Faculty Bibliography

Myelofibrosis is a chronic and progressive myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating symptoms and leukemic transformation. Ruxolitinib, an oral JAK1/2 inhibitor, is highly effective in ameliorating systemic symptoms and reducing splenomegaly. Current clinical research is focused on the evaluation of agents based on pre-clinical rationale that can result in disease course modification. Panobinostat is a pan-histone deacetylase inhibitor that has demonstrated clinical activity as a single agent in early phase trials of myelofibrosis. We previously conducted a phase I trial of panobinostat monotherapy in patients with myelofibrosis and determined 25mg thrice weekly as the recommended phase II dose. We then completed an investigator initiated, Simon 2-stage, phase II trial of 22 myelofibrosis patients at our single institution. After 6 cycles of therapy, the overall response rate by IWG-MRT criteria was 36% (8/22; 95% CI: 16-56%). The median percent reduction in spleen volume was 34% (range, 1.6%-73%) in eight evaluable patients. The average reduction in JAK2V617F allele burden was 6.8% (Range; -4.0% to 20.2%) and one patient obtained a complete molecular response. Six patients remained on therapy in the extension phase for a median of 18 months (range, 7-44). Treatment discontinuation was frequent due to patient/physician perception of therapy ineffectiveness. The optimal dosing of panobinostat for the treatment of MF remains somewhat ill-defined but appears to be most effective and better tolerated when administered at lower doses over a prolonged duration of therapy.

Virus-mediated gene delivery shows promise for the treatment of chronic pain. However, viral vectors have cytotoxicity. To avoid toxicities and limitations of virus-mediated gene delivery, we developed a novel nonviral hybrid vector: HIV-1 Tat peptide sequence modified with histidine and cysteine residues combined with a cationic lipid. The vector has high transfection efficiency with little cytotoxicity in cancer cell lines including HSC-3 (human tongue squamous cell carcinoma) and exhibits differential expression in HSC-3 ( approximately 45-fold) relative to HGF-1 (human gingival fibroblasts) cells. We used the nonviral vector to transfect cancer with OPRM1, the mu-opioid receptor gene, as a novel method for treating cancer-induced pain. After HSC-3 cells were transfected with OPRM1, a cancer mouse model was created by inoculating the transfected HSC-3 cells into the hind paw or tongue of athymic mice to determine the analgesic potential of OPRM1 transfection. Mice with HSC-3 tumors expressing OPRM1 demonstrated significant antinociception compared with control mice. The effect was reversible with local naloxone administration. We quantified beta-endorphin secretion from HSC-3 cells and showed that HSC-3 cells transfected with OPRM1 secreted significantly more beta-endorphin than control HSC-3 cells. These findings indicate that nonviral delivery of the OPRM1 gene targeted to the cancer microenvironment has an analgesic effect in a preclinical cancer model, and nonviral gene delivery is a potential treatment for cancer pain.

Background: Perioperative allogeneic blood transfusion is associated with poor oncologic outcomes in several malignancies. Its effect on recurrence and survival in distal cholangiocarcinoma (DCC) is unknown. Methods: All patients with DCC who underwent curative-intent pancreaticoduodenectomy at 10 institutions from 2000-2015 were included. 30-day mortalities were excluded. Primary outcomes were recurrence-free (RFS) and overall survival (OS). Results: Of 314 pts with DCC, 206 (66%) underwent curative-intent pancreaticoduodenectomy. Median age was 67yrs, and 53 pts (28%) received perioperative blood transfusions, with a median of 2 units. There were no differences in baseline demographics or operative data between transfusion and no-transfusion groups. Compared to no-transfusion, patients who received a transfusion were more likely to have (+)margins (28vs14%; p < 0.03) and major complications (46vs16%; p < 0.001). Receipt of neoadjuvant or adjuvant therapy was similar between groups. Transfusion was associated with lower median RFS (19vs32mos; p = 0.006) and OS (15vs29mos; p = 0.003), which persisted on multivariable (MV) analysis for both RFS (HR 1.8; 95%CI 1.1-3.1; p = 0.03)and OS (HR 1.9; 95%CI 1.1-3.2; p = 0.03), after controlling for portal vein resection, EBL, margin status, grade, LVI, LN status, and major complications. Similarly, transfusion of >= 2 pRBC units was associated with lower RFS (17vs32mos; p < 0.001) and OS (14vs29mos; p < 0.001), which again persisted on MV analysis for both RFS (HR 2.6; 95%CI 1.4-4.6; p = 0.002) and OS (HR 3.9; 95%CI 2.1-7.5; p < 0.001). The RFS and OS of patients transfused 1 unit was similar to those not transfused. Conclusions: Perioperative blood transfusion is associated with decreased RFS and OS after resection for distal cholangiocarcinoma, after accounting for known adverse pathologic factors. Volume of transfusion seems to exert an independent effect, as 1 unit is not associated with the same adverse effects as >= 2units. This supports the judicious use of perioperative transfusion; protocols should be developed and followed

