Electron Kebebew, MD, FACS

All Publications

• NOP53 as A Candidate Modifier Locus for Familial Non-Medullary Thyroid Cancer. Genes Orois, A., Gara, S. K., Mora, M., Halperin, I., Martinez, S., Alfayate, R., Kebebew, E., Oriola, J. 2019; 10 (11)

  Abstract

  Nonsyndromic familial non-medullary thyroid cancer (FNMTC) represents 3-9% of thyroid cancers, but the susceptibility gene(s) remain unknown. We designed this multicenter study to analyze families with nonsyndromic FNMTC and identify candidate susceptibility genes. We performed exome sequencing of DNA from four affected individuals from one kindred, with five cases of nonsyndromic FNMTC. Single Nucleotide Variants, and insertions and deletions that segregated with all the affected members, were analyzed by Sanger sequencing in 44 additional families with FNMTC (37 with two affected members, and seven with three or more affected members), as well as in an independent control group of 100 subjects. We identified the germline variant p. Asp31His in NOP53 gene (rs78530808, MAF 1.8%) present in all affected members in three families with nonsyndromic FNMTC, and not present in unaffected spouses. Our functional studies of NOP53 in thyroid cancer cell lines showed an oncogenic function. Immunohistochemistry exhibited increased NOP53 protein expression in tumor samples from affected family members, compared with normal adjacent thyroid tissue. Given the relatively high frequency of the variant in the general population, these findings suggest that instead of a causative gene, NOP53 is likely a low-penetrant gene implicated in FNMTC, possibly a modifier.

  View details for DOI 10.3390/genes10110899

  View details for PubMedID 31703244

• Resection of the Primary Tumor in Patients with Distant Thyroid Cancer Metastasis Is Associated with Longer Survival Sedaghati, M., Lin, D. T., Cisco, R. M., Kebebew, E. ELSEVIER SCIENCE INC. 2019: S82

  View details for Web of Science ID 000492740900141

• Pediatric vs Adult Adrenocortical Carcinoma: Different Rate of Surgical Treatment and Patient Outcome Sedaghati, M., Lin, D. T., Cisco, R. M., Kebebew, E. ELSEVIER SCIENCE INC. 2019: S81?S82

  View details for Web of Science ID 000492740900139

• Limited Utility of Circulating Cell-Free DNA Integrity as a Diagnostic Tool for Differentiating Between Malignant and Benign Thyroid Nodules With Indeterminate Cytology (Bethesda Category III) FRONTIERS IN ONCOLOGY Thakur, S., Tobey, A., Daley, B., Auh, S., Walter, M., Patel, D., Nilubol, N., Kebebew, E., Patel, A., Jensen, K., Vasko, V., Klubo-Gwiezdzinska, J. 2019; 9

  View details for DOI 10.3389/fonc.2019.00905

  View details for Web of Science ID 000486522500001

• Surgical Resection of Pheochromocytomas and Paragangliomas is Associated with Lower Cholesterol Levels. World journal of surgery Good, M. L., Malekzadeh, P., Ruff, S. M., Gupta, S., Copeland, A., Pacak, K., Nilubol, N., Kebebew, E., Patel, D. 2019

  Abstract

  BACKGROUND: Catecholamine excess in patients with pheochromocytomas or paragangliomas (PPGLs) can lead to hypertension, diabetes and hyperlipidemia. The aim was to investigate the prevalence of hyperlipidemia and the effect of surgical resection.METHODS: One hundred and thirty-two patients with PPGLs underwent an operation at the National Institutes of Health from 2009 to 2016, of which 54 patients met the inclusion criteria. Clinical demographics, BMI, genetic mutations, tumor size, perioperative catecholamine levels and perioperative lipid panels were retrospectively reviewed. Spearman correlation between catecholamines and lipid levels was evaluated. Paired Wilcoxon and paired t test were used to analyze differences in pre- and postoperative lipid levels.RESULTS: Preoperatively, 51 patients (94.4%) had elevated catecholamines, thirteen (24.1%) had elevated total cholesterol (TC) (>200mg/dL), nine (16.6%) had elevated LDL (>130mg/dL) and ten (18.5%) had elevated triglycerides (>150mg/dL). Serum and urinary metanephrine levels were positively associated with TC (r=0.2792, p=0.0372 and r=0.4146, p=0.0031, respectively) and LDL levels (r=0.2977, p=0.0259 and r=0.4434, p=0.0014, respectively). Mean TC decreased from 176.4 to 166.3mg/dL (p=0.0064) and mean HDL decreased from 56.7 to 53.2mg/dL (p=0.0253) after PPGL resection (median 3.1months (range 1.3-50.2) between lipid panels). Most patients with elevated TC (76.9%) had improvement with mean TC decreasing from 225 to 200.2mg/dL (p=0.0230). Of patients with elevated LDL, 66.7% had improvement with mean LDL decreasing from 149 to 131.1mg/dL (p=0.0313).CONCLUSIONS: The prevalence of hyperlipidemia in patients with PPGLs is 46%. Future prospective studies are needed to determine whether surgical resection improves TC and/or LDL levels.

