Thyroid Cancer Incidence and Tumor Size in New Mexico American Indians, Hispanics, and Non-Hispanic Whites, 1992 to 2019.

BACKGROUND: The incidence of thyroid cancer in the United States has risen dramatically since the 1970s, driven by an increase in the diagnosis of small tumors. There is a paucity of published New Mexico (NM) specific data regarding thyroid cancer. We hypothesized that due to New Mexico's unique geographic and cultural makeup, the incidence of thyroid cancer and tumor size at diagnosis in this state would differ from that demonstrated on a national level. METHODS: The New Mexico Tumor Registry (NMTR) was queried to include all NM residents diagnosed with thyroid cancer between 1992 and 2019. For 2010 to 2019, age-adjusted incidence rates were calculated via direct method using the 2000 United States population as the adjustment standard. Differences in incidence rate and tumor size by race/ethnicity and residence (metropolitan vs non-metropolitan) were assessed with rate ratios between groups. For 1992 to 2019, temporal trends in age-adjusted incidence rates for major race/ethnic groups in NM [Non-Hispanic White (NHW), Hispanic, and American Indian (AI)] were assessed by joinpoint regression using National Cancer Institute software. RESULTS: Our study included 3,161 patients for the time period 2010 to 2019, including NHW (1518), Hispanic (1425), and AI (218) cases. The overall incidence rates for NM AIs were lower than those for Hispanics and NHWs because of a decreased incidence of very small tumors (<1.1 cm). The incidence rates for large tumors (>5.1 cm) was equivalent among groups. In the early 2000s, Hispanics also had lower rates of small tumors when compared to NHWs but this trend disappeared over time. CONCLUSION: AIs in New Mexico have been left out of the nationwide increase in incidental diagnosis of small thyroid tumors. This same pattern was noted for Hispanics in the early 2000s but changed over time to mirror incidence rates for NHWs. These data are illustrative of the health care disparities that exist among New Mexico's population and how these disparities have changed over time.

Feasibility of a virtual reality course on adult tracheostomy safety skills.

The National Tracheostomy Safety Project has run high-quality, face-to-face skills courses since 2009. The aim of this project was to produce a virtual reality version of the established course and evaluate its impact on participant learning, and participant and faculty satisfaction. Healthcare staff and students were recruited and randomised to attend one of (1) a face-to-face traditional course (control); (2) a virtual reality course at a conference centre with on-site technical support; (3) a fully remote virtual reality course; the virtual reality groups were combined for the analysis of learning outcomes and satisfaction. The primary outcome was the difference in pre/post-course knowledge scores on a 30-item questionnaire; secondary outcomes included knowledge retention, usability, comfort/side effects and participant performance in a simulated tracheostomy emergency. Thirty-seven participants and 15 faculty participated in this study. There was no significant difference between mean pre/post-course scores from the face-to-face (from 21.1 to 23.1; +2) and combined virtual reality (from 17.1 to 21.1; +4) groups, with both showing improvement (p = 0.21). The mean System Usability Scale score for virtual reality was 76.8 (SD 12.6), which is above average; the median Simulator Sickness Questionnaire score was 7.5 (IQR 3.7-22.4), indicating minimal symptoms. All participants resolved the primary clinical problem in the simulated emergency, but the virtual reality (VR) group was slower overall (mean difference 61.8 s, p = 0.003). This technical feasibility study demonstrated that there was no difference in participant knowledge immediately after and 4 weeks following face-to-face and virtual reality courses. Virtual reality offers an immersive experience that can be delivered remotely and offers potential benefits of reducing travel and venue costs for attendees, therefore increasing the flexibility of training opportunities.

Safety, Tolerability, and Pharmacokinetics of Single- and Multiple-Ascending Doses of Sunobinop in Healthy Participants.

