Person: Sholl, Lynette
Loading...
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Sholl
First Name
Lynette
Name
Sholl, Lynette
37 results
Search Results
Now showing 1 - 10 of 37
Publication The fuzzy world of precision medicine: deliberations of a precision medicine tumor board(Future Medicine Ltd, 2017) McGraw, Sarah A; Garber, Judy; Janne, Pasi; Lindeman, Neal; Oliver, Nelly; Sholl, Lynette; Van Allen, Eliezer; Wagle, Nikhil; Garraway, Levi; Joffe, Steven; Gray, Stacy WAim: To understand how a cancer precision medicine tumor board (CPM-TB) made choices about return of results. Materials & methods: Observed CPM-TB deliberations and completed in-depth interviews with committee members. Results: Responding to complex evidence of ambiguous significance, deliberations of the CPM-TB were predicated on analytic validity and clinical utility. Members had concerns both about potential harms due to returning results based on weak evidence and about withholding potentially meaningful results. Group dynamics and the clinical experiences of individual committee members shaped their work. Conclusion: Both scientific evidence and the social context surrounding deliberations of a CPM-TB influenced decisions about return of results. Subjective elements, while present in any scientific endeavor, may carry more weight in the face of ambiguous findings.Publication Emerging Evidence for MicroRNAs as Regulators of Cancer Stem Cells(Molecular Diversity Preservation International (MDPI), 2011) Sethi, Aisha; Sholl, LynetteCancer stem cells are defined as a subpopulation of cells within a tumor that are capable of self-renewal and differentiation into the heterogeneous cell lineages that comprise the tumor. Many studies indicate that cancer stem cells may be responsible for treatment failure and relapse in cancer patients. The factors that regulate cancer stem cells are not well defined. MicroRNAs (miRNAs) are small non-coding RNAs that regulate translational repression and transcript degradation. miRNAs play a critical role in embryonic and inducible pluripotent stem cell regulation and emerging evidence supports their role in cancer stem cell evolution. To date, miRNAs have been shown to act either as tumor suppressor genes or oncogenes in driving critical gene expression pathways in cancer stem cells in a wide range of human malignancies, including hematopoietic and epithelial tumors and sarcomas. miRNAs involved in cancer stem cell regulation provide attractive, novel therapeutic targets for cancer treatment. This review attempts to summarize progress to date in defining the role of miRNAs in cancer stem cells.Publication The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine(BioMed Central, 2016) Garofalo, Andrea; Sholl, Lynette; Reardon, Brendan; Taylor-Weiner, Amaro; Amin-Mansour, Ali; Miao, Diana; Liu, David; Oliver, Nelly; MacConaill, Laura; Ducar, Matthew; Rojas-Rudilla, Vanesa; Giannakis, Marios; Ghazani, Arezou; Gray, Stacy; Janne, Pasi; Garber, Judy; Joffe, Steve; Lindeman, Neal; Wagle, Nikhil; Garraway, Levi; Van Allen, EliezerBackground: The diversity of clinical tumor profiling approaches (small panels to whole exomes with matched or unmatched germline analysis) may engender uncertainty about their benefits and liabilities, particularly in light of reported germline false positives in tumor-only profiling and use of global mutational and/or neoantigen data. The goal of this study was to determine the impact of genomic analysis strategies on error rates and data interpretation across contexts and ancestries. Methods: We modeled common tumor profiling modalities—large (n = 300 genes), medium (n = 48 genes), and small (n = 15 genes) panels—using clinical whole exomes (WES) from 157 patients with lung or colon adenocarcinoma. We created a tumor-only analysis algorithm to assess germline false positive rates, the impact of patient ancestry on tumor-only results, and neoantigen detection. Results: After optimizing a germline filtering strategy, the germline false positive rate with tumor-only large panel sequencing was 14 % (144/1012 variants). For patients whose tumor-only results underwent molecular pathologist review (n = 91), 50/54 (93 %) false positives were correctly