  View details for DOI 10.1007/s00268-019-05175-9

  View details for PubMedID 31531722

• The Immune Landscape of Cancer. Immunity Thorsson, V., Gibbs, D. L., Brown, S. D., Wolf, D., Bortone, D. S., Ou Yang, T., Porta-Pardo, E., Gao, G. F., Plaisier, C. L., Eddy, J. A., Ziv, E., Culhane, A. C., Paull, E. O., Sivakumar, I. K., Gentles, A. J., Malhotra, R., Farshidfar, F., Colaprico, A., Parker, J. S., Mose, L. E., Vo, N. S., Liu, J., Liu, Y., Rader, J., Dhankani, V., Reynolds, S. M., Bowlby, R., Califano, A., Cherniack, A. D., Anastassiou, D., Bedognetti, D., Mokrab, Y., Newman, A. M., Rao, A., Chen, K., Krasnitz, A., Hu, H., Malta, T. M., Noushmehr, H., Pedamallu, C. S., Bullman, S., Ojesina, A. I., Lamb, A., Zhou, W., Shen, H., Choueiri, T. K., Weinstein, J. N., Guinney, J., Saltz, J., Holt, R. A., Rabkin, C. S., Cancer Genome Atlas Research Network, Lazar, A. J., Serody, J. S., Demicco, E. G., Disis, M. L., Vincent, B. G., Shmulevich, I., Caesar-Johnson, S. J., Demchok, J. A., Felau, I., Kasapi, M., Ferguson, M. L., Hutter, C. M., Sofia, H. J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J. C., Zhang, J. J., Chudamani, S., Liu, J., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Cho, J., DeFreitas, T., Frazer, S., Gehlenborg, N., Getz, G., Heiman, D. I., Kim, J., Lawrence, M. S., Lin, P., Meier, S., Noble, M. S., Saksena, G., Voet, D., Zhang, H., Bernard, B., Chambwe, N., Dhankani, V., Knijnenburg, T., Kramer, R., Leinonen, K., Liu, Y., Miller, M., Reynolds, S., Shmulevich, I., Thorsson, V., Zhang, W., Akbani, R., Broom, B. M., Hegde, A. M., Ju, Z., Kanchi, R. S., Korkut, A., Li, J., Liang, H., Ling, S., Liu, W., Lu, Y., Mills, G. B., Ng, K., Rao, A., Ryan, M., Wang, J., Weinstein, J. N., Zhang, J., Abeshouse, A., Armenia, J., Chakravarty, D., Chatila, W. K., de Bruijn, I., Gao, J., Gross, B. E., Heins, Z. J., Kundra, R., La, K., Ladanyi, M., Luna, A., Nissan, M. G., Ochoa, A., Phillips, S. M., Reznik, E., Sanchez-Vega, F., Sander, C., Schultz, N., Sheridan, R., Sumer, S. O., Sun, Y., Taylor, B. S., Wang, J., Zhang, H., Anur, P., Peto, M., Spellman, P., Benz, C., Stuart, J. M., Wong, C. K., Yau, C., Hayes, D. N., Parker, J. S., Wilkerson, M. D., Ally, A., Balasundaram, M., Bowlby, R., Brooks, D., Carlsen, R., Chuah, E., Dhalla, N., Holt, R., Jones, S. J., Kasaian, K., Lee, D., Ma, Y., Marra, M. A., Mayo, M., Moore, R. A., Mungall, A. J., Mungall, K., Robertson, A. G., Sadeghi, S., Schein, J. E., Sipahimalani, P., Tam, A., Thiessen, N., Tse, K., Wong, T., Berger, A. C., Beroukhim, R., Cherniack, A. D., Cibulskis, C., Gabriel, S. B., Gao, G. F., Ha, G., Meyerson, M., Schumacher, S. E., Shih, J., Kucherlapati, M. H., Kucherlapati, R. S., Baylin, S., Cope, L., Danilova, L., Bootwalla, M. S., Lai, P. H., Maglinte, D. T., Van Den Berg, D. J., Weisenberger, D. J., Auman, J. T., Balu, S., Bodenheimer, T., Fan, C., Hoadley, K. A., Hoyle, A. P., Jefferys, S. R., Jones, C. D., Meng, S., Mieczkowski, P. A., Mose, L. E., Perou, A. H., Perou, C. M., Roach, J., Shi, Y., Simons, J. V., Skelly, T., Soloway, M. G., Tan, D., Veluvolu, U., Fan, H., Hinoue, T., Laird, P. W., Shen, H., Zhou, W., Bellair, M., Chang, K., Covington, K., Creighton, C. J., Dinh, H., Doddapaneni, H., Donehower, L. A., Drummond, J., Gibbs, R. A., Glenn, R., Hale, W., Han, Y., Hu, J., Korchina, V., Lee, S., Lewis, L., Li, W., Liu, X., Morgan, M., Morton, D., Muzny, D., Santibanez, J., Sheth, M., Shinbrot, E., Wang, L., Wang, M., Wheeler, D. A., Xi, L., Zhao, F., Hess, J., Appelbaum, E. L., Bailey, M., Cordes, M. G., Ding, L., Fronick, C. C., Fulton, L. A., Fulton, R. S., Kandoth, C., Mardis, E. R., McLellan, M. D., Miller, C. A., Schmidt, H. K., Wilson, R. K., Crain, D., Curley, E., Gardner, J., Lau, K., Mallery, D., Morris, S., Paulauskis, J., Penny, R., Shelton, C., Shelton, T., Sherman, M., Thompson, E., Yena, P., Bowen, J., Gastier-Foster, J. M., Gerken, M., Leraas, K. M., Lichtenberg, T. M., Ramirez, N. C., Wise, L., Zmuda, E., Corcoran, N., Costello, T., Hovens, C., Carvalho, A. L., de Carvalho, A. C., Fregnani, J. H., Longatto-Filho, A., Reis, R. M., Scapulatempo-Neto, C., Silveira, H. C., Vidal, D. O., Burnette, A., Eschbacher, J., Hermes, B., Noss, A., Singh, R., Anderson, M. L., Castro, P. D., Ittmann, M., Huntsman, D., Kohl, B., Le, X., Thorp, R., Andry, C., Duffy, E. R., Lyadov, V., Paklina, O., Setdikova, G., Shabunin, A., Tavobilov, M., McPherson, C., Warnick, R., Berkowitz, R., Cramer, D., Feltmate, C., Horowitz, N., Kibel, A., Muto, M., Raut, C. P., Malykh, A., Barnholtz-Sloan, J. S., Barrett, W., Devine, K., Fulop, J., Ostrom, Q. T., Shimmel, K., Wolinsky, Y., Sloan, A. E., De Rose, A., Giuliante, F., Goodman, M., Karlan, B. Y., Hagedorn, C. H., Eckman, J., Harr, J., Myers, J., Tucker, K., Zach, L. A., Deyarmin, B., Hu, H., Kvecher, L., Larson, C., Mural, R. J., Somiari, S., Vicha, A., Zelinka, T., Bennett, J., Iacocca, M., Rabeno, B., Swanson, P., Latour, M., Lacombe, L., Tetu, B., Bergeron, A., McGraw, M., Staugaitis, S. M., Chabot, J., Hibshoosh, H., Sepulveda, A., Su, T., Wang, T., Potapova, O., Voronina, O., Desjardins, L., Mariani, O., Roman-Roman, S., Sastre, X., Stern, M., Cheng, F., Signoretti, S., Berchuck, A., Bigner, D., Lipp, E., Marks, J., McCall, S., McLendon, R., Secord, A., Sharp, A., Behera, M., Brat, D. J., Chen, A., Delman, K., Force, S., Khuri, F., Magliocca, K., Maithel, S., Olson, J. J., Owonikoko, T., Pickens, A., Ramalingam, S., Shin, D. M., Sica, G., Van