Person: Laws, Edward
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Laws
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Edward
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Laws, Edward
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Publication Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors(Impact Journals LLC, 2016) Mei, Yu; Bi, Wenya; Greenwald, Noah; Du, Ziming; Agar, Nathalie Y. R.; Kaiser, Ursula; Woodmansee, Whitney; Reardon, David; Freeman, Gordon; Fecci, Peter E.; Laws, Edward; Santagata, Sandro; Dunn, Gavin P.; Dunn, IanPurpose Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. Methods: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. Results: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. Conclusions: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management.Publication The neurosurgical anatomy of the sphenoid sinus and sellar floor in endoscopic transsphenoidal surgery(Journal of Neurosurgery Publishing Group (JNSPG), 2011) Zada, Gabriel; Agarwalla, Pankaj Kumar; Mukundan, Srinivasan; Dunn, Ian; Golby, Alexandra J.; Laws, EdwardObject A considerable degree of variability exists in the anatomy of the sphenoid sinus, sella turcica, and surrounding skull base structures. The authors aimed to characterize neuroimaging and intraoperative variations in the sagittal and coronal surgical anatomy of healthy controls and patients with sellar lesions. Methods Magnetic resonance imaging studies obtained in 100 healthy adults and 78 patients with sellar lesions were reviewed. The following measurements were made on midline sagittal images: sellar face, sellar prominence, sellar angle, tuberculum sellae angle, sellar-clival angle, length of planum sphenoidale, and length of clivus. The septal configuration of the sphenoid sinus was classified as either simple or complex, according to the number of septa, their symmetry, and their morphological features. The following measurements were made on coronal images: maximum width of the sphenoid sinus and sellar face, and the distance between the parasellar and midclivus internal carotid arteries. Neuroimaging results were correlated with intraoperative findings during endoscopic transsphenoidal surgery. Results Three sellar floor morphologies were defined in normal adults: prominent (sellar angle of < 90°) in 25%, curved (sellar angle 90–150°) in 63%, flat (sellar angle > 150°) in 11%, and no floor (conchal sphenoid) in 1%. In healthy adults, the following mean measurements were obtained: sellar face, 13.4 mm; sellar prominence, 3.0 mm; sellar angle, 112°; angle of tuberculum sellae, 112°; and sellar-clival angle, 117°. Compared with healthy adults, patients with sellar lesions were more likely to have prominent sellar types (43% vs 25%, p = 0.01), a more acute sellar angle (102° vs 112°, p = 0.03), a more prominent sellar floor (3.8 vs 3.0 mm, p < 0.005), and more acute tuberculum (105° vs 112°, p < 0.01) and sellar-clival (105° vs 117°, p < 0.003) angles. A flat sellar floor was more difficult to identify intraoperatively and more likely to require the use of a chisel or drill to expose (75% vs 25%, p = 0.01). A simple sphenoid sinus configuration (no septa, 1 vertical septum, or 2 symmetric vertical septa) was noted in 71% of studies, and the other 29% showed a complex configuration (2 or more asymmetrical septa, 3 or more septa of any kind, or the presence of a horizontal septum). Intraoperative correlation was more challenging in cases with complex sinus anatomy; the most reliable intraoperative midline markers were the vomer, superior sphenoid rostrum, and bilateral parasellar and clival carotid protuberances. Conclusions Preoperative assessment of neuroimaging studies is critical for characterizing the morphological characteristics of the sphenoid sinus, sellar floor, tuberculum sellae, and clivus. The flat sellar type identified in 11% of people) or a complex sphenoid sinus configuration (in 29% of people) may make intraoperative correlation substantially more challenging. An understanding of the regional anatomy and its variability can improve the safety and accuracy of transsphenoidal and extended endoscopic skull base approaches.Publication Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas(2014) Brastianos, Priscilla; Taylor-Weiner, Amaro; Manley, Peter E.; Jones, Robert T.; Dias-Santagata, Dora; Thorner, Aaron R.; Rodriguez, Fausto J.; Bernardo, Lindsay A.; Schubert, Laura; Sunkavalli, Ashwini; Shillingford, Nick; Calicchio, Monica L.; Lidov, Hart; Taha, Hala; Martinez-Lage, Maria; Santi, Mariarita; Storm, Phillip B.; Lee, John Y. K.; Palmer, James N.; Adappa, Nithin D.; Scott, R. Michael; Dunn, Ian; Laws, Edward; Stewart, Chip; Ligon, Keith; Hoang, Mai; Van Hummelen, Paul; Hahn, William; Louis, David; Resnick, Adam C.; Kieran, Mark W.; Getz, Gad; Santagata, SandroPublication MAPK activation and HRAS mutation identified in pituitary spindle cell oncocytoma(Impact Journals LLC, 2016) Miller, Michael B.; Bi, Wenya; Ramkissoon, Lori A.; Kang, Yun Jee; Abedalthagafi, Malak; Knoff, David S.; Agarwalla, Pankaj Kumar; Wen, Patrick; Reardon, David; Alexander, Brian; Laws, Edward; Dunn, Ian; Beroukhim, Rameen; Ligon, Keith; Ramkissoon, Shakti H.Pituitary spindle cell oncocytoma (SCO) is an uncommon primary pituitary neoplasm that presents with mass effect on adjacent neurovascular structures, similar to non-hormone-producing pituitary adenomas. To determine the molecular etiology of SCO, we performed exome sequencing on four SCO cases, with matched normal controls, to assess somatic mutations and copy number alterations. Our analysis revealed a low mutation rate and a copy-neutral profile, consistent with the low-grade nature of this tumor. However, we identified a co-occurring somatic HRAS (p.Q61R) activating point mutation and MEN1 frameshift mutation (p.L117fs) present in a primary and recurrent tumor from one patient. Other SCOs demonstrated mutations in SND1 and FAT1, which are associated with MAPK pathway activation. Immunohistochemistry across the SCO cohort demonstrated robust MAPK activity in all cases (n=4), as evidenced by strong phospho-ERK staining, while phospho-AKT levels suggested only basal levels of PI3K pathway activation. Taken together, this identifies the MAPK signaling pathway as a novel therapeutic target for spindle cell oncocytoma, which may offer a powerful adjunct for aggressive tumors refractory to surgical resection.