12 results on '"Heestand, G."'
Search Results
2. 197P Clinical benefit of HER2-targeted therapies versus prior chemotherapy in refractory HER2 expressing and mutant gastrointestinal malignancies
- Author
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Khanna, V., Henry, A.S., Johnson, T.P., Heestand, G., Shaheen, S., Chong, C., Fisher, G.A., Jr., and Chen, C.
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- 2023
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3. Next-Generation Sequencing of Circulating Tumor DNA Reveals Frequent Alterations in Advanced Hepatocellular Carcinoma
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Ikeda, S, Tsigelny, IF, Skjevik, AA, Kono, Y, Mendler, M, Kuo, A, Sicklick, JK, Heestand, G, Banks, KC, Talasaz, A, Lanman, RB, Lippman, S, and Kurzrock, R
- Subjects
Adult ,Male ,Liver Cancer ,Hepatocellular carcinoma ,Oncology and Carcinogenesis ,Circulating Tumor DNA ,Rare Diseases ,Clinical Research ,Genetics ,Humans ,Prospective Studies ,Oncology & Carcinogenesis ,neoplasms ,Next‐generation sequencing ,Aged ,Cancer ,Tumor ,Liquid biopsy ,Liver Disease ,Carcinoma ,Human Genome ,High-Throughput Nucleotide Sequencing ,Hepatocellular ,Middle Aged ,Good Health and Well Being ,Next-generation sequencing ,Female ,Digestive Diseases ,Biomarkers - Abstract
BACKGROUND:Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood-derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC. MATERIALS AND METHODS:We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild-type allele fraction was calculated. RESULTS:All patients (100%) had somatic alterations (median = 3 alterations/patient [range, 1-8]); median mutant allele fraction, 0.29% (range, 0.1%-37.77%). Mutations were identified in several genes: TP53 (57% of patients), CTNNB1 (29%), PTEN (7%), CDKN2A (7%), ARID1A (7%), and MET (7%); amplifications, in CDK6 (14%), EGFR (14%), MYC (14%), BRAF (7%), RAF1 (7%), FGFR1 (7%), CCNE1 (7%), PIK3CA (7%), and ERBB2/HER2 (7%). Eleven patients (79%) had ≥1 theoretically actionable alteration. No two patients had identical genomic portfolios, suggesting the need for customized treatment. A patient with a CDKN2A-inactivating and a CTNNB1-activating mutation received matched treatment: palbociclib (CDK4/6 inhibitor) and celecoxib (COX-2/Wnt inhibitor); des-gamma-carboxy prothrombin level decreased by 84% at 2 months (1,410 to 242 ng/mL [normal: ≤7.4 ng/mL]; alpha fetoprotein [AFP] low at baseline). A patient with a PTEN-inactivating and a MET-activating mutation (an effect suggested by in silico molecular dynamic simulations) received sirolimus (mechanistic target of rapamycin inhibitor) and cabozantinib (MET inhibitor); AFP declined by 63% (8,320 to 3,045 ng/mL [normal: 0-15 ng/mL]). CONCLUSION:ctDNA derived from noninvasive blood tests can provide exploitable genomic profiles in patients with HCC. IMPLICATIONS FOR PRACTICE:This study reports that blood-derived circulating tumor DNA can provide therapeutically exploitable genomic profiles in hepatocellular cancer, a malignancy that is known to be difficult to biopsy.
