bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reirradiation After Surgery and Microvascular Reconstruction
Authors: Suh Jeffrey D. , Kim Brian Paul , Abemayor Elliot , Sercarz Joel A , Nabili Vishad , Liu Jerome H , Juillard Guy Jf , Blackwell Keith E 
Published: August 2008

ProblemTo evaluate the outcome and complications of reirradiation of recurrent head and neck cancer after salvage surgery and microvascular reconstruction.MethodsRetrospective Study. Twelve patients underwent salvage surgery with microvascular reconstruction for recurrent or new primary head and neck cancer in a previously irradiated field. Median prior RT dose was 63.0 Gy (range 30.0–72.8). Patients then underwent postoperative reirradiation, receiving a median total cumulative radiation dose of 115.0 Gy.ResultsThree patients (25%) experienced acute complications (<3 months) during reirradiation that resolved with conservative care. Four patients (33%) developed grade 3 or 4 late reirradiation complications (>3 months). There were no incidences of free flap failure. No patients suffered brain necrosis, spinal cord injury, or carotid rupture. The incidence of soft tissue necrosis and osteoradionecrosis was 8%. There were no treatment‐related mortalities. Six patients (50%) are alive without evidence of recurrent disease a median of 40 months after reirradiation (range 4–64 months).ConclusionFree flap reconstruction followed by reirradiation is not associated with an increased risk of perioperative, acute, or late complications. Microvascular free flaps allow for maximal resection and reliable reconstruction of previously irradiated cancers before high dose reirradiation, and may reduce the incidence of severe late complications and treatment related mortality.SignificanceReirradiation for recurrent head and neck squamous cell carcinoma remains controversial. However, increasing evidence has demonstrated improved survival and locoregional control with reirradiation at the cost of potentially severe or sometimes fatal radiation toxicity. We hypothesize that using well‐vascularized tissue and bone at the time of salvage surgery can reduce the incidence of reirradiation complications. This would allow patients at high risk for recurrence to more safely receive a second course of radiation therapy. To our knowledge this is the first report of the effects of microvascular reconstruction on complications and outcomes of patients undergoing salvage surgery and external beam reirradiation.
Targeted Liposomal Paclitaxel Raises Tumor Vessel Leakiness
Authors: Strieth Sebastian , Eichhorn Martin E , Alexander Werner , Sauer Birgitta , Teifel Michael , Michaelis Uwe , Berghaus Alexander , Dellian Marc 
Published: August 2008

ProblemPaclitaxel encapsulated in cationic liposomes (EndoTAG‐1) is a vascular targeting formulation for the treatment of solid tumors. It triggers intratumoral microthrombosis causing significant inhibition of tumor perfusion and tumor growth associated with endothelial cell apoptosis. Here, we quantified the effects of repeated EndoTAG‐1 therapy on tumor microvascular leakiness with respect to leukocyte‐endothelial cell interactions, the targeting property of cationic liposomes and the therapeutic combination with conventional cisplatin chemotherapy.MethodsUsing dorsal skinfold chamber preparations in Syrian Golden hamsters in vivo fluorescence microscopy experiments were performed after repeated EndoTAG‐1 treatment of A‐Mel‐3 tumors. Controls received glucose, paclitaxel alone or cationic liposomes devoid of paclitaxel. Extravasation of rhodamine‐labelled albumin was measured to calculate microvessel permeability and intratumoral leukocyte‐endothelial cell interactions were quantified. Subcutaneous tumor growth was evaluated after combination therapy followed by histological analysis.ResultsMicrovascular permeability was significantly increased only after treatment with EndoTAG‐1, while intratumoral leukocyte‐endothelial cell interactions were not affected by any treatment. In separate skinfold chamber experiments fluorescently‐labeled cationic liposomes kept their targeting property for tumor endothelial cells after repeated EndoTAG‐1 treatment and no signs of extravasation were observed. Subcutaneous A‐Mel‐3 tumor growth was significantly inhibited by the combination of cisplatin and EndoTAG‐1.ConclusionThese data show that vascular targeting with EndoTAG‐1 increases tumor microvessel leakiness probably due to vascular damage. This mechanism is not mediated by inflammatory leukocyte‐endothelial cell interactions. Manipulating the blood‐tumor barrier by repeated tumor microvessel targeting using EndoTAG‐1 can effectively be combined with tumor cell‐directed conventional cisplatin chemotherapy.SignificanceAntivascular therapy using liposomal paclitaxel (EndoTAG‐1) is currently undergoing Phase II clinical studies in human cancer patients. Referring to the present experimental data showing increased permeability of intratumoral microvessels combination therapy with conventional therapy appears to be a very promising strategy.SupportThis study was supported by grants of Munich Biotech AG, Neuried, Germany and by grants of the Novartis Foundation for Therapeutic Research, Nürnberg, Germany.
Understanding EMT in HNSCC
Authors: John Maie St 
Published: August 2008

