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Myeloid sarcoma (MS) is a rare tumor mass derived from the extramedullary proliferation of blasts of one or more of myeloid lineages. It usually occurs at an anatomical site other than the bone marrow (BM). Among the anatomical site which may be involved, female genital tract is a rare localization. When MS follows a previous history of myeloid pathology it is usually associated to a poor prognosis. To date this disease was managed with exploratory laparotomy or with surgical debulking. The authors report a case of laparosc6pic diagnosis of a pelvic myeloid sarcoma in a patient previously affected by acute mycloid leukemia, evidencing the importance of minimally invasive diagnosis and subsequent multidisciplinary management.

Background: Although recent high-resolution genome-wide profiling analysis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) samples has contributed to the identification of many novel somatic genetic alterations, a deep molecular characterization of adult ALL is still challenging, especially for those cases lacking recurrent fusion genes. Aims: In order to better molecularly dissect this ALL subgroup, we performed an integrative molecular approach including gene-candidate high-resolution screening and genome-wide profiling analyses. Methods: We retrospectively analyzed 28 newly diagnosed BCR-ABL1- negative BCP-ALL subjects (19 males/9 females; median age 41.5 years; negative for known fusion genes) and 28 BCR-ABL1-positive BCP-ALL subjects as a comparison group. In BCR-ABL1-negative ALL karyotype was normal in 10/28 (36%). Copy number alterations (CNA) of know leukemiarelated genes, such as IKZF1, CDKN2A/B, PAX5, EBF1, ETV6, BTG1, RB1, and genes within PAR1: CRLF2, CSF2RA, IL3RA have been assessed by the SALSA MLPA kit P335 IKZF1 (MRC Holland). In addition, sequence mutations have been investigated in TP53, CRLF2, JAK2, LEF1, PAX5 and IL7R by nextgeneration deep-sequencing (NGS) (Roche Applied Science; IRON-II study oligonucleotide primer plates). Positivity for newly described BCR-JAK2, PAX5- JAK2, ETV6-ABL1, EBF1-PDGFRB, NUP-ABL1 gene fusions occurring in BCR-ABL1-like ALL (Roberts KG et al., Cancer Cell. 2012) was assessed by PCR amplification and sequencing. Finally, SNP arrays (SNP 6.0, Affymetrix), gene expression profile analyses (GeneChip® Human Transcriptome Array 2.0) and whole exome sequencing (Illumina) were performed to more fully assess genomic complexity. Results: Overall, 76% of BCR-ABL1-negative subjects showed an abnormality of at least one of the analyzed known leukemia genes: 7 (25%) had one, 4 (14%) had two, 6 (21%) had three, and 6 (21%) had four or more alterations. In subjects showing no abnormalities, SNP arrays analysis revealed amplifications of chromosome 1q in 2/6 cases (33%). Deletions of CDKN2A/B were the most frequent (39%) and in 73%, they occurred together with other abnormalities, suggesting that multiple events are needed to induce the full leukemia phenotype. Other common CNA included: deletions of IKZF1 (25%), ETV6 (25%), PAX5 (14%), EBF1 (11%), PAR1 region (11%) and RB1 (7%). NGS showed mutations of JAK2 and CRLF2 in 7% (R683S/G) and 4% (F232C), respectively. No positivity for newly described fusion genes activating tyrosine kinase was confirmed. Importantly, subjects with no abnormalities showed better survival rates compared to those with one or more molecular alterations (p