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- 2018
4. A first in human, dose escalation trial of MSC2363318A – a dual p70S6K/Akt inhibitor, for patients with advanced malignancies
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Tsimberidou, A.M., primary, Verschraegen, C., additional, Heestand, G., additional, Kaleta, R., additional, Scheuenpflug, J., additional, Huck, B., additional, Weise, A., additional, and Kurzrock, R., additional
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- 2015
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5. Erratum: “Review of the National Ignition Campaign 2009-2012” [Phys. Plasmas 21, 020501 (2014)]
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Lindl, J. D., primary, Landen, O. L., additional, Edwards, J., additional, Moses, E. I., additional, Adams, J., additional, Amendt, P. A., additional, Antipa, N., additional, Arnold, P. A., additional, Atherton, L. J., additional, Azevedo, S., additional, Barker, D., additional, Barrios, M. A., additional, Bass, I., additional, Baxamusa, S. H., additional, Beeler, R., additional, Beeman, B. V., additional, Bell, P. M., additional, Benedetti, L. R., additional, Bernstein, L., additional, Berzak Hopkins, L., additional, Bhandarkar, S. D., additional, Biesiada, T., additional, Bionta, R. M., additional, Bleuel, D. L., additional, Bond, E. J., additional, Borden, M., additional, Bowers, M. W., additional, Bradley, D. K., additional, Browning, D., additional, Brunton, G. K., additional, Bude, J., additional, Burkhart, S. C., additional, Burr, R. F., additional, Butlin, B., additional, Caggiano, J. A., additional, Callahan, D. A., additional, Carpenter, A. C., additional, Carr, C. W., additional, Casey, D. T., additional, Castro, C., additional, Celeste, J., additional, Celliers, P. M., additional, Cerjan, C. J., additional, Chang, J., additional, Chiarappa-Zucca, M., additional, Choate, C., additional, Clancy, T. J., additional, Clark, D. S., additional, Cohen, S. J., additional, Collins, G. W., additional, Conder, A., additional, Cox, J. R., additional, Datte, P. S., additional, Deis, G. A., additional, Dewald, E. L., additional, Di Nicola, P., additional, Di Nicola, J. M., additional, Divol, L., additional, Dixit, S. N., additional, Döppner, T., additional, Draggoo, V., additional, Drury, O., additional, Dylla-Spears, R., additional, Dzenitis, E. G., additional, Dzenitis, J. M., additional, Eckart, M. J., additional, Eder, D. C., additional, Eggert, J. H., additional, Ehrlich, R. B., additional, Erbert, G. V., additional, Fair, J., additional, Farley, D. R., additional, Fedorov, M., additional, Felker, B., additional, Finucane, R., additional, Fisher, A., additional, Fittinghoff, D. N., additional, Folta, J., additional, Fortner, R. J., additional, Frazier, T., additional, Frieders, G., additional, Frieders, S., additional, Friedrich, S., additional, Fry, J., additional, Gaylord, J., additional, Glenn, S. M., additional, Glenzer, S. H., additional, Golick, B., additional, Gururangan, G., additional, Guss, G., additional, Haan, S. W., additional, Haid, B. J., additional, Hammel, B., additional, Hamza, A. V., additional, Hartouni, E. P., additional, Hatarik, R., additional, Hatch, B. W., additional, Hatchett, S. P., additional, Hawley, R., additional, Haynam, C., additional, Heebner, J., additional, Heestand, G., additional, Hermann, M. R., additional, Hernandez, V. J., additional, Hicks, D. G., additional, Hinkel, D. E., additional, Ho, D. D., additional, Holder, J. P., additional, Holunga, D., additional, Honig, J., additional, Horner, J., additional, House, R. K., additional, Hutton, M., additional, Izumi, N., additional, Jackson, M. C., additional, Jancaitis, K. S., additional, Jedlovec, D. R., additional, Johnson, M. A., additional, Jones, O. S., additional, Kalantar, D. H., additional, Kauffman, R. L., additional, Kegelmeyer, L., additional, Kerbel, G., additional, Key, M., additional, Khan, S. F., additional, Kimbrough, J. R., additional, Kirkwood, R., additional, Klingman, J. J., additional, Koch, J. A., additional, Kohut, T. R., additional, Koning, J. M., additional, Knittel, K. M., additional, Kozioziemski, B. J., additional, Krauter, G. W., additional, Krauter, K., additional, Kritcher, A., additional, Kroll, J., additional, Kruer, W. L., additional, LaCaille, G., additional, LaFortune, K. N., additional, Lagin, L. J., additional, Land, T. A., additional, Langdon, A. B., additional, Langer, S. H., additional, Larson, D. W., additional, Latray, D. A., additional, Laurence, T., additional, LePape, S., additional, Lerche, R. A., additional, Liao, Z., additional, Liebman, J., additional, London, R. A., additional, Lowe-Webb, R. R., additional, Ma, T., additional, MacGowan, B. J., additional, MacKinnon, A. J., additional, MacPhee, A. G., additional