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Proton Therapy for Partial Breast Irradiation: Rationale and Considerations

Choi, J Isabelle; Fox, Jana; Bakst, Richard; Hasan, Shaakir; Press, Robert H; Chhabra, Arpit M; Yeh, Brian; Simone, Charles B; Cahlon, Oren
In an era of continued advancements in personalized medicine for the treatment of breast cancer, select patients with early stage breast cancer may be uniquely poised to benefit from partial breast irradiation (PBI) delivered with proton therapy. PBI presents an opportunity to improve quality of life during treatment with a significantly shorter treatment duration. By targeting less non-target breast tissue, excess radiation exposure and resulting toxicities are also reduced. Proton therapy represents a precision radiotherapy technology that builds on these advantages by further limiting the normal tissue exposure to unnecessary radiation dose not only to uninvolved breast tissue but also the underlying thoracic organs including the heart and lungs. Herein, we present a concise review of the rationale for the use of proton therapy for PBI, evidence available to date, and practical considerations in the implementation and use of proton therapy for this indication.
PMCID:8069416
PMID: 33918662
ISSN: 2075-4426
CID: 5239222

High-Grade Glioma, Including Diffuse Intrinsic Pontine Glioma

Chapter by: Karajannis, Matthias A; Snuderl, Matija; Yeh, Brian K; Walsh, Michael F; Jain, Rajan; Sahasrabudhe, Nikhil A; Wisoff, Jeffrey H
in: Brain Tumors in Children by Gajjar, Amar; Reaman, Gregory H; Racadio, Judy M; Smith, Franklin O (Eds)
Cham : Springer, 2018
pp. 193-221
ISBN: 3319432052
CID: 3732452

Quality of the Patient Experience during Radiosurgery: Measurement toward Improvement

Kondziolka, Douglas; LoPresti, Melissa; Tyburczy, Amy; Golden, Cassandra; Seto, Timmy; Boulio, Lynda; Doody, Caitlyn; Yeh, Brian; Silverman, Joshua
BACKGROUND: All physicians seek to improve the patient experience. In an awake surgical procedure, the patient has a unique opportunity to comment on all aspects of care. The provision of a positive experience is part of quality health care. Our purpose was to define this experience to determine areas for improvement. METHODS: We evaluated 125 patients who underwent stereotactic radiosurgery using a frame-based, gamma knife technique. Patients were surveyed by a nurse practitioner across all elements of their procedural experience prior to same-day discharge. RESULTS: The radiosurgery was completed in all patients with same-day discharge. In an initial 100-patient cohort, 89 patients said they had received adequate oral and/or intravenous sedation before the procedure. All 100 patients said that they felt comfortable before stereotactic frame application, and all patients later remembered frame application. These patients described frame application as very or adequately comfortable (n = 73), minimally uncomfortable (n = 18), or very uncomfortable (n = 9). Neuroimaging was described as very or adequately comfortable (n = 93), minimally uncomfortable (n = 3), or very uncomfortable (n = 4). Radiosurgery in the gamma knife unit was found to be very or adequately comfortable (n = 99) or very uncomfortable (n = 1). We evaluated how 8 separate factors may have contributed to survey responses related to procedural comfort. These factors included intravenous line placement, delivery of sedation medications, application of the head frame, having the MRI, having radiosurgery on the gamma knife bed, removal of the stereotactic frame, communication with caregivers, and knowing what to expect beforehand. We asked the patients to rate their nursing care during the radiosurgery experience, and 'excellent' was chosen by all initial 100 patients. Other elements of the procedure were also studied as well as suggestions for improvement. As a secondary objective, we then modified our protocol to include sodium bicarbonate added to the local anesthetic for frame application and evaluated an additional cohort of 25 patients. CONCLUSIONS: Utilizing a system of physician and nursing education, together with pharmacological sedation and efficient procedural steps, patients said that intravenous line placement (91%), stereotactic frame application (74%), MRI (93%), receiving radiosurgery in the unit (99%), frame removal (84%), communication with caregivers (100%), and knowing what to expect beforehand (97%) were either very or adequately comfortable. Specific evaluations of care processes can lead to care improvement.
PMID: 27172769
ISSN: 1423-0372
CID: 2107802