Introduction. Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs. The recent WHO classification (2008) includes an indolent form (ISM), an aggressive form (ASM) and a leukemic subvariant (MCL). The c-kit mutation D816V is detectable in most adult patients with SM. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied. Methods. From 2008, 22 patients (male/female=11/11) affected by SM have been referred to our Institution. Among these, 12 (55%) presented with systemic symptoms associated with signs of organ involvement (skeletal lesions, ascites, liver function impairment or bon marrow disfunction), thus identifying an ASM. Therefore, since a first line therapy (IFNalfa, Imatinib and 2CdA in 56%, 11% and 33% of the patients, respectively) and supportive care with histamine receptor antagonists weren’t followed by a significant benefit, a personalized use of PKC412 was asked and obtained for 9 out of 12 ASM patients. Thus, from March 2011 9 (M/F =3/9) patients with ASM have been treated with PKC412, administered orally, at the dosage of 100 mg twice daily, without rest periods. The median age was 60 years (range 39-75); the median time from diagnosis was 6 months (range 2-53). Median serum tryptase level was 100 mcg/L(range 19.3-1160). C-kit mutation D816V was present in 8 out of 9 patients. Cytogenetic analysis was normal in all the patients. Results. Seven out of nine patients were evaluable for response. The median duration of therapy was 517 days (range 327-970+). According to European Criteria, a Major response was observed in one patient, and a partial response in 6 patients. Overall, the drug was well tolerated, and no serious adverse events were observed. All the patients obtained a quick and prolonged improvement of clinical symptoms, in terms of weight gain, bowel function and skeletal pain. At the bone marrow evaluation, the persistence of the D816V c-kit mutation was observed, despite a significant decrease of mast cell marrow involvement. Conclusions. In a small cohort of ASM patient, the prolonged therapy with PKC412 is safe and effective, mainly on symptoms improvement and haematological profile. Nevertheless, the persistence of the D816V c-kit mutation, despite significant responses, suggests that many other oncogenic factors may be responsible for the pathogenesis of the disease. UDS approaches are needed in order to clarify this issue. Acknowledgments. Work supported by European LeukemiaNet, AIRC, AIL, PRIN 2010-2011, University of Bologna, FP7 NGS-PTL project. Introduction. Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs. The recent WHO classification (2008) includes an indolent form (ISM), an aggressive form (ASM) and a leukemic subvariant (MCL). The c-kit mutation D816V is detectable in most adult patients with SM. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied. Methods. From 2008, 22 patients (male/female=11/11) affected by SM have been referred to our Institution. Among these, 12 (55%) presented with systemic symptoms associated with signs of organ involvement (skeletal lesions, ascites, liver function impairment or bon marrow disfunction), thus identifying an ASM. Therefore, since a first line therapy (IFNalfa, Imatinib and 2CdA in 56%, 11% and 33% of the patients, respectively) and supportive care with histamine receptor antagonists weren’t followed by a significant benefit, a personalized use of PKC412 was asked and obtained for 9 out of 12 ASM patients. Thus, from March 2011 9 (M/F =3/9) patients with ASM have been treated with PKC412, administered orally, at the dosage of 100 mg twice daily, without rest periods. The median age was 60 years (range 39-75); the median time from diagnosis was 6 months (range 2-53). Median serum tryptase level was 100 mcg/L(range 19.3-1160). C-kit mutation D816V was present in 8 out of 9 patients. Cytogenetic analysis was normal in all the patients. Results. Seven out of nine patients were evaluable for response. The median duration of therapy was 517 days (range 327-970+). According to European Criteria, a Major response was observed in one patient, and a partial response in 6 patients. Overall, the drug was well tolerated, and no serious adverse events were observed. All the patients obtained a quick and prolonged improvement of clinical symptoms, in terms of weight gain, bowel function and skeletal pain. At the bone marrow evaluation, the persistence of the D816V c-kit mutation was observed, despite a significant decrease of mast cell marrow involvement. Conclusions. In a small cohort of ASM patient, the prolonged therapy with PKC412 is safe and effective, mainly on symptoms improvement and haematological profile. Nevertheless, the persistence of the D816V c-kit mutation, despite significant responses, suggests that many other oncogenic factors may be responsible for the pathogenesis of the disease. UDS approaches are needed in order to clarify this issue. Acknowledgments. Work supported by European LeukemiaNet, AIRC, AIL, PRIN 2010-2011, University of Bologna, FP7 NGS-PTL project.

The activation of Chk1 has been demonstrated to influence response to chemotherapy in patients with BCR-ABL-positive chronic myeloid leukemia patients (Nieborowska-Skorska et al, Cell Cycle 2006). Chk1 and Chk2 are serine threonine kinase activated by different insults leading to DNA damage and involved in DNA repair and cell cycle control. Since, their role has not been established in BCR-ABL+ ALL, we investigated the expression of Chk1/Chk2 in blast cells from adult BCR-ABLpositive ALL patients (n=48) compared with normal bone marrow precursor cells (n=9) using the BioMark instrument (Fluidigm) and Fluidigm Dynamic Array 48 x 48. The expression of Chk1 but not Chk2 was higher (p=0,0005) in BCR-ABL+ leukemia patients (median value 0,69) compared with normal samples (median value 0,27). In order to better understand the biological role of Chk1 in ALL, we included in the analysis different B (BCR-ABL-positive: BV-173 and SUP-B15; BCR-ABL-negative: REH, NALM-6 and NALM-19) and T (MOLT-4, RPMI-8402 and CCRFCEM) leukemia cell lines. The expression of Chk1 was very homogeneous among the cell lines, with no difference between BCR-ABL-positive or negative cells. Since Chk1/2 inhibitors are currently available, we investigated the efficacy of Chk1/2 inhibition by PF-0477736 (Sigma) both as single agent and in combination with tyrosine kinase inhibitors (TKIs), imatinib and nilotinib, in BCR-ABL+ leukemia cell lines. Results showed that the combination (TKIs + Chk1/2 inhibitor) is more effective than the single inhibitors in inducing cell death. In conclusion, adult ALL patients show an higher expression of Chk1 compared with normal bone marrow precursor cells. This abnormal expression could be found also in different B-/T-ALL cell lines, suggesting that the inhibition of Chk1 could be a target for new therapeutic strategies in ALL.