, Malsbury, T. N., additional, Manes, K., additional, Manuel, A. M., additional, Mapoles, E. R., additional, Marinak, M. M., additional, Marshall, C. D., additional, Mason, D., additional, Masters, N., additional, Mathisen, D. G., additional, Matthews, I., additional, McCarville, T., additional, McNaney, J. M., additional, Meeker, D. J., additional, Meezan, N. B., additional, Menapace, J., additional, Michel, P., additional, Miller, P. E., additional, Milovich, J. L., additional, Mintz, M., additional, Montesanti, R., additional, Monticelli, M., additional, Moody, J. D., additional, Moran, M. J., additional, Moreno, J. C., additional, Munro, D. H., additional, Negres, R. A., additional, Nelson, J. R., additional, Norton, M., additional, Nostrand, M., additional, O'Brien, M., additional, Opachich, Y. P., additional, Orth, C., additional, Pak, A. E., additional, Palma, E. S., additional, Palmer, J. N. E., additional, Parham, T. G., additional, Park, H.-S., additional, Patel, P. K., additional, Patterson, R. W., additional, Peterson, J. E., additional, Peterson, J. L., additional, Phillips, T., additional, Prasad, R., additional, Primdahl, K., additional, Prisbrey, S. T., additional, Qiu, S. R., additional, Ralph, J. E., additional, Raman, K. S., additional, Ravizza, F., additional, Raymond, B., additional, Remington, B. A., additional, Rever, M. A., additional, Reynolds, J., additional, Richardson, M. J., additional, Riddle, A. C., additional, Rittmann, B., additional, Rosen, M. D., additional, Ross, J. S., additional, Rygg, J. R., additional, Sacks, R. A., additional, Salmon, J. T., additional, Salmonson, J. D., additional, Sater, J. D., additional, Saunders, R. L., additional, Sawicki, R., additional, Schaffers, K., additional, Schneider, D. H., additional, Schneider, M. B., additional, Scott, H. A., additional, Sepke, S. M., additional, Seugling, R., additional, Shaughnessy, D. A., additional, Shaw, M. J., additional, Shelton, R., additional, Shen, N., additional, Shingleton, N., additional, Simanovskaia, N., additional, Smalyuk, V., additional, Smauley, D. A., additional, Spaeth, M., additional, Spears, B. K., additional, Speck, D. R., additional, Spinka, T. M., additional, Springer, P. T., additional, Stadermann, M., additional, Stoeffl, W., additional, Stolken, J., additional, Stolz, C., additional, Storm, E., additional, Strozzi, D. J., additional, Suratwala, T., additional, Suter, L. J., additional, Taylor, J. S., additional, Thomas, C. A., additional, Tietbohl, G. L., additional, Tommasini, R., additional, Trummer, D., additional, VanWonterghem, B., additional, Von Rotz, R., additional, Wallace, R. J., additional, Walters, C. F., additional, Wang, A., additional, Warrick, A. L., additional, Weaver, S., additional, Weber, S. V., additional, Wegner, P. J., additional, Widmann, K., additional, Widmayer, C. C., additional, Williams, E. A., additional, Whitman, P. K., additional, Wilhelmsen, K., additional, Witte, M., additional, Wong, L., additional, Wood, R. D., additional, Yang, S., additional, Yeamans, C., additional, Young, B. K., additional, Yoxall, B., additional, Zacharias, R. A., additional, Zimmerman, G. B., additional, Batha, S., additional, Danly, C. R., additional, Fatherley, V., additional, Grim, G. P., additional, Guler, N., additional, Herrmann, H. W., additional, Kim, Y., additional, Kline, J. L., additional, Kyrala, G. A., additional, Leeper, R. J., additional, Martinson, D., additional, Merrill, F. E., additional, Olson, R. E., additional, Wilde, C., additional, Wilke, M. D., additional, Wilson, D. C., additional, Chandler, G. A., additional, Cooper, G. W., additional, Hahn, K. D., additional, Peterson, K. J., additional, Ruiz, C. L., additional, Chen, K. C., additional, Dorsano, N., additional, Emerich, M., additional, Gibson, C., additional, Hoover, D., additional, Hoppe, M., additional, Kilkenny, J. D., additional, Moreno, K., additional, Wilkens, H., additional, Woods, S., additional, Frenje, J. A., additional, Johnson, M. G., additional, Li, C. K., additional, Petrasso, R. D., additional, Rinderknecht, H., additional, Rosenberg, M., additional, Séguin, F. H., additional, Zylstra, A., additional, Garbett, W., additional, Graham, P., additional, Guymer, T., additional, Moore, A. S., additional, Bourgade, J.-L., additional, Gauthier, P., additional, Leidinger, J.-P., additional, Masse, L., additional, Philippe, F., additional, and Scott, R. H. H., additional
- Published
- 2014
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6. P5:01 A FIRST IN HUMAN, DOSE ESCALATION TRIAL OF MSC2363318A – A DUAL P70S6K/AKT INHIBITOR, FOR PATIENTS WITH ADVANCED MALIGNANCIES
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Tsimberidou, A. M., Verschraegen, C., Heestand, G., Kaleta, R., Scheuenpflug, J., Huck, B., Weise, A., and Kurzrock, R.
