Safety and stable survival of stem-cell-derived retinal organoid for 2 years in patients with retinitis pigmentosa.

Transplantation of induced pluripotent stem cell (iPSC)-derived retinal organoids into retinal disease animal models has yielded promising results, and several clinical trials on iPSC-derived retinal pigment epithelial cell transplantation have confirmed its safety. In this study, we performed allogeneic iPSC-derived retinal organoid sheet transplantation in two subjects with advanced retinitis pigmentosa (jRCTa050200027). The primary endpoint was the survival and safety of the transplanted retinal organoid sheets in the first year post-transplantation. The secondary endpoints were the safety of the transplantation procedure and visual function evaluation. The grafts survived in a stable condition for 2 years, and the retinal thickness increased at the transplant site without serious adverse events in both subjects. Changes in visual function were less progressive than those of the untreated eye during the follow-up. Allogeneic iPSC-derived retinal organoid sheet transplantation is a potential therapeutic approach, and the treatment's safety and efficacy for visual function should be investigated further.

Self-organization, quality control, and preclinical studies of human iPSC-derived retinal sheets for tissue-transplantation therapy.

Three-dimensional retinal organoids (3D-retinas) are a promising graft source for transplantation therapy. We previously developed self-organizing culture for 3D-retina generation from human pluripotent stem cells (hPSCs). Here we present a quality control method and preclinical studies for tissue-sheet transplantation. Self-organizing hPSCs differentiated into both retinal and off-target tissues. Gene expression analyses identified the major off-target tissues as eye-related, cortex-like, and spinal cord-like tissues. For quality control, we developed a qPCR-based test in which each hPSC-derived neuroepithelium was dissected into two tissue-sheets: inner-central sheet for transplantation and outer-peripheral sheet for qPCR to ensure retinal tissue selection. During qPCR, tissue-sheets were stored for 3-4 days using a newly developed preservation method. In a rat tumorigenicity study, no transplant-related adverse events were observed. In retinal degeneration model rats, retinal transplants differentiated into mature photoreceptors and exhibited light responses in electrophysiology assays. These results demonstrate our rationale toward self-organizing retinal sheet transplantation therapy.

Up-front single-session radiosurgery for large brain metastases-volumetric responses and outcomes.

BACKGROUND: Patients presenting with large brain metastases (LBM) pose a management challenge to the multidisciplinary neuro-oncologic team. Treatment options include surgery, whole-brain or large-field radiation therapy (WBRT), stereotactic radiosurgery (SRS), or a combination of these. OBJECTIVE: To determine if corticosteroid therapy followed by SRS allows for efficient minimally invasive care in patients with LBMs not compromised by mass effect. METHODS: We analyzed the change in tumor volume to determine the efficacy of single-session SRS in the treatment of LBM in comparison to other treatment modalities. Twenty-nine patients with systemic cancer and brain metastasis (≥ 2.7 cm in greatest diameter) who underwent single-session SRS were included. RESULTS: Among 29 patients, 69% of patients had either lung, melanoma, or breast cancer. The median initial tumor size (maximal diameter) was 32 mm (range 28-43), and the median initial tumor volume was 9.56 cm3 (range 1.56-25.31). The median margin dose was 16 Gy (range 12-18). The average percent decrease in tumor volume compared to pre-SRS volume was 55% on imaging at 1-2 months, 58% at 3-5 months, 64% at 6-8 months, and 57% at > 8 months. There were no adverse events immediately following SRS. Median corticosteroid use after SRS was 21 days. Median survival after radiosurgery was 15 months. CONCLUSION: Initial high-dose corticosteroid therapy followed by prompt single-stage SRS is a safe and efficacious method to manage patients with LBMs (defined as ≥ 2.7 cm).

Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle East Respiratory Syndrome Coronavirus.

BACKGROUND: REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. METHODS: Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. RESULTS: Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. CONCLUSIONS: REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.

Hearing loss and volumetric growth rate in untreated vestibular schwannoma.

