Nimodipine Treatment Protects Auditory Hair Cells from Cisplatin-Induced Cell Death Accompanied by Upregulation of LMO4.

Ototoxicity is one of the main dose-limiting side effects of cisplatin chemotherapy and impairs the quality of life of tumor patients dramatically. Since there is currently no established standard therapy targeting hearing loss in cisplatin treatment, the aim of this study was to investigate the effect of nimodipine and its role in cell survival in cisplatin-associated hearing cell damage. To determine the cytotoxic effect, the cell death rate was measured using undifferentiated and differentiated UB/OC-1 and UB/OC-2 cells, after nimodipine pre-treatment and stress induction by cisplatin. Furthermore, immunoblot analysis and intracellular calcium measurement were performed to investigate anti-apoptotic signaling, which was associated with a reduced cytotoxic effect after nimodipine pre-treatment. Cisplatin's cytotoxic effect was significantly attenuated by nimodipine up to 61%. In addition, nimodipine pre-treatment counteracted the reduction in LIM Domain Only 4 (LMO4) by cisplatin, which was associated with increased activation of Ak strain transforming/protein kinase B (Akt), cAMP response element-binding protein (CREB), and signal transducers and activators of transcription 3 (Stat3). Thus, nimodipine presents a potentially well-tolerated substance against the ototoxicity of cisplatin, which could result in a significant improvement in patients' quality of life.

Prophylactic nimodipine treatment for hearing preservation after vestibular schwannoma surgery: study protocol of a randomized multi-center phase III trial-AkniPro 2.

BACKGROUND: A previously performed phase III trial on 112 subjects investigating prophylactic nimodipine treatment in vestibular schwannoma (VS) surgery showed no clear beneficial effects on preservation of facial and cochlear nerve functions, though it should be considered that protection of facial nerve function was the primary outcome. However, the risk for postoperative hearing loss was halved in the nimodipine group compared to the control group (OR 0.49; 95% CI 0.18-1.30; p = 0.15). Accordingly, this phase III extension trial investigates the efficacy and safety of prophylactic nimodipine for hearing preservation in VS surgery. METHODS: This is a randomized, multi-center, two-armed, open-label phase III trial with blinded expert review and two-stage with interim analysis. Three hundred thirty-six adults with the indication for microsurgical removal of VS (Koos I-IV) and serviceable preoperative hearing (Gardner-Robertson scale (GR) 1-3) are assigned to either the therapy (intravenous nimodipine 1-2 mg/h from the day before surgery until the fifth postoperative day and standard of care) or the control group (surgery only and standard of care). The primary endpoint of the trial is postoperative cochlear nerve function measured before discharge according to GR 1-3 versus GR 4-5 (binary). Hearing function will be determined by pre- and postoperative audiometry with speech discrimination, which will be evaluated by a blinded expert reviewer. Furthermore, patient-reported outcomes using standardized questionnaires will be analyzed. DISCUSSION: Prophylactic parenteral nimodipine treatment may have a positive effect on hearing preservation in VS surgery and would improve patient's quality of life. Further secondary analyses are planned. Except for dose-depending hypotension, nimodipine is known as a safe drug. In the future, prophylactic nimodipine treatment may be recommended as a routine medication in VS surgery. VS can be considered as an ideal model for clinical evaluation of neuroprotection, since hearing outcome can be classified by well-recognized criteria. The beneficial effect of nimodipine may be transferable to other surgical procedures with nerves at risk and may have impact on basic research. TRIAL REGISTRATION: EudraCT 2019-002317-19, DRKS00019107 . 8th May 2020.

Prophylactic nimodipine treatment improves hearing outcome after vestibular schwannoma surgery in men: a subgroup analysis of a randomized multicenter phase III trial.

A 2016 published randomized multicenter phase III trial of prophylactic nimodipine treatment in vestibular schwannoma surgery showed only a tendency for higher hearing preservation rates in the treatment group. Gender was not included in statistical analysis at that time. A retrospective analysis of the trial considering gender, preoperative hearing, and nimodipine treatment was performed. The treatment group received parenteral nimodipine from the day before surgery until the seventh postoperative day. The control group was not treated prophylactically. Cochlear nerve function was determined by pure-tone audiometry with speech discrimination preoperatively, during in-patient care, and 1 year after surgery and classified according to the Gardner-Robertson grading scale (GR). Logistic regression analysis showed a statistically significant effect for higher hearing preservation rates (pre- and postoperative GR 1-4) in 40 men comparing the treatment (n = 21) and the control (n = 19) groups (p = 0.028), but not in 54 women comparing 27 women in both groups (p = 0.077). The results were also statistically significant for preservation of postoperative hearing with pre- and postoperative GR 1-3 (p = 0.024). There were no differences in tumor sizes between the treatment and the control groups in men, whereas statistically significant larger tumors were observed in the female treatment group compared with the female control group. Prophylactic nimodipine is safe, and an effect for hearing preservation in 40 men with preoperative hearing ability of GR 1-4 was shown in this retrospective investigation. The imbalance in tumor size with larger tumors in females of the treatment group may falsely suggest a gender-related effect. Further investigations are recommended to clarify whether gender has impact on nimodipine's efficacy.