- Abstract
Background: The PI3K/Akt/PTEN pathway regulates cellular functions including growth, proliferation and metabolism. Aberrant pathway signaling (PTEN loss of function, PIK3CA mutation, Akt amplification, etc.) occurs in >50% of all tumors, and pathway inhibition is used for the treatment of solid tumors and hematopoietic malignancies. Whereas mTOR inhibition activates a negative feedback loop, leading to Akt activation, dual p70S6K/Akt inhibition may improve pathway inhibition whilst blocking negative consequences of Akt activation via the feedback loop. MSC2363318A is a brain penetrant, kinase-selective, ATP competitive inhibitor of p70S6K, Akt1, and Akt3. MSC2363318A exhibits potent anti-proliferative activity in vitro, particularly in tumor cells with PI3K pathway genomic alterations, and antitumor activity in vivo, in xenograft models of breast, pancreatic and ovarian cancers, and glioblastoma. Trial design and current results: This is a standard 3 + 3 dose escalation study of single-agent MSC2363318A given orally daily in 21-day cycles. Eligible patients must have confirmed diagnosis of advanced malignancy with high prevalence of PI3K/Akt/ PTEN pathway genomic or molecular alterations. The primary objective is to determine maximum tolerated dose, identify dose limiting toxicities (DLTs) and establish a recommended phase 2 dose. Secondary objectives include characterization of pharmacodynamic and pharmacokinetic (PK) properties, and evaluation of predictive biomarkers for safety and efficacy. Observed antitumor activity in the dose escalation part will guide the selection of tumor specific cohorts for the expansion phase. Fifteen patients were treated at 5 dose levels ranging from 15–110 mg/day. To date, 1 DLT (G3 lipase increase) has been observed in 1 of 6 patients treated at the 60mg dose. Nine patients have discontinued treatment due to disease progression (n = 7), death (n = 1), or toxicity (n = 1). Best clinical response to date is stable disease (SD) lasting 6–36+ wks (n = 6). Longest SDs are 36+ wks (adenocystic carcinoma of the salivary gland) and 27 wks (recurrent small cell lung cancer). Updated safety, efficacy and biomarker data, individual examples of on target effects in tumor biopsies from the escalation phase, and preliminary PK data will be presented. [ABSTRACT FROM AUTHOR]
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- 2015
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7. COMPANION-002 A clinical trial of investigational drug CTX-009 plus paclitaxel vs paclitaxel in second line advanced BTC.
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Azad N, Hu Z, Sahin I, Iyer R, Aranha O, Hochster H, Pathak P, Paulson AS, Kalyan A, Liao CY, Tran N, Kelley RK, Heestand G, Cosgrove D, El-Khoueiry A, Borad M, Gabrail NY, Majeed U, Du L, Kamath S, Shumway N, Shroff R, Goyal L, Rosales M, and Javle M
- Abstract
Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone as second-line treatment for patients with advanced biliary tract cancer. The primary end point is ORR, and crossover is allowed. Clinical Trial Registration: NCT05506943 (ClinicalTrials.gov).
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- 2024
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8. Achievement of Target Gain Larger than Unity in an Inertial Fusion Experiment.