OBJECTIVE: In this study, the authors aimed to clarify the relationship between hearing loss and tumor volumetric growth rates in patients with untreated vestibular schwannoma (VS). METHODS: Records of 128 treatment-naive patients diagnosed with unilateral VS between 2012 and 2018 with serial audiometric assessment and MRI were reviewed. Tumor growth rates were determined from initial and final tumor volumes, with a median follow-up of 24.3 months (IQR 8.5-48.8 months). Hearing changes were based on pure tone averages, speech discrimination scores, and American Academy of Otolaryngology-Head and Neck Surgery hearing class. Primary outcomes were the loss of class A hearing and loss of serviceable hearing, estimated using the Kaplan-Meier method and with associations estimated from Cox proportional hazards models and reported as hazard ratios. RESULTS: Larger initial tumor size was associated with an increased risk of losing class A (HR 1.5 for a 1-cm3 increase; p = 0.047) and serviceable (HR 1.3; p < 0.001) hearing. Additionally, increasing volumetric tumor growth rate was associated with elevated risk of loss of class A hearing (HR 1.2 for increase of 100% per year; p = 0.031) and serviceable hearing (HR 1.2; p = 0.014). Hazard ratios increased linearly with increasing growth rates, without any evident threshold growth rate that resulted in a large, sudden increased risk of hearing loss. CONCLUSIONS: Larger initial tumor size and faster tumor growth rates were associated with an elevated risk of loss of class A and serviceable hearing.

Utility of multi-material three-dimensional print model in preoperative simulation for glioma surgery.

Although the three-dimensional (3D) printing technology has spread in the field of neurosurgery, the use of 3D print models concerning glioma surgery has rarely reported. For glioma surgery, some preoperative and intraoperative assistive methods have been developed to avoid injury to the cortex and fiber that are related to the neurological function. Furthermore, in order to perform preoperative simulation of glioma surgery, we created a 3D print model using a multi-material 3D printer that provided the flexibility of adjusting the color, hardness, and translucency of each structure arbitrarily. The use of 3D print model was demonstrated in one case involving an intramedullary tumor in the right temporal lobe. The tumor, optic radiation, brain parenchyma, tentorium, ventricle, and sinus were constructed in a single model in one printing process. Design of the degree of resection, insertion of the fence-post, and tumor resection paying attention to the optic radiation were simulated preoperatively using this model. The surgery was performed generally as the simulation and gross total removal of the tumor was achieved. This model was useful for understanding the degree of resection, adequate insertion of the fence-post, and the relationship of the tumor with other important structures. A variety of printing materials contributed to make the model realistic and to understand anatomical relationship. In conclusion, the 3D print model can supplement an image of some portions that are not visible perioperatively and serve as a preoperative assistant modality.

Prostate Cancer Detected by Choroidal Tumor and Complete Response to Hormonal Therapy: Case Report and Literature Review of 24 Patients With Choroidal Metastasis From Prostate Cancer.

Metastatic choroidal tumors derived from prostate cancer are rare. In this study, we report a patient who manifested a choroidal tumor as the initial presenting sign of prostate cancer and review 23 patients with choroidal metastasis of prostate cancer in the literature to answer a clinical question how the choroidal metastases would respond to hormonal therapy. A 73-year-old man presented with a choroidal tumor in the right eye. He was in good health and had no previous history except for current hemodialysis in 3 years due to chronic renal failure as a sequel to glomerulonephritis. With the diagnosis of a probable metastatic tumor, positron emission tomography was performed to disclose high-uptake sites in multiple bones, lymph nodes, and the prostate, together with multiple nodular lesions in bilateral lungs on computed tomography (CT) scan. Serum prostate-specific antigen (PSA) was elevated to 541 ng/mL, which supported prostate cancer as the primary site. He had degarelix injection, and the choroidal tumor resolved rapidly and became flat degeneration in a month. Prostate biopsy showed poorly differentiated adenocarcinoma, and he underwent surgical castration. He had no medication until 3 years later when he showed gradual increase of serum PSA up to 6.05 ng/mL and multiple bony metastases on CT scan. Bicalutamide, switched to enzalutamide and then to abiraterone, led to the undetectable level of serum PSA until the last visit with no relapse of the choroidal metastasis, 6.8 years after the initial visit. In the literature review of 24 patients with choroidal metastasis of prostate cancer, including this patient, 8 patients presented a choroidal tumor as the initial sign and the choroidal lesions mostly showed complete response to hormonal therapy. Among 13 patients who were frequently in the course of hormonal therapy, choroidal metastases showed complete or partial response to external beam radiation to the eye in 11 patients and episcleral plaque radiotherapy in 2 patients. In conclusion, metastatic choroidal tumors of prostate cancer would show good response to hormonal therapy when the therapy has not been initiated. Hormone-resistant choroidal metastases in the therapeutic course of prostate cancer could be managed successfully by external beam radiation to the eye.

Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: A case report.

RATIONALE: Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease of unknown etiology. GPA affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera. Retinal and choroidal manifestations are rare in GPA, but they often include choroidal neovascularization (CNV). PATIENT CONCERNS: A 36-year-old man was diagnosed with GPA. He had been taking oral steroid treatment for 8 years. He experienced disease recurrence and the dose of oral prednisolone was increased after steroid pulse therapy. Fundus examination showed small retinal pigment epithelial detachment and serous retinal detachment (SRD). Optical coherence tomography (OCT) revealed a protruded lesion inside the SRD. Fluorescein angiography (FA) showed a small, dot-shaped fluorescein leakage in the SRD, and indocyanine green fluorescein fundus angiography showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. We had to determine whether the protruded lesion inside the SRD was CNV secondary to the inflammation due to GPA or whether it was central serous chorioretinopathy (CSC)-like condition caused by high-dose steroid treatment. DIAGNOSES: We confirmed that the SRD was due to CSC but not CNV because the protruded lesion examined by B-scan OCT angiography (OCTA) showed no blood flow. INTERVENTIONS: We decided to reduce the dose of steroid. OUTCOMES: Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed. LESSONS: We therefore propose the effectiveness of this advanced function of OCTA for the examination of blood flow signal images to detect CNV.

Safety and immunogenicity of an intranasal sendai virus-based vaccine for human parainfluenza virus type I and respiratory syncytial virus (SeVRSV) in adults.

SeVRSV is a replication-competent Sendai virus (SeV)-based vaccine carrying the respiratory syncytial virus (RSV) fusion protein (F) gene. Unmanipulated, non-recombinant SeV is a murine parainfluenza virus type 1 (PIV-1) and serves as a Jennerian vaccine for human PIV-1 (hPIV-1). SeV protects African green monkeys (AGM) from infection after hPIV-1 challenge. The recombinant SeVRSV additionally targets RSV and protects AGM from lower respiratory infections after RSV challenge. The present study is the first to report on the safety, viral genome detection, and immunogenicity following SeVRSV vaccination of healthy adults. Seventeen and four healthy adults received intranasal SeVRSV and PBS, respectively, followed by six months of safety monitoring. Virus genome (in nasal wash) and vaccine-specific antibodies (in sera) were monitored for two and four weeks, respectively, post-vaccination. The vaccine was well-tolerated with only mild to moderate reactions that were also present in the placebo group. No severe reactions occurred. As expected, due to preexisting immunity toward hPIV-1 and RSV in adults, vaccine genome detection was transient. There were minimal antibody responses to SeV and negligible responses to RSV F. Results encourage further studies of SeVRSV with progression toward a clinical trial in seronegative children. Abbreviations: AE-adverse event; SAE-serious adverse event; SeV-Sendai virus; RSV-respiratory syncytial virus; PIV-1-parainfluenza virus-type 1; hPIV-1-human parainfluenza virus-type 1; F-RSV fusion protein; SeVRSV-recombinant SeV carrying the RSV F gene; Ab-antibody; MSW-medically significant wheezing; NOCMC-new onset chronic medical condition, mITT-modified Intent to Treat; ALRI-acute lower respiratory tract infection.

Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9.

The pseudokinase Trib1 functions as a myeloid oncogene that recruits the E3 ubiquitin ligase COP1 to C/EBPα and interacts with MEK1 to enhance extracellular signal-regulated kinase (ERK) phosphorylation. A close genetic effect of Trib1 on Hoxa9 has been observed in myeloid leukemogenesis, where Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. However, the mechanism underlying how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Herein, we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. Chromatin immunoprecipitation sequencing analysis identified increased histone H3K27Ac signals at super-enhancers of the Erg, Spns2, Rgl1, and Pik3cd loci, as well as increased messenger RNA expression of these genes. Modification of super-enhancer activity was mostly achieved via the degradation of C/EBPα p42 by Trib1, with a slight contribution from the MEK/ERK pathway. Silencing of Erg abrogated the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of acute myeloid leukemia (AML) cells with the BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential therapeutic target of Hoxa9-associated AML. Taken together, our study demonstrates a novel mechanism by which Trib1 modulates chromatin and Hoxa9-driven transcription in myeloid leukemogenesis.

Duration of Cellular and Humoral Responses after Quadrivalent Human Papillomavirus Vaccination in Healthy Female Adults with or without Prior Type 16 and/or 18 Exposure.

Human papillomavirus virus (HPV) vaccines aim to provide durable protection and are ideal to study the association of cellular with humoral responses. We assessed the duration and characteristics of immune responses provided by the quadrivalent HPV (4vHPV) vaccine in healthy female adults with or without prior exposure with type 16 and 18 HPV. In a prospective cohort, vaccine naïve females received three doses of 4vHPV vaccine and were followed for two years to assess cellular (intracellular cytokine staining, proliferation and B cell ELISpot assays) and humoral (multiplex L1/L2 viral-like particles (VLP) and M4 ELISAs) responses. Frequencies of vaccine-specific CD4+ T cells correlated with antibody responses. Higher HPV antibody titers were found at all time points in participants previously exposed to HPV, except for anti-HPV-18 at Day 187 (one week post the third vaccination). Retrospective cohorts enrolled females who had previously received two or three 4vHPV doses and tested antibody titers by M4 ELISA and pseudovirion neutralization assay along with memory B cells (MBCs). Almost all women enrolled in a retrospective cohort with two prior doses and all women enrolled in a retrospective cohort with three prior doses had sustained antibody and memory responses. Our findings indicate that HPV vaccination induces a long-lasting, robust cellular and humoral immune responses.

Long term results of primary radiosurgery for vestibular schwannomas.

BACKGROUND: Stereotactic radiosurgery (SRS) has become a primary option for management for both newly diagnosed vestibular schwannomas (VS), as well as VS that enlarge after initial observation. METHODS: A retrospective review of our prospectively maintained data base found 871 patients who underwent Gamma knife® SRS as their initial (primary) management between 1987 and 2008. Follow-up ranged from 1-25 years (median = 5.2 years) Median tumor volume was 0.9 cc (0.02-36) and median margin dose was 13 Gy (12-25). RESULTS: Progression free survival (PFS) after SRS was 97% at 3 years, 95% at 5 years, and 94% at 10 years. Freedom from delayed surgical resection was found in 98.7% of patients. Smaller tumor volume was significantly associated with improved PFS. There were 326 patients with serviceable hearing (Gardner-Robertson 1 or 2) at the time of SRS with audiological follow-up of ≥ 1 year. Serviceable hearing preservation rates after SRS were 89.8% at 1 year, 76.9% at 3 years, 68.4% at 5 years, 62.5% at 7 years, and 51.4% at 10 years. Factors associated with improved serviceable hearing preservation included younger age, Gardner-Robertson grade 1 at SRS, and absence of subjective complaints of dysequilibrium or vertigo (vestibulopathy). Fifty-one patients (5.8%) developed trigeminal neuropathy. Fourteen (1.6%) developed a transient House-Brackmann grade 2 or 3 facial neuropathy. CONCLUSIONS: In this report with extended follow-up, primary SRS achieved tumor growth control in 94% of patients. Optimization of long- term cranial nerve outcomes remains an important achievement of this management strategy for VS.

