Response of some head and neck cancers to epidermal growth factor receptor tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR.

PURPOSE: Small-molecule tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) have shown modest yet reproducible response rates in patients with squamous cell carcinoma of the head and neck (SCCHN). Somatic mutations in EGFR have recently been shown to be predictive of a clinical response in patients with non-small cell lung cancer (NSCLC) treated with these inhibitors. The objective of this study was to determine if such mutations, or recently reported mutations in ERBB2, also underlie EGFR-TKI responsiveness in SCCHN patients. EXPERIMENTAL DESIGN: We sequenced the kinase domain of EGFR and exon 20 of ERBB2 in tumor specimens from eight responsive patients. In addition, mutational analysis was done on tumor specimens from nine gefitinib nonresponders and 65 unselected cases of SCCHN. RESULTS: None of eight TKI-responsive specimens had mutations within the kinase domain of EGFR. EGFR amplification was also not associated with drug responsiveness. However, a single responsive case had a somatic missense mutation within exon 20 of ERBB2. CONCLUSION: Our data indicate that unlike NSCLC, EGFR kinase mutations are rare in unselected cases of SCCHN within the United States and are not linked to gefitinib or erlotinib responses in SCCHN. Alternative mechanisms, including ERBB2 mutations, may underlie responsiveness in this tumor type.     

Analysis of the MammaPrint breast cancer assay in a predominantly postmenopausal cohort.

PURPOSE: Most node-negative breast cancer patients are older and postmenopausal and are increasingly being offered adjuvant chemotherapy despite their low overall risk of distant relapse. A molecular diagnostic test with high negative predictive value (NPV) for distant metastasis in this subgroup would spare many older breast cancer patients adjuvant treatment. EXPERIMENTAL DESIGN: We determined the NPV and positive predictive value of the MammaPrint assay in breast cancer patients who were consecutively diagnosed and treated at the Massachusetts General Hospital between 1985 and 1997. Primary tumors from 100 patients with node-negative, invasive breast cancer (median age, 62.5 years; median follow-up, 11.3 years) were subjected to MammaPrint analysis and classified as being at either low or high risk for distant metastasis. RESULTS: The MammaPrint 70-gene signature displayed excellent NPV as in previous studies, correctly identifying 100% of women at low risk for distant metastases at 5 years. However, this assay had a lower positive predictive value (12% at 5 years) than previously observed. CONCLUSIONS: The MammaPrint assay was originally designed to identify younger breast cancer patients at low risk for distant metastasis, who might consequently be spared systemic treatment. We show here that the same signature has a very high NPV for distant recurrence after adjuvant treatment in older breast cancer patients.     

Gliosarcomas lack BRAFV600E mutation,but a subset exhibit β‐catenin nuclear localization

Gliosarcoma (GS) is a rare subtype of glioblastoma (GBM) characterized by both glial and mesenchymal components. Unlike GBM, there are no specific prognostic markers, and optimized treatments for patients with GS do not exist. Recent reports describe BRAF^V600E mutation in malignant peripheral nerve sheath tumors, and aberrant Wnt signaling and CTNNB1 (β‐catenin gene) mutations have been described in GBM. We sought to determine whether GS tumors harbor BRAF^V600E mutations or aberrant Wnt signaling, as indicated by nuclear localization of β‐catenin, by immunohistochemical detection. Forty‐eight (48) cases of primary and secondary adult GS (including recurrent ones) were evaluated by immunohistochemical techniques for the presence of nuclear β‐catenin and the BRAF^V600E mutation. A small subset (6/46, 13%) showed nuclear localization of β‐catenin. None of the cases harbored BRAF^V600E mutations (0/48). These results are the first to describe the presence of Wnt signaling pathway abnormalities, manifested by nuclear β‐catenin, in a subset, as well as the lack of BRAF^V600E mutation in GS. We propose a potential role for Wnt pathway alterations in the pathogenesis of a subset of GS.     

