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Transoral robotic surgery alone for oropharyngeal cancer: quality-of-life outcomes

Choby, Garret W; Kim, Jeehong; Ling, Diane C; Abberbock, Shira; Mandal, Rajarsi; Kim, Seungwon; Ferris, Robert L; Duvvuri, Umamaheswar
IMPORTANCE/OBJECTIVE:Few studies have examined quality-of-life (QOL) outcomes in patients who undergo transoral robotic surgery (TORS) alone (ie, without adjuvant radiotherapy or chemoradiotherapy). OBJECTIVE:To report QOL outcomes of patients with oropharyngeal squamous cell carcinoma who receive only TORS. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Medical records for all patients undergoing TORS for treatment of primary oropharyngeal squamous cell carcinoma from May 1, 2010, to March 31, 2014, at a tertiary care academic cancer center were examined from June through September 2014. Thirty-four patients who did not receive adjuvant therapy after TORS were included in the study. INTERVENTION/METHODS:Primary surgical resection via TORS. MAIN OUTCOMES AND MEASURES/METHODS:The University of Washington Quality of Life, version 4, questionnaire was completed by patients preoperatively and at 1-, 6-, 12-, and 24-month intervals after TORS. Demographic, clinicopathologic, and follow-up data were collected. RESULTS:Mean follow-up time was 14 months (May 1, 2010, to April 30, 2014). Most patients had T1 (20 [59%]) or T2 (13 [38%]) and N0 (13 [38%]) or N1 (16 [47%]) disease. Statistically significant improvement in QOL outcomes was noted in the following postoperative domains: chewing from 1 month (median, 50 [IQR, 50-100]) to 12 months (100 [IQR, 100-100]; P = .048), swallowing from 1 month (70 [IQR, 30-85]) to 6 months (100 [IQR, 70-100]; P = .047) and 1 to 24 months (100 [IQR, 70-100]; P = .048), pain from 1 month (38 [IQR, 25-75]) to 6 months (88 [IQR, 75-100]; P = .006) and 1 to 12 months after surgery (100 [IQR, 75-100]; P = .01), and activity from 1 month (63 [IQR, 50-88]) to 24 months (100 [IQR, 75-100]; P = .03). Two participants (6%) died during the follow-up period: 1 because of disease and 1 because of a myocardial infarction. Two patients (6%) required temporary gastrostomy tube placement, but none required tracheostomy. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Appropriately selected patients who undergo TORS alone for oropharyngeal squamous cell carcinoma experience acceptable short- and long-term QOL outcomes.
PMID: 25834991
ISSN: 2168-619x
CID: 5481402

HER3 inhibition potentiates anti-tumor effects of PI3K inhibitors in pre-clinical models of HNSCC [Meeting Abstract]

Davis, Kara S.; Khan, Nayel; Kemp, Carolyn; Kulkarni, Sucheta; Alvarado, Diego; LaVallee, Theresa; Grandis, Jennifer R.; Duvvuri, Umamaheswar
ISI:000371578503164
ISSN: 0008-5472
CID: 5482602

Accuracy of early-phase versus dual-phase single-photon emission computed tomography/computed tomography in the localization of parathyroid disease

Mandal, Rajarsi; Muthukrishnan, Ashok; Ferris, Robert L; de Almeida, John R; Duvvuri, Umamaheswar
OBJECTIVES/HYPOTHESIS/OBJECTIVE:Preoperative localization for parathyroid disease has improved in recent years with the advent of dual-phase (99m) Tc-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. However, dual-phase imaging is associated with increased cost, time, and radiation dose. The aim of this study was to investigate the need for late-phase imaging when using SPECT/CT for the preoperative localization of parathyroid disease. STUDY DESIGN/METHODS:Retrospective chart analysis. METHODS:A retrospective review of 75 patients who underwent preoperative imaging localization and subsequent surgical resection for parathyroid disease at a tertiary referral center was performed. Of these, 50 patients met study criteria including preoperative SPECT/CT imaging and specific reporting of early- and late-phase focal radiotracer uptake. Localization accuracy was verified with definitive surgical findings confirmed by histological analysis and evidence of biochemical cure. RESULTS:Accurate localization of adenoma(s) was seen in 78.0% of patients using dual-phase SPECT/CT. Early-phase imaging alone localized 76.0%, whereas late-phase imaging alone localized 74.0%. Sensitivity and specificity for dual-phase imaging was 84.8% and 89.6%, respectively. In comparison, early-phase localization alone was found to have a sensitivity/specificity of 84.4%/89.4%; sensitivity/specificity of late-phase scanning alone was found to be 80.4%/89.1%. Dual-phase SPECT/CT scanning did not provide a statistically significant improvement in adenoma localization when compared to early-phase scanning alone. CONCLUSIONS:Although further investigation is needed, the results of this study suggest that early-phase SPECT/CT scanning alone may obviate the need for dual-phase SPECT/CT scanning in the initial preoperative localization workup of parathyroid disease. LEVEL OF EVIDENCE/METHODS:4.
PMID: 25645695
ISSN: 1531-4995
CID: 5481352

