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Background: Parenting interventions during the first years of life on what and/or how to feed infants during complementary feeding can promote healthy eating habits. Objectives: An intervention promoting repeated exposure to a variety of vegetables [repeated vegetable exposure (RVE); what] and an intervention promoting responding sensitively to child signals during mealtime [video-feedback intervention to promote positive parenting-feeding infants (VIPP-FI); how] were compared, separately and combined (COMBI), with an attention control condition (AC). Primary outcomes were vegetable consumption and self-regulation of energy intake; secondary outcomes were child anthropometrics and maternal feeding practices (sensitive feeding, pressure to eat). Methods: Our 4-arm randomized controlled trial included 246 first-time Dutch mothers and their infants. Interventions started when infants were 4-6 mo old and ended at age 16 mo. The present study evaluated effects at 18 (t18) and 24 (t24) mo of age. Vegetable acceptance was assessed using three 24-h dietary recalls, self-regulation of energy intake by an eating-in-the-absence-of-hunger experiment and mother-report, and maternal feeding behavior by observation and mother-report. Results: Linear mixed model and ANOVA analyses revealed no follow-up group differences regarding child vegetable intake or self-regulatory behavior. The proportion of children with overweight was significantly lower in the COMBI group, compared with the VIPP-FI group at t18 (2% compared with 16%), and with the AC group at t24 (7% compared with 20%), although this finding needs to be interpreted cautiously due to the small number of infants with overweight and nonsignificant effects on the continuous BMI z-score measure (P values: 0.29-0.82). Finally, more sensitive feeding behavior and less pressure to eat was found in the VIPP-FI and COMBI groups, compared with the RVE and AC groups, mostly at t18 (significant effect sizes: D = 0.23-0.64). Conclusions: Interventions were not effective in increasing vegetable intake or self-regulation of energy intake. Future research might usefully focus on risk groups such as families who already experience problems around feeding. This trial is registered at clinicaltrials.gov as NCT03348176.

Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in ABCD1. Fibroblasts from 36 male patients with confirmed ALD, 26 healthy control subjects and 17 individuals without a family history of ALD, all with an uncertain clinical diagnosis and a VUS identified in ABCD1, were included. We performed a combination of tests: (i) a test for very-long-chain fatty acids (VLCFA) levels, (ii) a D3-C22:0 loading test to study the VLCFA metabolism and (iii) immunoblotting for ALD protein. All ALD patient fibroblasts had elevated VLCFA levels and a reduced peroxisomal ß-oxidation capacity (as measured by the D3-C16:0/D3-C22:0 ratio in the D3-C22:0 loading test) compared to the control subjects. Of the VUS cases, the VLCFA metabolism was not significantly impaired (most test results were within the reference range) in 6/17, the VLCFA metabolism was significantly impaired (most test results were within/near the ALD range) in 9/17 and a definite conclusion could not be drawn in 2/17 of the cases. Biochemical studies in fibroblasts provided clearly defined reference and disease ranges for the VLCFA metabolism. In 15/17 (88%) VUS we were able to classify the variant as being likely benign or pathogenic. This is of great clinical importance as new variants will be detected.

Simple Summary The role of radiotherapy in the treatment of perihilar cholangiocarcinoma has not yet been properly defined. In this prospective study, we therefore explored the addition to first-line chemotherapy of stereotactic body radiation therapy (SBRT) delivered in 15 fractions. Patients eligible for the study had been diagnosed with unresectable perihilar cholangiocarcinoma, and then had no progressive disease after completing treatment with 6–8 cycles of cisplatin-gemcitabine. Primary endpoints were feasibility and safety. Secondary endpoints were local control, progression-free survival, overall survival, and quality of life. As each patient completed the SBRT successfully and no dose-limiting toxicity was found, we consider this treatment to be both feasible and safe. The local control rate and overall survival were promising. However, due to the small sample size of this study, we urge the analysis of this treatment in a larger series of patients. Abstract Background: In unresectable pCCA, the standard of care is palliative chemotherapy. We investigated the feasibility and safety of adding stereotactic body radiation therapy (SBRT) after chemotherapy. Methods: Patients with unresectable pCCA, stage T1-T4N0-N1M0, ECOG 0-1, having finished 6–8 cycles of cisplatin and gemcitabine without disease progression were eligible. SBRT was planned in 15 fractions of 3.0–4.5 Gy. The primary endpoints were feasibility (defined as completing SBRT as planned) and toxicity, evaluated within 3 months after SBRT (CTCAE v4.03). A conventional “3 + 3” design was used, corresponding to a sample size of 6 patients. Dose-limiting toxicity (DLT) was defined as grade ≥ 4 hepatobiliary or grade ≥ 3 gastrointestinal toxicity. The secondary endpoints, measured from the start of radiotherapy, were local control, progression-free survival, overall survival, and quality of life (QoL). ClinicalTrials.gov identifier: NCT03307538. Results: Six patients were enrolled between November 2017 and March 2020. SBRT was delivered as planned. All patients were treated with 60Gy (15 × 4.0Gy). No SBRT-related DLT was observed. The most common grade ≥ 3 toxicity was cholangitis (n = 5). The median follow-up was 14 months. The 12-month local control rate was 80%. We observed no substantial changes in QoL. Conclusion: In patients with unresectable pCCA with stable disease after palliative chemotherapy, adding SBRT is feasible and safe. The observed local control merits an additional evaluation of effectiveness.