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Abu-Shawareb H, Acree R, Adams P, Adams J, Addis B, Aden R, Adrian P, Afeyan BB, Aggleton M, Aghaian L, Aguirre A, Aikens D, Akre J, Albert F, Albrecht M, Albright BJ, Albritton J, Alcala J, Alday C, Alessi DA, Alexander N, Alfonso J, Alfonso N, Alger E, Ali SJ, Ali ZA, Allen A, Alley WE, Amala P, Amendt PA, Amick P, Ammula S, Amorin C, Ampleford DJ, Anderson RW, Anklam T, Antipa N, Appelbe B, Aracne-Ruddle C, Araya E, Archuleta TN, Arend M, Arnold P, Arnold T, Arsenlis A, Asay J, Atherton LJ, Atkinson D, Atkinson R, Auerbach JM, Austin B, Auyang L, Awwal AAS, Aybar N, Ayers J, Ayers S, Ayers T, Azevedo S, Bachmann B, Back CA, Bae J, Bailey DS, Bailey J, Baisden T, Baker KL, Baldis H, Barber D, Barberis M, Barker D, Barnes A, Barnes CW, Barrios MA, Barty C, Bass I, Batha SH, Baxamusa SH, Bazan G, Beagle JK, Beale R, Beck BR, Beck JB, Bedzyk M, Beeler RG, Beeler RG, Behrendt W, Belk L, Bell P, Belyaev M, Benage JF, Bennett G, Benedetti LR, Benedict LX, Berger RL, Bernat T, Bernstein LA, Berry B, Bertolini L, Besenbruch G, Betcher J, Bettenhausen R, Betti R, Bezzerides B, Bhandarkar SD, Bickel R, Biener J, Biesiada T, Bigelow K, Bigelow-Granillo J, Bigman V, Bionta RM, Birge NW, Bitter M, Black AC, Bleile R, Bleuel DL, Bliss E, Bliss E, Blue B, Boehly T, Boehm K, Boley CD, Bonanno R, Bond EJ, Bond T, Bonino MJ, Borden M, Bourgade JL, Bousquet J, Bowers J, Bowers M, Boyd R, Boyle D, Bozek A, Bradley DK, Bradley KS, Bradley PA, Bradley L, Brannon L, Brantley PS, Braun D, Braun T, Brienza-Larsen K, Briggs R, Briggs TM, Britten J, Brooks ED, Browning D, Bruhn MW, Brunner TA, Bruns H, Brunton G, Bryant B, Buczek T, Bude J, Buitano L, Burkhart S, Burmark J, Burnham A, Burr R, Busby LE, Butlin B, Cabeltis R, Cable M, Cabot WH, Cagadas B, Caggiano J, Cahayag R, Caldwell SE, Calkins S, Callahan DA, Calleja-Aguirre J, Camara L, Camp D, Campbell EM, Campbell JH, Carey B, Carey R, Carlisle K, Carlson L, Carman L, Carmichael J, Carpenter A, Carr C, Carrera JA, Casavant D, Casey A, Casey DT, Castillo A, Castillo E, Castor JI, Castro C, Caughey W, Cavitt R, Celeste J, Celliers PM, Cerjan C, Chandler G, Chang B, Chang C, Chang J, Chang L, Chapman R, Chapman TD, Chase L, Chen H, Chen H, Chen K, Chen LY, Cheng B, Chittenden J, Choate C, Chou J, Chrien RE, Chrisp M, Christensen K, Christensen M, Christiansen NS, Christopherson AR, Chung M, Church JA, Clark A, Clark DS, Clark K, Clark R, Claus L, Cline B, Cline JA, Cobble JA, Cochrane K, Cohen B, Cohen S, Collette MR, Collins GW, Collins LA, Collins TJB, Conder A, Conrad B, Conyers M, Cook AW, Cook D, Cook R, Cooley JC, Cooper G, Cope T, Copeland SR, Coppari F, Cortez J, Cox J, Crandall DH, Crane J, Craxton RS, Cray M, Crilly A, Crippen JW, Cross D, Cuneo M, Cuotts G, Czajka CE, Czechowicz D, Daly T, Danforth P, Danly C, Darbee R, Darlington B, Datte P, Dauffy L, Davalos G, Davidovits S, Davis P, Davis J, Dawson S, Day RD, Day TH, Dayton M, Deck C, Decker C, Deeney C, DeFriend KA, Deis G, Delamater ND, Delettrez JA, Demaret R, Demos S, Dempsey SM, Desjardin R, Desjardins T, Desjarlais MP, Dewald EL, DeYoreo J, Diaz S, Dimonte G, Dittrich TR, Divol L, Dixit SN, Dixon J, Do A, Dodd ES, Dolan D, Donovan A, Donovan M, Döppner T, Dorrer C, Dorsano N, Douglas MR, Dow D, Downie J, Downing E, Dozieres M, Draggoo V, Drake D, Drake RP, Drake T, Dreifuerst G, Drury O, DuBois DF, DuBois PF, Dunham G, Durocher M, Dylla-Spears R, Dymoke-Bradshaw AKL, Dzenitis B, Ebbers C, Eckart M, Eddinger S, Eder D, Edgell D, Edwards