Volumetric growth rates of untreated vestibular schwannomas.

OBJECTIVE: There remains a large discrepancy among surgeons in expectations of vestibular schwannoma (VS) growth. The anticipated growth rate of a VS and its potential clinical impact are important factors when deciding whether to observe the lesion over time or to intervene. Previous studies of VS natural growth remain limited, mostly confined to linear measurements, often without high-resolution, thin-sequence imaging. The present study comprehensively assessed natural tumor growth rates using volumetric measurements. METHODS: Between 2012 and 2018, 212 treatment-naïve patients diagnosed with a unilateral VS were evaluated. A total of 699 MR images were assessed, with a range of 2-11 MR images per patient. All MR images preceded any intervention, with patients subsequently being observed through completion of data analysis (36%) or treated with stereotactic radiosurgery (32%) or microsurgical resection (32%). To determine precise tumor volumes, the tumor area was outlined on every slice, and the products of the area and slice thickness were summed (99% of scans were ≤ 1-mm slice thickness). A multilevel model with random effects was used to assess the mean volume change over time. Each tumor was categorized as one of the following: growing (volume increase by more than 20% per year), fast growing (volume increase by more than 100% per year), stable (volume change between 20% decrease and 20% increase per year), and shrinking (volume decrease by more than 20% per year). RESULTS: The mean VS volumetric growth rate was 33.5% per year (95% CI 26.9%-40.5%, p < 0.001). When assessing the frequencies of individual tumor annual growth rates, 66% demonstrated growth (30% fast growing), 33% were stable, and 1% exhibited shrinking over an average interval of 25 months. Larger tumors were associated with increased absolute growth, but there was no relationship between tumor size and proportional growth rate. There was also no relationship between patient age and tumor growth rate. CONCLUSIONS: This study comprehensively assessed VS volumetric growth rates using high-resolution images and was conducted in a large and diverse patient sample. The majority of the tumors exhibited growth, with about one-third growing at a rate of 100% per year. These findings may contribute to a consensus understanding of tumor behavior and inform clinical decisions regarding whether to intervene or observe.

Radiosurgery for Central Neurocytoma.

The classification of central neurocytoma (CN) by the WHO was upgraded to grade 2 in 1993 as it was recognized that at least some of these tumors can exhibit more aggressive behavior. Currently, as of 2016, CN is classified as WHO grade 2. Indeed, some atypical variants have been reported and residual postsurgical tumor is believed to have the potential for malignant transformation. Although gross total resection is usually curative for CN (5-year survival rate 99%), it is achieved in nearly 30-50% of cases due to its central location. Adjuvant treatments should be deliberately considered for the optimal management of CN. Recently, stereotactic radiosurgery is increasingly proposed as an adjuvant treatment for CN.

How to improve obliteration rates during volume-staged stereotactic radiosurgery for large arteriovenous malformations.