ProblemDown regulation of E‐cadherin is the hallmark of epithelial mesenchymal transition (EMT). The loss of E‐cadherin confers a more invasive phenotype and is one of the steps leading to metastasis. Our recent investigations indicate that inflammatory mediators are potent regulators of EMT in HNSCC.MethodsImmunohistochemical analysis of HNSCC tumor tissue specimens, in vitro analysis of E‐cadherin regulation in HNSCC cells, and in vivo analysis of tumor growth and metastasis ina murine model.ResultsAn inverse relationship between COX‐2 and E‐cadherin was demonstrated in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with exogenous IL‐1B, also caused the down regulation of E‐cadherin expression and up regulation of Cox‐2 expression in HNSCC cell lines in a concentration‐ and time‐dependent manner. IL‐1B ‐treated HNSCC cell lines demonstrated a significant decrease in E‐cadherin mRNA and an increase in the mRNA of the transcriptional repressors SNAIL and ZEB1. IL‐1B exposure led to enhanced ZEB1 and Snail binding at the chromatin level as determined by chromatin immunoprecipitation assays (ChIP). An inverse relationship between E‐cadherin and ZEB1 and a direct relationship between COX‐2 and ZEB1 were demonstrated by immunohistochemical staining of human HNSCC tissue sections. When HNSCC cell lines that over express Snail were injected into SCID mice, the primary tumor and metastatic burdens were significantly greater than HNSCC vector controls.ConclusionThese findings indicate that 1L‐1B modulates transcriptional repressors of E‐cadherin and thereby regulates COX‐2‐dependent E‐cadherin expression in HNSCC. This is the first report indicating the role of E‐cadherin transcriptional repressors in the inflammation‐induced promotion of EMT in HNSCC.SignificanceThis newly defined pathway for transcriptional regulation of E‐cadherin in HNSCC has important implications for targeted chemoprevention and therapy.SupportAA0–HNS Surgeon Scientist CDA.
Effect of Allergens and Tobacco Smoke on Laryngeal Mucosa
Authors: Belafsky Peter C , Mouadeb Debbie A. , Pinkerton Kent , Birchall Martin A , Konia Thomas 
Published: August 2008

ProblemEnvironmental factors such as second hand smoke and allergens are known to play an important part in the development of lower airway disease, specifically asthma. The effect of these common exposures on the larynx has been neglected. The purpose of this investigation was to investigate the effects of environmental tobacco smoke (ETS) and allergens on laryngeal mucosa.MethodsSeventeen guinea pigs were exposed by inhalation to: 1) air and saline, 2) air and house dust mite allergen (HDMA), 3) ETS and saline 4) HDMA and ETS. Exposures began at 3 weeks of age and lasted 10 weeks. Histology was evaluated in different subsets of the larynx for eosinophils and mucin, markers of inflammation.ResultsEosinophils in the supraglottis were elevated in the air/HDMA and ETS/HDMA groups (p<0.05). Animals exposed to HDMA were 4 times more likely to have > 10 eosinophils per HPF in the supraglottis than control animals (95% CI = 0.74, 20). Trends towards mucin hypersecretion in the subglottis of the ETS/air and ETS/HDMA groups were noted. Animals exposed to ETS and HDMA were 3.8 times more likely to have 25% of the subglottic epithelium stain PAS positive for mucin (95% CI =. 59, 23.66).ConclusionThe data suggest that environmental tobacco smoke and inhaled allergens contribute to the pathogenesis of laryngeal inflammation.SignificanceEnvironmental tobacco smoke and allergen exposure may play a role in the development of chronic laryngitis.
Localization of Phonation Integration Center in Rabbits
Authors: French Lesley C. , Ohno Tsunehisa , Omid Majdani , Zealear David L , Labadie Robert F , Rousseau Bernard 
Published: August 2008