MJ, Efthimion P, Eggert JH, Ehrlich B, Ehrmann P, Elhadj S, Ellerbee C, Elliott NS, Ellison CL, Elsner F, Emerich M, Engelhorn K, England T, English E, Epperson P, Epstein R, Erbert G, Erickson MA, Erskine DJ, Erlandson A, Espinosa RJ, Estes C, Estabrook KG, Evans S, Fabyan A, Fair J, Fallejo R, Farmer N, Farmer WA, Farrell M, Fatherley VE, Fedorov M, Feigenbaum E, Fehrenbach T, Feit M, Felker B, Ferguson W, Fernandez JC, Fernandez-Panella A, Fess S, Field JE, Filip CV, Fincke JR, Finn T, Finnegan SM, Finucane RG, Fischer M, Fisher A, Fisher J, Fishler B, Fittinghoff D, Fitzsimmons P, Flegel M, Flippo KA, Florio J, Folta J, Folta P, Foreman LR, Forrest C, Forsman A, Fooks J, Foord M, Fortner R, Fournier K, Fratanduono DE, Frazier N, Frazier T, Frederick C, Freeman MS, Frenje J, Frey D, Frieders G, Friedrich S, Froula DH, Fry J, Fuller T, Gaffney J, Gales S, Le Galloudec B, Le Galloudec KK, Gambhir A, Gao L, Garbett WJ, Garcia A, Gates C, Gaut E, Gauthier P, Gavin Z, Gaylord J, Geddes CGR, Geissel M, Génin F, Georgeson J, Geppert-Kleinrath H, Geppert-Kleinrath V, Gharibyan N, Gibson J, Gibson C, Giraldez E, Glebov V, Glendinning SG, Glenn S, Glenzer SH, Goade S, Gobby PL, Goldman SR, Golick B, Gomez M, Goncharov V, Goodin D, Grabowski P, Grafil E, Graham P, Grandy J, Grasz E, Graziani FR, Greenman G, Greenough JA, Greenwood A, Gregori G, Green T, Griego JR, Grim GP, Grondalski J, Gross S, Guckian J, Guler N, Gunney B, Guss G, Haan S, Hackbarth J, Hackel L, Hackel R, Haefner C, Hagmann C, Hahn KD, Hahn S, Haid BJ, Haines BM, Hall BM, Hall C, Hall GN, Hamamoto M, Hamel S, Hamilton CE, Hammel BA, Hammer JH, Hampton G, Hamza A, Handler A, Hansen S, Hanson D, Haque R, Harding D, Harding E, Hares JD, Harris DB, Harte JA, Hartouni EP, Hatarik R, Hatchett S, Hauer AA, Havre M, Hawley R, Hayes J, Hayes J, Hayes S, Hayes-Sterbenz A, Haynam CA, Haynes DA, Headley D, Heal A, Heebner JE, Heerey S, Heestand GM, Heeter R, Hein N, Heinbockel C, Hendricks C, Henesian M, Heninger J, Henrikson J, Henry EA, Herbold EB, Hermann MR, Hermes G, Hernandez JE, Hernandez VJ, Herrmann MC, Herrmann HW, Herrera OD, Hewett D, Hibbard R, Hicks DG, Higginson DP, Hill D, Hill K, Hilsabeck T, Hinkel DE, Ho DD, Ho VK, Hoffer JK, Hoffman NM, Hohenberger M, Hohensee M, Hoke W, Holdener D, Holdener F, Holder JP, Holko B, Holunga D, Holzrichter JF, Honig J, Hoover D, Hopkins D, Berzak Hopkins LF, Hoppe M, Hoppe ML, Horner J, Hornung R, Horsfield CJ, Horvath J, Hotaling D, House R, Howell L, Hsing WW, Hu SX, Huang H, Huckins J, Hui H, Humbird KD, Hund J, Hunt J, Hurricane OA, Hutton M, Huynh KH, Inandan L, Iglesias C, Igumenshchev IV, Ivanovich I, Izumi N, Jackson M, Jackson J, Jacobs SD, James G, Jancaitis K, Jarboe J, Jarrott LC, Jasion D, Jaquez J, Jeet J, Jenei AE, Jensen J, Jimenez J, Jimenez R, Jobe D, Johal Z, Johns HM, Johnson D, Johnson MA, Gatu Johnson M, Johnson RJ, Johnson S, Johnson SA, Johnson T, Jones K, Jones O, Jones M, Jorge R, Jorgenson HJ, Julian M, Jun BI, Jungquist R, Kaae J, Kabadi N, Kaczala D, Kalantar D, Kangas K, Karasiev VV, Karasik M, Karpenko V, Kasarky A, Kasper K, Kauffman R, Kaufman MI, Keane C, Keaty L, Kegelmeyer L, Keiter PA, Kellett PA, Kellogg J, Kelly JH, Kemic S, Kemp AJ, Kemp GE, Kerbel GD, Kershaw D, Kerr SM, Kessler TJ, Key MH, Khan SF, Khater H, Kiikka C, Kilkenny J, Kim Y, Kim YJ, Kimko J, Kimmel M, Kindel JM, King J, Kirkwood RK, Klaus L, Klem D, Kline JL, Klingmann J, Kluth G, Knapp P, Knauer J, Knipping J, Knudson M, Kobs D, Koch J, Kohut T, Kong C, Koning JM, Koning P, Konior S, Kornblum