Faculty Bibliography

Oral cancer patients report severe function-induced pain; severity is greater in females. We hypothesize that a neutrophil-mediated endogenous analgesic mechanism is responsible for sex differences in nociception secondary to oral squamous cell carcinoma (SCC). Neutrophils isolated from the cancer-induced inflammatory microenvironment contain β-endorphin protein and are identified by the Ly6G⁺ immune marker. We previously demonstrated that male mice with carcinogen-induced oral SCC exhibit less nociceptive behavior and a higher concentration of neutrophils in the cancer microenvironment compared to female mice with oral SCC. Oral cancer cells secrete granulocyte colony stimulating factor (G-CSF), a growth factor that recruits neutrophils from bone marrow to the cancer microenvironment. We found that recombinant G-CSF (rG-CSF, 5 μg/mouse, intraperitoneal) significantly increased circulating Ly6G⁺ neutrophils in the blood of male and female mice within 24 h of administration. In an oral cancer supernatant mouse model, rG-CSF treatment increased cancer-recruited Ly6G⁺ neutrophil infiltration and abolished orofacial nociceptive behavior evoked in response to oral cancer supernatant in both male and female mice. Local naloxone treatment restored the cancer mediator-induced nociceptive behavior. We infer that rG-CSF-induced Ly6G⁺ neutrophils drive an endogenous analgesic mechanism. We then evaluated the efficacy of chronic rG-CSF administration to attenuate oral cancer-induced nociception using a tongue xenograft cancer model with the HSC-3 human oral cancer cell line. Saline-treated male mice with HSC-3 tumors exhibited less oral cancer-induced nociceptive behavior and had more β-endorphin protein in the cancer microenvironment than saline-treated female mice with HSC-3 tumors. Chronic rG-CSF treatment (2.5 μg/mouse, every 72 h) increased the HSC-3 recruited Ly6G⁺ neutrophils, increased β-endorphin protein content in the tongue and attenuated nociceptive behavior in female mice with HSC-3 tumors. From these data, we conclude that neutrophil-mediated endogenous opioids warrant further investigation as a potential strategy for oral cancer pain treatment.

Medical innovators and regulators have increasingly recognized the importance of working with patients to design medical therapies and clinical trials that meet the needs of specific patient populations. For diseases such as Parkinson's disease (PD), a progressive, degenerative disease with few effective treatment options, traditional randomized clinical trials with a fixed statistical threshold may not reflect patients' perspectives on the trade-off between the risk of endorsing an ineffective therapy (false positive) and the risk of rejecting an effective therapy (false negative). This collaborative project, which involved academia, industry, FDA, patient-scientists and MJFF, developed and tested methods for incorporating patient preference information as explicit means to set significance levels in clinical trial design.
Method(s): With direct input from patients with PD, we developed a patient preference survey and deployed it online through Fox Insight for 6-weeks and received 2,752 complete responses (24.4%), allowing us to analyze differences in outcome priorities among various demographic groups. We then assigned weights to the consequences of errors based on identified patient preferences, and proposed a hypothetical clinical trial design optimized to maximize the values identified by patients.
Result(s): Movement symptoms, which are common endpoints in PD clinical trials, were ranked as most important, and psychological and cognitive symptoms, which are less commonly studied, were ranked as the next most important. Differences emerged from different groups within the patient population, depending upon how the disease manifested itself. Preferences from respondents with mild PD symptoms and no prior experience with deep brains stimulation (

Myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to evolve into accelerated and blast-phase disease (MPN-AP/BP), carrying a dismal prognosis. Conventional antileukemia therapy has limited efficacy in this setting. Thus, MPN-AP/BP is an urgent unmet clinical need. Modest responses to hypomethylating agents and single-agent ruxolitinib have been reported. More recently, combination of ruxolitinib and decitabine has demonstrated synergistic in vitro activity in human and murine systems. These observations led us to conduct a phase 1 study to explore the safety of combined decitabine and dose-escalated ruxolitinib in patients with MPN-AP/BP. A total of 21 patients were accrued to this multicenter study. Ruxolitinib was administered at doses of 10, 15, 25, or 50 mg twice daily in combination with decitabine (20 mg/m² per day for 5 days) in 28-day cycles. The maximum tolerated dose was not reached. The most common reasons for study discontinuation were toxicity/adverse events (37%) and disease progression (21%). Fourteen patients died during study treatment period or follow-up. The median overall survival for patients on study was 7.9 months (95% confidence interval, 4.1-not reached). Among evaluable patients, the overall response rate by protocol-defined criteria (complete remission with incomplete count recovery + partial remission) was 9/17 (53%) and by intention-to-treat analysis was 9/21 (42.9%). The combination of decitabine and ruxolitinib was generally well tolerated by patients with MPN-AP/BP and demonstrates potentially promising clinical activity. A phase 2 trial evaluating the efficacy of this combination regimen is ongoing within the Myeloproliferative Disorder Research Consortium.

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (PMF), frequently progress to more overt forms of MF and a type of acute leukemia termed MPN-accelerated phase/blast phase (MPN-AP/BP). Recent evidence indicates that dysregulation of the tumor suppressor tumor protein p53 (TP53) commonly occurs in the MPNs. The proteins MDM2 and MDM4 alter the cellular levels of TP53. We investigated in 1,294 patients whether abnormalities involving chromosomes 1 and 12, which harbor the genes for MDM4 and MDM2, respectively, and chromosome 17, where the gene for TP53 is located, are associated with MPN disease progression. Gain of 1q occurred not only in individuals with MPN-BP but also in patients with PV and ET, who, with further follow-up, eventually evolve to either MF and/or MPN-BP. These gains of 1q were most prevalent in patients with a history of PV and those who possessed the JAK2V617F driver mutation. The gains of 1q were accompanied by increased transcript levels of MDM4 In contrast, 12q chromosomal abnormalities were exclusively detected in patients who presented with MF or MPN-BP, but were not accompanied by further increases in MDM2/MDM4 transcript levels. Furthermore, all patients with a loss of 17p13, which leads to a deletion of TP53, had either MF or MPN-AP/BP. These findings suggest that gain of 1q, as well as deletions of 17p, are associated with perturbations of the TP53 pathway, which contribute to MPN disease progression.