Meir, E. G., Zhang, H., Eijckenboom, W., Gillis, A., Korpershoek, E., Looijenga, L., Oosterhuis, W., Stoop, H., van Kessel, K. E., Zwarthoff, E. C., Calatozzolo, C., Cuppini, L., Cuzzubbo, S., DiMeco, F., Finocchiaro, G., Mattei, L., Perin, A., Pollo, B., Chen, C., Houck, J., Lohavanichbutr, P., Hartmann, A., Stoehr, C., Stoehr, R., Taubert, H., Wach, S., Wullich, B., Kycler, W., Murawa, D., Wiznerowicz, M., Chung, K., Edenfield, W. J., Martin, J., Baudin, E., Bubley, G., Bueno, R., De Rienzo, A., Richards, W. G., Kalkanis, S., Mikkelsen, T., Noushmehr, H., Scarpace, L., Girard, N., Aymerich, M., Campo, E., Gine, E., Guillermo, A. L., Van Bang, N., Hanh, P. T., Phu, B. D., Tang, Y., Colman, H., Evason, K., Dottino, P. R., Martignetti, J. A., Gabra, H., Juhl, H., Akeredolu, T., Stepa, S., Hoon, D., Ahn, K., Kang, K. J., Beuschlein, F., Breggia, A., Birrer, M., Bell, D., Borad, M., Bryce, A. H., Castle, E., Chandan, V., Cheville, J., Copland, J. A., Farnell, M., Flotte, T., Giama, N., Ho, T., Kendrick, M., Kocher, J., Kopp, K., Moser, C., Nagorney, D., O'Brien, D., O'Neill, B. P., Patel, T., Petersen, G., Que, F., Rivera, M., Roberts, L., Smallridge, R., Smyrk, T., Stanton, M., Thompson, R. H., Torbenson, M., Yang, J. D., Zhang, L., Brimo, F., Ajani, J. A., Gonzalez, A. M., Behrens, C., Bondaruk, J., Broaddus, R., Czerniak, B., Esmaeli, B., Fujimoto, J., Gershenwald, J., Guo, C., Lazar, A. J., Logothetis, C., Meric-Bernstam, F., Moran, C., Ramondetta, L., Rice, D., Sood, A., Tamboli, P., Thompson, T., Troncoso, P., Tsao, A., Wistuba, I., Carter, C., Haydu, L., Hersey, P., Jakrot, V., Kakavand, H., Kefford, R., Lee, K., Long, G., Mann, G., Quinn, M., Saw, R., Scolyer, R., Shannon, K., Spillane, A., Stretch, O., Synott, M., Thompson, J., Wilmott, J., Al-Ahmadie, H., Chan, T. A., Ghossein, R., Gopalan, A., Levine, D. A., Reuter, V., Singer, S., Singh, B., Tien, N. V., Broudy, T., Mirsaidi, C., Nair, P., Drwiega, P., Miller, J., Smith, J., Zaren, H., Park, J., Hung, N. P., Kebebew, E., Linehan, W. M., Metwalli, A. R., Pacak, K., Pinto, P. A., Schiffman, M., Schmidt, L. S., Vocke, C. D., Wentzensen, N., Worrell, R., Yang, H., Moncrieff, M., Goparaju, C., Melamed, J., Pass, H., Botnariuc, N., Caraman, I., Cernat, M., Chemencedji, I., Clipca, A., Doruc, S., Gorincioi, G., Mura, S., Pirtac, M., Stancul, I., Tcaciuc, D., Albert, M., Alexopoulou, I., Arnaout, A., Bartlett, J., Engel, J., Gilbert, S., Parfitt, J., Sekhon, H., Thomas, G., Rassl, D. M., Rintoul, R. C., Bifulco, C., Tamakawa, R., Urba, W., Hayward, N., Timmers, H., Antenucci, A., Facciolo, F., Grazi, G., Marino, M., Merola, R., de Krijger, R., Gimenez-Roqueplo, A., Piche, A., Chevalier, S., McKercher, G., Birsoy, K., Barnett, G., Brewer, C., Farver, C., Naska, T., Pennell, N. A., Raymond, D., Schilero, C., Smolenski, K., Williams, F., Morrison, C., Borgia, J. A., Liptay, M. J., Pool, M., Seder, C. W., Junker, K., Omberg, L., Dinkin, M., Manikhas, G., Alvaro, D., Bragazzi, M. C., Cardinale, V., Carpino, G., Gaudio, E., Chesla, D., Cottingham, S., Dubina, M., Moiseenko, F., Dhanasekaran, R., Becker, K., Janssen, K., Slotta-Huspenina, J., Abdel-Rahman, M. H., Aziz, D., Bell, S., Cebulla, C. M., Davis, A., Duell, R., Elder, J. B., Hilty, J., Kumar, B., Lang, J., Lehman, N. L., Mandt, R., Nguyen, P., Pilarski, R., Rai, K., Schoenfield, L., Senecal, K., Wakely, P., Hansen, P., Lechan, R., Powers, J., Tischler, A., Grizzle, W. E., Sexton, K. C., Kastl, A., Henderson, J., Porten, S., Waldmann, J., Fassnacht, M., Asa, S. L., Schadendorf, D., Couce, M., Graefen, M., Huland, H., Sauter, G., Schlomm, T., Simon, R., Tennstedt, P., Olabode, O., Nelson, M., Bathe, O., Carroll, P. R., Chan, J. M., Disaia, P., Glenn, P., Kelley, R. K., Landen, C. N., Phillips, J., Prados, M., Simko, J., Smith-McCune, K., VandenBerg, S., Roggin, K., Fehrenbach, A., Kendler, A., Sifri, S., Steele, R., Jimeno, A., Carey, F., Forgie, I., Mannelli, M., Carney, M., Hernandez, B., Campos, B., Herold-Mende, C., Jungk, C., Unterberg, A., von Deimling, A., Bossler, A., Galbraith, J., Jacobus, L., Knudson, M., Knutson, T., Ma, D., Milhem, M., Sigmund, R., Godwin, A. K., Madan, R., Rosenthal, H. G., Adebamowo, C., Adebamowo, S. N., Boussioutas, A., Beer, D., Giordano, T., Mes-Masson, A., Saad, F., Bocklage, T., Landrum, L., Mannel, R., Moore, K., Moxley, K., Postier, R., Walker, J., Zuna, R., Feldman, M., Valdivieso, F., Dhir, R., Luketich, J., Pinero, E. M., Quintero-Aguilo, M., Carlotti, C. G., Dos Santos, J. S., Kemp, R., Sankarankuty, A., Tirapelli, D., Catto, J., Agnew, K., Swisher, E., Creaney, J., Robinson, B., Shelley, C. S., Godwin, E. M., Kendall, S., Shipman, C., Bradford, C., Carey, T., Haddad, A., Moyer, J., Peterson, L., Prince, M., Rozek, L., Wolf, G., Bowman, R., Fong, K. M., Yang, I., Korst, R., Rathmell, W. K., Fantacone-Campbell, J. L., Hooke, J. A., Kovatich, A. J., Shriver, C. D., DiPersio, J., Drake, B., Govindan, R., Heath, S., Ley, T., Van Tine, B., Westervelt, P., Rubin, M. A., Lee, J. I., Aredes, N. D., Mariamidze, A. 2019; 51 (2): 411?12