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study

Miller, David H; Fox, Robert J; Phillips, J Theodore; Hutchinson, Michael; Havrdova, Eva; Kita, Mariko; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; MacManus, David G; Yousry, Tarek A; Goodsell, Mary; Yang, Minhua; Zhang, Ray; Viglietta, Vissia; Dawson, Katherine T; Wilson, Kate; Antel, Jack; Ware, James; Polman, Chris; Kowey, Peter R; Chung, Raymond; Bakris, George; Richert, John; Seibert, Burt; Brandes, David; Brassat, David; Cohen, Bruce; Diem, Ricarda; Goldman, Myla; Herndon, Robert; Miller, Aaron; Tumani, Hayrettin; Alfaro-Vidal, Teresa; Crespo, Carolina; Foster, Jo; Hunter, Kelvin; Garcia-Gomez, Almudena; Santana, Virginia; Kneebone, Christopher; Fedulau, Aliaksandr; Likhachev, Sergey; Mikhailova, Elena; Naumova, Halina; Decoo, Danny; Gaer, Luc Vande; Sindic, Christian; Grgic, Sanja; Sinanovic, Osman; Suljic, Enra Mehmedika; Deleva, Nadezhda; Georgiev, Dimitar; Haralanov, Lyubomir; Ivanova, Sonyia; Manchev, Ivan; Minchev, Dimitar; Stamenova, Paraskeva; Tournev, Ivailo; Vacheva, Elena; Zahariev, Zahari; Bar-Or, Amit; Blevins, Gregg; Kremenchutzky, Marcelo; Veloso, Felix; Witt, Norbert; Vargas Howell, Roberto; Vindas, Alexander Parajeles; Habek, Mario; Rudež, Josip; Soldo-Butković, Silva; Vurdelja, Ranka Baraba; Doležil, David; Havrdova, Eva; Nova'k, Jiří; Vaclavik, Daniel; Antsov, Katrin; Gross-Paju, Katrin; Haldre, Sulev; Palu, Alla; Toomsoo, Toomas; Al Khedr, Abdullatif; Camu, William; Debouverie, Marc; Defer, Gilles; De Seze, Jérôme; Labauge, Pierre; Moreau, Thibault; Pelletier, Jean; Rumbach, Lucien; Daskalovska, Vera; Angnstwurm, Klemens; Benes, Heike; Berthele, Achim; Boldt, Hans-Jürgen; Christopher, Angelika; Derfuß, Tobias; Eisensehr, Ilonka; Emrich, Peter; Feneberg, Wolfgang; Hoffmann, Frank; Hohlfeld, Reinhard; Hüntemann, Reinhard; Kallmann, Boris-Alexander; Kieseier, Bernd; Landefeld, Harald; Lüer, Wilfried; Masri, Sabine; Nelles, Gereon; Oschmann, Patrick; Paschen, Christine; Reifschneider, Gerd; Sailer, Michael; Schimrigk, Sebastian; Spiegel-Meixensberger, Mechthild; Storch-Hagenlocher, Brigitte; Tackenberg, Björn; Tiel-Wilck, Klaus; Karageorgiou, Clementine; Papathanasopoulos, Panagiotis; Thomaides, Thomas; Vlaikidis, Nicholas; Arjundas, Deepak; Behari, Madhuri; Ghosh, Amitabha; Ghosh, Pahari; Ichaporia, Nasli Rustom; Khurana, Dheeraj; Kulkarni, Rahul Vitthal; Kumar, Suresh; Mehndiratta, Man Mohan; Mehta, Neeta Abhay; Misra, Usha Kant; Mukherji, Joy Dev; Nellikunja, Shankara; Salem, Abdul; Sethi, Prahlad Kumar; Shah, Shalin Dipinkumar; Singh, Gagandeep; Singh, Maneesh Kumar; Singh, Yash Pal; Srinivasa, Rangasetty; Vijayan, Krishnan; Sweeney, Bernard; Gilad, Ronit; Shahien, Radi; Paegle, Anita; Delgado, Cesar; Escamilla, Juan; Estañol, Bruno; Lopez, Minerva; Macias, Miguel