Evaluating hearing performance with cochlear implants within the same patient using daily randomization and imaging-based fitting - The ELEPHANT study.

BACKGROUND: Prospective research in the field of cochlear implants is hampered by methodological issues and small sample sizes. The ELEPHANT study presents an alternative clinical trial design with a daily randomized approach evaluating individualized tonotopical fitting of a cochlear implant (CI). METHODS: A single-blinded, daily-randomized clinical trial will be implemented to evaluate a new imaging-based CI mapping strategy. A minimum of 20 participants will be included from the start of the rehabilitation process with a 1-year follow-up period. Based on a post-operative cone beam CT scan (CBCT), mapping of electrical input will be aligned to natural place-pitch arrangement in the individual cochlea. The CI's frequency allocation table will be adjusted to match the electrical stimulation of frequencies as closely as possible to corresponding acoustic locations in the cochlea. A randomization scheme will be implemented whereby the participant, blinded to the intervention allocation, crosses over between the experimental and standard fitting program on a daily basis, and thus effectively acts as his own control, followed by a period of free choice between both maps to incorporate patient preference. With this new approach the occurrence of a first-order carryover effect and a limited sample size is addressed. DISCUSSION: The experimental fitting strategy is thought to give rise to a steeper learning curve, result in better performance in challenging listening situations, improve sound quality, better complement residual acoustic hearing in the contralateral ear and be preferred by recipients of a CI. Concurrently, the suitability of the novel trial design will be considered in investigating these hypotheses. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03892941. Registered 27 March 2019.

The diagnostic accuracy of 1.5 T versus 3 T non-echo-planar diffusion-weighted imaging in the detection of residual or recurrent cholesteatoma in the middle ear and mastoid.

PURPOSE AND BACKGROUND: This study retrospectively compares diagnostic performance of 1.5 T versus 3 T non-echo planar diffusion weighted imaging with or without additional T1 and T2 sequences in the detection of residual and/or recurrent cholesteatoma. METHODS: Patients with clinically suspected recurrent cholesteatoma or postoperative routine survey MR who subsequently underwent surgical procedure were retrospectively included (135 patients, 164 operated ears) from a large database. Patients underwent 1.5 T (128 ears) or 3 T MRI (36 ears), with non-echo planar DWI, T1 and T2 acquisitions. Two radiologists independently reassessed the images. Definitive surgical diagnosis was used as gold standard. Sensitivity, specificity and diagnostic odds ratio were evaluated. RESULTS: According to surgical diagnosis a cholesteatoma was present in 124 of 164 ears, corresponding with a prevalence of 75%. Sensitivity and specificity were lower for 3 T compared to 1.5 T, irrespective of whether additional T1 and T2-weighted sequences were used or not. Diagnostic odds ratios were higher for 1.5 T (34 and 12 for reader 1 and 2, respectively) compared to 3 T (3 and 4 for reader 1 and 2, respectively). Adding T1 and T2 sequences lowers sensitivity but increases specificity. CONCLUSION: Non-epi DWI for the detection of residual/recurrent cholesteatoma is preferably performed on 1.5 T scanners over 3 T. The use of additional sequences regarding detection of cholesteatoma is debatable as it lowers sensitivity but increases specificity. However, these sequences may also be of use in diagnosing complications and planning surgical procedures in some hospitals.

Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia.

In the search for genes that define critical steps of relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and can serve as prognostic markers, we performed targeted sequencing of 313 leukemia-related genes in 214 patients: 67 samples collected at the time of relapse and 147 at initial diagnosis. As relapse-specific genetic events, we identified activating mutations in NT5C2 (P=0.0001, Fisher's exact test), inactivation of TP53 (P=0.0007, Fisher's exact test) and duplication of chr17:q11.2-24.3 (P=0.0068, Fisher's exact test) in 32/67 of T-ALL relapse samples. Alterations of TP53 were frequently homozygous events, which significantly correlated with higher rates of copy number alterations in other genes compared with wild-type TP53 (P=0.0004, Mann-Whitney's test). We subsequently focused on mutations with prognostic impact and identified genes governing DNA integrity (TP53, n=8; USP7, n=4; MSH6, n=4), having key roles in the RAS signaling pathway (KRAS, NRAS, n=8), as well as IL7R (n=4) and CNOT3 (n=4) to be exclusively mutated in fatal relapses. These markers recognize 24/49 patients with a second event. In 17 of these patients with mostly refractory relapse and dire need for efficient treatment, we identified candidate targets for personalized therapy with p53 reactivating compounds, MEK inhibitors or JAK/STAT-inhibitors that may be incorporated in future treatment strategies.

