Combined VSV oncolytic virus and chemotherapy for squamous cell carcinoma.

OBJECTIVES: Vesicular stomatitis virus (VSV) is a negative-strand ribonucleic acid (RNA) virus that replicates specifically in tumor cells and has oncolytic effects in a variety of malignant tumors. We previously demonstrated recombinant VSV vectors incorporating viral fusion protein (rVSV-F) and interleukin 12 (rVSV-IL12) to have significant antitumor effects against squamous cell carcinoma (SCC) in a murine model. Here we evaluate the potential to combine a potent chemotherapeutic agent for SCC (cisplatin) with rVSV-F and rVSV-IL12 to improve efficacy. STUDY DESIGN: In vitro, three SCC cell lines were tested using rVSV-F and rVSV-IL12 with cisplatin, monitoring viral replication and cell survival. In an orthotopic floor of mouth murine SCC model, intratumoral injections of virus combined with systemic cisplatin were tested for tumor control and animal survival. RESULTS: In vitro, virus and cisplatin combination demonstrated rapid replication and enhanced tumor cell kill. Human keratinocytes were unaffected by virus and cisplatin. In vivo, combined rVSV-F with cisplatin reduced tumor burden and improved survival (P = .2 for both), while rVSV-IL12 monotherapy had better tumor control (P = .06) and survival (P = .024) than combination therapy. CONCLUSIONS: Addition of cisplatin did not affect the ability of either virus to replicate in or kill murine SCC cells in vitro. In vivo, combination therapy enhancedrVSV-F antitumor activity, but diminished rVSV-IL12 antitumor activity. Combination therapy may provide useful treatment for SCC with the development of more efficient viral vectors in combination with different chemotherapy agents or immunostimulatory agents.

Interleukin-12 expression enhances vesicular stomatitis virus oncolytic therapy in murine squamous cell carcinoma.

OBJECTIVES: Replication-competent, vesicular stomatitis virus (VSV) has been demonstrated to be an effective oncolytic agent in a variety of malignant tumors. Cytokine gene transfer has also been used as immunomodulatory therapy for cancer. To test the use of combining these two approaches, an oncolytic VSV vector (rVSV-IL12) was designed to express the murine interleukin 12 (IL12) gene. This cytokine-carrying oncolytic virus was compared with an analogous noncytokine-carrying fusogenic virus (rVSV-F) in the treatment of murine SCC VII squamous cell carcinoma (SCC). STUDY DESIGN AND SETTING: The authors performed in vitro testing of recombinant VSV-F and recombinant VSV-IL12 in SCC cell lines. In vivo testing of multiple direct intratumoral injections of rVSV-F or rVSV-IL12 in an orthotopic floor of mouth murine model was performed. Each cell line was tested using rVSV-F or rVSV-IL12 at multiplicity of infection of 0.01. The ability of each virus to replicate was tested by real-time reverse transcriptase-polymerase chain reaction over 48 hours to determine viral copies of RNA. Cell survival was determined by MTT assay over 72 hours. IL12 expression by rVSV-IL12-treated cells was determined by enzyme-linked immunosorbent assay. RESULTS: Both viruses demonstrated similar infection efficiency, viral replication, and cytotoxicity in vitro. In an SCC VII orthotopic floor of mouth model in immunocompetent C3H/HeJ mice, multiple intratumoral injections with each virus caused a significant reduction in tumor volume when compared with saline injections alone. The rVSV-IL12-treated tumors showed a striking reduction in tumor volume when compared with rVSV-F and saline-treated tumors (P < .005). This striking reduction in tumor volume translated into a substantial survival benefit in rVSV-IL12-treated animals. No treatment-related toxicity was observed in either group. CONCLUSION/SIGNIFICANCE: rVSV-IL12 is a novel oncolytic vesicular stomatitis virus that effectively expresses IL12 and significantly enhances the treatment of head and neck murine carcinoma. Such combined oncolytic and immunomodulatory strategies hold promise in the treatment of head and neck cancers.