Cochlear implant (CI) recipients have difficulty understanding speech in noise even at moderate signal-to-noise ratios. Knowing the mechanisms they use to understand speech in noise may facilitate the search for better speech processing algorithms. In the present study, a computational model is used to assess whether CI users' vowel identification in noise can be explained by formant frequency cues (F1 and F2). Vowel identification was tested with 12 unilateral CI users in quiet and in noise. Formant cues were measured from vowels in each condition, specific to each subject's speech processor. Noise distorted the location of vowels in the F2 vs F1 plane in comparison to quiet. The best fit model to subjects' data in quiet produced model predictions in noise that were within 8% of actual scores on average. Predictions in noise were much better when assuming that subjects used a priori knowledge regarding how formant information is degraded in noise (experiment 1). However, the model's best fit to subjects' confusion matrices in noise was worse than in quiet, suggesting that CI users utilize formant cues to identify vowels in noise, but to a different extent than how they identify vowels in quiet (experiment 2).

Objective To determine the impact of unilateral vagal sacrifice for vagal schwannoma on postoperative swallowing function. Study Design Case series, chart review. Setting Academic medical institution. Subjects and Methods Ten patients underwent vagus nerve sacrifice for vagal schwannoma resection. Archived pathology records dating from 1985 through 2012 at our institution were retrospectively queried for cases of vagal schwannoma with vagus nerve sacrifice. Medical records were abstracted for demographic and disease information as well as cranial nerve and swallowing function. Preoperative and postoperative cranial nerve function, subjective and objective measures of swallowing function, Functional Oral Intake Scale (FOIS) level, and need for vocal fold medialization were variables collected. Data were analyzed with summary statistics. Results The patients who underwent vagal sacrifice for vagal schwannoma at our institution had a mean age of 42.3 years (median, 44 years; range, 15-63 years) and follow-up of 35.6 months (median, 9 months; range, 1-115 months). Most presented with no preoperative cranial nerve deficit or difficulty swallowing. Immediately postoperatively, 90% had a vagus nerve deficit, but 50% had no subjective difficulty swallowing, and 70% had a FOIS level of 7 at postoperative hospital discharge. Within 1 month after surgery, 70% had normal swallowing function according to a modified barium swallow study. A full diet was tolerated by mouth within an average of 2.7 days (median, 2 days; range, 1-6 days) after surgery in this cohort. Seventy percent required vocal fold medialization postoperatively for incomplete glottic closure. Conclusion Vagal nerve sacrifice during resection of vagal schwannoma can be performed with normal postoperative swallowing function.