Comparison of Endocrine Dysfunction and Dosimetry in Pediatric Patients Treated With Proton Versus Photon Radiation Therapy for Medulloblastoma [Meeting Abstract]

Vatner, R; Shin, S; Legault, G; Rosman, M; Weyman, E; Chan, S; Yeh, BK; MacDonald, S; Tarbell, NJ; Allen, J; Yock, TI
ISI:000373215301743
ISSN: 1879-355x
CID: 2097992

Dosimetric Comparison of Proton Therapy, Volumetric Modulated Arc Therapy, and 3-D Conformal Radiation Therapy for the Treatment of Rectal Cancer: An Early Community Experience [Meeting Abstract]

Cooper, BT; Qu, J; Chon, BH; Tsai, HK; Mah, D; Du, KL; DeWyngaert, JK; Yeh, BK
ISI:000373215300448
ISSN: 1879-355x
CID: 2097902

Rewiring cellular morphology pathways with synthetic guanine nucleotide exchange factors

Yeh, Brian J; Rutigliano, Robert J; Deb, Anrica; Bar-Sagi, Dafna; Lim, Wendell A
Eukaryotic cells mobilize the actin cytoskeleton to generate a remarkable diversity of morphological behaviours, including motility, phagocytosis and cytokinesis. Much of this diversity is mediated by guanine nucleotide exchange factors (GEFs) that activate Rho family GTPases-the master regulators of the actin cytoskeleton. There are over 80 Rho GEFs in the human genome (compared to only 22 genes for the Rho GTPases themselves), and the evolution of new and diverse GEFs is thought to provide a mechanism for linking the core cytoskeletal machinery to a wide range of new control inputs. Here we test this hypothesis and ask if we can systematically reprogramme cellular morphology by engineering synthetic GEF proteins. We focused on Dbl family Rho GEFs, which have a highly modular structure common to many signalling proteins: they contain a catalytic Dbl homology (DH) domain linked to diverse regulatory domains, many of which autoinhibit GEF activity. Here we show that by recombining catalytic GEF domains with new regulatory modules, we can generate synthetic GEFs that are activated by non-native inputs. We have used these synthetic GEFs to reprogramme cellular behaviour in diverse ways. The GEFs can be used to link specific cytoskeletal responses to normally unrelated upstream signalling pathways. In addition, multiple synthetic GEFs can be linked as components in series to form an artificial cascade with improved signal processing behaviour. These results show the high degree of evolutionary plasticity of this important family of modular signalling proteins, and indicate that it may be possible to use synthetic biology approaches to manipulate the complex spatio-temporal control of cell morphology
PMID: 17515921
ISSN: 1476-4687
CID: 95094

Analysis of mutations in fibroblast growth factor (FGF) and a pathogenic mutation in FGF receptor (FGFR) provides direct evidence for the symmetric two-end model for FGFR dimerization

Ibrahimi, Omar A; Yeh, Brian K; Eliseenkova, Anna V; Zhang, Fuming; Olsen, Shaun K; Igarashi, Makoto; Aaronson, Stuart A; Linhardt, Robert J; Mohammadi, Moosa
Two competing models for fibroblast growth factor (FGF) receptor (FGFR) dimerization have recently emerged based on ternary FGF-FGFR-heparin crystal structures. In the symmetric two-end model, heparin promotes dimerization of two FGF-FGFR complexes by stabilizing bivalent interactions of the ligand and receptor through primary and secondary sites and by stabilizing direct receptor-receptor contacts. In the asymmetric model, there are no protein-protein contacts between the two FGF-FGFR complexes, which are bridged solely by heparin. To identify the correct mode of FGFR dimerization, we abolished interactions at the secondary ligand-receptor interaction site, which are observed only in the symmetric two-end model, using site-directed mutagenesis. Cellular studies and real-time binding assays, as well as matrix-assisted laser desorption ionization-time of flight analysis, demonstrate that loss of secondary ligand-receptor interactions results in diminished FGFR activation due to decreased dimerization without affecting FGF-FGFR binding. Additionally, structural and biochemical analysis of an activating FGFR2 mutation resulting in Pfeiffer syndrome confirms the physiological significance of receptor-receptor contacts in the symmetric two-end model and provides a novel mechanism for FGFR gain of function in human skeletal disorders. Taken together, the data validate the symmetric two-end model of FGFR dimerization and argue against the asymmetric model of FGFR dimerization
PMCID:543411
PMID: 15632068
ISSN: 0270-7306
CID: 50286