Importance Stroke remains the second leading cause of death worldwide. Approximately 10% to 15% of all strokes occur in young adults. Information on prognosis and mortality specifically in young adults is limited. Objective To determine short- and long-term mortality risk after stroke in young adults, according to age, sex, and stroke subtype; time trends in mortality; and causes of death. Design, Setting, and Participants Registry- and population-based study in the Netherlands of 15 527 patients aged 18 to 49 years with first stroke between 1998 and 2010, and follow-up until January 1, 2017. Patients and outcomes were identified through linkage of the national Hospital Discharge Registry, national Cause of Death Registry, and the Dutch Population Register. Exposures First stroke occurring at age 18 to 49 years, documented using International Classification of Diseases, Ninth Revision , and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision , codes for ischemic stroke, intracerebral hemorrhage, and stroke not otherwise specified. Main Outcomes and Measures Primary outcome was all-cause cumulative mortality in 30-day survivors at end of follow-up, stratified by age, sex, and stroke subtype, and compared with all-cause cumulative mortality in the general population. Results The study population included 15 527 patients with stroke (median age, 44 years [interquartile range, 38-47 years]; 53.3% women). At end of follow-up, a total of 3540 cumulative deaths had occurred, including 1776 deaths within 30 days after stroke and 1764 deaths (23.2%) during a median duration of follow-up of 9.3 years (interquartile range, 5.9-13.1 years). The 15-year mortality in 30-day survivors was 17.0% (95% CI, 16.2%-17.9%). The standardized mortality rate compared with the general population was 5.1 (95% CI, 4.7-5.4) for ischemic stroke (observed mortality rate 12.0/1000 person-years [95% CI, 11.2-12.9/1000 person-years]; expected rate, 2.4/1000 person-years; excess rate, 9.6/1000 person-years) and the standardized mortality rate for intracerebral hemorrhage was 8.4 (95% CI, 7.4-9.3; observed rate, 18.7/1000 person-years [95% CI, 16.7-21.0/1000 person-years]; expected rate, 2.2/1000 person-years; excess rate, 16.4/1000 person-years). Conclusions and Relevance Among young adults aged 18 to 49 years in the Netherlands who were 30-day survivors of first stroke, mortality risk compared with the general population remained elevated up to 15 years later.

Objectives Woman with a history of a previous cesarean section (CS) can choose between an elective repeat CS (ERCS) and a trial of labor (TOL), which can end in a vaginal birth after cesarean (VBAC) or an unplanned CS. Guidelines describe women’s rights to make an informed decision between an ERCS or a TOL. However, the rates of TOL and vaginal birth after CS varies greatly between and within countries. The objective of this study is to asses nation-wide implementation of counselling with a decision aid (DA) including a prediction model, on intended delivery compared to care as usual. We hypothesize that this may result in a reduction in practice variation without an increase in cesarean rates or complications. Methods In a multicenter controlled before and after cohort study we evaluate the effect of nation-wide implementation of a DA. Practice variation was defined as the standard deviation (SD) of TOL percentages. Results A total of 27 hospitals and 1,364 women were included. A significant decrease was found in practice variation (SD TOL rates: 0.17 control group vs. 0.10 intervention group following decision aid implementation, p=0.011). There was no significant difference in the ERCS rate or overall CS rates. A 21% reduction in the combined maternal and perinatal adverse outcomes was seen. Conclusions Nationwide implementation of the DA showed a significant reduction in practice variation without an increase in the rate of cesarean section or complications, suggesting an improvement in equality of care.