Objective Rhinoplasty, a surgical procedure that alters the shape or appearance of the nose while preserving or enhancing the nasal airway, ranks among the most commonly performed cosmetic procedures in the United States, with >200,000 procedures reported in 2014. While it is difficult to calculate the exact economic burden incurred by rhinoplasty patients following surgery with or without complications, the average rhinoplasty procedure typically exceeds $4000. The costs incurred due to complications, infections, or revision surgery may include the cost of long-term antibiotics, hospitalization, or lost revenue from hours/days of missed work. The resultant psychological impact of rhinoplasty can also be significant. Furthermore, the health care burden from psychological pressures of nasal deformities/aesthetic shortcomings, surgical infections, surgical pain, side effects from antibiotics, and nasal packing materials must also be considered for these patients. Prior to this guideline, limited literature existed on standard care considerations for pre- and postsurgical management and for standard surgical practice to ensure optimal outcomes for patients undergoing rhinoplasty. The impetus for this guideline is to utilize current evidence-based medicine practices and data to build unanimity regarding the peri- and postoperative strategies to maximize patient safety and to optimize surgical results for patients. Purpose The primary purpose of this guideline executive summary is to provide evidence-based recommendations for clinicians who either perform rhinoplasty or are involved in the care of a rhinoplasty candidate, as well as to optimize patient care, promote effective diagnosis and therapy, and reduce harmful or unnecessary variations in care. The target audience is any clinician or individual, in any setting, involved in the management of these patients. The target patient population is all patients aged >/=15 years. The guideline is intended to focus on knowledge gaps, practice variations, and clinical concerns associated with this surgical procedure; it is not intended to be a comprehensive reference for improving nasal form and function after rhinoplasty. Recommendations in this guideline concerning education and counseling to the patient are intended to include the caregiver if the patient is <18 years of age. Action Statements The Guideline Development Group made the following recommendations: (1) Clinicians should ask all patients seeking rhinoplasty about their motivations for surgery and their expectations for outcomes, should provide feedback on whether those expectations are a realistic goal of surgery, and should document this discussion in the medical record. (2) Clinicians should assess rhinoplasty candidates for comorbid conditions that could modify or contraindicate surgery, including obstructive sleep apnea, body dysmorphic disorder, bleeding disorders, or chronic use of topical vasoconstrictive intranasal drugs. (3) The surgeon, or the surgeon's designee, should evaluate the rhinoplasty candidate for nasal airway obstruction during the preoperative assessment. (4) The surgeon, or the surgeon's designee, should educate rhinoplasty candidates regarding what to expect after surgery, how surgery might affect the ability to breathe through the nose, potential complications of surgery, and the possible need for future nasal surgery. (5) The clinician, or the clinician's designee, should counsel rhinoplasty candidates with documented obstructive sleep apnea about the impact of surgery on nasal airway obstruction and how obstructive sleep apnea might affect perioperative management. (6) The surgeon, or the surgeon's designee, should educate rhinoplasty patients before surgery about strategies to manage discomfort after surgery. (7) Clinicians should document patient satisfaction with their nasal appearance and with their nasal function at a minimum of 12 months after rhinoplasty. The guideline development group made recommendations against certain actions: (1) When a surgeon, or the surgeon's designee, chooses to administer perioperative antibiotics for rhinoplasty, he or she should not routinely prescribe antibiotic therapy for a duration >24 hours after surgery. (2) Surgeons should not routinely place packing in the nasal cavity of rhinoplasty patients (with or without septoplasty) at the conclusion of surgery. The panel group made the following statement an option: (1) The surgeon, or the surgeon's designee, may administer perioperative systemic steroids to the rhinoplasty patient.

Oxytocin is a hypothalamic neuropeptide that has gained attention for the effects on social behavior. Recent findings shed new light on the mechanisms of oxytocin in synaptic plasticity and adaptively modifying neural circuits for social interactions such as conspecific recognition, pair bonding, and maternal care. Here, we review several of these newer studies on oxytocin in the context of previous findings, with an emphasis on social behavior and circuit plasticity in various brain regions shown to be enriched for oxytocin receptors. We provide a framework that highlights current circuit-level mechanisms underlying the widespread action of oxytocin

Both spatial and temporal cues determine the fate of immature neurons. A major challenge at the interface of developmental and systems neuroscience is to relate this spatiotemporal trajectory of maturation to circuit-level functional organization. This study examined the development of two extraocular motor nuclei (nIII and nIV), structures in which a motoneuron's identity, or choice of muscle partner, defines its behavioral role. We used retro-orbital dye fills, in combination with fluorescent markers for motoneuron location and birthdate, to probe spatial and temporal organization of the oculomotor (nIII) and trochlear (nIV) nuclei in the larval zebrafish. We describe a dorsoventral organization of the four nIII motoneuron pools, in which inferior and medial rectus motoneurons occupy dorsal nIII, while inferior oblique and superior rectus motoneurons occupy distinct divisions of ventral nIII. Dorsal nIII motoneurons are, moreover, born before motoneurons of ventral nIII and nIV. The order of neurogenesis can therefore account for the dorsoventral organization of nIII and may play a primary role in determining motoneuron identity. We propose that the temporal development of extraocular motoneurons plays a key role in assembling a functional oculomotor circuit. J. Comp. Neurol. 525:65-78, 2017. (c) 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.