Outcomes after resection and/or radiofrequency ablation for recurrence after treatment of colorectal liver metastases.

BACKGROUND: Repeat liver resection for colorectal liver metastases (CRLMs) is possible in a limited number of patients, with radiofrequency ablation (RFA) as an alternative for unresectable CRLMs. The aim of this study was to analyse survival rates with these interventions. METHODS: This was a database analysis of patients who underwent first and repeat interventions for synchronous and metachronous CRLMs between 2000 and 2013. Descriptive and survival statistics were calculated. RESULTS: Among 431 patients who underwent resection or RFA for CRLMs, 305 patients developed recurrences for which 160 repeat interventions (resection and/or RFA or ablative radiotherapy) were performed. In total, after 707 first or repeat interventions, 516 recurrences (73·0 per cent) developed, of which 276 were retreated curatively. At the time of first intervention, independent risk factors for death were lymph node-positive primary tumour (hazard ratio (HR) 1·40; P = 0·030), more than one CRLM (HR 1·53; P = 0·007), carcinoembryonic antigen level exceeding 200 ng/ml (HR 1·89; P = 0·020) and size of largest CRLM greater than 5 cm (HR 1·54; P = 0·014). The 5-year overall survival rates for liver resection and percutaneous RFA as first intervention were 51·9 and 53 per cent, with a median overall survival of 65·0 (95 per cent c.i. 47·3 to 82·6) and 62·1 (52·2 to 72·1) months, respectively. CONCLUSION: RFA had good oncological outcomes in patients with unresectable CRLMs. Radiofrequency ablation is progressively more applied with each additional intervention.

Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia.

Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P=0.002 and P=0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal residual disease are currently considered to have a good prognosis. In this group, deletion of IKZF1 and alteration of TP53 identify patients with significantly inferior outcome (P<0.001). In high-risk relapse patients, deletion of IKZF1 is strongly predictive of a second relapse after stem cell transplantation (P<0.001). We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in future risk assessment of children with relapsed ALL to indicate treatment intensification or intervention.

The diagnostic accuracy of non-echo-planar diffusion-weighted imaging in the detection of residual and/or recurrent cholesteatoma of the temporal bone.

BACKGROUND AND PURPOSE: Non-EPI DWI is a promising alternative to second-look surgery for the detection of residual and/or recurrent cholesteatoma. We evaluated the diagnostic accuracy, expressed as a positive predictive value, of MR imaging for the detection of residual and/or recurrent cholesteatoma in our hospital. MATERIALS AND METHODS: Fifty-six MR imaging studies were performed from 2005 to 2010 in patients having previously undergone surgery for cholesteatoma. Pre- and postgadolinium T1-weighted, T2-weighted, and non-EPI DWI sequences were performed and correlated with clinical and intraoperative findings. Twenty-seven patients underwent second-look surgery; 7 were under close clinical follow-up. Twenty-two patients without evidence of cholesteatoma were under regular follow-up (range, 14-44 months). RESULTS: Non-EPI DWI sequences showed increased DW signal intensity in 36 patients. Of those, 27 had second-look surgery, confirming cholesteatoma in 25 patients; in 1 patient, an empyema was diagnosed, and in the other patient, no cholesteatoma was found at surgery. In 2 patients who had not undergone surgery, increased DW signal intensity was accompanied by hyperintense signal intensity on T1-weighted images, consistent with transplanted fat in the postoperative cavity. The positive predictive value for detection of cholesteatoma was 93% (25/27). CONCLUSIONS: Residual and/or recurrent cholesteatomas after primary cholesteatoma surgery can be accurately detected by increased DW signal intensity on non-EPI DWI. However, DWI without conventional sequences increased the risk of misdiagnosis in our patient setting because transplanted fat within the postoperative cavity may show increased DW signal intensity.

A concise, stereocontrolled total synthesis of rippertenol.

The first total synthesis of the unique terpene rippertenol, a molecule with dense stereochemical complexity arrayed on a compact framework largely devoid of functional groups, is described. Key elements include orchestrated and unique applications of aldol condensations, Diels-Alder chemistry, and a ring expansion to advance a chiral starting material containing a single chiral center into the final target in a concise and diastereocontrolled manner.

Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a ß-galactosidase-activatable prodrug seco-analog of duocarmycin SA.

Breast cancer is the most common cause of cancer-related death worldwide, thus remaining a crucial health problem among women despite advances in conventional therapy. Therefore, new alternative strategies are needed for effective diagnosis and treatment. One approach is the use of oncolytic viruses for gene-directed enzyme prodrug therapy. Here, the lacZ-carrying vaccinia virus (VACV) strain GLV-1h68 was used in combination with a ß-galactosidase-activatable prodrug derived from a seco-analog of the natural antibiotic duocarmycin SA. Tumor cell infection with the VACV strain GLV-1h68 led to production of ß-galactosidase, essential for the conversion of the prodrug to the toxic compound. Furthermore, drug-dependent cell kill and induction of the intrinsic apoptosis pathway in tumor cells was also observed on combination therapy using the prodrug and the GLV-1h68 strain, despite the fact that VACV strains encode antiapoptotic proteins. Moreover, GI-101A breast cancer xenografts were effectively treated by the combination therapy. In conclusion, the combination of a ß-galactosidase-activatable prodrug with a tumor-specific vaccinica virus strain encoding this enzyme, induced apoptosis in cultures of the human GI-101A breast cancer cells, in which a synergistic oncolytic effect was observed. Moreover, in vivo, additional prodrug treatment had beneficial effects on tumor regression in GLV-1h68-treated GI-101A-xenografted mice.

Atropisomerism of aromatic carbamates.

ortho-Haloarylcarbamates like 1-4 show a high rotational barrier about the N--aryl bond of up to 91.6 kJ mol(-1) as found for 1, which was determined by 2D exchange NMR spectroscopy (EXSY). It was further demonstrated that the height of the barrier not only depends on the substituents at the axis of chirality, but is also influenced by electronic effects.

Synthesis of the first spacer containing prodrug of a duocarmycin analogue and determination of its biological activity.

The synthesis of the first spacer containing, duocarmycin analogue prodrug was realised, its biological properties evaluated and compared to its counterpart prodrug without a spacer unit. The synthesis comprises the manufacture of the new acetylated derivatives and of two double spacer systems, their activation and coupling to the pharmacophoric seco-drug (+)-. Unprecedented biological results were found as the new prodrug showed a fairly low QIC(50) value of 20, but on the other hand a high stability and very low DNA alkylation efficiency. These findings indicate a changed cytostatic mode of action induced by the self-immolative spacer moiety which was employed.

Determination of the biological activity and structure activity relationships of drugs based on the highly cytotoxic duocarmycins and CC-1065.

The natural antibiotics CC­1065 and the duocarmycins are highly cytotoxic compounds which however are not suitable for cancer therapy due to their general toxicity. We have developed glycosidic prodrugs of seco-analogues of these antibiotics for a selective cancer therapy using conjugates of glycohydrolases and tumour-selective monoclonal antibodies for the liberation of the drugs from the prodrugs predominantly at the tumour site. For the determination of structure activity relationships of the different seco-drugs, experiments addressing their interaction with synthetic DNA were performed. Using electro-spray mass spectrometry and high performance liquid chromatography, the experiments revealed a correlation of the stability of these drugs with their cytotoxicity in cell culture investigations. Furthermore, it was shown that the drugs bind to AT-rich regions of double-stranded DNA and the more cytotoxic drugs induce DNA fragmentation at room temperature in several of the selected DNA double-strands. Finally, an explanation for the very high cytotoxicity of CC-1065, the duocarmycins and analogous drugs is given.

Asymmetric synthesis and biological evaluation of glycosidic prodrugs for a selective cancer therapy.

A severe limitation in cancer therapy is the often insufficient differentiation between malign and benign tissue using known chemotherapeutics. One approach to decrease side effects is antibody-directed enzyme prodrug therapy (ADEPT). We have developed new glycosidic prodrugs such as (-)-(1S)-26 b based on the antibiotic (+)-duocarmycin SA ((+)-1) with a QIC(50) value of 3500 (QIC(50)=IC(50) of prodrug/IC(50) of prodrug+enzyme) and an IC(50) value for the corresponding drug (prodrug+enzyme) of 16 pM. The asymmetric synthesis of the precursor (-)-(1S)-19 was performed by arylation of the enantiomerically pure epoxide (+)-(S)-29 (> or = 98 % ee).