Angel; Punzo, Guillermo; Quiñones, Sandra; Renteria, Mariela; Santos, Jose; Gavriliuc, Mihail; Groppa, Stanislav; Odainic, Olesea; Timmings, Paul; Czlonkowska, Anna; Dorobek, Malgorzata; Drozdowski, Wieslaw; Fryze, Waldemar; Hertmanowska, Hanka; Kaminska, Anna; Kapelusiak-Pielok, Magdalena; Kleczkowska, Magdalena; Kochanowicz, Jan; Losy, Jacek; Nowacki, Przemyslaw; Nyka, Walenty; Pierzchala, Krystyna; Podemski, Ryszard; Potemkowski, Andrzej; Selmaj, Krzysztof; Stelmasiak, Zbigniew; Szczudlik, Andrzej; Tutaj, Andrzej; Wajgt, Andrzej; Zielinski, Tomasz; Balasa, Rodica; Ionescu-Dimancea, Valentin; Mihancea, Petru; Popescu, Cristian; Protosevici, Liviu Codrut; Miletić Drakulić, Svetlana; Nadj, Congor; Raicevic, Ranko; Vojinovic, Slobodan; Kahancová, Edita; Kurca, Egon; Lisý, L'ubomir; Turčáni, Peter; Arroyo, Rafael; Fernández, Oscar; Guijarro, Cristina; Izquierdo, Guillermo; Lopez, Fernando Sanchez; Montalbán, Xavier; Oreja-Guevara, Celia; Prieto, Jose Maria; Buchakchyys'ka, Nataliya; Chmyr, Galyna; Goloborodko, Alla; Kobys, Tetyana; Kushnir, Grygory; Lebedynets, Volodymyr; Lytvynenko, Nataliya; Moskovko, Sergii; Nehrych, Tetyana; Palamar, Borys; Pasyura, Igor; Ryabichenko, Tatyana; Voloshina, Nataliya; Apperson, Michelle; Applebee, Angela; Asher, Stephen; Ayala, Ricardo; Ayres, Donald; Azizi, S Ausim; Baker, Matthew; Bauer, Brendan; Bomprezzi, Roberto; Buckler, Richard; Carlini, Walter; Chinea, Angel; Cohan, Stanley; Crowell, Giles; Edwards, Keith; Eubank, Geoffery; Felton, Warren 3rd; Fodor, Patricia; Foley, John; Ford, Corey; Fox, Edward; Fox, Robert; Forester, Mary; Freedman, Steven; Garmany, George Jr; Gazda, Suzanne; Giang, Daniel; Glaun, Braeme; Gold, Scott; Gottesman, Malcolm; Gudesblatt, Mark; Herbert, Joseph; Herskowitz, Allan; Honeycutt, William; Huddlestone, John; Hull, Richard; Hunter, Samuel; Hutton, George; Jacobs, Dina; Janicki, Mark; Khatri, Bhupendra; Kinkel, Revere Philip; Kita, Mariko; Krolczyk, Stanley; Krupp, Lauren; LaGanke, Christopher; Levin, Michael; Licht, Jonathan; Luzzio, Christopher; Lynch, Sharon; Mattson, David; Mikol, Daniel; Miller, Tamara; Minagar, Alireza; Mitchell, Galen; Moses, Harold Jr; Negroski, Donald; Newman, Stephen; Pardo, Gabriel; Patel, Malti; Perel, Allan; Phillips, Joseph Jr; Picone, Mary Ann; Rammohan, Kottil; Rao, T Hemanth; Rinker, John 2nd; Sadiq, Saud; Schaeffer, John; Sheremata, William; Shin, Robert; Shubin, Richard; Silverman, Stuart; Smith, Robert; Stein, Lee; Stein, Michael; Steiner, David; Steingo, Brian; Sullivan, Herman; Sunter, William Jr; Vaishnav, Anand; Vasquez, Alberto; Voci, James; Warach, Jonathan; Weinstock-Guttman, Bianca; Williams, Mitzi; Wray, Sibyl
OBJECTIVE:To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study. METHODS:CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort). RESULTS:DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance. CONCLUSIONS:The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment.
PMCID:4371413
PMID: 25681448
ISSN: 1526-632x
CID: 5348212