  View details for DOI 10.1016/j.immuni.2019.08.004

  View details for PubMedID 31433971

• Long noncoding RNAs in thyroid cancer. Current opinion in endocrinology, diabetes, and obesity Sedaghati, M., Kebebew, E. 2019

  Abstract

  PURPOSE OF REVIEW: Our understanding of the molecular pathology events involved in thyroid cancer initiation and progression and its subtypes has markedly improved as a result of multiomic studies. Recently, long noncoding RNA (lncRNA) have been shown to have a role in cancer initiation and progression and have also been studied in thyroid cancer.RECENT FINDINGS: lncRNA are dysregulated in thyroid cancer. lncRNA have tumor suppressive and oncogenic function in thyroid cancer cells and play a role in some of the established genetic drivers of thyroid cancer initiation and progression. Lastly, some lncRNA are associated with clinicopathologic features of thyroid cancer and circulating blood lncRNA could potentially detect the presence of thyroid cancer.SUMMARY: We highlight the possible clinical utility of analyzing lncRNAs as biomarkers for thyroid cancer diagnosis and prognosis and their association with common genetic changes associated with thyroid cancer.

  View details for DOI 10.1097/MED.0000000000000497

  View details for PubMedID 31385810

• National Treatment Practice for Adrenocortical Carcinoma: Have they changed and have we made any progress? The Journal of clinical endocrinology and metabolism Tierney, J. F., Chivukula, S. V., Poirier, J., Pappas, S. G., Schadde, E., Hertl, M., Kebebew, E., Keutgen, X. 2019

  Abstract

  MINI-ABSTRACT: The NCDB was used to examine treatment patterns and survival in patients with adrenocortical carcinoma from 2006-2015. Adjuvant chemotherapy has been used more frequent for patients with resectable ACC since 2007. Survival for patients who undergo surgery with adjuvant chemotherapy has improved but remains low.Accepted for podium presentation at the 2018 Clinical Congress of the American College of Surgeons, Boston, Massachusetts, October 2018.BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials, published in 2007 and 2012, showed efficacy for adjuvant mitotane in resectable ACC and Etoposide/Doxorubicin/Cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials.METHODS: Patients diagnosed with ACC from 2006-2015 were identified. Treatment modalities were compared within that group, and with a historical cohort (1985-2005). Chi-square tests were performed and Cox proportional hazards models were created.RESULTS: 2752 patients from 2006-2015 were included. 38% of patients (1042) underwent surgery alone and 31% (859) underwent surgery with adjuvant therapy. Overall five-year survival for all stages after resection was 43% (median 41 months) in the contemporary cohort and 39% (median 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy (p = 0.005), and five-year survival with adjuvant chemotherapy improved (41% vs 25%, p = 0.02). Survival did not improve, however, in patients with unresectable tumors after 2011, compared to 2006-2011 (p = 0.79). Older age, tumor size ? 10cm, distant metastases, and positive margins were associated with lower survival after resection (HR range: 1.39-3.09, p < 0.03).CONCLUSIONS: Adjuvant therapy has been used more frequently in patients with resected ACC since 2007, and survival for those patients has improved, but remains low. More effective systemic therapies for patients with ACC and especially those with advanced stages are desperately needed.

  View details for DOI 10.1210/jc.2019-00915

  View details for PubMedID 31361313

• Solutions to Reduce Unnecessary Imaging-Reply. JAMA Oren, O., Kebebew, E., Ioannidis, J. P. 2019; 321 (22): 2243

  View details for DOI 10.1001/jama.2019.4021

  View details for PubMedID 31184737

• ONCOGENE PANEL SEQUENCING ANALYSIS IDENTIFIES CANDIDATE ACTIONABLE GENES IN ADVANCED WELL-DIFFERENTIATED GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS ENDOCRINE PRACTICE Tirosh, A., Killian, J., Zhu, Y., Petersen, D., Walling, J., Mor-Cohen, R., Neychev, V., Stevenson, H., Keutgen, X. M., Patel, D., Nilubol, N., Meltzer, P., Kebebew, E. 2019; 25 (6): 580?88

  View details for DOI 10.4158/EP-2018-0603

  View details for Web of Science ID 000472941800008

• Reply: Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment SURGERY el Lakis, M., Kebebew, E. 2019; 165 (6): 1246?47

  View details for DOI 10.1016/j.surg.2019.02.003

  View details for Web of Science ID 000472984500032

• Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors CANCER Tirosh, A., Mukherjee, S., Lack, J., Gara, S., Wang, S., Quezado, M. M., Keutgen, X. M., Wu, X., Cam, M., Kumar, S., Patel, D., Nilubol, N., Tyagi, M., Kebebew, E. 2019; 125 (8): 1247?57

  View details for DOI 10.1002/cncr.31930

  View details for Web of Science ID 000462932300007

• Reply: Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment. Surgery Lakis, M. E., Kebebew, E. 2019

  View details for PubMedID 30910232

• ONCOGENE PANEL SEQUENCING ANALYSIS IDENTIFIES CANDIDATE ACTIONABLE GENES IN ADVANCED WELL-DIFFERENTIATED GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists Tirosh, A., Killian, J. K., Zhu, Y. J., Petersen, D., Walling, J., Mor-Cohen, R., Neychev, V., Stevenson, H., Keutgen, X. M., Patel, D., Nilubol, N., Meltzer, P., Kebebew, E. 2019

  Abstract

  Purpose to report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET) and of other genetic alterations that may be associated with tumorigenesis Methods A phase II mutation targeted therapy trial was conducted in patients with advanced well differentiated G1/G2 GEP-NETs. Mutations found in mTOR pathway associated genes, led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor DNA from GEP-NETs were sequenced and compared with germline DNA, using the OncoVar-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called, and copy-number (CN) variant analysis was performed. Results Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NETs and 5 of other primary sites), harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n=26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chr 18 (p<0.05), and CN gain of chr 5, and loss of chr 13. CN losses in chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesion sequenced. Conclusions Wide DNA sequencing may identify candidate actionable genes, and lead to the identification of novel target genes for advanced well-differentiated GEP-NETs.

  View details for PubMedID 30865533

• Association of Thyrotropin Suppression With Survival Outcomes in Patients With Intermediate- and High-Risk Differentiated Thyroid Cancer. JAMA network open Klubo-Gwiezdzinska, J., Auh, S., Gershengorn, M., Daley, B., Bikas, A., Burman, K., Wartofsky, L., Urken, M., Dewey, E., Smallridge, R., Chindris, A., Kebebew, E. 2019; 2 (2): e187754

  Abstract

  Importance: Suppression of thyrotropin (often referred to as thyroid-stimulating hormone, or TSH) with levothyroxine used in management of intermediate- and high-risk differentiated thyroid cancer (DTC) to reduce the likelihood of progression and death is based on conflicting evidence.Objective: To examine a cohort of patients with intermediate- and high-risk DTC to assess the association of thyrotropin suppression with progression-free survival (PFS) and overall survival.Design, Setting, and Participants: This cohort study used a multicenter database analysis including patients from tertiary referral centers and local clinics followed up for a mean (SD) of 7.2 (5.8) years. Patients with DTC treated uniformly with total thyroidectomy and radioactive iodine between January 1, 1979, and March 1, 2015, were included. Among the 1012 patients, 145 patients were excluded due to the lack of longitudinal thyrotropin measurements.Exposures: Levothyroxine therapy to target thyrotropin suppression with dose adjustments based on changing thyrotropin goal.Main Outcomes and Measures: The primary outcome measures were overall survival and PFS. A Cox proportional hazards model was used to assess the contribution of age, sex, tumor size, histology, and lymph node and distant metastases at landmarks 1.5, 3.0, and 5.0 years. The patients were divided into 3 groups based on mean thyrotropin score before each landmark: (1) suppressed thyrotropin, (2) moderately suppressed or low-normal thyrotropin, and (3) low-normal or elevated thyrotropin.Results: Among 867 patients (557 [64.2%] female; mean [SD] age, 48.5 [16.5] years) treated with a median (range) cumulative dose of 151 (30-1600) mCi radioactive iodine, disease progression was observed in 293 patients (33.8%), and 34 patients (3.9%) died; thus, the study was underpowered in death events. Thyrotropin suppression was not associated with improved PFS at landmarks 1.5 (P=.41), 3.0 (P=.51), and 5.0 (P=.64) years. At 1.5 and 3.0 years, older age (hazard ratio [HR], 1.06; 95% CI, 1.03-1.08 and HR, 1.05; 95% CI, 1.01-1.08, respectively), lateral neck lymph node metastases (HR, 4.64; 95% CI, 2.00-10.70 and HR, 4.02; 95% CI, 1.56-10.40, respectively), and distant metastases (HR, 7.54; 95% CI, 3.46-16.50 and HR, 7.10; 95% CI, 2.77-18.20, respectively) were independently associated with subsequent time to progression, while at 5.0 years, PFS was shorter for patients with lateral neck lymph node metastases (HR, 3.70; 95% CI, 1.16-11.90) and poorly differentiated histology (HR, 71.80; 95% CI, 9.80-526.00).Conclusions and Relevance: Patients with intermediate- and high-risk DTC might not benefit from thyrotropin suppression. This study provides the justification for a randomized trial.

