tbuckley/cabot-search huggingface dataset:
RADT-06. VOLUME KINETICS FOLLOWING TWO-SESSION GAMMA KNIFE RADIOSURGERY FOR LARGE BRAIN METASTASES (BM)
Authors: Ethan Damron, Yoshua Esquenazi, Nitin Tandon, Tse-Kuan Yu, Hatim Chafi, Magda Martir, Shariq Khwaja, Mark Amsbaugh, Angel Blanco
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Resection is a well-established treatment for BM ≥ 2 cm, albeit with potential for perioperative complications and delays in systemic treatment. Staged stereotactic radiosurgery (S-SRS) may improve outcomes versus traditional SRS, representing an alternative to surgery in responders. We reviewed institutional outcomes using 2-session S-SRS, focusing on lesion volume kinetics. METHODS 25 patients with 27 lesions underwent S-SRS at our institution between 2014 and 2020. Tumor volumes (TV) were measured at both S-SRS sessions and on follow-up MRI studies. RESULTS Median age at S-SRS was 61 years (range (r:) 31–84). Nine patients (10 BM) were lost to follow-up. Two patients failed to receive their second S-SRS due to local progression. The median margin tumor doses at first and second S-SRS were 15 Gy (r: 12–18 Gy) and 15 Gy (r: 12–16 Gy). The median interval between stages was 32 days (r: 8–63), and median TV at the first and second stages were 9.3 cm3 (r: 1.5–34.7 cm3) and 3.3 cm3 (r: 0.76–26.1 cm3), respectively. The median absolute and relative decrement between S-SRS sessions was 3.7 cm3 (r: 2.8-16.5 cm3) and 49.5% (r: 17.1-87.1%), respectively. [1-2]-month, [3-5]-month, and [6-12]-month MRI scans were available for 17, 10, and 15 lesions. The median decrease in TV compared to baseline was 50.2%, 78.2%, 74.9%. Two of 17 lesions (12%) had initial control but subsequently experienced volumetric progression and required resection. There were no G3+ adverse events (AE). Crude tumor control was achieved in 14 of 17 individual lesions (82%). CONCLUSION Two-session S-SRS is an effective treatment modality for treating patients with large BM, which is feasible in over 80% of patients with sustained tumor control and early volumetric regression.
NCOG-09. EFFICACY OF HER2-TARGETED ANTIBODY THERAPY IN HER2-POSITIVE BREAST CANCER BRAIN METASTASES: A NATIONAL ANALYSIS
Authors: Alexander Hulsbergen, Marike Broekman, Timothy Smith, Ayal A Aizer, Bryan Iorgulescu
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Breast cancer brain metastases (BCBM) commonly develop in human epidermal growth factor 2-positive (HER2+) breast cancer, but BCBM patients are underrepresented in clinical trials, leading to a lack of knowledge on the efficacy of HER2-targeted therapy in this population. METHODS We analyzed clinical characteristics and outcomes of HER2+BCBM patients from the National Cancer Database 2010–2016, comprising 70% of newly-diagnosed cancers in the U.S, to assess overall survival (OS) associated with HER2-targeted monoclonal antibody therapy (HER2-mab; i.e. trastuzumab, pertuzumab, and trastuzumab emtansine; encoded as of 2013). Survival was estimated with Kaplan-Meier techniques and compared with landmark analysis and Cox regression. The landmark timepoint was selected at which 75% of HER2-mab patients received HER2-mab, which was within 58 days of diagnosis. RESULTS 1,059 HER2+BCBM patients were identified, 717 (67.7%) patients were estrogen receptor negative (ER-) and 342 (32.3%) were ER+. Median follow-up was 12.0 months, at the end of which 73.8% of patients were deceased. Median OS was 12.2 and 22.1 months for ER- and ER+ patients, respectively. Following FDA approvals of pertuzumab (2012) and ado-trastuzumab emtansine (2013), HER2-mab usage for HER2+BCBM patients rose from 53.6% in 2013 to 71.7% in 2016. 420 BCBM patients had complete data for landmark analyses: 70.0% (n=294) received HER2-mab and 30.0% (n=126) did not, in which HER2-mab was associated with significantly improved OS in both ER- (median 22.2 months, 95%CI: 18.2-25.4; vs. 9.5 mos, 95%CI: 6.3-10.7; p=0.0001) and ER+ (median 25.7 months, 95%CI: 21.4-not reached; vs. 19.6 months, 95%CI: 11.1-35.2; p=0.02) patients. In multivariable Cox landmark analysis adjusted for ER status, age at diagnosis, extracranial disease, chemotherapy, radiotherapy, and metastasectomy; HER2-mab demonstrated significantly improved OS (hazard ratio 0.59 vs. no HER2-mab, 95%CI: 0.44-0.77; p&amp;lt; 0.001). CONCLUSIONS In this large national study, HER2-mab was associated with substantially improved overall survival in HER2+ BCBM patients.