Factors Associated With Recurrence and Survival in Lymph Node-negative Gastric Adenocarcinoma: A 7-Institution Study of the US Gastric Cancer Collaborative

Jin, Linda X; Moses, Lindsey E; Squires, M Hart; Poultsides, George A; Votanopoulos, Konstantinos; Weber, Sharon M; Bloomston, Mark; Pawlik, Timothy M; Hawkins, William G; Linehan, David C; Strasberg, Steven M; Schmidt, Carl; Worhunsky, David J; Acher, Alexandra W; Cardona, Kenneth; Cho, Clifford S; Kooby, David A; Levine, Edward; Winslow, Emily R; Saunders, Neil D; Spolverato, Gaya; Maithel, Shishir K; Fields, Ryan C
OBJECTIVES/OBJECTIVE:To determine pathologic features associated with recurrence and survival in patients with lymph node-negative gastric adenocarcinoma. STUDY DESIGN/METHODS:Multi-institutional retrospective analysis. BACKGROUND:Lymph node status is among the most important predictors of recurrence after gastrectomy for gastric adenocarcinoma. Pathologic features predictive of recurrence in patients with node-negative disease are less well established. METHODS:Patients who underwent curative resection for gastric adenocarcinoma between 2000 and 2012 from 7 institutions of the US Gastric Cancer Collaborative were analyzed, excluding 30-day mortalities and stage IV disease. Competing risks regression and multivariate Cox regression were used to determine pathologic features associated with time to recurrence and overall survival. Differences in cumulative incidence of recurrence were assessed using the Gray method (for univariate nonparametric analyses) and the Fine and Gray method (for multivariate analyses) and shown as subhazard ratios (SHRs) and adjusted subhazard ratios (aSHRs), respectively. RESULTS:Of 805 patients who met inclusion criteria, 317 (39%) had node-negative disease, of which 54 (17%) recurred. By 2 and 5 years, 66% and 88% of patients, respectively, experienced recurrence. On multivariate competing risks regression, only T-stage 3 or higher was associated with shorter time to recurrence [aSHR = 2.7; 95% confidence interval (CI), 1.5-5.2]. Multivariate Cox regression showed T-stage 3 or higher [hazard ratio (HR) = 1.8; 95% CI, 1.2-2.8], lymphovascular invasion (HR = 2.2; 95% CI, 1.4-3.4), and signet ring histology (HR = 2.1; 95% CI, 1.2-3.6) to be associated with decreased overall survival. CONCLUSIONS:Despite absence of lymph node involvement, patients with T-stage 3 or higher have a significantly shorter time to recurrence. These patients may benefit from more aggressive adjuvant therapy and postoperative surveillance regimens.
PMID: 25607760
ISSN: 1528-1140
CID: 5295102

Conservative management of typical pediatric postauricular dermoid cysts

Linkov, Gary; Kanev, Paul M; Isaacson, Glenn
OBJECTIVE:Congenital dermoid cysts of the skull and face frequently arise in embryonic fusion planes. They may follow these planes to extend intratemporally or intracranially. Advanced imaging and operative techniques are generally recommended for these lesions. Postauricular temporal bone dermoid cysts seem to form a distinct subgroup with a lesser tendency toward deep extension. They may be amenable to more conservative management strategies. METHODS:With IRB-approval, we queried a prospectively-accrued computerized patient-care database to find all postauricular temporal dermoid lesions surgically managed by a single pediatric otolaryngologist from 2001 to 2014. We reviewed the English-language literature to identify similar series of surgically treated pediatric temporal bone dermoid cysts. RESULTS:Ten postauricular temporal dermoid cysts with pathological confirmation were identified in our surgical series. The average size of the lesions was 1.5 cm (0.3-3 cm). The average age at time of surgery was 4 years (6 months-17 years). No intracranial extension was observed at surgery. There were no recurrences noted on last follow-up (mean 65 months, range 10-150 months). A computerized literature review found no examples of intracranial extension among typical postauricular dermoid cysts. CONCLUSION/CONCLUSIONS:There was no intracranial or temporal extension in our series or among postauricular lesions described in the literature. Given the low incidence of deep extension we advocate neither advanced imaging nor routine neurosurgical consultation for typical postauricular lesions. Dissection in continuity with cranial periosteum facilitates intact removal of adherent lesions. Surgery is curative if the dermoid is removed intact.
PMID: 26318023
ISSN: 1872-8464
CID: 5241862