BACKGROUND\nOBJECTIVES\nMETHODS\nRESULTS\nCONCLUSION\nEating in the absence of hunger (EAH), the susceptibility to eat despite satiety, may increase overweight. While EAH has been established in school-aged children, less is known about it during toddlerhood.\nThis study assessed to what extent 18-month-old children eat in the absence of hunger, the stability of this behaviour at 24 months and the association of child eating behaviours with EAH.\nChildren were presented with four palatable finger foods (total 275 kcal) after dinner. Univariate GLM's assessed the association between EAH, child satiety and eating behaviours and energy intake of dinner at 18 and 24 months (n = 206 and 103, respectively). Another GLM was run to assess the association between EAH at both time points.\nMean (±SD) energy intakes from dinner and finger foods were 240 kcal (±117) and 40 kcal (±37), respectively. No association was found between energy intake of dinner and finger foods. Enjoyment of food was significantly related to intake of finger foods (P = .005). EAH at 18 months predicted EAH at 24 months.\nEighteen-month-old children ate in the absence of hunger, irrespective of satiety. Thus, preceding energy intake was not compensated for. Other factors, for example, enjoyment of food seem to determine finger food intake.

Contains fulltext : 232797.pdf (Publisher’s version ) (Open Access) PURPOSE: Although various studies have reported that stereotactic body radiation therapy (SBRT) for liver metastases has high local control rates and relatively low toxicity, most series included a small number of patients. We aimed to validate these outcomes in a large multi-institution patient cohort treated in accordance with a common protocol. METHODS AND MATERIALS: A shared web-based registry of patients with liver metastases treated with SBRT was developed by 13 centers (12 in the Netherlands and 1 in Belgium). All the centers had previously agreed on the items to be collected, the fractionation schemes, and the organs-at-risk constraints to be applied. Follow-up was performed at the discretion of the centers. Patient, tumor, and treatment characteristics were entered in the registry. Only liver metastases treated individually as independent targets and with at least 1 radiologic follow-up examination were considered for local control analysis. Toxicity of grade 3 or greater was scored according to the Common Terminology Criteria of Adverse Events (v4.03). RESULTS: Between January 1, 2013, and July 31, 2019, a total of 515 patients were entered in the web-based registry. The median age was 71 years. In total, 668 liver metastases were registered, and 447 were included for local control analysis. The most common primary tumor origin was colorectal cancer (80.3%), followed by lung cancer (8.9%) and breast cancer (4%). The most-used fractionation scheme was 3x18-20 Gy (36.0%), followed by 8x7.5 Gy (31.8%), 5x11-12 Gy (25.5%), and 12x5 Gy (6.7%). The median follow-up time was 1.1 years for local control and 2.3 years for survival. Actuarial 1-year local control was 87%; 1-year overall survival was 84%. Toxicity of grade 3 or greater was found in 3.9% of the patients. CONCLUSIONS: This multi-institutional study confirms the high rates of local control and limited toxicity in a large patient cohort. Stereotactic body radiation therapy should be considered a valuable part of the multidisciplinary approach to treating liver metastases.

Contains fulltext : 237460.pdf (Publisher’s version ) (Open Access) Early detection of congenital disorders by newborn screening (NBS) programs is essential to prevent or limit disease manifestation in affected neonates. These programs balance between the detection of the highest number of true cases and the lowest number of false-positives. In this case report, we describe four unrelated cases with a false-positive NBS result for very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Three neonates presented with decreased but not deficient VLCAD enzyme activity and two of them carried a single heterozygous ACADVL c.1844G>A mutation. Initial biochemical investigations after positive NBS referral in these infants revealed acylcarnitine and organic acid profiles resembling those seen in multiple acyl-CoA dehydrogenase deficiency (MADD). Genetic analysis did not reveal any pathogenic mutations in the genes encoding the electron transfer flavoprotein (ETF alpha and beta subunits) nor in ETF dehydrogenase. Subsequent further diagnostics revealed decreased levels of riboflavin in the newborns and oral riboflavin administration normalized the MADD-like biochemical profiles. During pregnancy, the mothers followed a vegan, vegetarian or lactose-free diet which probably caused alimentary riboflavin deficiency in the neonates. This report demonstrates that a secondary (alimentary) maternal riboflavin deficiency in combination with reduced VLCAD activity in the newborns can result in an abnormal VLCADD/MADD acylcarnitine profile and can cause false-positive NBS. We hypothesize that maternal riboflavin deficiency contributed to the false-positive VLCADD neonatal screening results.

