The somatic genomic landscape of glioblastoma.

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

Trends in Bone Marrow Sampling and Core Biopsy Specimen Adequacy in the United States and Canada: A Multicenter Study.

OBJECTIVES: To assess bone marrow (BM) sampling in academic medical centers. METHODS: Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed. RESULTS: BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years, men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias, nonphysician operators, and ancillary studies usage increased, while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent. CONCLUSIONS: CL is shorter than recommended and varies with patient age and sex, clinical circumstances, and center experience. While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.

Vortex disaggregation for flow cytometry allows direct histologic correlation: a novel approach for small biopsies and inaspirable bone marrows.

BACKGROUND: Many approaches to obtaining single cells from tissue for flow cytometric immunophenotyping are used; however, these methods result in tissue that is too disrupted for subsequent histologic examination. We introduce a new technique for cell dissociation of hematopoietic malignancies that preserves tissue for histology. This is especially important with small specimens for which this type of correlation is critical. METHODS: Fresh tissue from lymph node, gastrointestinal (GI) tract, skin, and other soft tissue biopsies, in addition to cores of inaspirable bone marrows, were briefly vortexed until the RPMI cell culture medium became cloudy. Larger specimens such as lymph nodes were sectioned before disaggregating, whereas smaller ones were vortexed in toto. Resultant flow cytometric analyses were compared with the histology and, in some cases, the immunohistochemistry (IHC) to determine whether the data were concordant. Cell suspensions of 104 specimens-composed of 48 lymph nodes, 19 bone marrow cores (BMCs), 11 GI biopsies, 11 skin/soft tissue biopsies, and 15 miscellaneous specimens-were prepared via vortex disaggregation. RESULTS: Flow cytometric analysis of 96 specimens (92.3%) showed adequacy of material and diagnostic correlation with the histology and IHC. Of the eight cases (7.7%) that were discordant, seven were attributable to significant specimen fibrosis or necrosis. With respect to tissue type, this method produced diagnostic cell suspensions for most lymph nodes (95.8%), GI biopsies (90.9%), and BMCs (89.5%); however, it was less useful for skin/soft tissue samples (81.8%). CONCLUSIONS: Disaggregation of tissue for flow cytometric analysis by vortexing appears to provide adequate and representative cellular material. This technique is ideal for inaspirable bone marrows and small biopsies where tissue preservation for histology is paramount.

Ethical use of tissue samples in genetic research.

Many centrally based cancer protocols have begun to address the ethical issues concerning tissue banking for genetic research. A multidisciplinary subcommittee of the Madigan Army Medical Center Institutional Review Board was established to determine the scope of the problem and offer a concise, user-friendly policy with guidelines on how to control and monitor the use of stored tissue for future genetic and molecular research. Our institution participates in 69 Southern Oncology Group or National Surgical Adjuvant Breast and Bowel Project protocols and 47 Children's Oncology Group protocols. Of these protocols, 22 of 69 and 36 of 47, respectively, asked for tissue to be stored for future biologic study. Only 4 of 69 and 3 of 47, respectively, deal with specific consent for future genetic/biologic research. The multidisciplinary committee developed a policy that dealt with the following areas: exempt status, waived consent, informed consent, deceased status, family studies, and information flow. An algorithm was created to establish a system of checks and balances concerning privacy, protection and an appeals process.

Working wives and housewives: do they differ in mental status and social adjustment?

Matched groups of working wives and housewives drawn from a community sample did not differ on current and past psychiatric symptoms, diagnosis, treatment, and social functioning. They did differ markedly on enjoyment in and satisfaction from their work. The working women derived considerably more satisfaction from their outside jobs than either they or the housewives did from their work in the home.

Two cases of concomitant acquired aplastic anemia and systemic mastocytosis.

Reactive bone marrow mast cells reliably lack the morphologic, immunophenotypic, and molecular features of systemic mastocytosis (SM). We report two unusual cases of acquired aplastic anemia (AA) in which multifocal aggregates of bone marrow mast cells fulfilled morphologic and immunophenotypic criteria for SM according to the World Health Organization 2008 classification. In the absence of clinical symptoms attributable to SM, the patients were treated with immunosuppressive therapy directed towards AA. Clinical follow-up and subsequent bone marrow examination revealed no evidence of overt SM in either patient. These cases represent, to our knowledge, the first reported instances in which criteria for SM have been fulfilled in the presence of AA. However, given the clinical courses followed by our patients, the incidental identification of mast cell lesions consistent with indolent SM may be of uncertain significance in the setting of AA.

Effects of changes in narrative time on eye movements and recognition responses.