Macrococcus canis and M. caseolyticus in dogs: occurrence, genetic diversity and antibiotic resistance.

BACKGROUND: The discovery of a new Macrococcus canis species isolated from skin and infection sites of dogs led us to question if Macrococcus spp. are common in dogs and are resistant to antibiotics. HYPOTHESIS/OBJECTIVES: To evaluate the occurrence of Macrococcus spp. in dogs, determine antibiotic resistance profiles and genetic relationships. ANIMALS: One hundred and sixty two dogs (mainly West Highland white terriers and Newfoundland dogs) were screened for the presence of Macrococcus, including six dogs with Macrococcus infections. METHODS: Samples were taken from skin, ear canal and oral mucosa using swabs. Macrococci were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry, 16S rRNA sequencing and nuc-PCR. Minimal inhibitory concentrations of 19 antibiotics were determined using broth microdilution. Resistance mechanisms were identified by microarray and sequencing of the fluoroquinolone-determining region of gyrA and grlA. Sequence type (ST) was determined by multilocus sequence typing. RESULTS: Out of the 162 dogs, six harboured M. caseolyticus (n = 6) and 13 harboured M. canis (n = 16). Six isolates of M. canis and one of M. caseolyticus were obtained from infection sites. The 22 M. canis strains belonged to 20 different STs and the seven M. caseolyticus strains to three STs. Resistance to antibiotics was mostly associated with the detection of known genes, with mecB-mediated meticillin resistance being the most frequent. CONCLUSION AND CLINICAL IMPORTANCE: This study gives some insights into the occurrence and genetic characteristics of antibiotic-resistant Macrococcus from dogs. Presence of M. canis in infection sites and resistance to antibiotics emphasized that more attention should be paid to this novel bacteria species.

Prophylactic nimodipine treatment and improvement in hearing outcome after vestibular schwannoma surgery: a combined analysis of a randomized, multicenter, Phase III trial and its pilot study.

OBJECTIVE In clinical routines, neuroprotective strategies in neurosurgical interventions are still missing. A pilot study (n = 30) and an analogously performed Phase III trial (n = 112) pointed to a beneficial effect of prophylactic nimodipine and hydroxyethyl starch (HES) in vestibular schwannoma (VS) surgery. Considering the small sample size, the data from both studies were pooled. METHODS The patients in both investigator-initiated studies were assigned to 2 groups. The treatment group (n = 70) received parenteral nimodipine (1-2 mg/hour) and HES (hematocrit 30%-35%) from the day before surgery until the 7th postoperative day. The control group (n = 72) was not treated prophylactically. Facial and cochlear nerve functions were documented preoperatively, during the inpatient care, and 1 year after surgery. RESULTS Pooled raw data were analyzed retrospectively. Intent-to-treat analysis revealed a significantly lower risk for hearing loss (Class D) 12 months after surgery in the treatment group compared with the control group (OR 0.46, 95% CI 0.22-0.97; p = 0.04). After exclusion of patients with preoperative Class D hearing, this effect was more pronounced (OR 0.38, 95% CI 0.17-0.83; p = 0.016). Logistic regression analysis adjusted for tumor size showed a 4 times lower risk for hearing loss in the treatment group compared with the control group (OR 0.25, 95% CI 0.09-0.63; p = 0.003). Facial nerve function was not significantly improved with treatment. Apart from dose-dependent hypotension (p < 0.001), the study medication was well tolerated. CONCLUSIONS Prophylactic nimodipine is safe and may be recommended in VS surgery to preserve hearing. Prophylactic neuroprotective treatment in surgeries in which nerves are at risk seems to be a novel and promising concept. Clinical trial registration no.: DRKS 00000328 ( https://drks-neu.uniklinik-freiburg.de/drks_web/ ).

Towards an optimal paradigm for intraoperative auditory nerve monitoring with auditory steady state responses.