RNA sequence analysis reveals ITGAL/CD11A as a stromal regulator of murine low-grade glioma growth

BackgroundEmerging insights from numerous laboratories have revealed important roles for nonneoplastic cells in the development and progression of brain tumors. One of these nonneoplastic cellular constituents, glioma-associated microglia (GAM), represents a unique population of brain monocytes within the tumor microenvironment that have been reported to both promote and inhibit glioma proliferation. To elucidate the role of GAM in the setting of low-grade glioma (LGG), we leveraged RNA sequencing meta-analysis, genetically engineered mouse strains, and human biospecimens.MethodsPublicly available disease-associated microglia (DAM) RNA-seq datasets were used, followed by immunohistochemistry and RNAScope validation. CD11a-deficient mouse microglia were used for in vitro functional studies, while LGG growth in mice was assessed using anti-CD11a neutralizing antibody treatment of Neurofibromatosis type 1 (Nf1) optic glioma mice in vivo.ResultsWe identified Itgal/CD11a enrichment in GAM relative to other DAM populations, which was confirmed in several independently generated murine models of Nf1 optic glioma. Moreover, ITGAL/CD11A expression was similarly increased in human LGG (pilocytic astrocytoma) specimens from several different datasets, specifically in microglia from these tumors. Using CD11a-knockout mice, CD11a expression was shown to be critical for murine microglia CX3CL1 receptor (Cx3cr1) expression and CX3CL1-directed motility, as well as glioma mitogen (Ccl5) production. Consistent with an instructive role for CD11a⁺ microglia in stromal control of LGG growth, antibody-mediated CD11a inhibition reduced mouse Nf1 LGG growth in vivo.ConclusionsCollectively, these findings establish ITGAL/CD11A as a critical microglia regulator of LGG biology relevant to future stroma-targeted brain tumor treatment strategies.     

Temporal,spatial, and genetic constraints contribute to the patterning and penetrance of murine neurofibromatosis-1 optic glioma

BackgroundBrain tumors are the most common solid tumors of childhood, but little is understood about the factors that influence their development. Pediatric low-grade gliomas in particular display unique temporal and spatial localization associated with different genetic mutations (eg, BRAF genomic alterations, mutations in the neurofibromatosis type 1 [NF1] gene) for reasons that remain unclear. NF1 low-grade gliomas typically arise in the optic pathway of young children as optic pathway gliomas (OPGs), likely from a cell of origin that resides within the third ventricular zone (TVZ). However, the factors that contribute to their distinct temporal patterning and penetrance have not been adequately explored.MethodsTVZ neuroglial progenitor cells (NPCs) were analyzed over the course of mouse brain development. Progenitors isolated by fluorescence-activated cell sorting (FACS) were assessed for functional and molecular differences. The impact of different germline Nf1 mutations on TVZ NPC properties was analyzed using genetically engineered mice.ResultsWe identify 3 individual factors that could each contribute to Nf1 optic glioma temporal patterning and penetrance. First, there are 3 functionally and molecularly distinct populations of mouse TVZ NPCs, one of which (“M” cells) exhibits the highest clonogenic incidence, proliferation, and abundance during embryogenesis. Second, TVZ NPC proliferation dramatically decreases after birth. Third, germline Nf1 mutations differentially increase TVZ NPC proliferation during embryogenesis.ConclusionsThe unique temporal patterning and penetrance of Nf1 optic glioma reflects the combined effects of TVZ NPC population composition, time-dependent changes in progenitor proliferation, and the differential impact of the germline Nf1 mutation on TVZ NPC expansion.     

Interim obturator in an infant with Treacher Collins syndrome: Review and chairside modification in impression making

Treacher Collins syndrome has been described as a syndrome involving 1st and 2nd branchial arches, affecting various organs in the craniofacial region. Affected infants report with nasal regurgitation and minimal dietary intake due to cleft palate, consequently show delayed and retarded growth. The situation is further complicated when the repair of the palatal defect is postponed due to delayed milestones. At this juncture, it is of paramount importance to intervene prosthetically and close the defect with the aid of an interim obturator. Herein we describe a simple, yet successful, chairside approach to make an impression of an infant without the aid of any kind of anesthesia.     

