Purpose: The tumor suppressor PTEN gene and the PIK3CA oncogene are frequently mutated in uterine endometrioid carcinoma (UEC). PTEN mutations are also common in complex atypical hyperplasia (CAH), the precursor lesion of UEC. The status of PIK3CA has not yet been explored in CAH. In this study, we evaluated both CAH and UEC for PTEN and PIK3CA mutations. Experimental Design: Neoplastic tissue was microdissected, and DNA was extracted from 29 cases of CAH. DNA was available from 44 UEC cases previously characterized for PTEN mutations. Direct DNA sequencing of exons 9 and 20 of the PIK3CA gene was done on all 73 cases. In addition, CAH cases were analyzed for PTEN mutations. Statistical analyses were done using the Fisher's exact test. Results: Two (7%) of 29 CAH and 17 (39%) of 44 UEC cases contained a PIK3CA mutation (P = 0.003). Fourteen (48%) of 29 CAH cases had a PTEN mutation, but none contained both a PTEN and PIK3CA mutation. Twenty-five (57%) of 44 UEC cases had a PTEN mutation, and 12 (48 %) of these 25 cases also contained a PIK3CA mutation. Coexistent PIK3CA and PTEN mutations were significantly correlated with UEC compared with CAH (P = 0.002), but the association in UEC did not reach statistical significance (P = 0.21). Conclusions: PIK3CA is the most commonly mutated oncogene in UEC; however, mutations are uncommon in CAH. Thus, mutations in PIK3CA, unlike PTEN mutations, are associated with invasion.These findings suggest that mutations in PIK3CA may serve as a marker of invasion with potential clinical use. Furthermore, PIK3CA and PTEN mutations may play distinct roles in endometrial tumorigenesis.Within the last 10 years, our knowledge of the molecular genetics of endometrial cancer has expanded with the discovery of mutations in genes, such as PTEN, K-RAS, CTNNB1, and TP53. These discoveries have led to a better understanding of the pathogenesis of endometrial cancer and its distinct histologic subtypes, broadly categorized as type I and II cancers, which are thought to arise via different pathogenetic pathways. Uterine endometrioid carcinoma (UEC) is the most common histologic subtype, representing >85% of cases. Not only is PTEN the most commonly mutated gene in UEC, the mutations also occur early in its pathogenesis as they are present at approximately the same frequency in complex atypical hyperplasias (CAH), the precursor lesion of UEC (1, 2).Recently, mutations of a novel oncogene (PIK3CA) were discovered in multiple human epithelial cancers, including UEC (3, 4). PIK3CA encodes the catalytic p110-a subunit of phosphatidylinositol 3-kinase (PI3K), a lipid kinase that generates phosphatidyl inositol-3,4,5-triphosphate by phosphorylating phosphatidyl inositol-3,4-diphosphate. This in turn activates the AKT/mammalian target of rapamycin oncogenic pathway, directly opposing the actions of the lipid phosphatase PTEN (5). It is unclear what role mutations in PIK3CA play during endometrial tumorigenesis and what, if any, additional role they confer over PTEN mutations. Recent literatur...

KPC-producing Klebsiella pneumoniae may appear susceptible to imipenem or meropenem by routine susceptibility testing. We report a series of patients with infectious caused by K. pneumoniae isolates that yielded imipenem-susceptible results but were subsequently KPC-positive by PCR. When these infections were treated with imipenem or meropenem, frequent clinical and microbiological failures were observed.

Primary myelofibrosis is a type of chronic myeloproliferative neoplasm characterized by progressive bone marrow failure with worsening cytopenia and in a subset of patients, progression to acute leukemia. Published data in patients with myelodysplastic syndromes have shown that the development of monocytosis in the course of myelodysplastic syndromes is associated with a poor prognosis. A similar occurrence has been only sporadically reported in patients with primary myelofibrosis. Over a period of four years we identified 10 out of 237 cases of primary myelofibrosis who developed persistent absolute monocytosis (41 Â 10 9 /l) during the course of disease (5 men and 5 women; median age/range: 68 years/52-82). Monocytosis developed at a median interval of 42 months from diagnosis (range: 1-180) and persisted for a median period of 23 months (range: 2-57). Five patients died after developing monocytosis (range: 20-188 months) and two experienced worsening disease and became transfusion dependent. Monocytosis was associated with increased white blood cells, decreased hemoglobin, decreased platelet count, and the presence of circulating blasts. In three cases, bone marrow biopsies after the onset of monocytosis showed marked myelomonocytic proliferation with morphological shifting from a typical primary myelofibrosis marrow appearance to aspects compatible with an overt 'secondary' chronic myelomonocytic leukemia. Before the development of monocytosis, 5 of 10 patients carried the JAK2V617F mutation; five patients showed karyotypic alterations. No change in JAK2 mutational status or cytogenetic evolution were associated with the development of monocytosis. Four of nine patients analyzed showed KRAS mutation in codon 12 or 13 with low allele burden. This is the first study correlating monocytosis developing in primary myelofibrosis patients with bone marrow morphology, laboratory data, molecular analysis and clinical follow-up. Development of monocytosis in patients with established primary myelofibrosis is associated with rapid disease progression and these patients should be considered as a high-risk group associated with short survival.