ALK+ anaplastic large cell lymphoma exhibits phosphatidylinositol-3 kinase/Akt activity with retained but inactivated PTEN--a report from the Children's Oncology Group.

BACKGROUND: ALK+ anaplastic large cell lymphoma (ALCL) is usually a disease of young patients. We investigated phosphatidylinositol-3 kinase (PI3K)/Akt pathway-associated factors in pediatric cases and cell lines. PROCEDURE: Patient materials consisted of tissue slides of ALK+/CD30+ ALCL from 33 patients treated on Pediatric Oncology Group protocols (9219, n = 8 and 9315, n = 25). Slides were examined by immunohistochemistry for phospho(p)-Akt and PTEN, the primary feedback regulator of the pathway, as well as for p27kip1 and stathmin-1. ALCL cell lines SUDHL-1 and Karpas-299 were examined for ALK, pALK, pAkt, p27/Kip1, PTEN, pPTEN, CD30, pSTAT3, and pSTAT5; ALK inhibition was performed using compound PF-2341066 and PTEN genes were sequenced. RESULTS: A majority of patients expressed pAkt, PTEN, and stathmin, with p27kip1 levels less than controls. Cell lines showed expression of ALK, pALK, pSTAT3, pSTAT5, CD30, pAkt, PTEN, and pPTEN, with p27 slightly less than positive controls, and germline PTEN DNA. There was evidence of phosphorylated PTEN (pPTEN) associated with inhibited function. Pharmacologic inhibition of activated ALK diminished pSTAT3, pSTAT5, and CD30 expression but not pAkt or pPTEN in cultured cell lines. CONCLUSION: We conclude that the PI3K/Akt pathway is activated in many, though not all, pediatric ALK+ ALCL. Our data suggest that activation of this pathway involves post-translational regulation of PTEN. Pharmacologic inhibition of activated ALK does not reduce modest levels of activated Akt as it does with the more abundant levels of activated STAT3 or STAT5. Future therapy of ALCL might, in selected patients, best combine agents inhibiting PI3K/Akt with those targeting ALK.

Parental monitoring as a moderator of the effect of family sexual communication on sexual risk behavior among adolescents in psychiatric care.

Authors examined if parental monitoring moderated effects of family sexual communication on sexual risk behavior among adolescents in psychiatric care. Seven hundred and eighteen parents reported upon quality of family discussions about sex-related topics and degree to which they monitor teen behavior. Adolescents reported the frequency of their own safe sex practices. Parental monitoring moderated the family communication quality-sexual risk behavior relationship among African American families. African American parents who perceived themselves as capable of open family sexual communication and frequent monitoring had adolescents who reported decreased sexual risk behavior. The moderator model was not supported among Caucasian and Hispanic families and findings did not depend upon gender. For African Americans, findings support the influential role of family processes in development of teen sexual risk behavior and suggest, for parents of teens receiving mental health services, learning communication and monitoring skills may be critical to their adolescent's sexual health.

Gadolinium-induced nephrogenic systemic fibrosis is associated with insoluble Gd deposits in tissues: in vivo transmetallation confirmed by microanalysis.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is an extremely debilitating systemic fibrosing disorder affecting renal failure patients. The association of NSF with gadolinium (Gd) containing magnetic resonance contrast agents was noted in 2006. Gd deposition in skin biopsies was demonstrated shortly thereafter. METHODS: We used automated scanning electron microscopy (SEM)/energy dispersive x-ray spectroscopy for in situ quantitative analysis of insoluble Gd-containing deposits, recording multi-elemental composition and spatial distribution of detected features. RESULTS: Gd was detected in all 29 patients (53 of 57 skin biopsies) with NSF, biopsied from 2 weeks to 3 years after Gd exposure. Gd concentration ranged from 1 to 2270 cps/mm(2) and was detected predominantly in the deep dermis and subcutaneous fibrous septa. Gd was found associated with Ca, P and sometimes Fe or Zn. Patients with sequential biopsies showed persistence or increase of Gd in tissues (6 of 11). Transmission electron microscopy (TEM) identified the intracellular deposits in fibrocytes and macrophages. CONCLUSIONS: The demonstration of insoluble tissue deposits of Gd with co-associated elements clearly confirms in vivo transmetallation and dissociation of soluble Gd-chelates. Toxic Gd(3+) may trigger fibrosis under permissive conditions, e.g., in renal insufficiency. Pathologists and clinicians need to be aware of this serious but preventable disease.