Auditory steady state responses (ASSR) may offer an alternative to brainstem auditory evoked potentials for monitoring of the auditory nerve during surgical procedures. In the current study, we evaluated the influence of noise on ASSR characteristics in total intravenous anesthesia (TIVA). Simulated ASSR in real noise recorded during surgery under TIVA were constructed with known parameters. Influence of amplitude, modulation frequency, averaging sweeps and detection threshold on ASSR were evaluated. High amplitude, more sweeps and a liberal threshold facilitated detection. High amplitude ASSR (80 nV) were detected in up to 45 % with 16 s of data, in 80-90 % with 112 s. Near-threshold ASSR were detected in 0.8-25 %. False positives ranged between 0.3 and 10.3 %. Number of sweeps did not influence false positives. Amplitude errors varied between -61 and +39 % and improved with more averages but not with different thresholds. Modulation rate demonstrated the strongest influence on all parameters. 110 Hz yielded best, 90 Hz the worst results. Choice of parameters strongly influences detection and characteristics of ASSR. Optimal parameters enabled detection after 16 s in 45 %. Due to specific noise characteristics, modulation has a critical impact, which is currently not sufficiently recognized in ASSR studies.

Prophylactic nimodipine treatment for cochlear and facial nerve preservation after vestibular schwannoma surgery: a randomized multicenter Phase III trial.

OBJECTIVE: A pilot study of prophylactic nimodipine and hydroxyethyl starch treatment showed a beneficial effect on facial and cochlear nerve preservation following vestibular schwannoma (VS) surgery. A prospective Phase III trial was undertaken to confirm these results. METHODS: An open-label, 2-arm, randomized parallel group and multicenter Phase III trial with blinded expert review was performed and included 112 patients who underwent VS surgery between January 2010 and February 2013 at 7 departments of neurosurgery to investigate the efficacy and safety of the prophylaxis. The surgery was performed after the patients were randomly assigned to one of 2 groups using online randomization. The treatment group (n = 56) received parenteral nimodipine (1-2 mg/hr) and hydroxyethyl starch (hematocrit 30%-35%) from the day before surgery until the 7th postoperative day. The control group (n = 56) was not treated prophylactically. RESULTS: Intent-to-treat analysis showed no statistically significant effects of the treatment on either preservation of facial nerve function (35 [67.3%] of 52 [treatment group] compared with 34 [72.3%] of 47 [control group]) (p = 0.745) or hearing preservation (11 [23.4%] of 47 [treatment group] compared with 15 [31.2%] of 48 [control group]) (p = 0.530) 12 months after surgery. Since tumor sizes were significantly larger in the treatment group than in the control group, logistic regression analysis was required. The risk for deterioration of facial nerve function was adjusted nearly the same in both groups (OR 1.07 [95% CI 0.34-3.43], p = 0.91). In contrast, the risk for postoperative hearing loss was adjusted 2 times lower in the treatment group compared with the control group (OR 0.49 [95% CI 0.18-1.30], p = 0.15). Apart from dose-dependent hypotension (p < 0.001), no clinically relevant adverse reactions were observed. CONCLUSIONS: There were no statistically significant effects of the treatment. Despite the width of the confidence intervals, the odds ratios may suggest but do not prove a clinically relevant effect of the safe study medication on the preservation of cochlear nerve function after VS surgery. Further study is needed before prophylactic nimodipine can be recommended in VS surgery.

Viability of intraoperative auditory steady state responses during intracranial surgery.

BACKGROUND: For intraoperative monitoring of auditory nerve function, the auditory steady-state response (ASSR) analysis may be an alternative to brain stem auditory evoked potentials, offering frequency specificity and short detection times. Clinical studies investigating the viability of ASSR under total intravenous anesthesia have not been performed. METHODS: During craniotomy under total intravenous anesthesia with propofol and remifentanil in 20 patients, ASSR were recorded. An additional control patient undergoing cerebellopontine angle surgery was included, in whom the auditory nerve could not be preserved. One-minute sinus tones (500, 1,000, 2,000 Hz) were applied with 60-, 70-, and 80-decibel hearing level. Stimuli were amplitude modulated with 40, 90, or 110 Hz and applied monaurally to the left and right ears. Time to detect a significant response and response amplitudes at 40, 90, or 110 Hz in the evoked EEG spectra was evaluated. RESULTS: Overall, 90-Hz ASSR were successfully detected in all 20 patients, 110 Hz in 18 patients, and 40 Hz in 14 patients after a median of 10 seconds. No ASSR could be detected in the control patient at the end of the surgical procedure. Time-to-significance and ASSR amplitudes were influenced by stimulus intensity, carrier, and modulation frequency (Scheirer-Ray-Hare test, P < 0.005). Ipsilateral responses were higher than contralateral (P < 0.0001). CONCLUSIONS: In conclusion, 90- and 110-Hz ASSR can be reliably detected under total intravenous anesthesia. Our results are in line with those from previous studies in awake patients. Auditory steady-state response during anesthesia may enable intraoperative frequency-specific audiometry and monitoring of the auditory nerve.