Sunobinop is an investigational, potent, selective partial agonist at the nociceptin/orphanin FQ peptide receptor in vitro. Three phase 1 studies were conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of escalating single- and multiple-dose administration of sunobinop in healthy participants. Study 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study. Study 2 was a randomized, double-blind, placebo-controlled, multiple-ascending dose study. Study 3 was a randomized, open-label, single-dose, 4-way crossover study of oral and sublingual sunobinop comparing morning (AM) and bedtime (PM) administration. Seventy participants were included. Systemic exposure (peak plasma concentration [Cmax], area under the plasma concentration-time curve from time 0 to the time of last quantifiable concentration [AUC0-t], and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf]) of sunobinop was characterized by dose proportionality from 0.6 to 2 mg and increased less than proportionally from 3 to 30 mg. The PKs of sunobinop were similar, regardless of AM or PM administration, for both the oral and sublingual formulations. The majority of absorbed sunobinop was excreted unchanged in the urine within 8 hours of dosing, thereby showing rapid elimination with no appreciable accumulation following 14 consecutive days of once-daily dosing and suggesting exclusive renal elimination. Most treatment-emergent adverse events (TEAEs) were mild in severity; 1 severe TEAE occurred and all TEAEs resolved by the end of the studies. Sunobinop was generally well-tolerated and safe across the range of doses evaluated and presents a clinical profile suitable for continued development.

The nociceptin/orphanin FQ receptor partial agonist sunobinop promotes non-REM sleep in rodents and patients with insomnia.

The potent and partial agonist sunobinop activates the nociceptin/orphanin-FQ peptide receptor and promotes non-REM sleep in rodents and patients with insomnia.

Predicting nodal metastases in squamous cell carcinoma of the oral tongue using artificial intelligence.

OBJECTIVE: The presence of occult nodal metastases in patients with squamous cell carcinoma (SCC) of the oral tongue has implications for treatment. Upwards of 30% of patients will have occult nodal metastases, yet a significant number of patients undergo unnecessary neck dissection to confirm nodal status. This study sought to predict the presence of nodal metastases in patients with SCC of the oral tongue using a convolutional neural network (CNN) that analyzed visual histopathology from the primary tumor alone. METHODS: Cases of SCC of the oral tongue were identified from the records of a single institution. Only patients with complete pathology data were included in the study. The primary tumors were randomized into 2 groups for training and testing, which was performed at 2 different levels of supervision. Board-certified pathologists annotated each slide. HALO-AI convolutional neural network and image software was used to perform training and testing. Receiver operator characteristic (ROC) curves and the Youden J statistic were used for primary analysis. RESULTS: Eighty-nine cases of SCC of the oral tongue were included in the study. The best performing algorithm had a high level of supervision and a sensitivity of 65% and specificity of 86% when identifying nodal metastases. The area under the curve (AUC) of the ROC curve for this algorithm was 0.729. CONCLUSION: A CNN can produce an algorithm that is able to predict nodal metastases in patients with squamous cell carcinoma of the oral tongue by analyzing the visual histopathology of the primary tumor alone.

Lymph Node Metastases in Papillary Thyroid Carcinoma can be Predicted by a Convolutional Neural Network: a Multi-Institution Study.

OBJECTIVES: The presence of nodal metastases in patients with papillary thyroid carcinoma (PTC) has both staging and treatment implications. However, lymph nodes are often not removed during thyroidectomy. Prior work has demonstrated the capability of artificial intelligence (AI) to predict the presence of nodal metastases in PTC based on the primary tumor histopathology alone. This study aimed to replicate these results with multi-institutional data. METHODS: Cases of conventional PTC were identified from the records of 2 large academic institutions. Only patients with complete pathology data, including at least 3 sampled lymph nodes, were included in the study. Tumors were designated "positive" if they had at least 5 positive lymph node metastases. First, algorithms were trained separately on each institution's data and tested independently on the other institution's data. Then, the data sets were combined and new algorithms were developed and tested. The primary tumors were randomized into 2 groups, one to train the algorithm and another to test it. A low level of supervision was used to train the algorithm. Board-certified pathologists annotated the slides. HALO-AI convolutional neural network and image software was used to perform training and testing. Receiver operator characteristic curves and the Youden J statistic were used for primary analysis. RESULTS: There were 420 cases used in analyses, 45% of which were negative. The best performing single institution algorithm had an area under the curve (AUC) of 0.64 with a sensitivity and specificity of 65% and 61% respectively, when tested on the other institution's data. The best performing combined institution algorithm had an AUC of 0.84 with a sensitivity and specificity of 68% and 91% respectively. CONCLUSION: A convolutional neural network can produce an accurate and robust algorithm that is capable of predicting nodal metastases from primary PTC histopathology alone even in the setting of multi-institutional data.

