High-Frequency Horizontal Semicircular Canal Function in Certain Menière's Disease.

OBJECTIVES: To characterize video head impulse testing (vHIT) in definitive Menière's disease and to investigate the relationship between vHIT results and other audiovestibular function tests. DESIGN: Fifty-four patients with certain Menière's disease, that is, patients with clinically definite Menière's disease and endolymphatic hydrops visualized by locally enhanced inner ear MR imaging, were recruited for this study. All patients underwent vHIT. The vestibular-ocular reflex gain at 60 ms and refixation saccades were the outcome parameters measured. Saccades were characterized by determining the saccade frequency, their mean latency, and their mean velocity. RESULTS: Seven of 54 patients had bilateral normal vHITs. Clearly pathologically vHITs with decreased gain and refixation saccades were observed in further seven patients. The majority of patients exhibited vHITs with refixation saccades but normal gain. Saccades mostly occurred bilaterally. There was no correlation between vHIT gain or saccades and caloric irrigation, cervical vestibular evoked myogenic potential or audiometry for Menière's ears. Furthermore, vHIT gain or saccades correlated neither with age nor with the duration of the disease. CONCLUSIONS: Pathological low vHIT gain values are rarely observed in patients with certain Menière's disease, while refixation saccades occur very frequently. In the majority of patients, saccades occur bilaterally. In Menière's disease, in contrast to vestibular neuritis, there is no compensatory decrease of saccade latency over time.

High Dose Chemotherapy with Autologous Stem Cell Transplantation in Hepatoblastoma does not Improve Outcome. Results of the GPOH Study HB99.

INTRODUCTION: The purpose of the German HB99 trial (1999-2008) for hepatoblastoma (HB), was primarily to analyse the effect of high dose (HD) chemotherapy with carboplatin/etoposide (CE) in high risk (HR) patients with extended tumors, vessel involvement, extrahepatic tumor or distant metastases. In standard risk (SR) patients the effect of treatment reduction was analysed. METHODS: HR patients received 2 cycles CE at conventional dose, followed by 2 at HD with subsequent autologous stem cell transplantation before delayed surgery. SR patients received 3-4 cycles of ifosfamide, cisplatin and doxorubicin (IPA) and delayed surgery. Analysis was on an intention to treat basis including resection rate, AFP decline, event free survival (EFS) and overall survival (OS). The patients with HD therapy were additionally analysed on an "as treated" basis. The results were compared to historical/published data. RESULTS: Of the 142 patients, the 5-y OS was 58% for the 57 HR patients and 94% for the 85 SR patients. The AFP decline after 2 cycles CE was ≥ 50% in > 90% of the patients. 12/18 (67%) patients treated with HD therapy showed an AFP decline after the first cycle (as treated). Tumor resection was possible in 89% of the patients. The median FU was 7.4 years. Late deaths occurred in 4 patients. CONCLUSION: Use of HD chemotherapy for HB did not improve patient outcomes, compared to contemporaneous and more recent trials (SIOPEL 4 trial). Reduction of therapy in SR patients was possible without worsening of results compared to previous trials. The tumor response to CE was good. CE can therefore be considered for relapse patients.

Correction to: Clinical manifestations of hydropic ear disease (Menière's).

In the original publication, Fig. 1 was incorrectly published with incomplete legends.

Clinical manifestations of hydropic ear disease (Menière's).

INTRODUCTION: Hydropic ear disease, initially described by and named after Prosper Menière, is one of the most frequent vertigo disorders and one of the most frequent inner ear disorders. It is the syndrome of endolymphatic hydrops which until 2007 could be diagnostically confirmed only by post-mortem histology. In the past, various attempts to formulate clinical diagnostic criteria have been undertaken but were hampered by the inability to ascertain the diagnosis in living patients. With the milestone achievement of endolymphatic hydrops imaging, today the pathology can be ascertained. In this study, we have performed a detailed analysis of the clinical features of hydropic ear disease for the first time by examining a large cohort of patients with morphologically confirmed endolymphatic hydrops using a detailed physician-administered neurotologic face-to-face interview. RESULTS: During a hydropic vertigo attack, the patients report nausea, vomiting, sweating, urge to defecate, urge to urinate, phosphenes, headache, photophobia, phonophobia and even transient loss of consciousness. A third of the patients does not experience auditory symptoms during the vertigo attacks. Vertigo attacks last less than 20 min in more than one-fourth of the patients. Audiometric hearing loss has its greatest diagnostic value at the frequencies of 1 kHz and below. Cochleovestibular symptom onset simultaneity is associated with a high frequency of drop-attacks. Migraine and autoimmune disorders are not associated with hydropic ear disease. CONCLUSION: This study marks the beginning of the clinical characterization of hydropic ear disease. The findings have important implications for the future formulation of clinical diagnostic criteria.