BACKGROUND AND PURPOSE: Cardiovascular risk factors, which are overall more prevalent in men, are considered the major risk factors for strokes amongst young adults. However, recent European data found the incidence of strokes to be higher in young women. Using a large U.S. claims sample, we examined sex differences in the index stroke rate of young adults. METHODS: We performed a retrospective cohort study of enrollees in a 10% random sample of PharMetrics, a nationally representative claims database of insured Americans from 2001 to 2014. Outcomes were index ischemic stroke events, based on inpatient admissions using ICD-9 codes. The index stroke rate was estimated from Poisson rate models with time varying covariates for two-year periods, stratified by sex and age groups. RESULTS: We identified 20,554 index strokes(50.4% women; mean age 63) including 5,198 in young adults ages 15-54. There was no difference by sex in the index stroke rate in the extremes of age groups 15-24 and ≥75 years old. However, in the 25-34 and 35-44 year age groups, more women had strokes than men (Incidence Rate Ratio(IRR) men:women 0.70, 95%CI:0.57-0.86; 0.87, 95%CI:0.78-0.98, respectively). In contrast, in the 45-54, 55-64 ,and 65-74 year age groups, more men had strokes(IRR 1.25 95%CI:1.16-1.33; 1.41 95%CI:1.18-1.34; 1.18 95%CI:1.12-125, respectively). CONCLUSIONS: More young women than men have strokes, suggesting possible importance of sex-mediated etiologies of stroke. Understanding these drivers is critical to stroke treatment and prevention efforts in young adults.

Item does not contain fulltext Patients with Parkinson's disease (PD) often compensate for their motor deficits by guiding their movements visually. A wide range of ocular and visual disorders threatens the patients' ability to benefit optimally from visual feedback. These disorders are common in patients with PD, yet they have received little attention in both research and clinical practice, leading to unnecessary - but possibly treatable - disability. Based on a literature search covering 50 years, we review the range of ocular and visual disorders in patients with PD, and classify these according to anatomical structures of the visual pathway. We discuss six common disorders in more detail: dry eyes; diplopia; glaucoma and glaucoma-like visual problems; impaired contrast and colour vision; visuospatial and visuoperceptual impairments; and visual hallucinations. In addition, we review the effects of PD-related pharmacological and surgical treatments on visual function, and we offer practical recommendations for clinical management. Greater awareness and early recognition of ocular and visual problems in PD might enable timely instalment of tailored treatments, leading to improved patient safety, greater independence, and better quality of life.

IntroductionWorldwide, 2 million patients aged 18–50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients.Methods and analysisThe Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18–50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence.Ethics and disseminationEthical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients.

ObjectiveTo investigate incidence of stroke and its subtypes in young adults, according to sex and age, and to study trends over time.MethodsWe established a nationwide cohort through linkage of national registries (hospital discharge, cause of death, and population register) with patients aged 18–50 years and those ≥50 years with first-ever ischemic stroke, intracerebral hemorrhage, or unspecified stroke, using ICD-9/ICD-10 codes between 1998 and 2010 in the Netherlands. Outcomes were yearly incidence of stroke stratified by age, sex, and stroke subtype, its changes over time, and comparison of incidence in patients 18–50 years to patients ≥50 years.ResultsWe identified 15,257 patients (53% women; mean age 41.8 years). Incidence increased exponentially with age (R2 = 0.99) and was higher for women than men, most prominently in the youngest patients (18–44 years). The relative proportion of ischemic stroke increased with age (18–24 years: 38.3%; 44–49 years: 56.5%), whereas the relative proportion of intracerebral hemorrhage decreased (18–24 years: 34.0%; 44–49 years: 18.3%). Incidence of any stroke in young adults increased (1998: 14.0/100,000 person-years: 2010: 17.2; +23%; p < 0.001), driven by an increase in those aged over 35 years and ischemic stroke incidence (46%), whereas incidence decreased in those ≥50 years (329.1%–292.2%; −11%; p = 0.009).ConclusionsIncidence of any stroke in the young increases with age in patients over 35, is higher in women than men aged 18–44 years, and has increased by 23% in one decade, through an increase in ischemic stroke. Incidence of intracerebral hemorrhage is comparable for women and men and remained stable over time.