This phase I study assessed the toxicity and safety of combining daily lapatinib with radiation therapy. Sequential tumor biopsies were obtained to evaluate changes in biomarkers, such as epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) signaling pathways.

Aims: The histopathological diagnosis of gastrointestinal stromal tumours (GIST) is typically made based on a combination of clinical and morphological features supported by immunohistochemistry studies. The aim of this study was to examine the staining quality, sensitivity, specificity and utility of antibodies used commonly in GIST diagnosis. Methods and results: Immunohistochemistry with a panel of antibodies [CD117, DOG1, protein kinase C (PKC)-theta, nestin, CD34, smooth muscle actin (SMA), desmin, S100 and CD171] was performed on whole sections from 187 GIST and 29 gastrointestinal mesenchymal tumours, and on several microarrays including 355 GISTs and 120 soft tissue sarcomas. Results showed that DOG1 and CD117 were the most sensitive and specific antibodies used in GIST diagnosis. PKC-theta and nestin were sensitive, but less specific, also staining other spindle cell tumours commonly considered in the differential diagnosis of GIST. CD34 staining was less sensitive than many of the other antibodies and of limited aid in diagnosis. The smooth muscle markers SMA and desmin, together with the neural marker S100, were unhelpful in confirming a diagnosis of GIST, but were particularly useful in the exclusion/diagnosis of other gastrointestinal mesenchymal tumour types. Conclusions: In the majority of histologically suspected GISTs a combination of CD117 and DOG1 immunostaining is sufficient to confirm the histological diagnosis.

HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G2/M progression of breast cancer cells. While investigating pathways of G2/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1.

8 págs, 1 tabla.-- Comunicación presentada a la XLV Reunión Científica de la Sociedad Española para el Estudio de los Pastos: "Producciones agroganaderas: gestión eficiente y conservación del medio natural" (Gijón, 28 de mayo al 3 de junio de 2005)., [ES] El trabajo se llevó a cabo en el departamento de Lavalle, Mendoza, Argentina. Las unidades de pastos, más importantes desde el punto de vista forrajero son: Algarrobal de Prosopis flexuosa; Matorral con Atriplex lampa (zampal); Matorral con Tricomaria usillo (usillar); Matorral degradado con Larrea cuneifolia (jarillal) y Medanal. Los objetivos del estudio fueron estimar la capacidad sustentadora de las diferentes unidades y la composición botánica de la ingesta de los caprinos. La estimación de dicha capacidad, expresada en hectáreas por Unidades Ganadera Caprinas (ha UGC–1), se realizó mediante el método de Point Quadrat modificado para el Monte. Y por medio del análisis microhistológico de heces se determinó la composición estacional de la ingesta., Los valores medios anuales de capacidad sustentadora fueron: Algarrobal, 1,2; Zampal, 1,7; Usillar, 3,5; Jarillal, 5,8 y Médanos, 4,3 ha UGC-1. La composición de la ingesta varió durante las estaciones, observándose una predominancia de las especies arbustivas, las gramíneas perennes aparecieron en muy baja frecuencia en todas las estaciones. El Algarrobal y el Zampal son las unidades de mayor importancia forrajera, presentando receptividades ganaderas más altas y una oferta forrajera más estable a lo largo del año, respecto del resto de las unidades de pastos analizadas., [EN] The work was carried out in the department of Lavalle, Mendoza, Argentina. The units of pastures, more important from the forage matter are: Algarrobal of Prosopis flexuosa; Shrubland with Atriplex lampa (zampal); Shrubland with Tricomaria usillo (usillar); Shrubland degraded with Larrea cuneifolia (jarillal) and Dunes. The aims of the study were to estimate the carrying capacity of the different units and the botanical composition of goat diets. The carrying capacity, expressed in hectares by Units Goat (ha UG-1), was measured by the method of Point Quadrat modified for Monte and the seasonal botanical composition of goat diets, was determined by microhistological analysis of faeces. The annual average values of carrying capacity were: Algarrobal, 1.2; Zampal, 1.7; Usillar, 3.5; Jarillal, 5.8 and Dunes, 4.3 ha UG-1. The composition of the diet varied during the seasons, the predominance of the shrubs species were observed, the perennial grass appeared in low frequency in all the seasons. The Algarrobal and the Zampal are the units of greater forage importance, where forage receptivity are higher and with more stable production throughout the year, respect to the others units of pastures analyzed.