YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma.

PURPOSE: YKL-40 is a secreted protein that has been reported to be overexpressed in epithelial cancers and gliomas, although its function is unknown. Previous data in a smaller sample set suggested that YKL-40 was a marker associated with a poorer clinical outcome and a genetically defined subgroup of glioblastoma. Here we test these findings in a larger series of patients with glioblastoma, and in particular, determine if tumor YKL-40 expression is associated with radiation response. EXPERIMENTAL DESIGN: Patients (n=147) with subtotal resections were studied for imaging-assessed changes in tumor size in serial studies following radiation therapy. An additional set (n=140) of glioblastoma patients who underwent a gross-total resection was tested to validate the survival association and extend them to patients with minimal residual disease. RESULTS: In the subtotal resection group, higher YKL-40 expression was significantly associated with poorer radiation response, shorter time to progression and shorter overall survival. The association of higher YKL-40 expression with poorer survival was validated in the gross-total resection group. In multivariate analysis with both groups combined (n = 287), YKL-40 was an independent predictor of survival after adjusting for patient age, performance status, and extent of resection. YKL-40 expression was also compared with genetically defined subsets of glioblastoma by assessing epidermal growth factor receptor amplification and loss at chromosome 10q, two of the common recurring aberrations in these tumors, using fluorescent in situ hybridization. YKL-40 was significantly associated with 10q loss. CONCLUSIONS: The findings implicate YKL-40 as an important marker of therapeutic response and genetic subtype in glioblastomas and suggest that it may play an oncogenic role in these tumors.     

Immunohistochemical expression of DNA repair proteins in familial breast cancer differentiate BRCA2-associated tumors.

PURPOSE: Morphologic and immunohistochemical studies of familial breast cancers have identified specific characteristics associated with BRCA1 mutation-associated tumors when compared with BRCA2 and non-BRCA1/2 tumors, but have not identified differences between BRCA2 and non-BRCA1/2 tumors. Because BRCA1 and BRCA2 genes participate in the DNA repair pathway, we have performed an immunohistochemical study with markers related to this pathway to establish the profile of the three groups. MATERIALS AND METHODS: We have studied two tissue microarrays that include 103 familial and 104 sporadic breast tumors, with a panel of DNA repair markers including ATM, CHEK2, RAD51, RAD50, XRCC3, and proliferating cell nuclear antigen. RESULTS: We found more frequent expression of CHEK2 in BRCA1 and BRCA2 tumors than in non-BRCA1/2 and sporadic tumors. We found absence of nuclear expression and presence of cytoplasmic expression of RAD51 in BRCA2 tumors that differentiate them from other familial tumors. We validated these results with a new series of patient cases. The final study with 253 familial patient cases (74 BRCA1, 71 BRCA2, 108 non-BRCA1/2), and 288 sporadic patient cases, has allowed us to confirm our preliminary results. Because BRCA2 tumors present a specific immunohistochemical profile for RAD51 and CHEK2 markers that is different from non-BRCA1/2 tumors, we have built a multivariate model with these markers that distinguish both tumors with an estimated probability of at least 76%. CONCLUSION: Our results suggest that BRCA2 tumors demonstrate more cytoplasmic and less nuclear RAD51 staining, and increased CHEK2 staining. This pattern may distinguish BRCA2 from familial non-BRCA1/2 tumors.     

Interobserver agreement in the diagnosis of pulmonary embolism with helical CT

PURPOSE: Our objective was to asses the interobserver agreement in the detection of pulmonary embolism (PE) with contrast-enhanced helical CT at the main pulmonary, lobar and segmental arteries. A prospective study was carried out in 51 patients with suspected PE. Finally, 29 patients were diagnosed of PE. SUBJECTS AND METHODS: All patients were studied with helical CT. Images (5 mm collimation, 1.5 pitch factor, 3 mm reconstruction interval) were obtained after bolus contrast injection (120 ml, 4 ml/s, 15 s delay time). All cases were blinded and independently interpreted in three ways: two radiologists with different level of expertise and two expert radiologists reading by consensus. Agreement was evaluated by means of the kappa test. RESULTS: Kappa values for thrombi detection expressed an excellent agreement at the main (between 0.802 and 0. 946), lobar (between 0.915 and 0.958) and segmental (between 0.879 and 0.718) levels. For all vessels, mean kappa values were similar and excellent for all three combinations of readers. Arteries with more discrepancies were located mainly at the anterior and posterior areas of the upper lobes. CONCLUSIONS: The high degree of agreement shown in this study indicates that helical CT is a reproducible test in the diagnosis of PE to the segmental level. Isolated readings and levels of expertise do not influence agreement.     

Immune responses of a meningococcal A + W outer membrane vesicle (OMV) vaccine with and without aluminium hydroxide adjuvant in two different mouse strains

Meningococci (Neisseria meningiditis) of serogroups A and W have caused large epidemics of meningitis in sub‐Saharan Africa for decades, and affordable and multivalent vaccines, effective in all age groups, are needed. A bivalent serogroup A and W (A + W) meningococcal vaccine candidate consisting of deoxycholate‐extracted outer membrane vesicles (OMV) from representative African disease isolates was previously found to be highly immunogenic in outbred mice when formulated with the adjuvant aluminium hydroxide (AH). OMV has been shown to have inherent adjuvant properties. In order to study the importance of AH and genetical differences between mice strains on immune responses, we compared the immunogenicity of the A + W OMV vaccine when formulated with or without AH in inbred C57BL/6J and BALB/cJ mice (Th1 and Th2 dominant strains, respectively). The immunogenicity of the vaccine was found to be comparable in the two mice strains despite their different immune profiles. Adsorption to AH increased anti‐OMV IgG levels and serum bactericidal activity (SBA). The immune responses were increased by each dose for the adsorbed vaccine, but the third dose did not significantly improve the immunogenicity further. Thus, a vaccine formulation with the A and W OMV will likely benefit from including AH as adjuvant.     

Shoulder impingement revisited: evolution of diagnostic understanding in orthopedic surgery and physical therapy

“Impingement syndrome” is a common diagnostic label for patients presenting with shoulder pain. Historically, it was believed to be due to compression of the rotator cuff tendons beneath the acromion. It has become evident that “impingement syndrome” is not likely an isolated condition that can be easily diagnosed with clinical tests or most successfully treated surgically. Rather, it is likely a complex of conditions involving a combination of intrinsic and extrinsic factors. A mechanical impingement phenomenon as an etiologic mechanism of rotator cuff disease may be distinct from the broad diagnostic label of “impingement syndrome”. Acknowledging the concepts of mechanical impingement and movement-related impairments may better suit the diagnostic and interventional continuum as they support the existence of potentially modifiable impairments within the conservative treatment paradigm. Therefore, it is advocated that the clinical diagnosis of “impingement syndrome” be eliminated as it is no more informative than the diagnosis of “anterior shoulder pain”. While both terms are ambiguous, the latter is less likely to presume an anatomical tissue pathology that may be difficult to isolate either with a clinical examination or with diagnostic imaging and may prevent potentially inappropriate surgical interventions. We further recommend investigation of mechanical impingement and movement patterns as potential mechanisms for the development of shoulder pain, but clearly distinguished from a clinical diagnostic label of “impingement syndrome”. For shoulder researchers, we recommend investigations of homogenous patient groups with accurately defined specific pathologies, or with subgrouping or classification based on specific movement deviations. Diagnostic labels based on the movement system may allow more effective subgrouping of patients to guide treatment strategies.