Faculty Bibliography

Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression-pre- or postsynaptic-is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity.

OBJECTIVE: To evaluate the safety, efficiency, cost effectiveness, and satisfaction of patients undergoing cochlear implantation under conscious sedation versus general anesthesia. STUDY DESIGN: Retrospective case review of 20 patients who underwent cochlear implantation under conscious sedation which was compared to 20 age-matched patients where surgery was performed under general anesthesia. METHODS: Perioperative times, length of stay, anesthesia drug costs, postoperative complications, and patient satisfaction were compared between the two groups. RESULTS: Conscious sedation was associated with decreased drug costs, surgery time, and anesthesia time. Length of stay was significantly longer for patients undergoing general anesthesia. Patient satisfaction was superior with conscious sedation. Perioperative morbidity was not significantly different between the two groups. CONCLUSION: Conscious sedation for cochlear implantation is a safe, efficient, and cost-effective alternative to general anesthesia. The efficacy of conscious sedation for cochlear implant surgery may expand the treatment of profound hearing loss to the elderly who are deemed too sick for general anesthesia or are fearful of the cognitive or medical consequences of general anesthesia.

BACKGROUND: Assessment of the retropharyngeal lymph nodes is essential in the treatment for oropharyngeal squamous cell carcinoma (SCC). Transoral robotic retropharyngeal lymph node dissection (RPLND) may provide valuable staging information and guide selection of adjuvant therapy in a transoral robotic surgery (TORS) treatment paradigm. METHODS: Outcomes were compared between 30 patients with oropharyngeal SCC with tonsillar primaries undergoing RPLND and 37 stage-matched cases without RPLND. RESULTS: Retropharyngeal metastasis was confirmed in 6 patients undergoing RPLND. Compared with 37 stage-matched controls, there were no differences in length of stay, length of feeding tube dependence, net change in perioperative weight, or rates of hemorrhage and postoperative complications. RPLND altered adjuvant treatment recommendations in 1 of 30 patients. CONCLUSION: RPLND is technically feasible by a purely transoral robotic approach. Its performance is not associated with worse swallowing outcomes or rates of complication. In select patients, RPLND may provide valuable staging information and guide the selection of adjuvant therapy.

BACKGROUND: Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1-blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years). METHODS: Six mutation-positive DIRA patients (children, ages 3-6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months. RESULTS: Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported. CONCLUSION: Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. TRIAL REGISTRATION: ClinicalTrials.gov NCT01801449. FUNDING: NIH, NIAMS, and NIAID.

Background: Beyond the most common adenocarcinoma type, several gallbladder cancer (GBC) histologies have been described as being associated with more favorable (papillary) or less favorable outcome (adenosquamous, mucinous, signet ring). We sought to examine the added value of histologic type and grade on the existing AJCC staging system for resected GBC. Methods: Patients who underwent resection of GBC from 1988-2013 were identified using the Surveillance Epidemiology End Results (SEER) registry. A prognostic score was created by assigning points for T stage, N stage, grade and histology based on the regression coefficient in multivariate analysis. The score was externally validated using the US Extrahepatic Biliary Malignancy Consortium (USEBMC) database (2000- 2015) and compared with the AJCC staging system. Results: Of 7,915 patients identified in SEER, 83% had adenocarcinoma, 7% papillary, 4% adenosquamous, 4% mucinous, and 2% signet ring. In the USEBMC database, the frequencies of the respective histologies were 86, 9, 2, 1 and 2%. Median survival per histologic type, for SEER and USEBMC respectively, were 45 and 110 mos for papillary, 16 and 24 mos for adenocarcinoma, 14 and 12mos for mucinous, 8 and 4mos for adenosquamous, and 9 and 15mos for signet ring (P between histologies < 0.001 for both cohorts). On multivariate analysis, T stage, N stage, grade and histology were independent predictors of survival. The developed prognostic score, based on points for each of these 4 variables, showed excellent discriminatory ability both in the SEER and USEBMC cohorts. The AUC for the prognostic score was significantly improved compared with the AJCC system (0.69 vs. 0.64, both P < 0.001 using SEER, and 0.76 vs. 0.66, both P < 0.001 using USEBMC). Conclusions: The incorporation of histology and grade into the TNM system allows for a simple and accurate tool to determine prognosis following resection of GBC. (Table Presented)

Background: Although several studies have reported on actuarial survival outcomes following resection of hilar cholangiocarcinoma, the characteristics of patients who actually reached the 5-year milestone have not been adequately described. Methods: Patients who underwent resection for hilar cholangiocarcinoma from 2000-2015 in 10 US academic institutions participating in the Extrahepatic Biliary Malignancy Consortium were analyzed. Patients alive at last encounter with less than 5 years of follow-up were excluded. The clinicopathologic characteristics, perioperative, and long-term outcomes of actual 5-yr survivors and of patients who died within 5 years were compared. Results: Of 328 patients explored, 257 (78%) underwent curative resection and had an actuarial 5-year survival of 17%. After excluding 63 survivors with < 5 years follow-up, 194 patients were further classified as 5-year survivors (n = 23, 12%) and non-5-yr survivors. None of the 5-yr survivors had preoperative systemic biliary sepsis, portal vein embolization, T3 tumors with unilateral portal vein or hepatic artery invasion, or T4 tumors necessitating main portal vein or hepatic artery resection. However, actual 5-year survival was still achieved in the setting of bile duct resection only, R1 margins, poor differentiation, lymphovascular or perineural invasion, nodal metastasis, intraoperative blood transfusion, and serious postoperative complications. Fiveyear survival did not equal cure, as five 5-year survivors experienced disease recurrence, 2 before and 3 after the 5-year mark. There were ten actual 7-year survivors and four actual 10-year survivors. Conclusions: Although nodal metastasis, poor differentiation, and R1 margins are established predictors of poor outcome for hilar cholangiocarcinoma, the mere presence of these factors does not preclude patients from achieving a 5-year survival. In contrast, preoperative biliary sepsis, T3 or T4 stage, and the necessity for vascular resection and reconstruction appear to be prohibitive in reaching the 5-year milestone. This information can be utilized in the perioperative counseling of patients with this challenging malignancy