Otoacoustic emissions at compensated middle ear pressure in children.

Middle ear pathology has a negative effect on the detectability of otoacoustic emissions. In this study, we investigated the effect of compensating a deviant static middle ear pressure while measuring transient evoked otoacoustic emissions (TEOAEs). In 59 children (mean age 4 years, 5 months) TEOAEs were measured twice in one session: first at ambient pressure and than at compensated middle ear pressure. On average, TEOAE amplitudes increased by 1.9 dB as a result of middle ear pressure compensation. The amplitude increase was largest in frequency bands centred at 1 and 2 kHz and a statistically significant correlation was found between the amount of compensated pressure and the TEOAE amplitude increase. In the higher frequency bands centred at 3 and 4 kHz, TEOAE amplitudes were almost insensitive to pressure compensation. These results show that measuring OAEs at compensated middle ear pressure enhances the amplitude of TEOAEs, and thus improves the detectability.

Predictive value of neonatal MRI with respect to late MRI findings and clinical outcome. A study in infants with periventricular densities on neonatal ultrasound.

PURPOSE: The aim of this study was to correlate hypoxic-ischemic white matter damage on neonatal MRI with MRI appearance and neurological outcome at the age of 1 1/2 years. PATIENTS AND METHODS: A sequential cohort of infants with periventricular densities on neonatal ultrasound was studied with neonatal MRI. Images of 46 infants with a mean gestational age of 31 weeks were obtained at a mean age of 20 days after birth and at 1 1/2 years. To establish agreement between the neonatal and follow-up MRI (general, motor, and visual scores), the weighted Cohen's kappa test was used. To establish the predictive power of neonatal MRI with respect to the neurologic indices at the age of 1 1/2 years, the sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: There was a moderately good to good agreement between the general, motor, and visual neonatal and follow-up MRI scores: weighted kappa = 0.59 (95% CI: 0.44 - 0.74), 0.82 (95% CI: 0.72 - 0.93), and 0.70 (95% CI: 0.56 - 0.84), respectively. Neonatal MRI scores provided a good prediction of the three neurological outcome measures (developmental delay, cerebral palsy, and cerebral visual impairment): sensitivity, specificity, and predictive values were high, with little difference between the three MRI scores. The 32 patients with (nearly) normal neonatal MRI scores were neurologically (nearly) normal at 1 1/2 years on all three outcome measures, whereas 8 patients with seriously abnormal neonatal MRI scores were neurologically abnormal at 1 1/2 years on all three outcome measures. CONCLUSION: Neonatal MRI is able to predict the precise localization and size of perinatal leukomalacia on follow-up MRI and provides a good prediction of neurological outcome at 1 1/2 years.

A two-step scenario for hearing assessment with otoacoustic emissions at compensated middle ear pressure (in children 1-7 years old).

OBJECTIVE: Otoacoustic emissions (OAEs) are widely used for assessing congenital and early-acquired sensorineural hearing loss in young children. Middle ear pathology has a negative effect on the presence of OAEs. In this study we investigated whether measuring OAEs at compensated middle ear pressure (CMEP) resulted in a higher pass rate than at ambient pressure. Secondly, we analysed the influence of 12 different pass definitions on the pass rates. METHODS: One hundred and eleven children (age 1-7 years, mean 4 years and 5 months) were measured twice in one session: first at ambient pressure and then at CMEP. RESULTS: The study showed a higher pass rate of OAEs at CMEP than at ambient pressure. A two-step scenario reduced the number of fails by 18-26%, depending on the pass/fail definition used. CONCLUSION: Measuring OAEs at CMEP results in higher pass rates. Secondly, pass/fail definitions have a large influence on pass rates and this issue deserves further attention. Further studies must be done, before this method is readily applicable to universal neonatal screening.

Mould constituents in the middle ear, a hearing-aid complication.

During the placement of a mould for a hearing-aid by a hearing-aid dispenser, moulding material entered the middle ear through pre-existent perforations in the tympanic membrane in both ears. Besides hearing loss, there were no other symptoms. Surgical removal of the moulding material by tympanotomy was necessary, and was complicated by encirclement of the ossicles by the material. All the material could be removed and the hearing was saved. Recommendations for an improved procedure of mould-making are made including more detailed information of the otoscopic findings at the prescriptions for hearing-aid moulds.