IntroductionFor patients with perihilar cholangiocarcinoma (CCA), surgery is the only treatment modality that can result in cure. Unfortunately, in the majority of these patients, the tumours are found to be unresectable at presentation due to either local invasive tumour growth or the presence of distant metastases. For patients with unresectable CCA, palliative chemotherapy is the standard treatment yielding an estimated median overall survival (OS) of 12–15.2 months. There is no evidence from randomised trials to support the use of stereotactic body radiation therapy (SBRT) for CCA. However, small and most often retrospective studies combining chemotherapy with SBRT have shown promising results with OS reaching up to 33–35 months.Methods and analysisThis study has been designed as a single-centre phase I feasibility trial and will investigate the addition of SBRT after standard chemotherapy in patients with unresectable perihilar CCA (T1-4 N0-1 M0). A total of six patients will be included. SBRT will be delivered in 15 fractions of 3–4.5 Gy (risk adapted). The primary objective of this study is to determine feasibility and toxicity. Secondary outcomes include local tumour control, progression-free survival (PFS), OS and quality of life. Length of follow-up will be 2 years. As an ancillary study, the personalised effects of radiotherapy will be measured in vitro, in patient-derived tumour and bile duct organoid cultures.Ethics and disseminationEthics approval for the STRONG trial has been granted by the Medical Ethics Committee of Erasmus MC Rotterdam, the Netherlands. It is estimated that all patients will be included between October 2017 and October 2018. The results of this study will be published in a peer-reviewed journal, and presented at national and international conferences.Trial registration numberNCT03307538; Pre-results.

Contains fulltext : 196605.pdf (Publisher’s version ) (Closed access) Epidemiological evidence suggests that the incidence of ischaemic stroke in young adults (18-50 years) has increased substantially. These patients have a long life expectancy after stroke, and the costs of long-term care pose huge challenges to health-care systems. Although the current recommendations for treatment of young and old (>50 years) patients with stroke are similar, the optimal management of young adult patients with stroke is unknown. They are usually not included in trials, and specific subanalyses limited to young adult patients with stroke are usually not done, owing to lower incidence of stroke and lower prevalence of vascular risk factors in young adults. Progress has been made in identifying patients with a considerable risk of stroke occurrence, such as those with patent foramen ovale. Future prevention studies might result in a decrease in the incidence of stroke and its sequelae in young adults. The development of guidelines specifically devoted to the management of stroke in young adults will be an important step in achieving this aim.

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Contains fulltext : 167983.pdf (Publisher’s version ) (Closed access) Parkinson's disease is a common neurodegenerative disorder, resulting in both motor and non-motor symptoms that significantly reduce quality of life. Treatment consists of both pharmaceutical and non-pharmaceutical treatment approaches. Neurorehabilitation is an important non-pharmaceutical treatment approach, and a prime component of this is formed by the training of behavioural adaptations that can assist patients to cope better with their motor and non-motor symptoms. Optimal delivery of neurorehabilitation requires a tailor-made, personalized approach. In this review we discuss the great potential for growth in the field of neurorehabilitation. Specifically, we will focus on four relatively new developments: visual rehabilitation (because Parkinson patients are very dependent on optimal vision); cueing delivered by wearable devices (allowing for objective, continuous, and quantitative detection of mobility problems, such that cueing can be delivered effectively in an on-demand manner - i.e., with external cues being delivered only at a time when they are needed most); exergaming (to promote compliance with exercise programs); and telemedicine (allowing for delivery of expert rehabilitation advice to the patient's own home). Evidence in these new fields is growing, based on good clinical trials, fuelling hope that state-of-the-art neurorehabilitation can make a real impact on improving the quality of life of patients affected by Parkinson's disease.

Contains fulltext : 152088.pdf (Publisher’s version ) (Closed access) BACKGROUND AND PURPOSE: Thyroid diseases are common and often affect quality of life (QoL). No cross-culturally validated patient-reported outcome measuring thyroid-related QoL is available. The purpose of the present study was to test the cross-cultural validity of the newly developed thyroid-related patient-reported outcome ThyPRO, using tests for differential item functioning (DIF) according to language version. METHODS: The ThyPRO consists of 85 items summarized in 13 multi-item scales and one single item. Scales cover physical and mental symptoms, well-being and function as well as social and daily function and cosmetic concerns. Translation applied standard forward-backward methodology with subsequent cognitive interviews and reviews. Responses (N = 1,810) to the ThyPRO were collected in seven countries: UK (n = 166), The Netherlands (n = 147), Serbia (n = 150), Italy (n = 110), India (n = 148), Denmark (n = 902) and Sweden (n = 187). Translated versions were compared pairwise to the English version by examining uniform and nonuniform DIF, i.e., whether patients from different countries respond differently to a particular item, although they have identical level of the concept measured by the item. Analyses were controlled for thyroid diagnosis. DIF was investigated by ordinal logistic regression, testing for both statistical significance and magnitude (DeltaR (2) > 0.02). Scale level was estimated by the sum score, after purification. RESULTS: For twelve of the 84 tested items, DIF was identified in more than one language. Eight of these were small, but four were indicative of possible low translatability. Twenty-one instances of DIF in single languages were identified, indicating potential problems with the particular translation. However, only seven were of a magnitude which could affect scale scores, most of which could be explained by sample differences not controlled for. CONCLUSION: The ThyPRO has good cross-cultural validity with only minor cross-cultural invariance and is recommended for use in international multicenter studies.