Wavefront- and topography-guided ablation in myopic eyes using Zyoptix

PURPOSE: To evaluate the results of wavefront- and topography-guided ablation in myopic eyes using Zyoptix (Bausch & Lomb). SETTING: Eye Research Center and Dr. Agarwal's Eye Hospital, Chennai, India. METHODS: This observational case study comprised 150 eyes with myopia and compound myopic astigmatism. Preoperatively, the patients had corneal topography with Orbscan IIz (Bausch & Lomb) and wavefront analysis with the Zywave aberrometer (Bausch & Lomb) in addition to the routine workup before laser in situ keratomileusis (LASIK). The results were assimilated using Zylink software (Bausch & Lomb), and a customized treatment plan was formulated. Laser in situ keratomileusis was performed with the Technolas 217 system (Bausch & Lomb). The patients were followed for at least 6 months. RESULTS: The mean preoperative best corrected visual acuity (BCVA) (in decimal equivalent) was 0.83 (20/25) +/- 0.18 (SD) (range 0.33 to 1.00) and the mean postoperative (6 months) BCVA, 1.00 (20/20) +/- 0.23 (range 0.33 to 1.50). Three eyes (2%) lost 2 or more lines of best spectacle-corrected visual acuity. The safety index was 1.20. The mean preoperative uncorrected visual acuity (UCVA) was 0.06 (20/350) +/- 0.02 (range 0.01 to 0.50) and the mean postoperative UCVA, 0.88 (20/25) +/- 0.36 (range 0.08 to 1.50). The efficacy index was 14.66. The mean preoperative spherical equivalent (SE) was -5.25 +/- 1.68 diopters (D) (range -0.87 to -15.00 D) and the mean postoperative SE (6 months), -0.36 +/- 0.931 D (range -4.25 to +1.25 D). At 6 months, the UCVA was 1.00 (6/6) or better in 105 eyes (69.93%) and 0.5 (6/12) or better in 126 eyes (83.91%). The postoperative aberrations were decreased compared with the preoperative aberrations. One eye (0.66%) had a free cap during LASIK with subsequent loss of 2 lines of BCVA and induced higher-order aberrations (HOAs). Nine patients (11.2%) complained of halos at night. CONCLUSIONS: Wavefront- and topography-guided LASIK leads to improve visual performance by decreasing HOAs. Scotopic visual complaints may be reduced with this method.     

Effect of Ceramic Thickness and Luting Agent Shade on the Color Masking Ability of Laminate Veneers

The main objective of the study was to recognize the effect of ceramic thickness and luting agent on the extent to which the restoration masks color variations that may be present in the underlying dental structure. Two pressable ceramics were used: Lithium disilicate reinforced (IPS e.max- Ivoclar Vivadent) and Leucite reinforced (Cergo- Dentsply). Fifteen ceramic discs were manufactured from each ceramic and divided into three groups, according to the thickness (0.5, 1, 1.5 mm). To simulate the color of a dark underlying dental structure, background discs, color C3, with 20 mm diameter, were made using resin composite. The ceramic discs with varying thicknesses were seated on the dark background of the resin composite with either resinous opaque cement or resinous cement. The color parameters were determined by the CIE Lab system of colors using a spectrophotometer and color differences (ΔE) were calculated. The results were then statistically analyzed, using ANOVA test and Tukey HSD test. The ΔE values of both ceramic systems were affected by both the luting agent and the ceramic thickness (P < 0.05). The use of an opaque luting agent resulted in an increase of the ΔE* values for all ceramics tested, regardless of the thickness. For the 1.5-mm thick veneers, higher values in the color parameters were obtained for both ceramic materials. The color masking ability of ceramics used for laminate veneers is significantly affected by the thickness of the ceramic and the shade of the luting agent used.     

Randomized trial of oral versus sublingual misoprostol 24 h after mifepristone for medical abortion

Aim  

The objective is to present a rare case of late diagnosis of Cornelia de Lange syndrome.