Infections and edema

Linkov, Gary; Soliman, Ahmed M S
Infectious and inflammatory conditions of the head and neck may present with impaired airways. An understanding of the pathophysiology will allow for accurate diagnosis and prompt intervention. Preintervention discussion and planning by members of the airway team are crucial in developing a primary and backup plans for safely securing the airway.
PMID: 25999006
ISSN: 1932-2275
CID: 5241852

Pitch adaptation patterns in bimodal cochlear implant users: over time and after experience

Reiss, Lina A J; Ito, Rindy A; Eggleston, Jessica L; Liao, Selena; Becker, Jillian J; Lakin, Carrie E; Warren, Frank M; McMenomey, Sean O
OBJECTIVES/OBJECTIVE:Pitch plasticity has been observed in Hybrid cochlear implant (CI) users. Does pitch plasticity also occur in bimodal CI users with traditional long-electrode CIs, and is pitch adaptation pattern associated with electrode discrimination or speech recognition performance? The goals of this study were to characterize pitch adaptation patterns in long-electrode CI users, to correlate these patterns with electrode discrimination and speech perception outcomes, and to analyze which subject factors are associated with the different patterns. DESIGN/METHODS:Electric-to-acoustic pitch matches were obtained in 19 subjects over time from CI activation to at least 12 months after activation, and in a separate group of 18 subjects in a single visit after at least 24 months of CI experience. Audiometric thresholds, electrode discrimination performance, and speech perception scores were also measured. RESULTS:Subjects measured over time had pitch adaptation patterns that fit one of the following categories: (1) "Pitch-adapting," that is, the mismatch between perceived electrode pitch and the corresponding frequency-to-electrode allocations decreased; (2) "Pitch-dropping," that is, the pitches of multiple electrodes dropped and converged to a similar low-pitch; and (3) "Pitch-unchanging," that is, the electrode pitches did not change. Subjects measured after CI experience had a parallel set of adaptation patterns: (1) "Matched-pitch," that is, the electrode pitch was matched to the frequency allocation; (2) "Low-pitch," that is, the pitches of multiple electrodes were all around the lowest frequency allocation; and (3) "Nonmatched-pitch," that is, the pitch patterns were compressed relative to the frequency allocations and did not fit either the matched-pitch or low-pitch categories. Unlike Hybrid CI users which were mostly in the pitch-adapting or matched-pitch category, the majority of bimodal CI users were in the latter two categories, pitch-dropping/low-pitch or pitch-unchanging/nonmatched-pitch. Subjects with pitch-adapting or matched-pitch patterns tended to have better low-frequency thresholds than subjects in the latter categories. Changes in electrode discrimination over time were not associated with changes in pitch differences between electrodes. Reductions in speech perception scores over time showed a weak but nonsignificant association with dropping-pitch patterns. CONCLUSIONS:Bimodal CI users with more residual hearing may have somewhat greater similarity to Hybrid CI users and be more likely to adapt pitch perception to reduce mismatch with the frequencies allocated to the electrodes and the acoustic hearing. In contrast, bimodal CI users with less residual hearing exhibit either no adaptation, or surprisingly, a third pattern in which the pitches of the basal electrodes drop to match the frequency range allocated to the most apical electrode. The lack of association of electrode discrimination changes with pitch changes suggests that electrode discrimination does not depend on perceived pitch differences between electrodes, but rather on some other characteristics such as timbre. In contrast, speech perception may depend more on pitch perception and the ability to distinguish pitch between electrodes, especially since during multielectrode stimulation, cues such as timbre may be less useful for discrimination.
PMCID:4336615
PMID: 25319401
ISSN: 1538-4667
CID: 5092002