interpreted as uncertain variants. Increased germline false positives were observed in tumor-only sequencing of non-European compared with European ancestry patients (p < 0.001; Fisher’s exact) when basic germline filtering approaches were used; however, the ExAC database (60,706 germline exomes) mitigated this disparity (p = 0.53). Matched and unmatched large panel mutational load correlated with WES mutational load (r2 = 0.99 and 0.93, respectively; p < 0.001). Neoantigen load also correlated (r2 = 0.80; p < 0.001), though WES identified a broader spectrum of neoantigens. Small panels did not predict mutational or neoantigen load. Conclusions: Large tumor-only targeted panels are sufficient for most somatic variant identification and mutational load prediction if paired with expanded germline analysis strategies and molecular pathologist review. Paired germline sequencing reduced overall false positive mutation calls and WES provided the most neoantigens. Without patient-matched germline data, large germline databases are needed to minimize false positive mutation calling and mitigate ethnic disparities. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0333-9) contains supplementary material, which is available to authorized users.Publication Tumoral cavitation in patients with non-small-cell lung cancer treated with antiangiogenic therapy using bevacizumab(E-MED LTD, 2012) Nishinoa, Mizuki; Cryer, Sarah K.; Okajim, Yuka; Sholl, Lynette; Hatabu, Hiroto; Rabin, Michael; Jackman, David M; Johnson, BruceRationale and objectives: To investigate the frequency and radiographic patterns of tumoral cavitation in patients with non-small cell lung cancer (NSCLC) treated with bevacizumab, and correlate the imaging findings with the pathology, clinical characteristics and outcome. Materials and methods: Seventy-two patients with NSCLC treated with bevacizumab therapy were identified retrospectively. Baseline and follow-up chest computed tomography scan were reviewed to identify tumoral cavitation and subsequent filling in of cavitation. Radiographic cavitation patterns were classified into 3 groups. The clinical and outcome data were correlated with cavity formation and patterns. Results: Out of 72 patients, 14 patients developed cavitation after the initiation of bevacizumab therapy (19%; median time to event, 1.5 months; range 1.0–24.8 months). Three radiographic patterns of tumoral cavitation were noted: (1) development of cavity within the dominant lung tumor (n = 8); (2) development of non-dominant cavitary nodules (n = 3); and (3) development of non-dominant cavitary nodules with adjacent interstitial abnormalities (n = 3). Eleven patients (79%) demonstrated subsequent filling in of cavitation (the time from the cavity formation to filling in; median 3.7 months; range 1.9–22.7 months). No significant difference was observed in the clinical characteristics, including smoking history, or in the survival between patients who developed cavitation and those who did not. Smoking history demonstrated a significant difference across 3 radiographic cavitation patterns (P = 0.006). Hemoptysis was noted in 1 patient with cavity formation and 4 patients without, with no significant difference between the 2 groups. Conclusion: Tumoral cavitation occurred in 19% in patients with NSCLC treated with bevacizumab and demonstrated 3 radiographic patterns. Subsequent filling in of cavitation was noted in the majority of cases.Publication Medical Oncologists’ Experiences in Using Genomic Testing for Lung and Colorectal Cancer Care(American Society of Clinical Oncology (ASCO), 2017) Gray, Stacy; Kim, Benjamin; Sholl, Lynette; Cronin, Angel; Parikh, Aparna R.; Klabunde, Carrie N.; Kahn, Katherine L.; Haggstrom, David A.; Keating, NancyPurpose: Genomic testing improves outcomes for many at-risk individuals and patients with cancer; however, little is known about how genomic testing for non–small-cell lung cancer (NSCLC) and colorectal cancer (CRC) is used in clinical practice. Patients and Methods: In 2012 to 2013, we surveyed medical oncologists who care for patients in diverse practice and health care settings across the United States about their use of guideline- and non–guideline-endorsed genetic tests. Multivariable regression models identified factors that are associated with greater test use. Results: Of oncologists, 337 completed the survey (participation rate, 53%). Oncologists reported higher use of guideline-endorsed tests (eg, KRAS for CRC; EGFR for NSCLC) than non–guideline-endorsed tests (eg, OncotypeDX Colon; ERCC1 for NSCLC). Many oncologists reported having no patients with CRC who had mismatch repair and/or microsatellite instability (24%) or germline Lynch syndrome (32%) testing, and no patients with NSCLC who had ALK testing (11%). Of oncologists, 32% reported that five or fewer patients had KRAS and EGFR testing for CRC and NSCLC, respectively. Oncologists, rather than pathologists or surgeons, ordered the vast majority of tests. In multivariable analyses, fewer patients in nonprofit integrated health care delivery systems underwent testing than did patients in hospital or office-based single-specialty group settings (all P < .05). High patient volume and patient requests (CRC only) were also associated with higher test use (all P < .05). Conclusion: Genomic test use for CRC and NSCLC varies by test and practice characteristics. Research in specific clinical contexts is needed to determine whether the observed variation reflects appropriate or inappropriate care. One potential way to reduce unwanted variation would be to offer widespread reflexive testing by pathology for guideline-endorsed predictive somatic tests.Publication EGFRMutation Is a Better Predictor of Response to Tyrosine Kinase Inhibitors in Non–Small Cell Lung Carcinoma Than FISH, CISH, and Immunohistochemistry(Oxford University Press (OUP), 2010) Sholl, Lynette; Xiao, Yun; Joshi, Victoria; Yeap, Beow; Cioffredi, Leigh-Anne; Jackman, David M; Lee, Charles; Janne, Pasi; Lindeman, NealAbout 10% of patients with non–small cell lung carcinoma (NSCLC) respond to epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs). More than 75% of “responders” have activating mutations in EGFR. However, mutation analysis is not widely available, and proposed alternatives (in situ hybridization and immunohistochemical analysis) have shown inconsistent associations with outcome. Fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), immunohistochemical analysis, and DNA sequencing were compared in this study of 40 NSCLC samples from TKI-treated patients. Response rates were 12 of 19 in EGFR-mutant vs 1 of 20 EGFR wild-type tumors (P = .0001), 7 of 19 FISH+ vs 4 of 17 FISH– tumors (not significant [NS]), 5 of 16 CISH+ vs 6 of 21 CISH– tumors (NS), and 3 of 9 immunohistochemically positive vs 7 of 22 immunohistochemically negative tumors (NS). EGFR mutation was associated with improved progression-free survival (P = .0004). Increased copy number (FISH or CISH) and protein expression (immunohistochemical) did not independently predict outcome. Thus, EGFR sequence analysis was the only method useful for predicting response and progression-free survival following TKI therapy in NSCLC.Publication Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors(American Association for Cancer Research (AACR), 2012) Ercan, Dalia; Xu, Chunxiao; Yanagita, Masahiko; Monast, Calixte S.; Pratilas, Christine A.; Montero, Juan; Butaney, Mohit; Shimamura, Takeshi; Sholl, Lynette; Ivanova, Elena; Tadi, Madhavi; Rogers, Andrew; Repellin, Claire; Capelletti, Marzia; Maertens, Ophelia; Goetz, Eva Marie; Letai, Anthony; Garraway, Levi; Lazzara, Matthew J.; Rosen, Neal; Gray, Nathanael; Wong, Kwok-Kin; Janne, PasiThe clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib resistant EGFR mutant NSCLC patient. In addition, the WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rationale combination therapies that should be evaluated in clinical trials.Publication An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma(2016) Drier, Yotam; Cotton, Matthew J.; Williamson, Kaylyn; Gillespie, Shawn M.; Ryan, Russell J.H.; Kluk, Michael J.; Carey, Christopher D.; Rodig, Scott; Sholl, Lynette; Afrogheh, Amir H.; Faquin, William; Queimado, Lurdes; Qi, Jun; Wick, Michael J.; El-Naggar, Adel K.; Bradner, James E; Moskaluk, Christopher A.; Aster, Jon; Knoechel, Birgit; Bernstein, BradleyTranslocation events are frequent in cancer and may create chimeric fusions or ‘regulatory rearrangements’ that drive oncogene overexpression. Here we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a recurrent theme in adenoid cystic carcinoma (ACC). Whole-genome sequencing data and chromatin maps reveal distinct chromosomal rearrangements that juxtapose super-enhancers to the MYB locus. Chromosome conformation capture confirms that the translocated enhancers interact with the MYB promoter. Remarkably, MYB protein binds to the translocated enhancers, creating a positive feedback loop that sustains its expression. MYB also binds enhancers that drive different regulatory programs in alternate cell lineages in ACC, cooperating with TP63 in myoepithelial cells and a Notch program in luminal epithelial cells. Bromodomain inhibitors slow tumor growth in ACC primagraft models in vivo. Thus, our study identifies super-enhancer translocations that drive MYB expression and provides insight into downstream MYB functions in the alternate ACC lineages.Publication Kinase Domain Activation of FGFR2 Yields High-Grade Lung Adenocarcinoma Sensitive to a Pan-FGFR Inhibitor in a Mouse Model of NSCLC(American Association for Cancer Research (AACR), 2014) Tchaicha, J. H.; Akbay, Esra A.; Altabef, A.; Mikse, O. R.; Kikuchi, E.; Rhee, K.; Liao, R; Bronson, Roderick; Sholl, Lynette; Meyerson, Matthew; Hammerman, Peter S.; Wong, Kwok-KinSomatic mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) are present in 4-5% of patients diagnosed with non-small cell lung cancer (NSCLC). Amplification and mutations in FGFR genes have been identified in patients with NSCLC and clinical trials are testing the efficacy of anti-FGFR therapies. FGFR2 and other FGFR kinase family gene alterations have been found in both lung squamous cell carcinoma and lung adenocarcinoma though mouse models of FGFR driven lung cancers have not been reported. Here, we generated a genetically engineered mouse model (GEMM) of NSCLC driven by a kinase domain mutation in FGFR2. Combined with p53 ablation, primary grade III/IV adenocarcinoma was induced in the lung epithelial compartment exhibiting locally invasive and pleiotropic tendencies largely made up of multinucleated cells. Tumors were acutely sensitive to pan-FGFR inhibition. This is the first FGFR2-driven lung cancer GEMM, which can be applied across different cancer indications in a preclinical setting.Publication Intrathymic cyst: Clinical and radiological features in surgically resected cases(Elsevier BV, 2014) Araki, Tetsuro; Sholl, Lynette; Gerbaudo, Victor; Hatabu, Hiroto; Nishino, MichiyaAIM To investigate radiological and clinical characteristics of pathologically proven cases of intrathymic cysts. MATERIALS AND METHODS The study population consisted of 18 patients (five males, 13 females; median age 56 years) with pathologically confirmed intrathymic cysts who underwent thymectomy and had preoperative chest computed tomography (CT) available for review. The patient demographics, clinical presentation, and preoperative radiological diagnoses were reviewed. CT images were evaluated for shape, contour, location of the cysts and the presence of adjacent thymic tissue, mass effect, calcifications, and septa. The size and CT attenuations of the cysts were measured. RESULTS The most common CT features of intrathymic cysts included oval shape (9/18; 50%), smooth contour (12/18; 67%), midline location (11/18; 61%), the absence of visible adjacent thymic tissue (12/18; 67%), and the absence of calcification (16/18; 89%). The mean longest diameter and the longest perpendicular diameter were 25 mm (range 17–49 mm) and 19 mm (range 10–44 mm), respectively. The mean CT attenuation was 38 HU (range 6–62 HU) on contrast-enhanced CT, and was 45 HU (range 26–64 HU) on unenhanced CT (p=0.41). The CT attenuation was >20 HU in 15 of 18 patients (83%). Preoperative radiological diagnosis included thymoma in 11 patients. CONCLUSION In surgically removed, pathologically proven cases of intrathymic cyst, the CT attenuation was >20 HU in most cases, leading to the preoperative diagnosis of thymoma. Awareness of the spectrum of imaging findings of the entity is essential to improve the diagnostic accuracy and patient management.