OBJECTIVEThe management of large-volume arteriovenous malformations (AVMs) with stereotactic radiosurgery (SRS) remains challenging. The authors retrospectively tested the hypothesis that AVM obliteration rates can be improved by increasing the percentage volume of an AVM that receives a minimal threshold dose of radiation.METHODSIn 1992, the authors prospectively began to stage anatomical components in order to deliver higher single doses to AVMs > 15 cm3 in volume. Since that time 60 patients with large AVMs have undergone volume-staged SRS (VS-SRS). The median interval between the first stage and the second stage was 4.5 months (2.8-13.8 months). The median target volume was 11.6 cm3 (range 4.3-26 cm3) in the first-stage SRS and 10.6 cm3 (range 2.8-33.7 cm3) in the second-stage SRS. The median margin dose was 16 Gy (range 13-18 Gy) for both SRS stages.RESULTSAVM obliteration after the initial two staged volumetric SRS treatments was confirmed by MRI alone in 4 patients and by angiography in 11 patients at a median follow-up of 82 months (range 0.4-206 months) after VS-SRS. The post-VS-SRS obliteration rates on angiography were 4% at 3 years, 13% at 4 years, 23% at 5 years, and 27% at 10 years. In multivariate analysis, only ≥ 20-Gy volume coverage was significantly associated with higher total obliteration rates confirmed by angiography. When the margin dose is ≥ 17 Gy and the 20-Gy SRS volume included ≥ 63% of the total target volume, the angiographically confirmed obliteration rates increased to 61% at 5 years and 70% at 10 years.CONCLUSIONSThe outcomes of prospective VS-SRS for large AVMs can be improved by prescribing an AVM margin dose of ≥ 17 Gy and adding additional isocenters so that ≥ 63% of the internal AVM dose receives more than 20 Gy.

Pulmonary Tumor Thrombotic Microangiopathy Induced by Prostate Cancer.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal, malignancy-related respiratory complication; we herein report a PTTM case induced by metastatic prostate cancer. An 81-year-old Japanese man developed dyspnea. High-resolution computed tomography (HRCT) revealed ground-glass opacities spread across bilateral lung fields. Pulmonary microvascular aspiration cytology detected prostate cancer cells. As PTTM was highly suspected, docetaxel chemotherapy was performed immediately. His respiratory condition and HRCT findings improved temporarily, but he died approx. 6 weeks after admission. Autopsy showed fibrocellular intimal proliferation of small pulmonary arterioles, which confirmed the diagnosis of PTTM induced by prostate cancer. As in the present case, it is often difficult to confirm the presence of not only tumor embolization but also fibrocellular intimal proliferation before the patient's death.

Caregiver and adolescent factors associated with delayed completion of the three-dose human papillomavirus vaccination series.

BACKGROUND: Delayed completion of human papillomavirus vaccination (4vHPV) series is common. We sought to identify factors associated with delay. METHODS: This substudy was part of a large prospective, multi-site study recruiting 9-17 year old girls at the time of their third 4vHPV dose to assess immunogenicity associated with prolonged dosing intervals. At participating sites, parents/legal guardians (caregivers) of all enrolled girls (9-17 years old) and enrolled girls aged 14-17 years were approached for participation. Caregivers completed a questionnaire measuring adolescent and caregiver sociodemographic characteristics, caregiver attitudes and beliefs about on-schedule HPV vaccination and HPV vaccine safety, adolescent's health behaviors, barriers to accessing health care, provider office vaccination practices and a Rapid Estimate of Adult Literacy in Medicine (REALM). Participating girls completed a separate questionnaire measuring their attitudes and beliefs about on-schedule HPV vaccination and HPV vaccine safety. Delay was defined as receiving the third 4vHPV dose >12 months after the first. Bivariate, multinomial logistic regression and multivariate logistic regression analyses were used to identify factors predicting delayed completion. RESULTS: Questionnaires were completed by 482 caregivers and 386 adolescents; 422 caregivers completed a REALM. Delayed 4vHPV dosing occurred in most adolescents (67%). In multivariate analyses, predictors of delayed completion included caregiver demographic factors (self-reported black vs. white race and high school or less education vs. college or more) and an interaction between caregiver's inability to get an immunization appointment as soon as needed and adolescent's type of insurance. CONCLUSIONS: Caregiver's race and educational level, accessibility of immunization appointments, and adolescent's insurance type were found to be related to delays in completion of 4vHPV, but caregiver or adolescent attitudes and beliefs about on-schedule HPV vaccination or HPV vaccine safety were not. Therefore, interventions to improve adherence to recommended vaccination schedules could benefit from a focus on improving access to immunizations. ClinicalTrials.gov (NCT01030562).

Neuron-specific knockdown of the Drosophila fat induces reduction of life span, deficient locomotive ability, shortening of motoneuron terminal branches and defects in axonal targeting.