ProblemThe midbrain periaqueductal gray (PAG) serves as a phonation integration center, coordinating respiratory, laryngeal, and orofacial activity during vocalization. The objective of this pilot study was to explore electrical excitation of the midbrain PAG for eliciting vocalization using an in‐vivo rabbit preparation and determine the feasibility of using image guidance for improved localization of target midbrain structures.MethodsPilot experiments were conducted using four New Zealand White (NZW) breeder rabbits. In the first experiment, a stereotaxic frame was used to guide stimulation of the midbrain PAG without the use of image guidance. Decisions regarding track placements were directed by a stereotaxic atlas of the NZW rabbit brain. Histologic stains of axial brain sections were then obtained to determine electrode track positioning. In a subsequent experiment, magnetic resonance imaging (MRI) and computed tomography (CT) scans were obtained and used to localize midbrain structures for advanced planning capabilities.ResultsWithout the use of image guidance, phonation was feasible, measuring 80–100 Hz using electrical excitation of the midbrain PAG (0.5 to 1.5 mA, 200 Hz, 2 second train duration). However, precise localization of the midbrain PAG proved technically challenging. Using CT and MRI data, scans could be loaded onto an image guided surgical system and combined using an image fusion tool for advanced planning.ConclusionThe authors demonstrate the feasibility of electrical excitation of the midbrain PAG to produce vocalization in rabbits using a stereotaxic brain atlas and offer an alternative approach using image guidance for advanced planning and more precise localization of target midbrain structures.SignificanceThe biomechanical forces of phonation and dynamic nature of vocal fold remodeling have created a need for chronic animal preparations to investigate these reparative processes in‐vivo. Image guided techniques may improve the feasibility of brain stimulation techniques for eliciting and studying time dependent changes in vocal fold remodeling.SupportNIH‐NIDCD R03 DC008400.
Nerve‐Induced Rabbit Phonation: Temporal Phonation Stability
Authors: Rousseau Bernard , Ge Pingjiang , French Lesley C , Ohno Tsunehisa , Zealear David L , Ossoff Robert H 
Published: August 2008

ProblemIn‐vivo phonation using animals with layered structure similarities and phonation characteristics akin to humans are needed for the study of vocal fold reparative processes. The authors’ previous studies have demonstrated the feasibility of eliciting vocalization in a flow‐controlled in‐vivo rabbit preparation. In the current study, the authors provide information relative to temporal stability of nerve elicited rabbit phonation.MethodsEight New Zealand White breeder rabbits received pulsatile current to the laryngeal nerves with airflow delivered at a constant rate. Measurements of vocal intensity and fundamental frequency were recorded every 5, 30, and 90 minutes after the onset of phonation. Pearson correlations were used to investigate relationships among vocal intensity and fundamental frequency.ResultsPhonation was elicited with fundamental frequency and intensity ranging from 300 to 1000 Hz and 68 to 80 dB SPL, respectively at 5 minutes, 55 to 840 Hz and 70 to 79 dB SPL at 30 minutes, and 51 to 438 Hz and 68 to 76 dB SPL measured at 90 minutes. Correlation coefficients revealed predictable relationships among the dependent variables over time.ConclusionContinuous, audible phonation within the range of human phonation was produced over a 90 minute duration using an in‐vivo rabbit preparation. Expected relationships between vocal intensity and fundamental frequency were observed over time.SignificanceConsidering the vocal fold microarchitectural properties and phonation characteristics of the rabbit, the in‐vivo preparation described may provide a useful small animal option for investigations of phonation dependent tissue remodeling, maintenance of the vocal fold lamina propria, and development of pathology.SupportNIH‐NIDCD R03 DC008400.
Cochlear Nerve Stimulation With Optical Radiation
Authors: Richter Claus‐Peter , Fishman Andrew J , Izzo Agnella D 
Published: August 2008