The evolution of osseous metaplasia in localized cutaneous nephrogenic systemic fibrosis: a case report.

Gadolinium (Gd) is associated with nephrogenic systemic fibrosis (NSF), a severe disorder mimicking scleroderma with involvement of the skin, lungs, heart, liver, and muscles. There is strong evidence that specific Gd-containing contrast agents (GCCAs) used in magnetic resonance imaging can cause NSF when administered to patients with chronic kidney disease. We present the 8-year history of cutaneous NSF with osseous metaplasia that occurred in a 56-year-old man with dialysis-dependent renal failure who was exposed to GCCA [gadopentate dimeglumine (Magnevist; Bayer Schering Pharma AG, Pittsburgh, PA)]. Three months after exposure to GCCA, he developed pruritic, pigmented patches that slowly coalesced and darkened over 8 years. Although not recognized at onset, skin biopsy showed typical histology of NSF affecting the entire dermis: CD34/procollagen I spindle cells associated with fibrosis. Biopsy performed 6 years later showed superficial scar-like fibrosis that was CD34/procollagen I and had numerous elastocollagenous balls (refractile elastic fibers surrounded by coarse collagen). Biopsy 7 years later showed the superimposition of osseous metaplasia on elastocollagenous balls. Both of these later biopsies had typical NSF histology affecting the deep dermis and subcutis. Over time, there was progressive diminishment of CD34 and procollagen I+ cells and an increase in FXIIIa+ and CD68 cells. Scanning electron microscopy and energy-dispersive x-ray spectroscopy showed Gd deposits in all areas of typical NSF histology but not in the regions of scar-like fibrosis, elastocollagenous balls, or osseous metaplasia. We suspect that the later changes may represent a late, involuting stage of NSF.

School engagement among urban adolescents of color: does perception of social support and neighborhood safety really matter?

In this study we examined the effects of risk factors (perceived neighborhood crime/delinquency problems, neighborhood incivilities) and protective factors (teacher support, family support, peer support) on the school engagement of 123 urban adolescents of color. Age and gender were also examined to determine if different ages (younger or older) or genders (male or female) significantly modified the relationship between the risk factors and school engagement. Results indicated that perceived neighborhood incivilities was uniquely predictive of school engagement. Contrary to hypotheses, different levels of the perceived social support variables did not modify the effects of risky neighborhood conditions on adolescent's perceived school engagement. Age, but not gender, significantly modified the relationship between perceived family social support and perceived neighborhood crime on adolescents' reported levels of school engagement. The implications of the results for prevention and intervention programs that address school engagement among early adolescents of color are considered.

Tissue distribution and kinetics of gadolinium and nephrogenic systemic fibrosis.

Gadolinium (Gd) released from Gd-based MR contrast agents is the likely etiologic agent of nephrogenic systemic fibrosis (NSF). The biodistribution and kinetics of both chelated Gd and free Gd(3+) are reviewed, including demonstrations of Gd in tissues of NSF patients. The purpose of this review is to consolidate the available information on distribution, metabolism, excretion and retention of Gd with particular emphasis on the possible mechanisms in the development of NSF. We also raise serious concern about the growing tissue burden of Gd with the release of Gd from its chelates and its yet unknown consequences. The development of NSF as well as potential long-term consequences of tissue Gd retention represent a part of the spectrum of Gd toxicity.

Subjective well-being in urban adolescents of color.

Relationships among predictors and criteria of subjective well-being were examined in a sample of 151 urban adolescents of color, ages 12-15. The relative strengths of family, peer, and school-related support and esteem in predicting three measures of subjective well-being (life satisfaction, positive affect, and negative affect) were explored. Results suggested that sense of worth in one's family explained a significant amount of variance in subjective well-being variables, above and beyond the contributions of individual, school, and peer-related variables. Implications for prevention and mental health promotion with urban adolescents of color are discussed based on these findings.

Automated scanning electron microscopy and x-ray microanalysis for in situ quantification of gadolinium deposits in skin.