Fusogenic vesicular stomatitis virus for the treatment of head and neck squamous carcinomas.

OBJECTIVES: This study investigates the efficacy of recombinant fusogenic VSV [rVSV-NDV/F(L289A) or rVSV-F] in the treatment of head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN AND SETTING: The in vitro replication and cytotoxicity of rVSV-F were studied in two human SCC cell lines, in one murine SCC cell line, and in human keratinocytes. The effects on tumor size and animal survival were investigated following in vivo rVSV-F treatment of floor-of-mouth tumor model C3H/HeJ mice. RESULTS: Recombinant VSV-F preferentially induced rapid syncytia formation, and replicated in (P < 0.04) and killed (P < 1 x 10(-13)) all three SCC lines tested. The virus had no observable effect on human keratinocytes. Tumor size was smaller (P < 0.03) and overall survival was better (P < 0.001) for treated animals than for control animals. CONCLUSION/SIGNIFICANCE: Recombinant VSV-F confers a modest survival benefit for HNSCC in this orthotopic murine model. This oncolytic virus holds promise as a novel cancer treatment for recurrent HNSCC.

Very far-advanced otosclerosis: stapedotomy or cochlear implantation.

CONCLUSION: Every patient with severe or profound hearing loss must have a temporal bone high-resolution computed tomography (CT) scan. Stapedotomy is a simple, safe and low-cost procedure compared with cochlear implantation and can provide very good results. This can justify our decision to propose stapedotomy at the initial treatment in patients with very far-advanced otosclerosis. In cases of hearing failure after stapes surgery, cochlear implantation is an option. OBJECTIVE: This study aimed to find the best first intention treatment of very far-advanced otosclerosis. MATERIALS AND METHODS: This was a retrospective study and included 14 patients with non-measurable preoperative bone and air conduction thresholds and otosclerosis on temporal bone high-resolution CT scan. Stapes surgery followed by a well fitted hearing aid was the initial treatment in 11 patients and cochlear implantation in 7 patients, including 4 patients who had poor results after stapedotomy. Objective and subjective audiometric results were studied and compared between stapedotomy and cochlear implantation groups. RESULTS: Objective and subjective results were statistically better in the cochlear implant group than in the stapedotomy group. However, four patients in the stapedotomy group had comparable results to the patients with cochlear implants.

Binaurality in middle ear implant recipients using contralateral digital hearing AIDS.

OBJECTIVE: For some patients, conventional hearing aids might have disadvantages that clearly limit the benefit of using them. The middle ear implant, Vibrant Soundbridge hearing prosthesis offers an approach to help such patients. Our study's objective was to identify the binaurality in a well-fitted digital hearing aid worn in the contralateral ear in recipients experienced with use of the Vibrant Soundbridge middle ear implant device. STUDY DESIGN: In a prospective study, warble-tone thresholds and stereophony were evaluated for the following conditions: (1) binaural unaided-with the middle ear implant inactive and the behind-the-ear hearing aid removed; (2) middle ear implant alone-middle ear implant active, behind-the-ear hearing aid removed; (3) middle ear implant plus behind-the-ear omnidirectional-middle ear implant active, behind-the-ear active; and (4) behind-the-ear omnidirectional alone-middle ear implant inactive, behind-the-ear omnidirectional active. Behind-the-ear omnidirectional and behind-the-ear is defined as the behind-the-ear active in the omnidirectional or directional response, respectively. Behind-the-ear is a contralateral digital hearing aid to the middle ear implant. Benefits such as improved sound detection, speech perception in quiet and in noise, and sound quality were investigated. The evaluation of subjective hearing benefit was based on the Abbreviated Profile of Hearing Aid Benefit (APHAB) test. Paired t tests (subject) were used to analyze the differences between mean thresholds for the different test conditions. SETTING: Tertiary referral center. PATIENTS: Eight adults (aged 45-68 yr) had undergone implantation with a single Vibrant Soundbridge at least 12 months before starting the study. These eight subjects presented no contraindication for contralateral hearing aid use. Patients were fitted 5 weeks before testing with a Siemens Signia digital behind-the-ear hearing aid in the side contralateral to the Vibrant Soundbridge. RESULTS: Five weeks after use of the contralateral hearing aid together with the middle ear implant, mean differences in warble-tone thresholds between Conditions 2 and 3 and between Conditions 3 and 4 were both statistically significant. The mean differences in speech reception thresholds were in line with the mean differences in average warble-tone thresholds. The mean speech reception threshold for the middle ear implant plus behind-the-ear omnidirectional condition was slightly worse (3 dB) than that for the middle ear implant alone condition; however, this difference was not statistically significant. Whereas speech reception threshold difference between Condition 1 and Condition 4 was not statistically significant (60 dB and 61 dB, respectively). The mean difference for the 0-degree azimuth alone was statistically significant (p < 0.05) for the conditions middle ear implant alone and middle ear implant plus behind-the-ear omnidirectional. The middle ear implant alone appears to give good sensitivity at 2 kHz for any direction. Increasing scores indicate greater percentages of problems. Percentages of problems were on average lower for the middle ear implant when used with the contralateral digital hearing aid based on the global score. CONCLUSION: The use of a middle ear implant Vibrant Soundbridge together with a contralateral digital hearing aid improved functional gain and speech perception thresholds in quiet, especially for the sound coming from the front of the patient. The use of a middle ear implant together with a contralateral digital hearing did not significantly improve hearing in noise.