Utilisation of multi-frequency VEMPs improves diagnostic accuracy for Meniere's disease.

To determine whether vestibular evoked myogenic potential (VEMP) measurements that combine the VEMP 500/1000 Hz frequency tuning ratio and the inter-aural asymmetry ratio can reliably detect unilateral Meniere's disease ears as compared to healthy controls. Forty-two consecutive patients with certain unilateral Meniere's disease (as confirmed using a locally enhanced inner ear MRI (LEIM)) were assessed. Cervical vestibular evoked myogenic potentials (cVEMP) and ocular vestibular evoked myogenic potentials (oVEMP) were recorded at 500 and 1000 Hz. The VEMP amplitudes, asymmetry ratios, and the 500/1000 Hz amplitude ratios were compared with those of 21 age-matched healthy controls. A multi-frequency VEMPs score that combined: (1) the cVEMP 500/1000 Hz amplitude ratio, (2) the oVEMP 500/1000 Hz amplitude ratio, (3) the 500 Hz cVEMP asymmetry ratio, (4) the 1000 Hz cVEMP asymmetry ratio, produced a ROC curve with an area under the curve (AUC) of 0.814. The inclusion of audiology data further improved the result to 0.906. This score can be used to discriminate with a good degree of clinical accuracy between Meniere's ears (unilateral) and those of healthy controls. Multi-frequency VEMP analysis offers a simple, cost-effective solution to the diagnostic difficulties presented by Meniere's disease.

Hepatoblastoma Relapse-Findings from the German HB99 Trial and the German Liver Tumor Registry.

Survival rates for HB patients have improved; however, outcomes for patients who relapse remain poor. A retrospective review of information gathered for the HB99 study and the German Liver Tumor Registry identified 25 relapse patients (6.9%, 25/362). The median time from initial diagnosis to first relapse was 13 months (range: 5-66 months). Two patients relapsed >36 months after initial diagnosis. A total of 68% (17/25) of relapses were metastatic, 24% local, and 8% combined. 67% of local relapses were alive at the last follow-up, in contrast to 53% of metastatic and 0% of combined relapses. At the last follow-up, 73% (8/11) of patients with lung relapses were still alive (0/4 with peritoneal, 1/2 with CNS involvement). A total of 20% of the patients had AFP-negative relapses, 64% of the relapse patients achieved a second complete remission, 69% were still in complete second remission at the last follow-up (median FU of 66 months), and 83% (5/6) of irinotecan-naïve patients who received relapse treatment including irinotecan were in second complete remission at the last follow-up. The 3-year overall survival/event-free survival from relapse was 63%/48% respectively. There is a good chance that HB patients will achieve a second remission despite a first relapse. However, patients who suffer further relapses tend to have a poorer prognosis.

Cortisol response in children with cancer and fever during chemotherapy: A prospective, observational study using random serum cortisol levels.

BACKGROUND: Glucocorticoids are crucial components of the treatment of leukemia and lymphoma. High doses can lead to suppression of the hypothalamic-pituitary-adrenal (HPA) axis and be causative for an impaired stress response during infection. This study aims to evaluate the cortisol response in pediatric oncologic patients during febrile episodes. METHODS: Totally, 75 children and adolescents (5 months-18 years) with fever during chemotherapy were consecutively enrolled in this study. In total, 47 patients received glucocorticoids as part of their treatment. Random serum cortisol and adrenocorticotropic hormone (ACTH) were analyzed in every patient. A low cortisol response (LCR) was defined as a cortisol level < 14.6 µg/dL. RESULTS: In total, 52 (69%) patients had a cortisol level < 14.6 µg/dL during fever. There was no significant difference between patients who received glucocorticoids and those who did not. Significantly lower cortisol levels were measured ≤7 days after last glucocorticoid intake compared to later time points. Nearly all patients treated with dexamethasone or prophylactic posaconazole demonstrated a LCR under stress (fever). CONCLUSION: The incidence of an impaired HPA axis in pediatric cancer patients might be underestimated since 69% of the children in our study had a LCR during fever. Intake of dexamethasone, posaconazole and a time period of ≤7 days from the last glucocorticoid intake were additional risk factors for an LCR. However, we could not confirm that patients with a LCR fared worse than patients with a high cortisol response (HCR). Therefore, a different cortisol threshold may be necessary for defining an impaired HPA axis in febrile oncologic patients without concomitant symptoms of AI.