Structure-based mutational analyses in FGF7 identify new residues involved in specific interaction with FGFR2IIIb

Sher, Ifat; Yeh, Brian K; Mohammadi, Moosa; Adir, Noam; Ron, Dina
Receptor binding specificity is an essential element in regulating the diverse activities of fibroblast growth factors (FGFs). FGF7 is ideal to study how this specificity is conferred at the structural level, as it interacts exclusively with one isoform of the FGF-receptor (FGFR) family, known as FGFR2IIIb. Previous mutational analysis suggested the importance of the beta4/beta5 loop of FGF7 in specific receptor recognition. Here a theoretical model of FGFR2IIIb/FGF7 complex showed that this loop interacts with the FGFR2IIIb unique exon. In addition, the model revealed new residues that either directly interact with the FGFR2IIIb unique exon (Asp63, Leu142) or facilitate this interaction (Arg65). Mutations in these residues reduced both receptor binding affinity and biological activity of FGF7. Altogether, these results provide the basis for understanding how receptor-binding specificity of FGF7 is conferred at the structural level
PMID: 14527678
ISSN: 0014-5793
CID: 68524

Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors

Yeh, Brian K; Igarashi, Makoto; Eliseenkova, Anna V; Plotnikov, Alexander N; Sher, Ifat; Ron, Dina; Aaronson, Stuart A; Mohammadi, Moosa
Binding specificity between fibroblast growth factors (FGFs) and their receptors (FGFRs) is essential for mammalian development and is regulated primarily by two alternatively spliced exons, IIIb ('b') and IIIc ('c'), that encode the second half of Ig-like domain 3 (D3) of FGFRs. FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b). Here, we report the crystal structure of the ligand-binding portion of FGFR2b bound to FGF10. Unique contacts between divergent regions in FGF10 and two b-specific loops in D3 reveal the structural basis by which alternative splicing provides FGF10-FGFR2b specificity. Structure-based mutagenesis of FGF10 confirms the importance of the observed contacts for FGF10 biological activity. Interestingly, FGF10 binding induces a previously unobserved rotation of receptor Ig domain 2 (D2) to introduce specific contacts with FGF10. Hence, both D2 and D3 of FGFR2b contribute to the exceptional specificity between FGF10 and FGFR2b. We propose that ligand-induced conformational change in FGFRs may also play an important role in determining specificity for other FGF-FGFR complexes
PMCID:151329
PMID: 12591959
ISSN: 0027-8424
CID: 39297

Structural basis for activation of fibroblast growth factor signaling by sucrose octasulfate

Yeh, Brian K; Eliseenkova, Anna V; Plotnikov, Alexander N; Green, David; Pinnell, Jared; Polat, Tulay; Gritli-Linde, Amel; Linhardt, Robert J; Mohammadi, Moosa
Sucrose octasulfate (SOS) is believed to stimulate fibroblast growth factor (FGF) signaling by binding and stabilizing FGFs. In this report, we show that SOS induces FGF-dependent dimerization of FGF receptors (FGFRs). The crystal structure of the dimeric FGF2-FGFR1-SOS complex at 2.6-A resolution reveals a symmetric assemblage of two 1:1:1 FGF2-FGFR1-SOS ternary complexes. Within each ternary complex SOS binds to FGF and FGFR and thereby increases FGF-FGFR affinity. SOS also interacts with the adjoining FGFR and thereby promotes protein-protein interactions that stabilize dimerization. This structural finding is supported by the inability of selectively desulfated SOS molecules to promote receptor dimerization. Thus, we propose that SOS potentiates FGF signaling by imitating the dual role of heparin in increasing FGF-FGFR affinity and promoting receptor dimerization. Hence, the dimeric FGF-FGFR-SOS structure substantiates the recently proposed 'two-end' model, by which heparin induces FGF-FGFR dimerization. Moreover, the FGF-FGFR-SOS structure provides an attractive template for the development of easily synthesized SOS-related heparin agonists and antagonists that may hold therapeutic potential
PMCID:139814
PMID: 12242295
ISSN: 0270-7306
CID: 39589