H, Kot LB, Kozioziemski B, Kozlowski M, Kozlowski PM, Krammen J, Krasheninnikova NS, Krauland CM, Kraus B, Krauser W, Kress JD, Kritcher AL, Krieger E, Kroll JJ, Kruer WL, Kruse MKG, Kucheyev S, Kumbera M, Kumpan S, Kunimune J, Kur E, Kustowski B, Kwan TJT, Kyrala GA, Laffite S, Lafon M, LaFortune K, Lagin L, Lahmann B, Lairson B, Landen OL, Land T, Lane M, Laney D, Langdon AB, Langenbrunner J, Langer SH, Langro A, Lanier NE, Lanier TE, Larson D, Lasinski BF, Lassle D, LaTray D, Lau G, Lau N, Laumann C, Laurence A, Laurence TA, Lawson J, Le HP, Leach RR, Leal L, Leatherland A, LeChien K, Lechleiter B, Lee A, Lee M, Lee T, Leeper RJ, Lefebvre E, Leidinger JP, LeMire B, Lemke RW, Lemos NC, Le Pape S, Lerche R, Lerner S, Letts S, Levedahl K, Lewis T, Li CK, Li H, Li J, Liao W, Liao ZM, Liedahl D, Liebman J, Lindford G, Lindman EL, Lindl JD, Loey H, London RA, Long F, Loomis EN, Lopez FE, Lopez H, Losbanos E, 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- Abstract
On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.
- Published
- 2024
- Full Text
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9. Beyond EGFR inhibitors in advanced colorectal cancer: Targeting BRAF and HER2.
- Author
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Dao V and Heestand G
- Subjects
- Animals, Mice, Humans, Proto-Oncogene Proteins B-raf genetics, Mutation, Panitumumab therapeutic use, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology
- Abstract
The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes for rat sarcoma virus (RAS) wild-type advanced colorectal cancer patients, however, durable responses and 5-year overall survival rates remain limited. BRAF V600E somatic mutation and human epidermal growth factor receptor (HER2) amplification/overexpression have been separately implicated in primary resistance to anti-EGFR therapeutic strategies via aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in poorer outcomes. In addition to being a negative predictive biomarker for anti-EGFR therapy, BRAF V600E mutation and HER2 amplification/overexpression serve as positive predictors of response to therapies targeting these respective tumor promoters. This review will highlight key clinical studies that support the rational use of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and HER2-targeted therapies, often in combination with other targeted agents, cytotoxic chemotherapy, and immune checkpoint inhibitors. We discuss current challenges with BRAF and HER2-targeted therapies in metastatic colorectal cancer and potential opportunities for improvement., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GMH: Stock ownership/employment—Roche/Genentech. Consulting—Eisai, Elevation Oncology, Exelixis, (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
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10. Lawson Criterion for Ignition Exceeded in an Inertial Fusion Experiment.
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A, Work K, Workman JB, Wright J, Wu M, Wuest C, Wysocki FJ, Xu H, Yamaguchi M, Yang B, Yang ST, Yatabe J, Yeamans CB, Yee BC, Yi SA, Yin L, Young B, Young CS, Young CV, Young P, Youngblood K, Zacharias R, Zagaris G, Zaitseva N, Zaka F, Ze F, Zeiger B, Zika M, Zimmerman GB, Zobrist T, Zuegel JD, and Zylstra AB
- Abstract
For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.
- Published
- 2022
- Full Text
- View/download PDF
11. Next-Generation Sequencing of Circulating Tumor DNA Reveals Frequent Alterations in Advanced Hepatocellular Carcinoma.