Outcomes of Patients Treated for Hepatoblastoma with Low Alpha-Fetoprotein and/or Small Cell Undifferentiated Histology: A Report from the Children's Hepatic Tumors International Collaboration (CHIC).

Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported SMARCB1 mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children's Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels. Upon retrospective review, they were re-classified as rhabdoid tumors (n = 11), HB with SCU component (n = 41), and HB with low AFP (n = 14). Seven were excluded for erroneously low AFP levels. Overall survival was 0% for patients with rhabdoid tumors, 76% for patients with HB with SCU component, and 64% for patients with HB with AFP less than 100 ng/mL. Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors. When rhabdoid tumors are excluded, the presence of SCU component and low AFP at diagnosis were not associated with poor prognosis in patients diagnosed with HB.

Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma.

Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin, the current treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony and tumor spheroid formation capabilities, cell cycle arrest, and induction of apoptosis of hepatoblastoma cells. Mechanistically, mebendazole causes blockage of microtubule formation and transcriptional downregulation of genes encoding the unwindosome, which are highly expressed in chemoresistant tumors. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model without side effects. In conclusion, our results strongly support the clinical use of mebendazole in the treatment of chemoresistant hepatoblastoma and highlight the potential theranostic value of unwindosome-associated genes.

Relationship Between the Extent of Endolymphatic Hydrops and the Severity and Fluctuation of Audiovestibular Symptoms in Patients With Menière's Disease and MRI Evidence of Hydrops.

OBJECTIVE: To characterize the short-, middle-, and long-term occurrence of vertigo attacks in a large population of Menière's disease (MD) and to investigate the relationship between the extent of endolymphatic hydrops (ELH) and the severity of audiovestibular symptoms. STUDY DESIGN: Prospective observational study. METHODS: One hundred ninety-two patients with clinically definite MD participated in this study. The degree of ELH was visualized by locally enhanced inner ear magnetic resonance imaging. The occurrence and intensity of vertigo attacks, hearing loss, tinnitus, and aural fullness were documented in patient diaries. RESULTS: There was no significant correlation between the extent of cochlear or vestibular hydrops and the number of definite vertigo days, neither with regard to a short-term nor with regard to a middle-term time period. There was also no correlation between the extent of ELH and the intensity or activity of the coexisting aural symptoms hearing loss, tinnitus, and aural fullness. The duration of the disease significantly correlated with the extent of both cochlear and vestibular hydrops, but not with the number of definite vertigo days. CONCLUSION: The ELH was progressive in the long-term course of the disease in this large population of definite MD patients, but short-term and middle-term fluctuations of the symptom severity did not involve measurable variations of the ELH. Furthermore, the symptom severity did not decrease with increasing disease duration.

Kaposiform hemangioendothelioma in children: a benign vascular tumor with multiple treatment options.

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor affecting infants and young children. Although benign, it can be associated with an aggressive locally growing tumor and/or a life-threatening Kasabach-Merritt phenomenon (KMP). To date, only reviews of limited cases have been performed. We, therefore, conducted a comprehensive literature search to collect relevant data and make recommendations for future treatment trials. METHODS: Review of the available literature between 1993 and 2017 revealed a total of 105 publications involving 215 patients of less than 21 years of age. To this, we added 12 from our department and 4 from the Cooperative Weichteilsarkomstudie database. RESULTS: We found that KMP was present in 79% of the infants, in 47% of the 1-5-year olds, in 43% of the 6-12-year olds, and in 10% of the 13-21-year-old patients. KMP was present in nearly all (94%) patients with retroperitoneal tumors and in all patients with extra-regional tumors. The median size of a KHE without KMP was 12 cm2 as compared to 49 cm2 when associated with a KMP. With complete (not further classifiable if R0 or R1) resection, all patients were cured. If inoperable, response regarding KMP/regression of tumor size was seen in 29/28% with steroid-, 47/39% with vincristine-, 44/43% with interferon alpha-, 65/61% with anti-platelet agents-, and in 97/100% with sirolimus-containing therapies. CONCLUSIONS: Patients with progressive KHE should undergo resection whenever it is considered a safe option. If inoperable, sirolimus should be the first choice for treating KMP and reducing tumor size.

The Effect of Elevated Intracranial Pressure on Frequency Tuning of Air-Conducted Ocular Vestibular Myogenic Potentials in Ménière's Disease Patients.

