografía se suelen observar tumoraciones bien delimitadas, separadas del tejido mamario normal. Macroscópicamente son tumores bien definidos, compuestos de tejido glandular mamario de características benignas, estroma fibrosa y tejido graso en cantidades variables, en ocasiones seudoencapsulados. La correlación de las manifestaciones clínicas y las pruebas de imagen con la histología es completamente necesaria, debido a la falta de especificidad citológica y arquitectural de los hamartomas. Este artículo describe un caso de hamartoma mamario de 11 cm de diámetro en una mujer de 46 años de edad (AU)

For many years, mammary hamartoma was considered to be an under-diagnosed disease. However, with the increasing use of diagnostic procedures in breast tumors (mammography, ultrasound, fine needle aspiration cytology and core needle biopsy), diagnosis of this entity has increased. Mammary hamartomas normally manifest as painless, mobile, palpable lumps without adherence to skin or muscle. Mammography shows well-circumscribed tumors, separated from adjacent normal breast tissue. Macroscopically they are well-defined tumors, consisting of benign mammary glandular tissue, fibrous stroma and fat in variable proportions, sometimes with a pseudoencapulation. Because of the lack of cytological and architectural specificity of hamartomas, correlation between clinical manifestations, imaging techniques and histology is essential. This report describes a case of an 11-cm mammary hamartoma in a 46-year-old woman (AU)

Malignant degeneration of presacral teratoma in the Currarino anomaly.

The autosomal dominant Currarino anomaly (CA) comprises a presacral mass, partial sacral agenesis, and anorectal defects. Chronic constipation in childhood related to anorectal defects is the most common presenting symptom and hemisacrum the most frequent malformation. The presacral mass may be an anterior meningomyelocele, teratoma, hamartoma, dermoid cyst, neuroenteric cyst, or a combination of these. Sepsis and meningitis are frequent serious problems related to the anterior meningomyelocele, whilst malignant transformation of presacral teratoma is a rare, severe complication in CA. Here, we report on a three-generation family segregating the CA, presenting with anorectal defects, severe constipation, and sacral involvement in affected relatives. Teratoma was the most frequent component of the presacral mass. In this kindred a 22-year-old man died of a neuroendocrine tumor, probably related to malignant change in a presacral teratoma. A novel mutation in HLXB9 consisting of a 24-bp deletion and insertion of 2-bp into exon 1, was identified in all patients and in also three asymptomatic members of this family. Anterior meningomyelocele is the most frequently reported component of the presacral masses in CA; however, presacral teratomas carry an inherent risk for malignancy that must be considered in the counseling, surgical treatment options, and follow-up of CA patients.

Nocardiosis sistémica de evolución fatal en una niña previamente sana / Systemic nocardiasis of fatal outcome in a previously healthy female child

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