Particulate levodopa nose-to-brain delivery targets dopamine to the brain with no plasma exposure.

Levodopa (L-DOPA) is an oral Parkinson's Disease drug that generates the active metabolite - dopamine (DA) in vivo. However, oral L-DOPA exhibits low oral bioavailability, limited brain uptake, peripheral DA-mediated side effects and its poor brain bioavailability can lead to long-term complications. Here we show that L-DOPA forms stable (for at least 5 months) 300 nm nanoparticles when encapsulated within N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ). A nano-in-microparticle GCPQ-L-DOPA formulation (D50 = 7.2 µm), prepared by spray-drying, was stable for one month when stored at room and refrigeration temperatures and was capable of producing the original GCPQ-L-DOPA nanoparticles upon aqueous reconstitution. Nasal administration of reconstituted GCPQ-L-DOPA nanoparticles to rats resulted in significantly higher DA levels in the brain (Cmax of 94 ng g-1 above baseline levels 2 h post-dosing) when compared to nasal administration of L-DOPA alone, with DA being undetectable in the brain with the latter. Furthermore, nasal GCPQ-L-DOPA resulted in higher levels of L-DOPA in the plasma (a 17-fold increase in the Cmax, when compared to L-DOPA alone) with DA undetectable in the plasma from both formulations. These data provide evidence of effective delivery of DA to the brain with the GCPQ-L-DOPA formulation.

Worse Pituitary Adenoma Surgical Outcomes Predicted by Increasing Frailty, Not Age.

PURPOSE: Increasing patient age has been associated with worse outcomes after pituitary adenoma resection in previous studies, but the prognostic value of frailty compared with advancing age on pituitary adenoma resection outcomes has not been clearly evaluated. METHODS: The National Surgical Quality Improvement Program from 2015 to 2019 was queried for data for patients aged >18 years who underwent pituitary adenoma resection (n = 1454 identified patients). Univariate and multivariate analyses of age and frailty (5-factor modified frailty index [mFI-5]) were performed on 30-day mortality, major complications, extended length of stay (eLOS), discharge destination, and readmission and reoperation. The receiver operating characteristic curve analysis was performed to compare effect of age and mFI-5. RESULTS: On univariate analysis, increasing frailty was significantly associated with greater risk of unplanned readmission (frail: odds ratio [OR], 1.9; 95% confidence interval [CI], 1.2-3.2; severely frail: OR, 6.9; 95% CI, 2.4-19.8) and a major complication (frail: OR, 3.6; 95% CI, 2.1-6.1). Severe frailty was also associated with nonhome discharge (OR, 10.6; 95% CI, 3.2-35.8) and eLOS (OR, 4.5; 95% CI, 1.5-13.4). Increasing age was not associated with any of these outcome measures. Multivariate analysis also demonstrated similar trends. In receiver operating characteristic curve analysis, the mFI-5 score showed higher discrimination for major complications compared with age (area under the curve: 0.624 vs. 0.503; P < 0.001). CONCLUSION: Increasing frailty, and not advancing age, was an independent predictor for major complications, unplanned readmissions, eLOS, and nonhome discharge after pituitary adenoma resection, suggesting frailty to be superior to age in preoperative risk stratification in this patient population.