  View details for PubMedID 30707227

• Association of Thyrotropin Suppression With Survival Outcomes in Patients With Intermediate- and High-Risk Differentiated Thyroid Cancer JAMA NETWORK OPEN Klubo-Gwiezdzinska, J., Auh, S., Gershengorn, M., Daley, B., Bikas, A., Burman, K., Wartofsky, L., Urken, M., Dewey, E., Smallridge, R., Chindris, A., Kebebew, E. 2019; 2 (2)

  View details for DOI 10.1001/jamanetworkopen.2018.7754

  View details for Web of Science ID 000465423800032

• Risk Haplotypes Uniquely Associated with Radioiodine Refractory Thyroid Cancer Patients of High African Ancestry. Thyroid : official journal of the American Thyroid Association Hurst, Z., Liyanarachchi, S., He, H., Brock, P., Sipos, J. A., Nabhan, F., Kebebew, E., Green, P., Cote, G. J., Sherman, S. I., Walker, C. J., Chang, Y. S., Xue, S., Hollingsworth, B., Li, W., Genutis, L., Menq, E., de la Chapelle, A., Jhiang, S. M. 2019

  Abstract

  BACKGROUND: Thyroid cancer patients with radioiodine refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. We hypothesize that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment and/or immune surveillance are associated with RAI-R disease.METHODS: Whole-genome genotyping data analysis was performed on 1,145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, 9 of whom were RAI-R. Germline variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (N=7), who were later determined to be AA patients of >80% African ancestry (N=37). This prompted us to focus on germline SNPs uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of common somatic mutations BRAFV600E, NRASQ61R, and HRASQ61R, in AA patients whose primary tumor samples were available (N=28/55).RESULTS: We identified TG, BRCA1 and NSMCE2 haplotypes uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (N=4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (N=4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in 3/4 patients with the NSMCE2 haplotype. The incidence of BRAFV600E appears lower in papillary thyroid carcinoma (PTC) from AA patients of >80% African ancestry (N=3/14, 21%) than in AA patients of <80% African ancestry (N=6/9, 67%), albeit only approaching statistical significance (p=0.077). The tumors available from three RAI-R AA patients were negative for BRAFV600E, NRASQ61R, HRASQ61R.CONCLUSIONS: The identification of candidate RAI-R risk haplotypes may allow early stratification of clinical manifestations of RAI-R disease followed by early intervention and personalized treatment strategies. Functional annotation of candidate RAI-R risk haplotypes may provide insight into the mechanisms underlying RAI-R disease.

  View details for PubMedID 30654714

• Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors. Cancer Tirosh, A., Mukherjee, S., Lack, J., Gara, S. K., Wang, S., Quezado, M. M., Keutgen, X. M., Wu, X., Cam, M., Kumar, S., Patel, D., Nilubol, N., Tyagi, M. V., Kebebew, E. 2019

  Abstract

  BACKGROUND: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs.METHODS: Thirty-three tissue samples were analyzed: they included samples from sporadic (n=9), von Hippel-Lindau (VHL)-related (n=10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n=10) as well as normal islet cells (n=4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools.RESULTS: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs.CONCLUSIONS: MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.

  View details for PubMedID 30620390

• Curbing Unnecessary and Wasted Diagnostic Imaging. JAMA Oren, O., Kebebew, E., Ioannidis, J. P. 2019

  View details for PubMedID 30615023

• MicroRNA-210 May Be a Preoperative Biomarker of Malignant Pheochromocytomas and Paragangliomas. The Journal of surgical research Ruff, S. M., Ayabe, R. I., Malekzadeh, P., Good, M. L., Wach, M. M., Gonzales, M. K., Tirosh, A., Nilubol, N., Pacak, K., Kebebew, E., Patel, D. 2019; 243: 1?7

  Abstract

  Currently, no reliable predictive clinical or laboratory tests exist that can accurately distinguish between benign and malignant pheochromocytomas or paragangliomas (PPGLs). The aim of this study was to investigate if serum microRNA-210 (miR-210) levels could be a marker of malignancy in patients with PPGLs.Preoperative serum from patients with PPGLs was collected on the day of surgery. Clinical demographics, germline mutation status, primary tumor size, postoperative biochemical response, and the development of malignant disease were prospectively collected. Total microRNA was extracted from preoperative serum samples, and miR-210 levels were measured by quantitative real-time reverse transcription-polymerase chain reaction and normalized to miR-16. Prognostic variables were compared using univariable and multivariable analyses.Of the 35 patients, 10 (29%) were diagnosed with malignant PPGLs and 25 patients (71%) were diagnosed with benign PPGLs (median follow-up 72.5 mo). Sixty-nine percent of patients had a pheochromocytoma (n = 24/35) compared with 31% of patients with paraganglioma (n = 11/35). The most common germline mutation was succinate dehydrogenase complex subunit B (SDHB) (n = 10). On univariable analysis, lower serum miR-210 expression level (2.3 ± 0.5 versus 3.1 ± 1.2, P = 0.013) and larger primary tumor size (6.7 ± 5.0 cm versus 4.1 ± 2.3 cm, P = 0.043) were significantly associated with malignant disease. No significant prognostic variables were found on multivariable analysis.In this pilot study, low serum miR-210 expression levels and large primary tumors were identified to be markers of PPGL malignancy on univariable analysis. Given the initial encouraging results in a small cohort, further investigation is warranted to determine if serum miR-210 levels are prognostic.

  View details for DOI 10.1016/j.jss.2019.04.086

  View details for PubMedID 31146085

• Adrenocortical tumors have a distinct, long, non-coding RNA expression profile and LINC00271 is downregulated in malignancy. Surgery Buishand, F. O., Liu-Chittenden, Y., Fan, Y., Tirosh, A., Gara, S. K., Patel, D., Meerzaman, D., Kebebew, E. 2019

  Abstract

  Adrenocortical carcinoma is an aggressive malignancy with a low but variable overall survival rate. The role of in adrenocortical carcinoma is poorly understood. Thus, in this study we performed long noncoding RNA expression profiling in adrenocortical carcinomas, adrenocortical adenomas, and normal adrenal cortex.Long noncoding RNA expression profile using Human LncRNA/mRNA Expression Microarray V3.0 (Arraystar, Inc, Rockville, MD) was analyzed in samples from 11 adrenocortical adenomas, 9 adrenocortical carcinomas, and 5 normal adrenal cortex. Differentially expressed long noncoding RNAs were validated using TaqMan, real-time quantitative polymerase chain reaction with additional samples. The dataset from the adrenocortical carcinoma Cancer Genome Atlas Programproject was used to evaluate the prognostic utility of long noncoding RNAs.Unsupervised hierarchical clustering showed distinct clustering of adrenocortical carcinoma samples compared with normal adrenal cortex and adrenocortical adenoma samples by long noncoding RNA expression profiles. A total of 874 long noncoding RNAs were differentially expressed between adrenocortical carcinoma and normal adrenal cortex. LINC00271 expression level was associated with prognosis, patients with low LINC00271 expression survived a shorter time than patients with high LINC00271 expression. Low LINC00271 expression was positively associated with WNT signaling, cell cycle, and chromosome segregation pathways.Adrenocortical carcinoma has a distinct long noncoding RNA expression profile. LINC00271 is downregulated in adrenocortical carcinoma and appears to be involved in biologic pathways commonly dysregulated in adrenocortical carcinoma.