OBJECTIVE: To investigate the effect of increased intracranial pressure on ocular vestibular-evoked myogenic potential (oVEMP) amplitudes and frequency tuning in patients with Ménière's disease (MD) to elucidate whether oVEMPS recorded under such conditions could provide a simple and accurate diagnostic test for MD. SETTING: Tertiary referral center for otology and neurotology. PATIENTS: Ten patients with certain unilateral MD (mean age = 48.2 yr, range 25-75 yr, 6 males and 4 females) as confirmed by a locally enhanced inner ear MRI (LEIM) were enrolled in this study. DESIGN: Air-conducted tone-burst oVEMP amplitudes were measured in response to 500 Hz and 1000 Hz in the horizontal plane (0 degree), a 20-degree head-down position. RESULTS: Tilting the patients from the horizontal position to the 20-degree head-down position led to a large reduction in oVEMP amplitudes to the 500 Hz tone burst (3.02 µV vs 1.17 µV, p = 0.005) and to a smaller one in the 1000 Hz tone burst (2.28 µV vs 1.78 µV, p = 0.013) in the Ménière's ear. Accordingly, the 500/1000 Hz frequency-tuning ratio was significantly decreased in the Ménière's ear as a result of this manoeuver (1.36 vs 0.75, p = 0.005). CONCLUSION: oVEMP amplitudes and frequency tuning in MD patients show a similar behavior to that found in healthy control subjects. oVEMP testing of putative MD patients in the tilted position is therefore unlikely to be diagnostically useful.

Effect of Spatial Orientation of the Horizontal Semicircular Canal on the Vestibulo-Ocular Reflex.

OBJECTIVE: To determine if an alignment of the horizontal semi-circular canal (hSCC) with the plane of rotation would enhance the vestibular-ocular reflex (VOR) gain result as it has been previously suggested. STUDY DESIGN: Comparative study of a physiological vestibular function test in healthy subjects. SETTING: Tertiary referral center for otology and neurotology. PATIENTS: Twenty two healthy volunteers were recruited for this study. Their mean age was 25.6 years and the sex distribution was 14:8 (M:F). None of the subjects had a history of audiovestibular disorders. INTERVENTION: The video Head Impulse Test (v-HIT) was performed with the hSCC in the conventional position (head upright, horizontal gaze) and also with the hSCC in-line with the earth horizontal. MAIN OUTCOME MEASURES: depending on the alignment of the hSCC with the plane of head rotation. RESULTS: There was no significant difference between the results, either for the VOR gain at 60 ms, or the regression slope gain, when the two alternative head positions were compared. CONCLUSIONS: The data acquired in this study show that the VOR as measured by the v-HIT is not enhanced by aligning the plane of the hSCC with the plane of rotation during the testing procedure. Hence, we recommend that the positioning of the patient, with the head upright and a horizontal gaze direction should be routinely used in the clinical evaluation of the angular VOR by v-HIT.

The longitudinal impact of macular telangiectasia (MacTel) type 2 on vision-related quality of life.

PURPOSE: To determine the longitudinal impact of idiopathic macular telangiectasia (MacTel) type 2 on vision-specific quality of life (QoL). METHODS: Participants with MacTel type 2 and controls with no vision impairment were recruited at baseline. All underwent a full ophthalmic examination and the interview-administered 28-item Impact of Vision Impairment (IVI) questionnaire at baseline, to gather information on sociodemographic factors and vision-specific QoL. The MacTel patients were reassessed at 24 months. RESULTS: For the MacTel participants (n = 22), the median (range) age and visual acuity were 64 years (45-87) and 20/32 (20/13-20/63) in the better eye, respectively. The corresponding median values in the control group (n = 38) were 57 years (41-68) and 20/25 or better in both eyes, respectively. Rasch analysis showed that the IVI and its three subscales had sufficient psychometric validity and possessed interval level estimates. The control group had almost twice the level of vision-specific QoL than did the MacTel group at baseline on all IVI scores (P < 0.001 for all). At 24 months, we found no significant change in any of the IVI scores in the MacTel group. Similarly, there was no significant difference in visual acuity in the better or worse eyes in that group after 2 years. CONCLUSIONS: Persons with MacTel type 2 had poorer overall vision-related QoL than did healthy controls. Several aspects of vision-related QoL and distance visual acuity did not significantly change after 24 months. Longer follow-up assessment periods are needed to determine the longitudinal impact of this condition on vision-related QoL.