ProblemNeural prosthetic devices are artificial extensions to the body that restore or supplement nervous system function that was lost during disease or injury. The devices stimulate remaining neural tissue with electric current, providing some input to the nervous system. Hereby, the challenge for neural prostheses is to stimulate remaining neurons selectively. However, electrical current spread does not easily allow stimulation of small neuron populations. In neural prostheses developments, particular success has been realized in the cochlear prostheses development. The devices bypass damaged hair cells in the auditory system by direct electrical stimulation of the auditory nerve. Stimulating discrete spiral ganglion cell populations in cochlear implant users’ ears is similar to the encoding of small acoustic frequency bands in a normal‐hearing person's ear. In contemporary cochlear implants, however, the injected electric current is spread widely along the scala tympani and across turns. Consequently, stimulation of spatially discrete spiral ganglion cell populations is difficult.MethodsSpiral ganglion cells in guinea pigs were stimulated with laser pulses from an Aculight Capella infrared laser.ResultsWith our experiments we demonstrate that extreme spatially selective stimulation is possible using light.ConclusionOur long‐term goal is to develop and build an optical cochlear implant prosthesis to stimulate small populations of spiral ganglion cells.SignificanceOur long‐term goal is to develop and build an optical cochlear implant prosthesis to stimulate small populations of spiral ganglion cells.SupportThis project has been funded with federal funds from the National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN260‐2006‐00006‐C / NIH No. N01‐DC‐6‐0.
Cortical Processing of Pitch: Excitation or Inhibition?
Authors: Harris Robert L , Nagina Subrati , Jones Steve John 
Published: August 2008

ProblemAlthough tonotopicity provides frequency representation, it does not provide an explicit representation of pitch for complex sounds. For conventional stimuli, it is not possible to vary pitch without varying the spectrum of the sound. It is possible using a regular interval noise(RIN). RIN isolates the neural response associated with the perception of pitch. Several recent studies have identified a specific region in the auditory cortex that contains a cortical representation of pitch.MethodsRIN auditory evoked potentials to: 1) determine over what range of temporal periods of RIN evoked a pitch onset response (POR); 2) determine how many cycles of RIN are required for its detection; 3) investigate inter‐hemispheric predominance of the POR; 4) investigate if different periodicities are represented in different cortical regions; 5) determine if the degree of refractoriness of the POR is similar when the same pitches occur at regular, short intervals, as when infrequent occurrences of a particular pitch are interspersed with other pitches at the same short intervals.Results1) a pitch onset response is evoked over the whole range of periodicities giving rise to a sense of musical pitch; 2) at most periodicities less than 2 cycles of RIN are required in order to evoke a response; 3) no marked interhemispheric differences were revealed; 4) evidence for a “periodotopic” distribution of responses was inconclusive; 5) the refractory properties of the response mainly suggested a common neuronal population, but with small degree of pitch specificity.ConclusionThere is a striking apparent disparity between human studies, which suggest a large increase in both metabolic and electrophysiological activity when random noise becomes periodic, at whatever pitch, and the animal literature which suggests only a few pitch‐selective neurons are excited. We propose a model that explains the observed differences: that the large neuronal population response represents widespread inhibition.SignificanceThe investigation of patients with auditory processing disorders.
Inflammation and Sudden Hearing Loss
Authors: Kassner Stefan S , Stern‐Straeter Jens , Bran Gregor , Hoermann Karl , Kinscherf Ralf , Goessler Ulrich R. 
Published: August 2008

ProblemAlthough sudden hearing loss (SHL) remains to be a frequent indication for emergency treatment in ENT departments, the pathogenesis leading to this disease is yet unknown. There is increasing evidence that vascular risk factors like hypercholesterolemia and chronic inflammation contribute to a disease‐provoking environment and, thus, enhance the risk for sudden hearing loss. We have shown in the past that patients with acute ischemic stroke display signifantly elevated plasma levels of oxLDL as well as significantly elevated gene expression of proinflammatory (CD40, TNF‐alpha and COX‐2), proapoptotic (Caspase‐3 and PARP) and proadhesive (CD38) genes. The aim of our study was to elucidate the possible role of hypercholesterolemia, inflammation and oxidative stress in sudden hearing loss and to show possible parallels with ischemic events like stroke.MethodsMononuclear cells from patients with SHL and healthy controls were isolated from blood and plasma. Analysis was performed using ELISA and FACS‐analysis.ResultsWe measured the levels of blood lipids, oxLDL, TNF‐alpha and CD40L in the plasma of patients with sudden hearing loss in comparison to healthy controls using ELISAs. Furthermore, we isolated mononuclear cells from the blood of patients and controls and measured the protein expression of proinflammatory (CD40, TNF‐alpha and COX‐2), proapoptotic (Caspase‐3 and PARP), oxidative stress associated (Mn‐SOD) and adhesion relevant (CD38) proteins by FACS‐analysis and ELISA.ConclusionWe found that both plasma levels of the above mentioned markers and protein expression in mononuclear cells showed distinct changes compared to healthy controls.SignificanceWe therefore postulate that a proinflammatory environment and oxidative stress might trigger the onset of sudden hearing loss and influence the clinical outcome.
Ototoxicity in Guinea Pigs: NO Levels in Cochlear Fluids
Authors: Yonamine Fernando Kaoru , Mendes Jose Arruda , Okada Daniel Mochida , Onishi Ektor T , Suemitsu Higa Elisa Mieko , Mouro Margareth Gori , Neto Jose Mendes 
Published: August 2008