  View details for DOI 10.1016/j.surg.2019.04.067

  View details for PubMedID 31522749

• Lysyl Oxidase is a key player in BRAF/MAPK pathway-driven thyroid cancer aggressiveness. Thyroid : official journal of the American Thyroid Association Boufraqech, M., Patel, D., Nilubol, N., Powers, A. S., King, T., Shell, J., Lack, J., Zhang, L., Gara, S. K., Gunda, V., Klubo-Gwiezdzinska, J., Kumar, S., Fagin, J. A., Knauf, J., Parangi, S., Venzon, D. J., Quezado, M., Kebebew, E. 2018

  Abstract

  BACKGROUND: BRAF mutation is the most common somatic mutation in thyroid cancer. The mechanism associated with BRAF mutant tumor aggressiveness remains unclear. Lysyl oxidase (LOX) is highly expressed in aggressive thyroid cancers, and involved in cancer metastasis. The objective is to determine whether LOX mediates the effect of the activated MAPK pathway in thyroid cancer.METHODS: The prognostic value of LOX and its association with BRAF mutation was analyzed in the TCGA and an independent cohort. Inhibition of mutant BRAF and the MAPK pathway, and overexpression of BRAF mutant and mouse models of BRAFV600E were used to test the effect on LOX expression.RESULTS: In the TCGA cohort, LOX expression was higher in BRAF mutant tumors compared to wild-type tumors (P<0.0001).Patients with BRAF mutant tumors with high LOX expression had a shorter disease-free survival (DFS) (P=0.03) compared to patients with BRAF mutation and low LOX group. In the independent cohort, a significant positive correlation between LOX and percentage of BRAF mutated cells was found. The independent cohort confirmed high LOX expression to be associated with a shorter DFS (P=0.01). Inhibition of BRAFV600E and MEK decreased LOX expression. Conversely overexpression of mutant BRAF increased LOX expression. The mice with thyroid-specific expression of BRAFV600E, showed a strong LOX and p-ERK expressions in tumor tissue. Inhibition of BRAFV600E in transgenic and orthotopic mouse models significantly reduced the tumor burden as well as LOX and p-ERK expressions.CONCLUSIONS: Our data suggests that BRAFV600E tumors with high LOX expression are associated with more aggressive disease. The biological underpinnings of the clinical findings were confirmed by showing that BRAF and the MAPK pathway regulate LOX expression.

  View details for PubMedID 30398411

• ASO Author Reflections: Systemic Inflammatory Markers in Pancreatic Neuroendocrine Tumors. Annals of surgical oncology Gaitanidis, A., Patel, D., Kebebew, E. 2018

  View details for PubMedID 30353397

• Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment. Surgery El Lakis, M., Giannakou, A., Nockel, P. J., Wiseman, D., Gara, S. K., Patel, D., Sater, Z. A., Kushchayeva, Y. Y., Klubo-Gwiezdzinska, J., Nilubol, N., Merino, M. J., Kebebew, E. 2018

  Abstract

  BACKGROUND: There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer.METHODS: We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database.RESULTS: A total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (P?=?.04) and had a greater rate of T1 disease (P?=?.019), lymph node metastasis (P?=?.002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ?3 affected family members presented at a younger age (P?=?.04), had a lesser female-to-male ratio (P?=?.04), and had a greater rate of lymph node metastasis (P?=?.009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (P?=?.003) but not in those diagnosed by screening ultrasonography (P?=?.58).CONCLUSION: Patients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ?3 first-degree relatives affected.

  View details for PubMedID 30327187

• Metastatic neuroendocrine tumors of the gastrointestinal tract and pancreas: A surgeon's plea to centering attention on the liver. Seminars in oncology Keutgen, X. M., Schadde, E., Pommier, R. F., Halfdanarson, T. R., Howe, J. R., Kebebew, E. 2018

  Abstract

  Over 50% of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have stage IV disease at presentation and the most likely organ to be affected by metastases is the liver. Hepatic involvement and hepatic tumor burden is a key prognostic factor affecting survival of these patients and 80% eventually die of liver failure due to tumor dissemination within the liver. This commentary explores the efficacy and limitations of systemic treatments in patients with GEP-NETs and liver metastases. Landmark randomized trials using systemic therapies including sandostatin (PROMID), lanreotide (CLARINET), everolimus (RADIANT 3 and 4), sunitinib and Peptide Receptor Radionuclide Therapy (NETTER-1) have not shown efficacy in reducing liver tumor burden in patients with stage IV GEP-NETs with liver metastases as outlined in this review. Although often overlooked, surgical debulking has been associated with a significant survival advantage in large retrospective studies and in our opinion should remain an important therapeutic option for patients with stage IV GEP-NETs and liver metastases.

  View details for PubMedID 30318110

• Cumulative Radiation Exposures from CT Screening and Surveillance Strategies for von Hippel-Lindau-associated Solid Pancreatic Tumors. Radiology Tirosh, A., Journy, N., Folio, L. R., Lee, C., Leite, C., Yao, J., Kovacs, W., Linehan, W. M., Malayeri, A., Kebebew, E., de Gonzalez, A. B. 2018: 180687

  Abstract

  Purpose To assess the potential ionizing radiation exposure from CT scans for both screening and surveillance of patients with von Hippel-Lindau (VHL) syndrome. Materials and Methods For this retrospective study, abdomen-pelvic (AP) and chest-abdomen-pelvic (CAP) CT scans were performed with either a three-phase (n = 1242) or a dual-energy virtual noncontrast protocol (VNC; n = 149) in 747 patients with VHL syndrome in the National Institutes of Health Clinical Center between 2009 and 2015 (mean age, 47.6 years ± 14.6 [standard deviation]; age range, 12-83 years; 320 women [42.8%]). CT scanning parameters for patients with pancreatic neuroendocrine tumors (PNETs; 124 patients and 381 scans) were compared between a tumor diameter-based surveillance protocol and a VHL genotype and tumor diameter-based algorithm (a tailored algorithm) developed by three VHL clinicians. Organ and lifetime radiation doses were estimated by two radiologists and five radiation scientists. Cumulative radiation doses were compared between the PNET surveillance algorithms by analyses of variance, and a two-tailed P value less than .05 indicated statistical significance. Results Median cumulative colon doses for annual CAP and AP CT scans from age 15 to 40 years ranged from 0.34 Gy (5th-95th percentiles, 0.18-0.75; dual-energy VNC CT) to 0.89 Gy (5th-95th percentiles, 0.42-1.0; three-phase CT). For the current PNET surveillance protocol, the cumulative effective radiation dose from age 40 to 65 years was 682 mSv (tumors < 1.2 cm) and 2125 mSv (tumors > 3 cm). The tailored algorithm could halve these doses for patients with initial tumor diameter less than 1.2 cm (P < .001). Conclusion CT screening of patients with von Hippel-Lindau syndrome can lead to substantial radiation exposures, even with dual-energy virtual noncontrast CT. A genome and tumor diameter-based algorithm for pancreatic neuroendocrine tumor surveillance may potentially reduce lifetime radiation exposure. © RSNA, 2018 Online supplemental material is available for this article.