Predicting nodal metastases in papillary thyroid carcinoma using artificial intelligence.

BACKGROUND: The presence of nodal metastases is important in the treatment of papillary thyroid carcinoma (PTC). We present our experience using a convolutional neural network (CNN) to predict the presence of nodal metastases in a series of PTC patients using visual histopathology from the primary tumor alone. METHODS: 174 cases of PTC were evaluated for the presence or absence of lymph metastases. The artificial intelligence (AI) algorithm was trained and tested on its ability to discern between the two groups. RESULTS: The best performing AI algorithm demonstrated a sensitivity and specificity of 94% and 100%, respectively, when identifying nodal metastases. CONCLUSION: A CNN can be used to accurately predict the likelihood of nodal metastases in PTC using visual data from the primary tumor alone.

Hoarseness Caused by a Penetrating Proximal Descending Thoracic Aortic Ulcer and Pseudoaneurysm.

We present a case of an 87-year-old female with new-onset hoarseness of unclear etiology. Imaging demonstrated a penetrating aortic ulcer (PAU) in the proximal descending thoracic aorta with an associated pseudoaneurysm that enlarged to a depth of 32 mm over 2 years. This patient was diagnosed with hoarseness being secondary to left recurrent laryngeal nerve (LRLN) palsy, a variant of Ortner syndrome. Patient was treated with endovascular stent-grafting successfully covering of the PAU and pseudoaneurysm with zone 3 proximal landing zone. The patient had moderate improvement in hoarseness after 1 year of follow-up. Endovascular repair is indicated for symptomatic patients with PAUs complicated by enlarging pseudoaneurysms or rupture. Endovascular treatment is effective with low procedural morbidity and mortality. In this case, the PAU and associated pseudoaneurysm at the level of the ligamentum arteriosum caused compression on the LRLN, resulting in a nerve palsy and hoarseness. This case highlights the importance of vascular imaging for patients presenting with unclear etiology of hoarseness or other signs of LRLN palsy. Therefore, aortic arch abnormalities, a variant of Ortner syndrome, even though rare, should be on the differential diagnosis of new onset hoarseness.

Pharmacological evaluation of NSAID-induced gastropathy as a "Translatable" model of referred visceral hypersensitivity.

AIM: To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity. METHODS: Gastric ulcer pain was induced by the oral administration of indomethacin to male, CD1 mice (n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential (TRP), sodium and acid-sensing ion channels (ASICs) as well as opioid receptors and guanylate cyclase C (GC-C). RESULTS: Results showed that two opioids and a GC-C agonist, morphine, asimadoline and linaclotide, respectively, the TRP antagonists, AMG9810 and HC-030031 and the sodium channel blocker, carbamazepine, elicited a dose- and/or time-dependent attenuation of referred visceral hypersensitivity, while the ASIC blocker, amiloride, was ineffective at all doses tested. CONCLUSION: Together, these findings implicate opioid receptors, GC-C, and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly, these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.

A randomized, double-blind, positive-controlled, 3-way cross-over human experimental pain study of a TRPV1 antagonist (V116517) in healthy volunteers and comparison with preclinical profile.

This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P < 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P = 0.004 and P < 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P = 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P < 0.0001) reduced by celecoxib. Stimulus-response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue.

Preclinical Pharmacological Approaches in Drug Discovery for Chronic Pain.