Facial nerve paralysis following cochlear implant surgery.

OBJECTIVES: Facial nerve paralysis is a rare but devastating complication of cochlear implant surgery. The aims of the study were to define the incidence of facial nerve paralysis in our series and understand possible mechanisms of injury. STUDY DESIGN: Retrospective chart review and case reports. METHODS: Charts were reviewed of all 705 patients implanted between 1980 and 2002 at the authors' institutions to identify those with postoperative facial nerve weakness and determine incidence. For patients with facial nerve weakness, onset, degree, and timing of paralysis were noted; clinical findings were correlated to operative report findings. The method of treatment was noted, and the final facial nerve function outcome was recorded. RESULTS: Five patients (one child and four adults) were found to have postoperative facial nerve weakness, for an incidence of 0.71%. This complication was delayed in all cases, ranging from 18 hours to 19 days postoperatively. All patients were treated with steroids or steroids combined with antiviral medication, and all ultimately recovered normal facial function. CONCLUSIONS: In the study series, the incidence of facial nerve paralysis following cochlear implant surgery was 0.71%. Possible mechanisms of injury included heating injury and viral reactivation. All patients presented with a delayed facial nerve paralysis and did recover normal facial nerve function.

Speech perception and speech intelligibility in children after cochlear implantation.

OBJECTIVE: This study aimed to evaluate the long-term speech perception and speech intelligibility of congenitally and prelingually deaf children after cochlear implantation. It was a longitudinal study following 63 congenitally or prelingually deaf children up to 5 years after implantation. They each received a nucleus multichannel cochlear implant before they were 10 years old. METHODS: Perception is evaluated using the Test for the Evaluation of Voice Perception and Production (TEPP) and concerns closed- and open-set word and sentence perception without lip-reading. The intelligibility is classified according to the Speech Intelligibility Rating (SIR). The evaluations have been made every 3 months for 1 year, then at 18 months, 2 years, 3 years and 5 years after the cochlear implantation. RESULTS: After 5 years of implantation, the median percentage of closed-words speech perception (CSW) is 95.5%-93.67% for closed-sentence speech perception (CSS) and 76.3% for open-sentence speech perception (OSS); the median Speech Intelligibility Rating is 3.83. CONCLUSIONS: Congenitally and prelingually deaf children who receive cochlear implant before the age of 10 years develop speech perception and speech intelligibility abilities. The closed-set perception progresses quickly and seems to reaching a plateau at 5 years post implantation. The improvement of open-sentence perception is not significant until the first year post implantation. The speech intelligibility improves regularly the five first year post implantation.