  View details for PubMedID 30299237

• Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors NATURE COMMUNICATIONS Gara, S., Lack, J., Zhang, L., Harris, E., Cam, M., Kebebew, E. 2018; 9: 4172

  Abstract

  Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is unknown if there is molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37-57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs.

  View details for PubMedID 30301885

• Radioguided Surgery With Gallium 68 Dotatate for Patients With Neuroendocrine Tumors. JAMA surgery El Lakis, M., Gianakou, A., Nockel, P., Wiseman, D., Tirosh, A., Quezado, M. A., Patel, D., Nilubol, N., Pacak, K., Sadowski, S. M., Kebebew, E. 2018

  Abstract

  Importance: Neuroendocrine tumors (NETs) express somatostatin receptors, which can be targeted with radiolabeled peptides. In a variety of solid tumors, radioguided surgery (RGS) has been used to guide surgical resection. Gallium 68 (68Ga) dota peptides have been shown to be more accurate than other radioisotopes for detecting NETs. A pilot study previously demonstrated the feasibility and safety of 68Ga-dotatate RGS for patients with NETs.Objective: To evaluate what intraoperative techniques and thresholds define positive lesions that warrant resection during 68Ga-dotatate RGS.Design, Setting, and Participants: This prospective cohort study, conducted between October 23, 2013, and February 14, 2018, included 44 patients with NETs who underwent 68Ga-dotatate RGS.Intervention: Gallium 68-dotatate RGS.Main Outcomes and Measures: The in vivo and ex vivo tumor to background ratio (TBR) was assessed for resected lesions and correlated with the histopathologic findings.Results: Forty-four patients (22 women and 22 men; mean [SD] age, 51.0 [13.7] years) had 133 lesions detected on preoperative imaging scans, with a diagnosis of a pancreatic NET (19 of 44 [43%]), gastrointestinal NET (22 of 44 [50%]), and pheochromocytoma or paraganglioma (3 of 44 [7%]). The TBR was obtained by normalizing to the omentum (106 of 133 [79.7%]) or other solid organs (27 of 133 [20.3%]). The omentum had a significantly lower mean (SD) count than other solid organs for background count activity 3 hours after injection (22.1 [17.0] vs 34.5 [39.0]; P<.001). The lesions containing NETs had a higher TBR than those that did not contain NETs (18.9 vs 4.4; P<.001). On a receiver operating characteristic curve analysis, a TBR of 2.5 had a sensitivity of 90% and a specificity of 25%, and a TBR of 16 had a sensitivity of 54% and a specificity of 81%.Conclusions and Relevance: A TBR of 2.5 or greater is a highly sensitive threshold for indicating a lesion to be consistent with a NET on histologic findings and thus warranting surgical resection. The omentum should be used as the background count activity for 68Ga-dotatate RGS for patients with abdominal NETs.

  View details for PubMedID 30267071

• Aggressive resection of neuroendocrine tumor (NET) liver metastases: NET neutral or gain? Surgery Cisco, R., Lin, D., Kebebew, E. 2018

  View details for PubMedID 30266442

• Incidence and management of postoperative hyperglycemia in patients undergoing insulinoma resection ENDOCRINE Nockel, P., Tirosh, A., El Lakis, M., Gaitanidis, A., Merkel, R., Patel, D., Nilubol, N., Sadowski, S. M., Cochran, C., Gorden, P., Kebebew, E. 2018; 61 (3): 422?27

  Abstract

  It has been proposed that rebound hyperglycemia after resection of insulinoma indicates a biochemical cure. However, there is scant objective data in the literature on the rate and need for intervention in hyperglycemia in patients undergoing resection of insulinoma. The goal of our study was to evaluate the rate of postoperative hyperglycemia, any predisposing factors, and the need for intervention in a prospective cohort study of all patients undergoing routine glucose monitoring.A retrospective analysis of 33 patients who had an insulinoma resected and who underwent routine postoperative monitoring of blood glucose (every hour for the first six hours then every four hours for the first 24?h) was performed. Hyperglycemia was defined as glucose greater than 180?mg/dL (10?mmol/l).Twelve patients (36%) developed hyperglycemia within 24?h (range 1-16?h). In patients with hyperglycemia, the mean maximum plasma glucose level was 221.5?mg/dL (range 97-325?mg/dL) (12.3?mmol/l), and four (33%) patients were treated with insulin. There was no significant difference in age, gender, body mass index (BMI), tumor size, biochemical profile, or surgical approach and extent of pancreatectomy between patients who developed hyperglycemia and those who did not. Pre-excision and post-excision intraoperative insulin levels were evaluated in 14 of 33 patients. The percentage decrease of the intraoperative insulin levels was not significantly different between patients who developed hyperglycemia and those who did not. All patients with postoperative hyperglycemia had normalization of their glucose levels, and none were discharged on anti-hyperglycemic agents.Hyperglycemia is common after insulinoma resection, and a subset of patients require transient treatment with insulin.

  View details for PubMedID 29923016

• Predictors of Survival in Adrenocortical Carcinoma: An Analysis From the National Cancer Database JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Tella, S., Kommalapati, A., Yaturu, S., Kebebew, E. 2018; 103 (9): 3566?73

  Abstract

  Adrenocortical Carcinoma (ACC) is rare and knowledge on the prognostic factors and survival outcomes is limited.To describe predictors of survival and overall survival (OS) outcomes of ACC.Retrospective review of ACC patients from National Cancer Database (NCDB).Nationwide cancer registry based study.Pathologically confirmed 3185 ACC patients identified from NCDB between 2004 and 2015.Baseline description, survival outcomes, and predictors of survival were evaluated in patients with ACC.Median age at diagnosis of ACC was 55 (range:18-90) years and did not differ by sex or stage of disease at diagnosis. On multivariate analysis, increasing age (p < 0.0001), higher Charlson comorbidity index (p < 0.0001), high tumor grade (p < 0.0001), stage IV disease (p=0.002), no surgical therapy (p < 0.0001), and performance of lymphadenectomy during surgery (p=0.02) were associated with poor prognosis. In stage I-III disease, patients treated with surgical resection had significantly better median OS (63 vs 8 months, p <0.001). In stage IV disease, patients treated with surgery (19 vs 6 months, p < 0.001), and post-surgical radiation (29 vs 10 months, p < 0.001) or chemotherapy (22 vs 13 months, p=0.004) had a better median OS.OS of ACC varied with increasing age, higher comorbidity index, grade and stage of the disease at presentation. In addition, we noted improved survival with surgical resection of primary tumor, irrespective of the stage of the disease though, post-surgical chemo or radiation benefitted only in stage IV disease.