Enteral or parenteral nimodipine treatment: a comparative pharmacokinetic study.

UNLABELLED: BACKGROUND AND STUDY AIMS/OBJECT: Oral nimodipine is recommended to reduce poor outcome related to aneurysmal subarachnoid hemorrhage (SAH). In addition, animal experiments and clinical trails revealed a beneficial effect of enteral and parenteral nimodipine for the regeneration of cranial nerves following skull base, laryngeal, and maxillofacial surgery. Despite these findings there is a lack of pharmacokinetic data in the literature, especially concerning its distribution in nerve tissue. PATIENTS/MATERIAL AND METHODS: Samples were taken from a consecutive series of 57 patients suffering from skull base lesions and treated with nimodipine prophylaxis from the day before surgery until the seventh postoperative day. Both groups received standard dosages for enteral (n = 25) and parenteral (n = 32) nimodipine . Nimodipine levels were measured in serum, cerebrospinal fluid (CSF), and tissue samples, including vestibular nerves. RESULTS: Nimodipine levels were significantly higher following parenteral as compared with enteral administration for intraoperative serum (p < 0.001), intraoperative CSF (p < 0.001), tumor tissues (p = 0.01), and postoperative serum (p < 0.001). In addition, nimodipine was significantly more frequently detected in nerve tissue following parenteral administration (Fisher's exact test, p = 0.015). CONCLUSIONS: From a pharmacokinetic point of view, parenteral nimodipine medication leads to higher levels in serum and CSF. Furthermore, traces are more frequently found in nerve tissue following parenteral as compared with enteral nimodipine administration, at least in the early course.

Neuroprotective efficacy of prophylactic enteral and parenteral nimodipine treatment in vestibular schwannoma surgery: a comparative study.

UNLABELLED: BACKGROUND AND STUDY AIMS/OBJECT: Oral nimodipine improves neurologic outcome after aneurysmal subarachnoid hemorrhage. In addition, the neuroprotective efficacy of nimodipine has been revealed following skull base, laryngeal, and maxillofacial surgery. Pharmacokinetic investigations showed nimodipine to reach higher serum levels following parenteral versus enteral administration. Furthermore, a correlation between nimodipine levels in serum, cerebrospinal fluid, and nerve tissue could be quantified. These observations raise the question whether the proven neuroprotective effect of nimodipine is related to its serum level. PATIENTS/MATERIAL AND METHODS: A consecutive series of 37 patients with vestibular schwannoma treated with nimodipine from the day before surgery until the seventh postoperative day was analyzed retrospectively. Both groups received standard dosages for enteral (n = 17) and parenteral (n = 20) nimodipine medication. Nimodipine levels were measured in pre- and postoperative serum and cerebrospinal fluid samples. Cochlear and facial nerve functions were documented before surgery, in the early postoperative course, and 1 year after surgery. RESULTS: Facial nerve outcome was significantly better in the group with parenteral nimodipine medication (p = 0.038). Logistical regression analysis revealed a seven times smaller risk for a deterioration of facial nerve function in the group with parenteral treatment. There was no difference in hearing preservation between both groups despite tumor size tending to be larger in the parenteral group. Intraoperative (p = 0.004), postoperative (p = 0.001), and serum and cerebrospinal fluid (p = 0.024) nimodipine levels were significantly higher following parenteral administration as compared with enteral administration. Both groups were comparable regarding tumor size and extent of resection. CONCLUSIONS: These results support a dependency of nimodipine's neuroprotective efficacy on its serum levels. Parenteral nimodipine treatment produces higher serum levels and has a higher neuroprotective potency in vestibular schwannoma surgery compared with enteral treatment.

The woman of Pritschoena: an example of the German neolithic neurosurgery in Saxony-Anhalt.

We present an outstanding example of successful prehistoric double trephination dating between 2700 and 2200 BC, most likely to the Corded Ware culture, at the end of the Neolithic Age. The particularity of this case is the presence of a double trephination, one frontal over the sinus sagittal superior and one parietal right. There is evidence that the patient survived months to years after the operations. The purpose of the procedure is not known. The case confirms the astonishing degree of technical skills reached in Saxony-Anhalt over 4500 years ago without anesthetic, antiseptic, or technologic aids.