ProblemOtotoxicity continues to be the most common side effect of gentamicin, and its physiopathology is still unclear. Currently the main accepted theory relates the ototoxicity with over production of free radicals, like nitric oxide (NO). Objective: To analyze the NO levels in the cochlear fluids of guinea pigs exposes to gentamicin and its relation with ototoxicity and propose an experimental model to study ototoxicity and drugs that may prevent it.MethodsSix guinea pigs were used, divided in two groups: a) Study – submitted to intraperitoneal injections of gentamicin, (135mg/kg/day) for 14days; b) Control ‐ submitted to intraperitoneal injections of distilled water, daily, for 14days; the hearing loss was evaluated with Preyer's reflex. On 14 day the guinea pigs were sacrificed and the cochlear fluids were collected for dosage of the nitric oxide through the chemiluminescence method (NOA‐TM 280).ResultsThe Preyer's reflex was absent at the end of the experiment in the Study group, what did not happen in the control group. The average of the nitric oxide levels of the guinea pigs of the study group was 26.2μ and the Control group 11.26μM.ConclusionIt was possible to measure nitric oxide levels in guinea pigs cochlear fluids. The results reinforce the role of nitric oxide in ototoxicity induced by gentamicin.SignificanceExperimental study (Level 2).
Phase I and Animal Studies of the TACA Implanted Hearing Aid
Authors: Slattery William H , Richmond Keith Neu , Kunz Lawrence Leroy , Janis Abram Daved 
Published: August 2008

ProblemHearing aid technologies are lacking in terms of cosmesis and comfort, encumber activities such as showering and swimming, and can distort the user's voice due to occlusion effect. The Transcutaneous Air Conduction Aid (TACA) has been developed as an alternative for patients with mild‐to‐moderate high‐frequency sensorineural hearing loss. This new device is designed to bring amplified sound into an open ear canal in an invisible manner. This study presents our investigation into the additional challenge of a percutaneous device at risk for marsupialization and infection at the device‐skin interface.MethodsTACA phantoms, coated with a fibrous titanium mesh biomaterial, were tested in long‐term preclinical implantation studies. Histomorphometric comparison of mesh coated and uncoated TACA phantoms was performed in 3 rabbits at 90 and 180 days. A follow‐up study in 7 rabbits was performed to temporally characterize wound healing around the mesh coated implants from 1–13 weeks. Based on promising animal results, a phase I FDA human trial was conducted lasting 6 months.ResultsPreliminary histomorphometric studies (N=18 phantoms with mesh, 6 without mesh) in 3 rabbits demonstrated that the titanium mesh biomaterial prevented marsupialization and infection at 90 and 180 days. The follow‐up study of 42 mesh‐coated phantoms in 7 rabbits demonstrated that the epidermal seal was reestablished around the percutaneous projection at 3 weeks, with supporting vascularized connective tissue ingrowth complete at 6 weeks. The human phase I data demonstrated connective tissue ingrowth and epidermal sealing with no evidence of marsupialization or infection.ConclusionThe TACA may offer an alternative for patients with sensorineural mild‐to‐moderate sloping high frequency hearing loss. Percutaneous implant studies in rabbits and man demonstrated the safety of this novel percutaneous device.SignificancePreclinical and clinical demonstration of feasibility and safety.SupportThis work was supported by Implanted Acoustics, Santa Clarita, California.