In recent years, animal behavioral models, particularly those used in pain research, have been increasingly scrutinized and criticized for their role in the poor translation of novel pharmacotherapies for chronic pain. This chapter addresses the use of animal models of pain used in drug discovery research. It highlights how, when, and why animal models of pain are used as one of the many experimental tools used to gain better understanding of target mechanisms and rank-order compounds in the iterative process of establishing structure-activity relationship. Together, these models help create an "analgesic signature" for a compound and inform the indications most likely to yield success in clinical trials. In addition, the authors discuss some often underappreciated aspects of currently used (traditional) animal models of pain, including simply applying basic pharmacological principles to study design and data interpretation as well as consideration of efficacy alongside side effect measures as part of the overall conclusion of efficacy. This is provided to add perspective regarding current efforts to develop new models and endpoints both in rodents and in larger animal species as well as assess cognitive and/or affective aspects of pain. Finally, the authors suggest ways in which efficacy evaluation in animal models of pain, whether traditional or new, might better align with clinical standards of analysis, citing examples where applying effect size and number needed to treat estimations to animal model data suggest that the efficacy bar often may be set too low preclinically to allow successful translation to the clinical setting.

Robustness of arterial blood gas analysis for assessment of respiratory safety pharmacology in rats.

Whole body plethysmography using unrestrained animals is a common technique for assessing the respiratory risk of new drugs in safety pharmacology studies in rats. However, wide variations in experimental technique make cross laboratory comparison of data difficult and raise concerns that non-appropriate conditions may mask the deleterious effects of test compounds - in particular with suspected respiratory depressants. Therefore, the objective of this study was to evaluate the robustness of arterial blood gas analysis as an alternative to plethysmography in rats. We sought to do this by assessing the effect of different vehicles and times post-surgical catheterization on blood gas measurements, in addition to determining sensitivity to multiple opioids. Furthermore, we determined intra-lab variability from multiple datasets utilizing morphine and generated within a single lab and lastly, inter-lab variability was measured by comparing datasets generated in two separate labs. Overall, our data show that arterial blood gas analysis is a measure that is both flexible in terms of experimental conditions and highly sensitive to respiratory depressants, two key limitations when using plethysmography. As such, our data strongly advocate the adoption of arterial blood gas analysis as an investigative approach to reliably examine the respiratory depressant effects of opioids.

Protective role of G-CSF in dextran sulfate sodium-induced acute colitis through generating gut-homing macrophages.

Granulocyte colony-stimulating factor (G-CSF) is a pleiotropic cytokine best known for its role in promoting the generation and function of neutrophils. G-CSF is also found to be involved in macrophage generation and immune regulation; however, its in vivo role in immune homeostasis is largely unknown. Here, we examined the role of G-CSF in dextran sulfate sodium (DSS)-induced acute colitis using G-CSF receptor-deficient (G-CSFR(-/-)) mice. Mice were administered with 1.5% DSS in drinking water for 5days, and the severity of colitis was measured for the next 5days. GCSFR(-/-) mice were more susceptible to DSS-induced colitis than G-CSFR(+/+) or G-CSFR(-/+) mice. G-CSFR(-/-) mice harbored less F4/80(+) macrophages, but a similar number of neutrophils, in the intestine. In vitro, bone marrow-derived macrophages prepared in the presence of both G-CSF and macrophage colony-stimulating factor (M-CSF) (G-BMDM) expressed higher levels of regulatory macrophage markers such as programmed death ligand 2 (PDL2), CD71 and CD206, but not in arginase I, transforming growth factor (TGF)-ß, Ym1 (chitinase-like 3) and FIZZ1 (found in inflammatory zone 1), and lower levels of inducible nitric oxide synthase (iNOS), CD80 and CD86 than bone marrow-derived macrophages prepared in the presence of M-CSF alone (BMDM), in response to interleukin (IL)-4/IL-13 and lipopolysaccharide (LPS)/interferon (IFN)-γ, respectively. Adoptive transfer of G-BMDM, but not BMDM, protected G-CSFR(-/-) mice from DSS-induced colitis, and suppressed expression of tumor necrosis factor (TNF)-α, IL-1ß and iNOS in the intestine. These results suggest that G-CSF plays an important role in preventing colitis, likely through populating immune regulatory macrophages in the intestine.