EXTH-63. IN VITRO DRUG SCREENING BASED ON IN SILICO DATA IDENTIFIES NEW THERAPEUTIC AGENTS FOR AGGRESSIVE MENINGIOMA
Authors: Gerhard Jungwirth, Junguo Cao, Tao Yu, Rolf Warta, Andreas Unterberg, Christel Herold-Mende
Journal: Neuro-Oncology (2020)

Abstract The mainstay of treatment for progressive or recurrent meningiomas is surgery and/or radiotherapy. Patients with refractory cancer might benefit from systemic treatment options. However, to date, no effective chemotherapy is available for these patients. For this reason, novel inhibitors for the treatment of aggressive meningiomas are urgently needed. Therefore, we used our previously published Affymetrix microarray dataset (GSE74385) consisting of 62 meningiomas enriched with 28 WHO°III MGMs to screen substantially expressed genes that can be targeted by available inhibitors. For each targeted gene, three compounds were selected based on their clinical development. This filter process resulted in 107 drugs targeting 57 different genes. Most compounds were oncology-related (n = 94, 88%) with the remaining compounds being non-oncology agents (n = 13, 12%). Thereafter, a 2-stage screening strategy was employed. First, drugs were screened at a single dose (2.5 µM) in two malignant meningioma cell lines (NCH93 and IOMM-Lee) with CellTiter-Glo (Promega). Only drugs resulting in a cell viability of 50% or less of either cell line were considered for further validation. Remaining drug candidates (n = 33) exclusively belonged to the oncology-related group, consisting of 4 FDA-approved antineoplastic drugs (12%). The other drugs are currently tested in clinical trials (24% in phase III, 39% in phase II, and 24% in phase I). Drug candidates were further analyzed in a six-point dose-response scheme ranging from 0.1 nM to 10 µM in three meningioma cell lines (Ben-Men-1, NCH93, IOMM-Lee). The top 5 drugs were selected based on the lowest mean of z-transformed area under the curve. Resulting drugs and corresponding targets are: OTSSP167 (MELK), Panobinostat (HDAC), Picropodophyllin (IGF-1R), KPT-9274 (PAK4 and NAMPT), and BI-2536 (PLK1). Taken together, our drug screening approach utilized in silico data to identify potential inhibitors for the treatment of aggressive meningiomas warranting further preclinical investigation.