In two experiments we examined how temporal aspects of narrative events influence comprehension. In Experiment 1 participants read paragraphs in which a critical event was followed by a phrase that signaled a time shift (After an hour versus After a moment). Consistent with earlier findings (e.g., Zwaan, 1996), fixation durations were longer on the phrase that signaled a larger time shift. However, there was no evidence that a larger time shift affected the accessibility of event information in Experiment 1, when the dependent measure was ease of anaphor comprehension, or in Experiment 2, when a recognition probe task was used. Although the discontinuation of an event (Maurice stopped versus was painting) did not affect anaphor reading times, it did lead to longer recognition times for the event. These results indicate that at least some event aspects remain accessible following a change in time and that the dependent measure can have a critical impact on the conclusions.

Using peripheral smear review, age and absolute lymphocyte count as predictors of abnormal peripheral blood lymphocytoses diagnosed by flow cytometry.

Absolute lymphocytosis in the elderly raises the possibility of malignancy and generally warrants further investigation. To better correlate clinical variables with the frequency of neoplastic lymphoid processes in this population, we retrospectively reviewed archived flow cytometric analyses from peripheral blood specimens on patients of 50 years of age and older that had been deemed suspicious for a lymphoproliferative process after peripheral smear review. Age, absolute lymphocyte count (ALC), white blood cell count and relative lymphocyte count were correlated with the results of flow cytometry. Of 71 total cases, 42 (59%) had an abnormal immunophenotype. Independent variables that showed significant differences between normal and abnormal immunophenotype were mean age (p = 0.001) and ALC (p = 0.0032). We combined age and absolute lymphocyte count variables to look for the best possible cutoff values to predict the likelihood of an abnormal immunophenotype. ALC cutoff values of >or=4 x 10(9) cells/L for patients over 67 years of age, and >6.7 x 10(9) cells/L for patients between 50 and 67 years of age, had a high sensitivity for detecting an abnormal immunophenotype.

From the combat medic to the forward surgical team: the Madigan model for improving trauma readiness of brigade combat teams fighting the Global War on Terror.

BACKGROUND: Medics assigned to combat units have a notable paucity of trauma experience. Our goal was to provide intense trauma refresher training for the conventional combat medic to better prepare them for combat casualty care in the War on Terror. MATERIALS AND METHODS: Our Tactical Combat Casualty Care Course (TC3) consisted of the following five phases: (1) One and one-half-day didactic session; (2) Half-day simulation portion with interactive human surgical simulators for anatomical correlation of procedures and team building; (3) Half-day of case presentations and triage scenarios from Iraq/Afghanistan and associated skills stations; (4) Half-day live tissue lab where procedures were performed on live anesthetized animals in a controlled environment; and (5) One-day field phase where live anesthetized animals and surgical simulators were combined in a real-time, field-training event to simulate realistic combat injuries, evacuation problems, and mass casualty scenarios. Data collection consisted of surveys, pre- and posttests, and after-action comments. RESULTS: A total of 1317 personnel participated in TC3 from October 2003 through May 2005. Over the overlapping study period from December 2004 to April 2005, 327 soldiers participated in the formal five-phase course. Three hundred four (94%) students were combat medics who were preparing for combat operations in Iraq or Afghanistan. Of those completing the training, 97% indicated their confidence and ability to treat combat casualties were markedly improved. Moreover, of those 140 medics who took the course and deployed to Iraq for 1 year, 99% indicated that the principles taught in the TC3 course helped with battlefield management of injured casualties during their deployment. CONCLUSION: The hybrid training model is an effective method for training medical personnel to deal with modern battle injuries. This course increases the knowledge and confidence of combat medics deploying and fighting the Global War on Terrorism.

Whipple disease: a case report and review of the literature.

Whipple disease is a chronic, relapsing, and multisystem disease. It presents a diagnostic challenge for both clinicians and pathologists. Recent advances in isolation and culture have identified the organism responsible for the disease to be a member of the order Actinomycetes designated Tropheryma whipplei. Several immune system changes have been noted in patients with Whipple disease, but whether these are primary or secondary is as yet undetermined. Long-term antibiotic therapy is required, and relapses are common, especially with central nervous system involvement.

Do readers make inferences about conversational topics?

When we read that two protagonists in a story chatted together for a couple of minutes, do we draw inferences about the topic of the conversation on the basis of information presented earlier in the text? Participants read passages in which protagonists part and later reunite; the passages ended with a sentence either that implied conversation or did not. In Experiment 1, participants' continuation sentences indicated that inferences about the topic of conversation were drawn. Recognition probe data in Experiment 2 provided more immediate evidence of such inferences. Experiment 3 addressed a possible confound in Experiment 2 and again provided evidence that readers inferred the continuation of the conversation. In Experiments 4 and 5, we investigated the effect of having the targeted conversational topic be a secret that should not be shared between the protagonists. The results are discussed in terms of the collaboration between passive, memory-based text processing and schema-driven comprehension processes.