- Author
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Ikeda S, Tsigelny IF, Skjevik ÅA, Kono Y, Mendler M, Kuo A, Sicklick JK, Heestand G, Banks KC, Talasaz A, Lanman RB, Lippman S, and Kurzrock R
- Subjects
- Adult, Aged, Carcinoma, Hepatocellular pathology, Female, Humans, Male, Middle Aged, Prospective Studies, Biomarkers, Tumor genetics, Carcinoma, Hepatocellular genetics, Circulating Tumor DNA genetics, High-Throughput Nucleotide Sequencing methods
- Abstract
Background: Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood-derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC., Materials and Methods: We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild-type allele fraction was calculated., Results: All patients (100%) had somatic alterations (median = 3 alterations/patient [range, 1-8]); median mutant allele fraction, 0.29% (range, 0.1%-37.77%). Mutations were identified in several genes: TP53 (57% of patients), CTNNB1 (29%), PTEN (7%), CDKN2A (7%), ARID1A (7%), and MET (7%); amplifications, in CDK6 (14%), EGFR (14%), MYC (14%), BRAF (7%), RAF1 (7%), FGFR1 (7%), CCNE1 (7%), PIK3CA (7%), and ERBB2/HER2 (7%). Eleven patients (79%) had ≥1 theoretically actionable alteration. No two patients had identical genomic portfolios, suggesting the need for customized treatment. A patient with a CDKN2A -inactivating and a CTNNB1 -activating mutation received matched treatment: palbociclib (CDK4/6 inhibitor) and celecoxib (COX-2/Wnt inhibitor); des-gamma-carboxy prothrombin level decreased by 84% at 2 months (1,410 to 242 ng/mL [normal: ≤7.4 ng/mL]; alpha fetoprotein [AFP] low at baseline). A patient with a PTEN -inactivating and a MET -activating mutation (an effect suggested by in silico molecular dynamic simulations) received sirolimus (mechanistic target of rapamycin inhibitor) and cabozantinib (MET inhibitor); AFP declined by 63% (8,320 to 3,045 ng/mL [normal: 0-15 ng/mL])., Conclusion: ctDNA derived from noninvasive blood tests can provide exploitable genomic profiles in patients with HCC., Implications for Practice: This study reports that blood-derived circulating tumor DNA can provide therapeutically exploitable genomic profiles in hepatocellular cancer, a malignancy that is known to be difficult to biopsy., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)
- Published
- 2018
- Full Text
- View/download PDF
12. A Novel Biomarker Panel Examining Response to Gemcitabine with or without Erlotinib for Pancreatic Cancer Therapy in NCIC Clinical Trials Group PA.3.
- Author
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Shultz DB, Pai J, Chiu W, Ng K, Hellendag MG, Heestand G, Chang DT, Tu D, Moore MJ, Parulekar WR, and Koong AC
- Subjects
- Antineoplastic Agents administration & dosage, Deoxycytidine administration & dosage, Deoxycytidine therapeutic use, Double-Blind Method, Erlotinib Hydrochloride administration & dosage, Humans, Placebos, Gemcitabine, Antineoplastic Agents therapeutic use, Biomarkers, Tumor blood, Deoxycytidine analogs & derivatives, Erlotinib Hydrochloride therapeutic use, Pancreatic Neoplasms drug therapy
- Abstract
Purpose: NCIC Clinical Trials Group PA.3 was a randomized control trial that demonstrated improved overall survival (OS) in patients receiving erlotinib in addition to gemcitabine for locally advanced or metastatic pancreatic cancer. Prior to therapy, patients had plasma samples drawn for future study. We sought to identify biomarkers within these samples., Experimental Design: Using the proximity ligation assay (PLA), a probe panel was built from commercially available antibodies for 35 key proteins selected from a global genetic analysis of pancreatic cancers, and used to quantify protein levels in 20 uL of patient plasma. To determine if any of these proteins levels independently associated with OS, univariate and mulitbaraible Cox models were used. In addition, we examined the associations between biomarker expression and disease stage at diagnosis using Fisher's exact test. The correlation between Erlotinib sensitivity and each biomarkers was assessed using a test of interaction between treatment and biomarker., Results and Conclusion: Of the 569 eligible patients, 480 had samples available for study. Samples were randomly allocated into training (251) and validation sets (229). Among all patients, elevated levels of interleukin-8 (IL-8), carcinoembryonic antigen (CEA), hypoxia-inducible factor 1-alpha (HIF-1 alpha), and interleukin-6 were independently associated with lower OS, while IL-8, CEA, platelet-derived growth factor receptor alpha and mucin-1 were associated with metastatic disease. Patients with elevated levels of receptor tyrosine-protein kinase erbB-2 (HER2) expression had improved OS when treated with erlotinib compared to placebo. In conclusion, PLA is a powerful tool for identifying biomarkers from archived, small volume serum samples. These data may be useful to stratify patient outcomes regardless of therapeutic intervention., Trial Registration: ClinicalTrials.gov NCT00040183.
- Published
- 2016
- Full Text
- View/download PDF
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