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

Oral cancer patients report severe pain during function. Inflammation plays a role in the oral cancer microenvironment; however, the role of immune cells and associated secretion of inflammatory mediators in oral cancer pain has not been well defined. In this study, we utilized two oral cancer mouse models: a cell line supernatant injection model and the 4-nitroquinoline-1-oxide (4NQO) chemical carcinogenesis model. We used the two models to study changes in immune cell infiltrate and orofacial nociception associated with oral squamous cell carcinoma (oSCC). Oral cancer cell line supernatant inoculation and 4NQO-induced oSCC resulted in functional allodynia and neuronal sensitization of trigeminal tongue afferent neurons. While the infiltration of immune cells is a prominent component of both oral cancer models, our use of immune-deficient mice demonstrated that oral cancer-induced nociception was not dependent on the inflammatory component. Furthermore, the inflammatory cytokine, tumor necrosis factor alpha (TNFa), was identified in high concentration in oral cancer cell line supernatant and in the tongue tissue of 4NQO-treated mice with oSCC. Inhibition of TNFa signaling abolished oral cancer cell line supernatant-evoked functional allodynia and disrupted T cell infiltration. With these data, we identified TNFa as a prominent mediator in oral cancer-induced nociception and inflammation highlighting the need for further investigation in neural-immune communication in cancer pain.

The perirhinal cortex (PRh) is a key region downstream of auditory cortex (ACx) that processes familiarity linked mnemonic signaling. In gerbils, ACx-driven EPSPs recorded in PRh neurons are largely shunted by GABAergic inhibition (Kotak et al. 2015). To determine whether inhibitory shunting prevents the induction of excitatory long-term potentiation (e-LTP), we stimulated ACx-recipient PRh in a brain slice preparation using theta burst stimulation (TBS). Under control conditions, without GABA blockers, the majority of PRh neurons exhibited long-term depression. A very low concentration of bicuculline increased EPSP amplitude, but under this condition TBS did not significantly increase e-LTP induction. Since PRh synaptic inhibition included a GABAB receptor-mediated component, we added a GABAB receptor antagonist. When both GABAA and GABAB receptors were blocked, TBS reliably induced e-LTP in a majority of PRh neurons. We conclude that GABAergic transmission is a vital mechanism regulating e-LTP induction in the PRh, and may be associated with auditory learning.

Background/Purpose: The reconstruction of the wide Tessier #4 cleft is classically limited by persistent lower lid ectropion/medical canthal disruption or the incorporation of unaesthetically located scars which violate the subunit border principle of facial reconstruction. We present a novel repair technique which: can be applied at infancy; does not require tissue expansion; restores stable lower eyelid and medial canthal position; and respects the subunit border principle of facial repair. Methods/Description: A neonate with a complete, wide, Tessier #4 facial cleft presents with an over 2/3rd lower eyelid loss. Presurgical tape therapy was applied to lengthen the lateral tissues transversely and vertically. A Tenzel flap extended to a Schrudde cervicofacial flap was planned to radically mobilize the lower eyelid to the medial canthus in a tension-free manner. A robust vascular supply was maintained to this large flap using a deep plane dissection. Results: Surgical repair was performed at 3 months of age. No tissue expansion was used. A Tenzel pattern flap was mobilized in the subcutaneous plane. This flap was raised in continuity with a Schrudde cervicofacial flap raised in the deep plane. Facial nerves were directly visualized and preserved during the operation. A conjunctival flap was raised from the floor of the orbit was used to reconstruct the posterior lamella of the lower eyelid. The Tenzel/Schrudde flap was rotated, without tension over the defect and to the nose/cheek junction. At the time of inset, there was redundant flap skin superiorly at the level of the lower eyelid and medially at the area of the medial canthus. This redundancy was incorporated into the reconstruction to prevent ectropion and medial canthus disruption. Suspensory sutures were applied to the infraorbital rim and pyriform aperture to prevent sagging of the flap. A Millard repair was used to reconstruct the lip at the level of the philtrum. The flap demonstrated 100% take despite radical mobilization. The final scar followed the philtral line, the nasal/cheek junction, the subcilliary line and the anterior auricular/retro auricular border. Lower eyelid and medial canthal position was stable after 6 months. Facial nerve function was preserved with this approach. Conclusions: A Tenzel/Schrudde deep-plane cervicofacial flap can be safely applied to infants with a wide Tessier #4 facial cleft. No tissue expansion is needed. This is the first repair technique which places final scars perfectly along the subunit borders of the face while preserving lower eyelid and medial canthal position, even in the patient with significant lower eyelid loss