Evaluating a groundwater supply contamination incident attributed to Marcellus Shale gas development.

High-volume hydraulic fracturing (HVHF) has revolutionized the oil and gas industry worldwide but has been accompanied by highly controversial incidents of reported water contamination. For example, groundwater contamination by stray natural gas and spillage of brine and other gas drilling-related fluids is known to occur. However, contamination of shallow potable aquifers by HVHF at depth has never been fully documented. We investigated a case where Marcellus Shale gas wells in Pennsylvania caused inundation of natural gas and foam in initially potable groundwater used by several households. With comprehensive 2D gas chromatography coupled to time-of-flight mass spectrometry (GCxGC-TOFMS), an unresolved complex mixture of organic compounds was identified in the aquifer. Similar signatures were also observed in flowback from Marcellus Shale gas wells. A compound identified in flowback, 2-n-Butoxyethanol, was also positively identified in one of the foaming drinking water wells at nanogram-per-liter concentrations. The most likely explanation of the incident is that stray natural gas and drilling or HF compounds were driven ∼ 1-3 km along shallow to intermediate depth fractures to the aquifer used as a potable water source. Part of the problem may have been wastewaters from a pit leak reported at the nearest gas well pad-the only nearby pad where wells were hydraulically fractured before the contamination incident. If samples of drilling, pit, and HVHF fluids had been available, GCxGC-TOFMS might have fingerprinted the contamination source. Such evaluations would contribute significantly to better management practices as the shale gas industry expands worldwide.

Longitudinal voice outcomes following laryngeal reinnervation via vagus-to-recurrent laryngeal nerve anastomosis after vagal nerve sacrifice: a case series.

OBJECTIVE: This study aimed to describe longitudinal voice outcomes of vagus-to-recurrent laryngeal nerve anastomosis following operative vagal nerve sacrifice. METHODS: Two patients who underwent anastomosis were assessed by a multidisciplinary voice team at 1, 4, 9, 12, and 18 months after vagal sacrifice. RESULTS: Long-term changes in voice function based on auditory perceptual measures of voice quality and visual perceptual changes in glottal closure were observed and maintained for 18 months after vagus-to-recurrent laryngeal nerve anastomosis in 2 patients with proximal vagal nerve sacrifice. Patients achieved acceptable voice outcomes and elected not to undergo further treatment, which was supported by Voice Handicap Index scores. CONCLUSION: Gradual restoration of voice following operative vagal sacrifice can be achieved over an 18-month period using vagus-to-recurrent laryngeal nerve anastomosis and warrants further investigation in appropriately selected patients.

An industry perspective on the role and utility of animal models of pain in drug discovery.

In recent years, animal behavioral models, particularly those used in pain research, have been increasingly scrutinized and criticized for their role in the poor translation of novel pharmacotherapies for chronic pain. This article addresses the use of animal models of pain from the perspective of industrial drug discovery research. It highlights how, when, and why animal models of pain are used as one of the many experimental tools used to gain better understanding of target mechanisms and rank-order compounds in the iterative process of establishing structure-activity relationships (SAR). Together, these models help create an 'analgesic signature' for a compound and inform the indications most likely to yield success in clinical trials. In addition, the authors discuss some often under-appreciated aspects of currently used (traditional) animal models of pain, including how industry balances efficacy with side effect measures as part of the overall conclusion of efficacy. This is provided to add perspective regarding current efforts to develop new models and endpoints both in rodents and larger animal species as well as assess cognitive and/or affective aspects of pain. Finally, the authors suggest ways in which efficacy evaluation in animal models of pain, whether traditional or new, might better align with clinical standards of analysis, citing examples where applying effect size and NNT estimations to animal model data suggest that the efficacy bar often may be set too low preclinically to allow successful translation to the clinical setting.

A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma.

OBJECTIVES: The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy. MATERIALS AND METHODS: Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0-2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines. RESULTS: Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression. CONCLUSIONS: The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted.