Molecular determinants of cetuximab efficacy.

PURPOSE: To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab. PATIENTS AND METHODS: Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction. RESULTS: There were 21 women and 18 men with a median age of 64 years (range, 35 to 83 years). Higher gene expression levels of VEGF were associated with resistance to cetuximab (P = .038; Kruskal-Wallis test). The combination of low gene expression levels of Cox-2, EGFR, and IL-8 was significantly associated with overall survival (13.5 v 2.3 months; P = .028; log-rank test). Both findings were independent of skin toxicity that was itself significantly correlated to survival. Patients with a lower mRNA amount of EGFR had a longer overall survival compared with patients that had a higher mRNA amount (7.3 v 2.2 months; P = .09; log-rank test). Patients with lower expression of Cox-2 had a significantly higher rate of grade 2 to 3 skin reactions under cetuximab treatment. CONCLUSION: This pilot study suggests that gene expression levels of Cox-2, EGFR, IL-8, and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in single-agent cetuximab treatment.     

High-dose (131)I-tositumomab (anti-CD20) radioimmunotherapy for non-Hodgkin's lymphoma: adjusting radiation absorbed dose to actual organ volumes.

Radioimmunotherapy (RIT) using (131)I-tositumomab has been used successfully to treat relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). Our approach to treatment planning has been to determine limits on radiation absorbed dose to critical nonhematopoietic organs. This study demonstrates the feasibility of using CT to adjust for actual organ volumes in calculating organ-specific absorbed dose estimates. METHODS: Records of 84 patients who underwent biodistribution studies after a trace-labeled infusion of (131)I-tositumomab for RIT (January 1990 and April 2003) were reviewed. Serial planar gamma-camera images and whole-body NaI probe counts were obtained to estimate (131)I-antibody source-organ residence times as recommended by the MIRD Committee. The source-organ residence times for standard man or woman were adjusted by the ratio of the MIRD phantom organ mass to the CT-derived organ mass. RESULTS: The mean radiation absorbed doses (in mGy/MBq) for our data using the MIRD model were lungs = 1.67; liver = 1.03; kidneys = 1.08; spleen = 2.67; and whole body = 0.3; and for CT volume-adjusted organ volumes (in mGy/MBq) were lungs = 1.30; liver = 0.92; kidneys = 0.76; spleen = 1.40; and whole body = 0.22. We determined the following correlation coefficients between the 2 methods for the various organs: lungs, 0.49 (P = 0.0001); liver, 0.64 (P = 0.004); kidneys, 0.45 (P = 0.0004); spleen, 0.22 (P = 0.0001); and whole body, 0.78 (P = 0.0001), for the residence times. For therapy, patients received mean (131)I administered activities of 19.2 GBq (520 mCi) after adjustment for CT-derived organ mass compared with 16.0 GBq (433 mCi) that would otherwise have been given had therapy been based only using standard MIRD organ volumes-a statistically significant difference (P = 0.0001). CONCLUSION: We observed large variations in organ masses among our patients. Our treatments were planned to deliver the maximally tolerated radiation dose to the dose-limiting normal organ. This work provides a simplified method for calculating patient-specific radiation doses by adjusting for the actual organ mass and shows the value of this approach in treatment planning for RIT.     

Pathological laughter and crying in patients with multiple system atrophy-cerebellar type.

In the cerebellar type of multiple system atrophy (MSA-C), the burden of pathological changes involves the cerebellum and its associated brainstem structures in the basis pontis and the inferior olivary nucleus, and as a result, the clinical phenotype is dominated early on by the cerebellar dysfunction. We report our clinical and post mortem findings in a patient with MSA-C who exhibited pathological laughter in the absence of any congruent changes of mood. A review of the clinical notes of 27 other patients with MSA-C revealed a problem with pathological laughter, or crying, or both in 9 more patients. Our finding of about 36% occurrence suggests that the problem of dysregulation of emotional expression is more prevalent in MSA-C than the paucity of reports in the literature suggests. Our findings are consistent with the view that the cerebellum and its interconnected structures may be involved in the regulation of emotional expression.     

MR imaging of cerebellopontine angle and internal auditory canal lesions at 1.5 T

The high-field, thin-section (3-5 mm) MR imaging characteristics of 49 cerebellopontine angle and internal auditory canal lesions were reviewed. The diverse abnormalities include 20 acoustic neurinomas, eight neurinomas of other cranial nerves (six involving the fifth cranial nerve and two involving cranial nerves IX-XI), seven meningiomas, five subdural fluid collections, four brainstem tumors with exophytic components, three glomus jugulare tumors, one epidermoid tumor, and one basilar artery aneurysm. T1-, T2-, and proton-density-weighted images were obtained in all cases. T1-weighted images most accurately showed the margins of the seventh and eighth nerves in the internal auditory canal and were most sensitive in detecting small tumors in the cerebellopontine angle. Differentiation of meningioma from acoustic neurinoma by MR was provided most reliably by separation of the meningioma from the porus acusticus and seventh and eighth nerves and not by signal-intensity differences. A hypointense vascular rim was noted on MR in seven of 13 extracanalicular acoustic tumors and in three of seven meningiomas.     

Differences in lifespan and rate of turnover between phytohaemagglutinin responsive cells of the bone marrow and of peripheral lymphoid organs.

Radioautographic analyses were performed on PHA stimulated cultures of in vivo labelled cells obtained from mice previously injected with 3H-TdR to selectively label either cells with a rapid renewal rate (RR) or a slow renewal rate (SR). ha responsive cells in the bone marrow (BM) were found to be virtually all RR cells, whereas both RR and SR cells from lymph nodes (LN) and spleen (Spl) were stimulated by this mitogen. However, RR cells were proportionately more responsive to PHA than SR cells in all tissues examined. Only one out of 200 BM PHA blasts belonged to the SR subclass, whereas the RR/SR ratio was approximately 1/1 for LN and 2/1 for Spl. Control experiments demonstrated that significant in vitro re-utilization of 3H-TdR from dying cells did not occur in the cultures. These results support a growing body of evidence that BM PHA responsive cells are precursor T-cells which are known to have a rapid turnover rate.     

Evaluation of six commercial kits for detection of human immunoglobulin M antibodies to Toxoplasma gondii. The FDA Toxoplasmosis Ad Hoc Working Group.

As a result of reports received by the Food and Drug Administration (FDA) of false-positive results obtained with FDA-cleared in vitro diagnostic kits for the detection of Toxoplasma-specific human immunoglobulin M (IgM) antibodies, an FDA-sponsored evaluation of six kits was performed. A battery of 258 serum specimens, including 30 specimens drawn 1 to 5 months after initial Toxoplasma infection and 228 specimens from Toxoplasma IgG-positive individuals, Toxoplasma IgG-negative individuals, rheumatoid factor-positive persons, and persons determined to be Toxoplasma IgM positive by commercially available assays, was assembled, randomly assorted, and coded. The battery was tested at the FDA with six commercially available kits, at the Palo Alto Medical Foundation (PAMF) by the PAMF double-sandwich IgM enzyme-linked immunosorbent assay (PAMF IgM ELISA), and at the Centers for Disease Control and Prevention (CDC) by the CDC EIA IgM. The results of the PAMF IgM ELISA that were obtained with the battery were considered to be the "gold standard" for this study; specificity rates were computed by considering the PAMF results to be 100% specific. Sensitivity and specificity rates were found to be as follows: CDC EIA IgM, 100 and 99.1%, respectively; Abbott IMx Toxo IgM, version 1, 100 and 77.5%, respectively; Abbott IMx Toxo IgM, version 2, 93.3 and 97.3%, respectively; Abbott Toxo-M EIA, 100 and 84.2%, respectively; BioMérieux Vitek VIDAS Toxo IgM, 100 and 98.6%, respectively; BioWhittaker Toxocap-M, 100 and 95.9%, respectively; Gull Toxo IgM, 97 and 85.6%, respectively; and Sanofi Diagnostics Pasteur Platelia Toxo IgM, 100 and 96.8%, respectively. Although the extent of false-positive reactions with these kits cannot be calculated because the study was retrospective and sample choices were biased, the results may be useful as an indicator of the relative specificities of these kits.     

Ontogeny of leukocyte populations in the ileal Peyer's patch of sheep.

Enzyme- and immunohistochemical methods were used to characterize the leukocyte populations present in the ileal Peyer's patches of sheep foetuses between 68 and 135 d of gestation and particularly in the period around 100 d of gestation, when active lymphopoiesis begins. A wide variety of leukocytes including IgM+, CD5+, CD4+, CD8+ cells, and MgATPase+ dendritic cells were present at an early stage. Groups of IgM+ cells were seen immediately beneath the epithelium as early as 70 d of gestation. Conventional morphometric and computer-assisted morphometric techniques were used to confirm the significant expansion of these cell populations from 90 d of gestation. IgM+ and CD5+ cells were responsible for the vast majority of the increase in cell numbers. It was concluded that a diverse leukocyte population was present at the initiation of active lymphopoiesis in the ileal PP of the sheep foetus and that all members of this population were associated with the emergence of the dome/follicle primordia from which the B-cell follicle develops.     

Visual enhancement of touch in spatial body representation

Perception of our own bodies is based on integration of visual and tactile inputs, notably by neurons in the brain's parietal lobes. Here we report a behavioural consequence of this integration process. Simply viewing the arm can speed up reactions to an invisible tactile stimulus on the arm. We observed this visual enhancement effect only when a tactile task required spatial computation within a topographic map of the body surface and the judgements made were close to the limits of performance. This effect of viewing the body surface was absent or reversed in tasks that either did not require a spatial computation or in which judgements were well above performance limits. We consider possible mechanisms by which vision may influence tactile processing.     

Neuropsychological evidence for a topographical learning mechanism in parahippocampal cortex

The Parahippocampal Place Area (PPA; Epstein & Kanwisher, 1998) is a region within posterior parahippocampal cortex that responds selectively to visual stimuli that convey information about the layout of local space. Here we describe two patients who suffered damage to the PPA after vascular incidents. Both subsequently exhibited memory problems for topographical materials and were unable to navigate unassisted in unfamiliar environments. Performance on a continuous n-back visual memory test was significantly lower for novel scene-like stimuli than for novel object-like stimuli. In contrast, performance was normal on a famous landmark recognition task and on two perceptual tasks that required on-line analysis of scene geometry. Both patients were able to produce accurate maps of premorbidly learned places but were unable to produce accurate maps of new places. These results converge with previous neuroimaging work to demonstrate that the PPA (1) is selectively involved in processing information about the geometry of surrounding space, and (2) may play a more critical role in the encoding of this information into memory than in the initial perceptual processing, recognition, or recall of this information.