  View details for PubMedID 29982685

• Neural monitoring in endocrine neck surgery GLAND SURGERY El Lakis, M., Kebebew, E. 2018; 7: S86?S88

  View details for DOI 10.21037/gs.2018.03.08

  View details for Web of Science ID 000440690800014

• Identification of Differential Transcriptional Patterns in Primary and Secondary Hyperparathyroidism JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Sadowski, S., Pusztaszeri, M., Brulhart-Meynet, M., Petrenko, V., De Vito, C., Sobel, J., Delucinge-Vivier, C., Kebebew, E., Regazzi, R., Philippe, J., Triponez, F., Dibner, C. 2018; 103 (6): 2189?98

  Abstract

  Hyperparathyroidism is associated with hypercalcemia and the excess of parathyroid hormone secretion; however, the alterations in molecular pattern of functional genes during parathyroid tumorigenesis have not been unraveled. We aimed at establishing transcriptional patterns of normal and pathological parathyroid glands (PGs) in sporadic primary (HPT1) and secondary hyperparathyroidism (HPT2).To evaluate dynamic alterations in molecular patterns as a function of the type of PG pathology, a comparative transcript analysis was conducted in subgroups of healthy samples, sporadic HPT1 adenoma and hyperplasia, and HPT2.Normal, adenomatous, HPT1, and HPT2 hyperplastic PG formalin-fixed paraffin-embedded samples were subjected to NanoString analysis. In silico microRNA (miRNA) analyses and messenger RNA-miRNA network in PG pathologies were conducted. Individual messenger RNA and miRNA levels were assessed in snap-frozen PG samples.The expression levels of c-MET, MYC, TIMP1, and clock genes NFIL3 and PER1 were significantly altered in HPT1 adenoma compared with normal PG tissue when assessed by NanoString and quantitative reverse transcription polymerase chain reaction. RET was affected in HPT1 hyperplasia, whereas CaSR and VDR transcripts were downregulated in HPT2 hyperplastic PG tissue. CDH1, c-MET, MYC, and CaSR were altered in adenoma compared with hyperplasia. Correlation analyses suggest that c-MET, MYC, and NFIL3 exhibit collective expression level changes associated with HPT1 adenoma development. miRNAs, predicted in silico to target these genes, did not exhibit a clear tendency upon experimental validation.The presented gene expression analysis provides a differential molecular characterization of PG adenoma and hyperplasia pathologies, advancing our understanding of their etiology.

  View details for PubMedID 29659895

• The Immune Landscape of Cancer IMMUNITY Thorsson, V., Gibbs, D. L., Brown, S. D., Wolf, D., Bortone, D. S., Yang, T., Porta-Pardo, E., Gao, G. F., Plaisier, C. L., Eddy, J. A., Ziv, E., Culhane, A. C., Paull, E. O., Sivakumar, I., Gentles, A. J., Malhotra, R., Farshidfar, F., Colaprico, A., Parker, J. S., Mose, L. E., Nam Sy Vo, Liu, J., Liu, Y., Rader, J., Dhankani, V., Reynolds, S. M., Bowlby, R., Califano, A., Cherniack, A. D., Anastassiou, D., Bedognetti, D., Rao, A., Chen, K., Krasnitz, A., Hu, H., Malta, T. M., Noushmehr, H., Pedamallu, C., Bullman, S., Ojesina, A. I., Lamb, A., Zhou, W., Shen, H., Choueiri, T. K., Weinstein, J. N., Guinney, J., Saltz, J., Holt, R. A., Rabkin, C. E., Lazar, A. J., Serody, J. S., Demicco, E. G., Disis, M. L., Vincent, B. G., Shmulevich, L., Canc Genome Atlas Res Network 2018; 48 (4): 812-+

  Abstract

  We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-? dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-? dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

  View details for PubMedID 29628290

• Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas CANCER CELL Liu, Y., Sethi, N. S., Hinoue, T., Schneider, B. G., Cherniack, A. D., Sanchez-Vega, F., Seoane, J. A., Farshidfar, F., Bowlby, R., Islam, M., Kim, J., Chatila, W., Akbani, R., Kanchi, R. S., Rabkin, C. S., Willis, J. E., Wang, K. K., McCall, S. J., Mishra, L., Ojesina, A. I., Bullman, S., Pedamallu, C., Lazar, A. J., Sakai, R., Thorsson, V., Bass, A. J., Laird, P. W., Canc Genome Atlas Res Network 2018; 33 (4): 721-+

  Abstract

  We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.

  View details for PubMedID 29622466

• Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation CELL Malta, T. M., Sokolov, A., Gentles, A. J., Burzykowski, T., Poisson, L., Weinstein, J. N., Kaminska, B., Huelsken, J., Omberg, L., Gevaert, O., Colaprico, A., Czerwinska, P., Mazurek, S., Mishra, L., Heyn, H., Krasnitz, A., Godwin, A. K., Lazar, A. J., Stuart, J. M., Hoadley, K. A., Laird, P. W., Noushmehr, H., Wiznerowicz, M., Cancer Genome Atlas Res Network 2018; 173 (2): 338-+

  Abstract

  Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.

  View details for PubMedID 29625051

• Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas CELL REPORTS Campbell, J. D., Yau, C., Bowlby, R., Liu, Y., Brennan, K., Fan, H., Taylor, A. M., Wang, C., Walter, V., Akbani, R., Byers, L., Creighton, C. J., Coarfa, C., Shih, J., Cherniack, A. D., Gevaert, O., Prunello, M., Shen, H., Anur, P., Chen, J., Cheng, H., Hayes, D., Bullman, S., Pedamallu, C., Ojesina, A. I., Sadeghi, S., Mungall, K. L., Robertson, A., Benz, C., Schultz, A., Kanchi, R. S., Gay, C. M., Hegde, A., Diao, L., Wang, J., Ma, W., Sumazin, P., Chiu, H., Chen, T., Gunaratne, P., Donehower, L., Rader, J. S., Zuna, R., Al-Ahmadie, H., Lazar, A. J., Flores, E. R., Tsai, K. Y., Zhou, J. H., Rustgi, A. K., Drill, E., Shen, R., Wong, C. K., Stuart, J. M., Laird, P. W., Hoadley, K. A., Weinstein, J. N., Peto, M., Pickering, C. R., Chen, Z., Van Waes, C., Canc Genome Atlas Res Network 2018; 23 (1): 194-+

  Abstract

  This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ?Np63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

  View details for PubMedID 29617660

• Neural monitoring in endocrine neck surgery. Gland surgery El Lakis, M., Kebebew, E. 2018; 7 (Suppl 1): S86?S88

  View details for PubMedID 30178784

  View details for PubMedCentralID PMC6107598

• Four-Gland Exploration Versus Focused Parathyroidectomy for Hyperparathyroidism Jaw Tumor Syndrome DIFFICULT DECISIONS IN ENDOCRINE SURGERY: AN EVIDENCE-BASED APPROACH Patel, D., Kebebew, E., Angelos, P., Grogan, R. H. 2018: 227?37

  View details for DOI 10.1007/978-3-319-92860-9_20

  View details for Web of Science ID 000466535000021