Objective: Mutations in the transient receptor potential vanilloid 4 gene ( TRPV4) can induce a great diversity of neuropathies. Together with these neuropathies, hearing loss can occur. This study is focused on providing an audiometric phenotype description of a Dutch family with spinal muscular atrophy caused by a mutation in TRPV4. Methods: A neurological examination was repeated and pure tone and speech audiometry were performed. Results: A large variety in neurological symptoms as well as variation in audiometric characteristics was observed. The severity of hearing loss is mild to moderate and the audiogram configuration is highly variable. The hearing loss of these patients has a progressive nature in general. The frequencies that deteriorate significantly differ between family members. When compared to presbyacusis patients, speech recognition scores of patients with a TRPV4 mutation are not clearly different. Conclusion: The function of TRPV4 in the inner ear is still elusive but it is suggested that TRPV4 is required for maintenance of cochlear function in stress conditions, like acoustic injury. We can neither confirm nor reject this based on the results obtained in this family. Therefore, one might consider advising patients with a TRPV4 mutation to avoid exposure to environmental influences such as noise exposure.

Purpose/objective(s) Patients with perihilar cholangiocarcinoma (pCCA) can only be cured by surgery. The standard of care for those with inoperable tumors is palliative chemotherapy. In an attempt to control the disease locally without adding severe toxicity in patients with unresectable pCCA, we investigated the safety and feasibility of adding stereotactic body radiation therapy (SBRT) after chemotherapy. Materials/methods Patients were eligible with a diagnosis of unresectable pCCA, stage T1-T4N0-N1M0 (AJCC staging 7th edition), ECOG performance status of 0-1, and having finished 6-8 cycles chemotherapy treatment (cisplatin and gemcitabine). SBRT was planned in 15 fractions of 3.0-4.5Gy, aiming for a biologically effective dose > 80.5Gy, while not exceeding organs at risk (OAR) constraints. The primary endpoints were feasibility, defined as completing SBRT as planned, and toxicity evaluated within 3 months of treatment. A conventional '3+3'-design was used, corresponding to a sample size of 6 patients. Toxicity was scored with the CTCAE v4.03 grading system. Dose-limiting toxicity (DLT) was defined as grade ≥4 hepatobiliary or grade ≥3 gastrointestinal toxicity. Secondary endpoints, measured from start of radiotherapy, were local control, progression-free survival (RECIST 1.1), overall survival, and quality of life (QoL). QoL was measured using the QLQ-C30, EQ-5D-5L, and QLQ-BIL21 questionnaires. Results Six patients were enrolled between 1 November 2017 and 30 March 2020. All patients completed 6-8 cycles of chemotherapy. They were staged T4N0-1M0, each with unresectable disease due to vascular involvement. SBRT was completed as planned. A dose of 60Gy (15×4.0Gy) was prescribed at the 80% isodose. Due to OAR constraints, especially duodenum, the median PTV coverage was limited to 82.4% (75.7%-89.6%). No SBRT related DLT was observed. The most common grade ≥3 toxicity was cholangitis (n = 5), which could be resolved by improving biliary drainage. The 12-month local control rate was 80%. Metastases emerged in the form of peritoneal metastases/ascites (n = 3) and/or liver metastases (n = 1). Three of the 4 patients who developed distant metastases had lymph-node-positive disease at baseline. After a median follow up of 14 months, 4 of 6 patients were still alive. We observed no substantial changes in QoL. Median QLQ-C30 'global health status' scores were 75.0 at baseline, 3 months and 12 months. Conclusion Fractionated SBRT following standard chemotherapy was a feasible and safe local therapy option for unresectable pCCA, albeit with the use of hard constraints for OAR. Cholangitis was often observed, but was reversible and QoL was maintained. Based upon the observed safety and the promising local control, additional evaluation of effectiveness in larger studies is warranted.