Observational learning occurs when an animal capitalizes on the experience of another to change its own behavior in a given context. This form of learning is an efficient strategy for adapting to changes in environmental conditions, but little is known about the underlying neural mechanisms. There is an abundance of literature supporting observational learning in humans and other primates, and more recent studies have begun documenting observational learning in other species such as birds and rodents. The neural mechanisms for observational learning depend on the species' brain organization and on the specific behavior being acquired. However, as a general rule, it appears that social information impinges on neural circuits for direct learning, mimicking or enhancing neuronal activity patterns that function during pavlovian, spatial or instrumental learning. Understanding the biological mechanisms for social learning could boost translational studies into behavioral interventions for a wide range of learning disorders.

Measuring how the brain encodes and processes an animal's own motion presents major technical challenges. New approaches demonstrate the viability and merit of measuring vestibular responses throughout the entire brain.

BACKGROUND:Frailty is defined as a disability in those of advanced age, often with comorbidities, poor nutritional status, cognitive decline, and reduced functional status. OBJECTIVES/OBJECTIVE:The purpose of this article is to discuss the concept of frailty, assess the use of a comprehensive geriatric assessment (CGA), and understand the implications for treatment to maintain or enhance physical, functional, and cognitive health of older adult patients with cancer. METHODS:Literature about frailty in older adult patients diagnosed with cancer was reviewed to determine evidence-based assessment and treatment options. FINDINGS/RESULTS:About half of all older adult patients with cancer experience some degree of frailty. CGA is a useful way to evaluate frailty and the extent of limitations. Many frailty-specific tools have been developed. Evidence-based strategies are available to address limitations associated with frailty in older adult patients with cancer.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To determine if a long segment of trachea can be transplanted as a vascularized organ and to determine if a tracheal transplant is a potential surgical option for a long-segment circumferential tracheal defect. STUDY DESIGN/METHODS:Animal model. METHODS:Four (two donors and two recipients) adult domestic Yorkshire swine were used. Two sets of transplants were performed from a donor to recipient pig. The transplant was placed heterotopically (not in continuity with the airway), and the recipient animals were monitored for 14 days to ensure the transplants were well vascularized. Immunosuppressive therapies included methylprednisolone, cyclosporine, and azathioprine. Gross as well as histological examination of multiple tissues types including mucosa, cartilage, muscle, and blood vessels were performed postsacrifice on day 14. RESULTS:Recipient animal weights ranged from 40 to 42 kilograms. Both recipient pigs survived the full 14 days of study and exhibited normal activity and appetite. Ischemia time of transplanted grafts ranged from 63 to 72 minutes. Transplanted tracheas included a minimum of 15 cartilaginous rings and measured greater than 10 cm in length. Both grafts maintained a robust blood supply throughout the duration of study. CONCLUSIONS:The entire visceral compartment can be reliably transplanted, either as a single component (trachea) or as a chimeric flap with multiple components (trachea, esophagus, larynx, and pharynx). Further studies in the swine model should be considered to study the effects of transplanting the trachea orthotopically into the native airway. Further studies are needed into the reliability of this technique of transplantation in humans. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 128:S1-S9, 2018.

OBJECTIVES:Human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is a unique form of head and neck cancer with improved prognosis. We assessed survival for stage I patients with low- or intermediate-risk pathologic features with surgery alone compared with surgery with adjuvant radiation (RT) or chemoradiation (CRT). MATERIALS AND METHODS:We identified patients with stage I HPV+ OPSCC (after restaging with 8th edition staging system) treated with surgery alone, adjuvant RT or CRT in the National Cancer Data Base from 2010 to 2013. We compared survival for low-risk patients (≤1 metastatic lymph nodes with no adverse features) and intermediate-risk patients (2-4 metastatic lymph nodes, microscopic extranodal extension (ENE) or lymphovascular invasion). RESULTS:We examined 1677 patients with median follow-up of 43.9 months. In the intermediate-risk group, 4-year overall survival was 94.0% with surgery alone, 91.5% with adjuvant RT and 92.0% with adjuvant CRT (p = 0.72). There were similar rates of overall survival in the low-risk group. In multivariable models accounting for clinicopathologic differences the dose of adjuvant RT was not associated with mortality. On Cox proportional hazard modeling, adjuvant RT (HR 0.94; CI 0.43-2.08) or CRT (HR 0.96; CI 0.45-2.11) did not significantly improved survival compared with surgery alone in the intermediate-risk group (reference). Similar results were seen in the low-risk group. The composite number of pathologic risk features significantly improved risk stratification. CONCLUSION:We provide observational evidence that adjuvant RT or CRT does not provide a survival benefit for stage I HPV+ OPSCC with low- or intermediate-risk pathologic features.

The auditory system can theoretically encode frequencies by either the rate or place of stimulation within the cochlea. Previous work with cochlear implants has demonstrated that both changes in timing and place can be described as pitch changes but are perceptually orthogonal. Using multidimensional scaling, the present experiment extends the previous findings that timing and place changes are perceptually orthogonal into the cochlear apex using long 31-mm electrode arrays. However, temporal cues seem to be more reliable across subjects at the apex while place cues seem to be more reliable at the middle of the cochlea.