The Prognostic Impact of the Donor/Recipient CMV Serostatus in Patients with Different Chronic Hematological Disorders after Allogeneic Hematopoietic Stem Cell Transplantation: A Report from the Infectious Diseases Working Party of EBMT
Authors: Martin Schmidt-Hieber, Gloria Tridello, Malgorzata Mikulska, Nina Knelange, Didier Blaise, Gérard Socié, Liisa Volin, Nicolaas Schaap, Nathalie Fegueux, Per Ljungman, Ibrahim Yakoub-Agha, Noel Milpied, Johan Maertens, Patrice Chevallier, Jakob R. Passweg, Jan J Cornelissen, Nigel H. Russell, Charles Craddock, Jean-Henri Bourhis, Thierry Lamy, Péter Reményi, Jean-Yves Cahn, Mauricette Michallet, Silvia Montoto, Nicolaus Kröger, Bertram Glass, Jan Styczynski
Journal: Blood (2017)
STEM-26. SMALL MOLECULE DRUG CBL0137 INHIBITS THE FACT COMPLEX AND SENSITIZES GLIOBLASTOMA CANCER STEM CELLS TO RADIOTHERAPY
Authors: Miranda Tallman, Abigail Zalenski, Amanda Deighen, Morgan Schrock, Sherry Mortach, Treg Grubb, Preetham Kastury, Kristin Huntoon, Matthew Summers, Monica Venere
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is a malignant brain tumor with nearly universal recurrence. GBM cancer stem cells (CSCs), a subpopulation of radio- and chemo-resistant cancer cells capable of self-renewal, contribute to the high rate of recurrence. The anti-cancer agent, CBL0137, inhibits the FACT (facilitates chromatin transcription) complex leading to cancer cell specific cytotoxicity. Here, we show that CBL0137 sensitized GBM CSCs to radiotherapy using both in vitro and in vivo models. Treatment of CBL0137 combined with radiotherapy led to increased DNA damage in GBM patient specimens and failure to resolve the damage led to decreased cell viability. Using clonogenic assays, we confirmed that CBL0137 radiosensitized the CSCs. To validate that combination therapy impacted CSCs, we used an in vivo subcutaneous model and showed a decrease in the frequency of cancer stem cells present in tumors as well as decreased tumor volume. Using an orthotopic model of GBM, we confirmed that treatment with CBL0137 followed by radiotherapy led to significantly increased survival compared to either treatment alone. Radiotherapy remains a critical component of patient care for GBM, even though there exists a resistant subpopulation. Radio-sensitizing agents, including CBL0137, pose an exciting treatment paradigm to increase the efficacy of irradiation, especially by inclusively targeting CSCs.
Echocardiographic Patient Selection for Cardiac Resynchronization Therapy: Betting on a Dead Horse?⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Ole A. Breithardt
Journal: JACC. Cardiovascular imaging (2009)
Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy
Authors: Kenta Hirai, Daiki Ousaka, Yosuke Fukushima, Maiko Kondo, Takahiro Eitoku, Yusuke Shigemitsu, Mayuko Hara, Kenji Baba, Tatsuo Iwasaki, Shingo Kasahara, Shinichi Ohtsuki, Hidemasa Oh
Journal: Science Translational Medicine (2020)

Cardiosphere-derived exosomes improve cardiac function in dilated cardiomyopathy and provide safety lead-in results for further clinical translation.
CTIM-12. RANDOMIZED PHASE 2 STUDY OF NIVOLUMAB (NIVO) PLUS EITHER STANDARD OR REDUCED DOSE BEVACIZUMAB (BEV) IN RECURRENT GLIOBLASTOMA (rGBM)
Authors: Manmeet Ahluwalia, David Peereboom, Yasmeen Rauf, Justin Lathia, Tyler Alban, Cathy Schilero, Marci Ciolfi, Corey LaForest-Roys, Lakshmi Nayak, Eudocia Lee, Patrick Wen, David Reardon
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Trials with anti-PD1 in rGBM have shown limited efficacy. VEGF is highly upregulated proangiogenic growth factor in GBM contributing to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF may be a promising approach in rGBM. METHODS 90 patients with first-recurrent GBM were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) and bevacizumab at standard (10 mg/kg; Arm A) or low dose (3 mg/kg; Arm B) IV Q2 weeks. Eligibility also required KPS≥ 70% and dexamethasone ≤ 4 mg/day. Stratification included extent of resection, age, performance status and MGMT methylation status. Single cell RNA sequencing with CITE-seq was used to analyze blood samples from pre- and 8 weeks post-treatment among 8 responders and 8 non-responders. RESULTS 90 patients were enrolled (May 2018- Jan 2020) and median follow-up is 7.5 months. Characteristics in 2 arms were comparable. Median age was 60.5 years (range 27–86), median KPS was 80. 35 patients were MGMT methylated, 53 unmethylated and 2 indeterminate. Estimated progression free survival (PFS) and median overall survival (OS) in arm A are 6.13 and 10.85 months and 4.59 and 9.61 months in Arm B, respectively. Single cell RNA sequencing with CITE-seq was used to analyze blood samples from 16 patients, baseline and 8 weeks post treatment. Standard dose bevacizumab treated patients had decreased myeloid derived suppressor cells and an inflammatory response gene signature at 8 weeks. Most frequent toxicities included fatigue (52.8%), headache (32.6%), diarrhea (31.5%), proteinuria (25.8) and hypertension (23.6%). Toxicity was comparable between 2 arms, except hypertension was more common in arm A. CONCLUSIONS PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared to historical benchmarks of bevacizumab monotherapy. Ongoing response evaluation and immunocorrelative data will be presented.
Rescue of multiple class II CFTR mutations by elexacaftor+tezacaftor+ivacaftor mediated in part by the dual activities of elexacaftor as both corrector and potentiator
Authors: Onofrio Laselva, Claire Bartlett, Tarini N.A. Gunawardena, Hong Ouyang, Paul D.W. Eckford, Theo J. Moraes, Christine E. Bear, Tanja Gonska
Journal: European Respiratory Journal (2020)

Positive results in pre-clinical studies of the triple combination of elexacaftor, tezacaftor and ivacaftor, performed in airway epithelial cell cultures obtained from patients harbouring the class II cystic fibrosis transmembrane conductance regulator (CFTR) mutation F508del-CFTR, translated to impressive clinical outcomes for subjects carrying this mutation in clinical trials and approval of Trikafta.Encouraged by this correlation, we were prompted to evaluate the effect of the elexacaftor, tezacaftor and ivacaftor triple combination on primary nasal epithelial cultures obtained from individuals with rare class II CF-causing mutations (G85E, M1101K and N1303K) for which Trikafta is not approved.Cultures from individuals homozygous for M1101K responded better than cultures harbouring G85E and N1303K after treatment with the triple combination with respect to improvement in regulated channel function and protein processing. A similar genotype-specific effect of the triple combination was observed when the different mutations were expressed in HEK293 cells, supporting the hypothesis that these modulators may act directly on the mutant proteins. Detailed studies in nasal cultures and HEK293 cells showed that the corrector, elexacaftor, exhibited dual activity as both corrector and potentiator, and suggested that the potentiator activity contributes to its pharmacological activity.These pre-clinical studies using nasal epithelial cultures identified mutation genotypes for which elexacaftor, tezacaftor and ivacaftor may produce clinical responses that are comparable to, or inferior to, those observed for F508del-CFTR.
QOLP-09. HEALTH ECONOMIC EVALUATION OF LOW-GRADE GLIOMA MANAGEMENT: A SYSTEMATIC REVIEW
Authors: Nima Hamidi, Ajay Fernandez, Kyle Tuohy, Alireza Mansouri
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diffuse low-grade gliomas (DLGGs, WHO Grade II gliomas) comprise 13-16% of all primary brain tumors. Although there has been a paradigmatic shift toward upfront maximal safe resection (MSR) for these heterogeneous tumors, it is important to consider the health economic perspective of this approach, compared with the traditional watch-and-wait approach, as well. OBJECTIVE To conduct a systematic review of the health economic literature on the range of DLGG management options. METHODS Following the PRISMA guidelines, Medline, EMBASE, The Central Registration Depository (CRD), EconPapers, and EconLit were searched for ‘cost-effectiveness’, ‘health economics’ and ‘Low-grade glioma’. Grade I tumors were excluded. Pre-specified variables were extracted. All currencies were converted to USD. RESULTS Among 258 abstracts, 28 were selected for full-text screening, and 3 were selected for this review. A European study evaluated the role of intraoperative electrical stimulation (IES). Although IES was associated with higher direct costs upfront ($38,662.70 vs $32,116.10), this was offset by less long-term indirect costs ($12,222.30 vs $31,927.10; p=0.023), greater QALY (4.8 vs 2.9; p=0.001), and an incremental cost-effectiveness ratio (ICER) of $1,842.50. Another study evaluated the cost-effectiveness of adjuvant PCV+RT vs RT alone, finding greater QALY for the former (9.94 vs 5.17) and an ICER of $10,186 per QALY gained. A third study evaluated the cost-effectiveness of adding 18F-fluoroethyl-L-tyrosine (FET) PET to MRI, compared to preoperative MRI alone. This resulted in an ICER of $7,193.58 for the baseline scenario (lowest reimbursement) and $10,236.12 for the morbidity-adjusted reimbursement rate scenario (highest reimbursement). There were no studies evaluating the health economics of maximal upfront surgical resection to the watch-and-wait approach. CONCLUSION We found a limited number of studies reporting on the health economics of DLGGs. Given the paradigmatic transition toward more aggressive upfront surgical resection, DLGG-specific health economic analyses are underway.
NCCN Guidelines Insights: Soft Tissue Sarcoma, Version 1.2021
Authors: Margaret von Mehren, John M. Kane, Marilyn M. Bui, Edwin Choy, Mary Connelly, Sarah Dry, Kristen N. Ganjoo, Suzanne George, Ricardo J. Gonzalez, Martin J. Heslin, Jade Homsi, Vicki Keedy, Ciara M. Kelly, Edward Kim, David Liebner, Martin McCarter, Sean V. McGarry, Christian Meyer, Alberto S. Pappo, Amanda M. Parkes, I. Benjamin Paz, Ivy A. Petersen, Matthew Poppe, Richard F. Riedel, Brian Rubin, Scott Schuetze, Jacob Shabason, Jason K. Sicklick, Matthew B. Spraker, Melissa Zimel, Mary Anne Bergman, Giby V. George
Journal: Journal of the National Comprehensive Cancer Network (2020)

The NCCN Guidelines for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with soft tissue sarcomas. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including the development of a separate and distinct guideline for gastrointestinal stromal tumors (GISTs); reconception of the management of desmoid tumors; inclusion of further recommendations for the diagnosis and management of extremity/body wall, head/neck sarcomas, and retroperitoneal sarcomas; modification and addition of systemic therapy regimens for sarcoma subtypes; and revision of the principles of radiation therapy for soft tissue sarcomas.
Neoadjuvant Radiation Lobectomy and Immunotherapy for Angioinvasive HCC Resulting in Complete Pathologic Response
Authors: Harris Liou, Kabir Mody, Ashton W. Boyle, Andrew P. Keaveny, Kristopher P. Croome, Justin M. Burns, Denise M. Harnois, Tushar C. Patel, Beau Toskich
Journal: Hepatology (2020)
RARE-63. CYST WALL OF ADAMANTINOMATOUS CRANIOPHARYNGIOMA CONTAINS TUMOR CELLS THAT COULD LEAD TO RECURRENCE AFTER SURGERY
Authors: Chuan Zhao, Ye Wang, Hongxing Liu, Xueling Qi, Zhongqing Zhou, Ching Lau, Zhixiong Lin
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Adamantinomatous craniopharyngioma (ACP) is the primary subtype of craniopharyngioma in children, frequently with mutations in exon 3 of the CTNNB1 gene. Most ACP consists of both a solid tumor and one or more cysts. Despite surgical resection of the solid tumor followed by radiation, recurrence involving the cystic component is common, suggesting that the cyst wall contains tumor cells. We present here conclusive molecular pathology evidence of the presence of tumor cells in the cyst wall similar to those in the solid tumor. METHODS We used standard H&amp;E staining and immunohistochemistry (IHC) to compare the histopathology characteristics between the matched cyst wall and solid tumor of 11 cases of ACP as well as their CTNNB1 expression and exon 3 mutation. RESULTS Samples of the cyst wall and solid tumor were collected separately during the operation of 11 cases of ACP through careful dissection. The cyst wall showed the nested cell clusters and peripheral palisading epithelium which are identical to those in the solid tumor. The cyst wall and solid tumor both showed Ki67 and nuclear β-catenin expression by IHC. There is no difference in the transcription level of CTNNB1 between the cyst wall and the solid tumor, both being significantly higher than that in normal brain tissue. Exon 3 mutations of the CTNNB1 gene of the cyst wall and the solid tumor are identical in each case. CONCLUSION Follow-up of clinical cases suggests that tumor cells in residual cyst wall may be the cause of recurrence after surgery.
Low-Dose Bisphenol A in a Rat Model of Endometrial Cancer: A CLARITY-BPA Study
Authors: Yuet-Kin Leung, Jacek Biesiada, Vinothini Govindarajah, Jun Ying, Ady Kendler, Mario Medvedovic, Shuk-Mei Ho
Journal: Environmental Health Perspectives (2020)

BACKGROUND: Bisphenol A (BPA) is known to be biologically active in experimental models even at low levels of exposure.However, its impact on endometrial cancer remains unclear.OBJECTIVES: This study aimed to investigate whether lifelong exposure to different doses of BPA induced uterine abnormalities and molecular changes in a rat model.METHODS: Sprague-Dawley rats were exposed to 5 doses of BPA [0, 25, 250, 2,500, or 25,000 lg=kg body weight (BW)/d] or 2 doses of 17aethynylestradiol (EE2) (0.05 and 0:5 lg=kg BW/d) starting from gestational day 6 up to 1 y old according to the CLARITY-BPA consortium protocol.The BW, uterus weight, and histopathology end points of the uteri were analyzed at postnatal (PND) day 21, 90, and 365.Estrous cycling status was evaluated in PND90 and PND365 rats.Transcriptomic analyses of estrus stage uteri were conducted on PND365 rats.RESULTS: Based on the analysis of the combined effects of all testing outcomes (including immunohistological, morphological, and estrous cycle data) in a semiblinded fashion, using statistical models, 25 lg=kg BW/d BPA [BPA(25)], or 250 lg=kg BW/d BPA [BPA(250)] exerted effects similar to that of EE2 at 0:5 lg=kg BW/d in 1-y-old rats.Transcriptome analyses of estrus stage uteri revealed a set of 710 genes shared only between the BPA(25) and BPA(250) groups, with 115 of them predicted to be regulated by estradiol and 57 associated with female cancers.An interesting finding is that the expression of 476 human orthologous genes in this rat BPA signature robustly predicted the overall survival (p = 1:68 × 10 -5 , hazard ratio = 2:62) of endometrial cancer patients.DISCUSSION: Lifelong exposure of rats to low-dose BPA at 25 and 250 lg=kg BW/d altered the estrous cycle and uterine pathology with similarity to EE2.The exposure also disrupted a unique low-dose BPA-gene signature with predictive value for survival outcomes in patients with endometrial cancer.
The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas
Authors: Alvin P. Makohon-Moore, Evan J. Lipson, Jody E. Hooper, Amanda Zucker, Jungeui Hong, Craig M. Bielski, Akimasa Hayashi, Collin Tokheim, Priscilla Baez, Rajya Kappagantula, Zachary Kohutek, Vladimir Makarov, Nadeem Riaz, Michael A. Postow, Paul B. Chapman, Rachel Karchin, Nicholas D. Socci, David B. Solit, Timothy A. Chan, Barry S. Taylor, Suzanne L. Topalian, Christine A. Iacobuzio-Donahue
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes. Experimental Design: Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression. Results: For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance. Conclusions: In 4 patients who received immunotherapy, we found 1–3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.