Mutations in FAT4 gene, one of the human FAT family genes, have been identified in Van Maldergem syndrome (VMS) and Hennekam lymphangiectasia-lymphedema syndrome (HS). The FAT4 gene encodes a large protein with extracellular cadherin repeats, EGF-like domains and Laminin G-like domains. FAT4 plays a role in tumor suppression and planar cell polarity. Drosophila contains a human FAT4 homologue, fat. Drosophila fat has been mainly studied with Drosophila eye and wing systems. Here, we specially knocked down Drosophila fat in nerve system. Neuron-specific knockdown of fat shortened the life span and induced the defect in locomotive abilities of adult flies. In consistent with these phenotypes, defects in synapse structure at neuromuscular junction were observed in neuron-specific fat-knockdown flies. In addition, aberrations in axonal targeting of photoreceptor neuron in third-instar larvae were also observed, suggesting that fat involves in axonal targeting. Taken together, the results indicate that Drosophila fat plays an essential role in formation and/or maintenance of neuron. Both VMS and HS show mental retardation and neuronal defects. We therefore consider that these two rare human diseases could possibly be caused by the defect in FAT4 function in neuronal cells.

[Transient charles bonnet syndrome after excision of a right occipital meningioma: a case report].

Charles Bonnet syndrome is a condition characterized by visual hallucinations. These simple or complex visual hallucinations are more common in elderly individuals with impaired peripheral vision. The current report describes a case of transient Charles Bonnet syndrome appearing after the removal of a meningioma. The patient was a 61-year-old man who already had impaired visual acuity due to diabetic retinopathy. Brain MRI revealed a cystic tumor severely compressing the right occipital lobe. Starting on day 2 postoperatively, the patient was troubled by recurring visual hallucinations involving people, flowers, pictures, and familiar settings(the train and a coffee shop). These continued for 3.5 months. This period roughly coincided with the time for the occipital lobe to recover from the compression caused by the tumor, a fact that was confirmed by several MRI scans. ¹²³I-IMP SPECT performed 1 month after the surgical operation showed an area of hypoperfusion in the right parieto-occipital lobe. Based on the patient's clinical course and MRI findings, the mechanism of onset of visual hallucinations in this patient was put forward. The release of pressure in the brain by tumor removal and subsequent recovery changed the blood flow to the brain. This triggered visual hallucinations in the patient, who was already predisposed to developing Charles Bonnet syndrome because of diabetic retinopathy. This case is interesting since it indicates that central neurological factors, as well as visual deficits, may induce the appearance of visual hallucinations in Charles Bonnet syndrome.

Cerebellar hemorrhage secondary to cerebellopontine angle metastasis from thyroid papillary carcinoma.

A 63-year-old woman presented with a metastatic focus of papillary thyroid carcinoma in the cerebellopontine angle manifesting as lateral gazing nystagmus and slurred speech. Computed tomography demonstrated massive hemorrhage in the left cerebellar hemisphere. She was treated conservatively. Her symptoms resolved completely, but she experienced progressive deterioration in auditory acuity and ataxia over the next 6 months. Magnetic resonance imaging with gadolinium demonstrated an enhanced mass in the left cerebellopontine angle, and she was scheduled for elective resection of the tumor. Left retrosigmoid craniotomy was performed, and the tumor was subtotally removed except for a small amount at the junction of the trigeminal nerve and the pons. Histological examination confirmed a diagnosis of metastatic papillary thyroid carcinoma. The patient then underwent adjuvant gamma knife radiosurgery. Her clinical course was unremarkable, and her hypoacusis and ataxia resolved completely. Postoperative gallium scintigraphy revealed no residual tumor and no other systemic metastases. Hemorrhagic cerebellar metastasis from papillary thyroid carcinoma is extremely rare, but early recognition of metastatic cerebellar tumor should prompt immediate treatment to avoid the development of hearing loss, ataxia, and tonsillar herniation.