Gadolinium (Gd) has been identified as a possible causative agent of an emerging cutaneous and systemic fibrosing disorder, nephrogenic systemic fibrosis (NSF), which can cause serious disability and even death. To date, there are only two known associations with this disorder--renal insufficiency and Gd enhanced magnetic resonance imaging (MRI). We developed an automated quantitative scanning electron microscopy (SEM) and Energy dispersive x-ray spectroscopy (EDS) method for Gd in tissue of NSF patients. Freshly cut paraffin block surfaces examined using the variable pressure mode under standardized conditions and random search of the tissue area allow in situ detection and semiquantitative morphometric (volumetric) analysis of insoluble higher atomic number features using backscattered electron imaging. We detected Gd ranging from 1 to 2270 cps/mm2 in 57 cutaneous biopsies of NSF. Gd was associated with P, Ca, and usually Na in tissue deposits. Our method reproducibly determines the elemental composition, relative concentration, and spatial distribution of detected features within the tissue. However, we cannot detect features below our spatial resolution, nor concentrations below the detection limit of our SEM/EDS system. The findings confirm transmetallation and release of toxic Gd ions in NSF and allow dose-response analysis at the histologic level.

A case of colorectal cancer with metastasis to the chest wall and subsequent hematoma formation.

We report a rare case of a patient with colorectal cancer with chest wall metastases. The development of bleeding at the site of the metastasis ultimately resulted in the development of a hematoma, necessitating resection of the tumor along with part of the chest wall. Literature on chest wall metastases of colonic adenocarcinoma is reviewed and discussed. The teaching point is that a chest wall mass seen on imaging should prompt consideration of metastatic cancer in the differential diagnosis. The colon is a rare though reported primary site.

Activation of mammalian target of rapamycin in diffuse large B-cell lymphoma: a clinicopathological study.

Cell signaling by a highly conserved serine/threonine kinase mammalian target of rapamycin (mTOR) has been shown to play a critical role in cell proliferation. We analyzed the immunohistochemical expression of mTOR, pmTOR and bcl-2 in 55 patients with diffuse large B-cell lymphoma and correlated it with clinical parameters and clinical outcomes. On univariate analysis, higher expression of mTOR was associated with male gender, older age, and higher IPI score. Patients with a high total mTOR score showed a trend toward shorter survival. Based on our results we propose that use of targeted therapy with mTOR inhibitors, in a subset of diffuse large B-cell lymphoma patients may help improve patient survival.

Nephrogenic systemic fibrosis: histology and gadolinium detection.

The association between gadolinium (Gd)-containing MR imaging contrast agents and the development of nephrogenic systemic fibrosis (NSF) is well recognized. The authors review the histopathologic features, methodology, and results of analysis of tissues for Gd in NSF. Scanning electron microscopy/energy dispersive x ray spectroscopy (SEM/EDS) provides sensitive detection of individual Gd-containing deposits in situ. Secondary ion mass spectroscopy has far greater sensitivity for detection of Gd than SEM/EDS and allows correlation at the cellular level. Inductively coupled plasma mass spectrometry is the recognized method for full quantitative analysis of Gd in tissues but requires destruction of the tissue and does not allow spatial correlation. In practice, the different analytic techniques provide complementary data and can be selected based on the information required.

Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications.

Nephrogenic systemic fibrosis (NSF) is a painful and debilitating fibrosing disorder of the skin and systemic tissues. It is associated with exposure to Gd, used in MRIs and MRAs, in patients with renal insufficiency. We here present an illustrative example of a young patient who underwent multiple Gd-enhanced scans, both before and after developing severe NSF. We examined biopsy tissues for quantification of detectable insoluble Gd deposits using automated scanning electron microscopy/energy dispersive X-ray spectroscopy. High concentrations of Gd associated with calcium and phosphorus in skin persisted even 3 years after the last exposure to Gd. Such long-term retention of Gd raises further concerns about the utility and safety of Gd-based contrast agents. Residual Gd chelates, after initial and rapid renal clearance, can dissociate into insoluble, toxic Gd(3+) that precipitates with tissue anions. Bone serves as a site for Gd storage. Subsequent clearance and mobilization from such stores may explain the variable latency of onset of NSF. We hypothesize that long-term persistence and slow release of Gd(3+) from bone stores can be a cause for concern of Gd-associated toxicity with long latency.