Classification of middle fossa floor dehiscence syndromes

Gupta, Kunal; Sabry, Hatem A; Dogan, Aclan; Coppa, Nicholas D; McMenomey, Sean; Delashaw, Johnny B; Raslan, Ahmed M
OBJECT/OBJECTIVE:Middle fossa floor dehiscence (MFFD) can present as multiple syndromes depending on dehiscence location, tissue herniation, and dural integrity. The authors propose a classification system for MFFD with the potential to guide clinical decision making. METHODS:A retrospective analysis of the electronic medical records (years 1995-2012) of patients who had undergone temporal craniotomy for the surgical repair of an MFFD syndrome at a single institution was undertaken. Reviewed data included demographic, operative, presentation, and outcome details. Middle fossa floor dehiscence was classified as follows: Class A, bony dehiscence without herniation of the brain and/or meninges; Class B, herniation of the brain and/or meninges through the middle fossa floor without CSF leakage; Class C, dehiscence with CSF leakage without meningitis; or Class D, dehiscence with meningitis. RESULTS:Fifty-one patients, 22 males and 29 females, were included in the analysis. The mean age was 48.7 ± 15.5 years, mean body mass index was 32.65 ± 6.86 kg/m(2), and mean symptom duration was 33 ± 42 months. Seven patients underwent repeat surgery for symptomatic recurrence; therefore, there were 58 surgical encounters. Repair included bony reconstruction with hydroxyapatite with or without resection of encephaloceles and/or repair of a dural defect. According to the MFFD classification system described, 15, 8, 27, and 8 cases were categorized as Class A, B, C, and D, respectively. The prevalence of hearing loss was 87%, 63%, and 70% in Classes A, B, and C, respectively. Vestibular symptoms were more prevalent in Class A. Seven patients reported persistent symptoms at the last follow-up. Transient complications were similar in each classification (13%-25%), and a single permanent complication related to anesthesia was observed. There were no mortalities or severe neurological morbidities in the series. CONCLUSIONS:Middle fossa floor dehiscence has a spectrum of clinical presentations. A classification system may help to clarify the diagnosis and guide therapy. Surgery, the mainstay of treatment, is safe and well tolerated.
PMID: 25554855
ISSN: 1933-0693
CID: 5092012

MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma

Mohan, Suresh; Vander Broek, Robert; Shah, Sujay; Eytan, Danielle F; Pierce, Matthew L; Carlson, Sophie G; Coupar, Jamie F; Zhang, Jialing; Cheng, Hui; Chen, Zhong; Van Waes, Carter
PURPOSE/OBJECTIVE:Head and neck squamous cell carcinomas exhibit variable sensitivity to inhibitors of the PI3K/mTOR pathway, an important target of genomic alterations in this cancer type. The mitogen-activated protein kinase kinase (MEK)/ERK/activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) pathways are also frequently co-activated, but their roles in resistance mechanisms to PI3K/mTOR inhibitors and as therapeutic targets in head and neck squamous cell carcinoma (HNSCC) are not well defined. EXPERIMENTAL DESIGN/METHODS:We determined the IC50s of dual PI3K/mTOR inhibitor PF-05212384 (PF-384) by XTT assays in 14 HNSCC lines with PI3K/Akt/mTOR cascade alterations. In two resistant models, we further characterized the molecular, cellular, and in vivo attributes and effects of combining PF-384 with MEK inhibitor PD-0325901 (PD-901). RESULTS:PF-384 IC50s varied between 0.75 and 133 nmol/L in 14 HNSCC lines with overexpression or mutations of PIK3CA, and sensitivity correlated with increased phospho-AKT(T308/S473). In resistant UMSCC-1 and -46 models, PF-384 increased G0-/G1-phase accumulation but weakly induced sub-G0 cell death. PF-384 inhibited direct targets of PI3K/mTOR, but incompletely attenuated co-activated ERK and UMSCC-1 xenograft growth in vivo. PD-901 strongly inhibited MEK/ERK targets, and the combination of PF-384 and PD-901 inhibited downstream NF-κB and AP-1 transactivation, and IL8 and VEGF production in vitro. PD-901 potently inhibited tumor growth alone and with PF384, enhanced antiproliferative, apoptotic, and anti-angiogenesis activity in vivo. CONCLUSIONS:PI3K/mTOR inhibitor PF-384 exhibits variable activity in a panel of HNSCC cell lines with differing PIK3CA expression and mutation status. MEK inhibitor PD-901 overcomes resistance and enhances antitumor effects observed with PF-384 in vivo.
PMCID:4558307
PMID: 25977343
ISSN: 1557-3265
CID: 5005472