Publications by authors named "Hiroshi Masuda"

174 Publications

Novel 60 GHz Band Spatial Synthetic Exposure Setup to Investigate Biological Effects of 5G and Beyond Wireless Systems on Human Body.

Front Public Health 2021 6;9:777712. Epub 2021 Dec 6.

Department of Environmental Medicine, Kurume University School of Medicine, Fukuoka, Japan.

The global spread of 5th generation (5G) wireless systems causes some concern about health effects of millimeter waves (MMW). To investigate biological effects of local exposure to 5G-MMW on human body, a novel 60 GHz band exposure setup was developed, and its performance was validated. A spatial synthetic beam-type exposure setup using two dielectric lens antennas was proposed to achieve high intensity 60 GHz irradiation to the target area of human skin. Variety distributions and intensities of electromagnetic fields at the exposed area, which is modified by incident angles of the combined beams, were simulated using finite-difference time-domain methods. The exposure performance we estimated was verified by temperature elevations of surface in a physical arm-shaped silicone phantom during the MMW exposure. The interference fringes generated in the exposed area due to the combined two-directional beam radiations were observed both in the simulation and in the phantom experiment but eliminated by applying an orthogonalizing polarized feeding structure. Under these exposure conditions, the local temperature changes, which could evoke warmth sensations, were obtained at the target area of the human forearm skin, which means the achievement of exposure performance we intended.
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http://dx.doi.org/10.3389/fpubh.2021.777712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8685201PMC
December 2021

Deep learning-based diagnosis of temporal lobe epilepsy associated with hippocampal sclerosis: An MRI study.

Epilepsy Res 2021 Dec 21;178:106815. Epub 2021 Nov 21.

Department of Neurosurgery, Brain Research Institute, Niigata University, Japan.

Purpose: The currently available indicators-sensitivity and specificity of expert radiological evaluation of MRIs-to identify mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) are deficient, as they cannot be easily assessed. We developed and investigated the use of a novel convolutional neural network trained on preoperative MRIs to aid diagnosis of these conditions.

Subjects And Methods: We enrolled 141 individuals: 85 with clinically diagnosed mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis International League Against Epilepsy (HS ILAE) type 1 who had undergone anterior temporal lobe hippocampectomy were assigned to the MTLE-HS group, and 56 epilepsy clinic outpatients diagnosed as nonepileptic were assigned to the normal group. We fine-tuned a modified CNN (mCNN) to classify the fully connected layers of ImageNet-pretrained VGG16 network models into the MTLE-HS and control groups. MTLE-HS was diagnosed using MRI both by the fine-tuned mCNN and epilepsy specialists. Their performances were compared.

Results: The fine-tuned mCNN achieved excellent diagnostic performance, including 91.1% [85%, 96%] mean sensitivity and 83.5% [75%, 91%] mean specificity. The area under the resulting receiver operating characteristic curve was 0.94 [0.90, 0.98] (DeLong's method). Expert interpretation of the same image data achieved a mean sensitivity of 73.1% [65%, 82%] and specificity of 66.3% [50%, 82%]. These confidence intervals were located entirely under the receiver operating characteristic curve of the fine-tuned mCNN.

Conclusions: Deep learning-based diagnosis of MTLE-HS from preoperative MR images using our fine-tuned mCNN achieved a performance superior to the visual interpretation by epilepsy specialists. Our model could serve as a useful preoperative diagnostic tool for ascertaining hippocampal atrophy in patients with MTLE.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106815DOI Listing
December 2021

[Adult Prepubertal-Type Teratoma Diagnosed Using Fish Analysis : A Case Report].

Hinyokika Kiyo 2021 Oct;67(10):471-474

The Department of Urology, Teikyo University Chiba Medical Center.

A 34-year-old man visited our hospital complaining of a small painless left scrotal mass. His serum alpha-fetoprotein and human chorionic gonadotropin-beta levels were normal. Ultrasonography revealed a solitary 14 mm mass. Magnetic resonance imaging revealed a mass with high intensity on T2-weighted imaging. Computed tomography revealed a heterogeneous tumor in the left scrotum. Left high orchiectomy was performed. The histopathological diagnosis was a teratoma without germ cell neoplasia in situ (GCNIS). Fluorescence in situ hybridization analysis showed no appearance of i(12p). The patient was clinically diagnosed as having a prepubertal-type testicular teratoma. Adult teratomas contain GCNIS and are aggressively treated as malignant germ cell tumors. However, a prepubertal-type teratoma is benign and does not relapse. It is essential to validate the appearance of i(12p) to differentiate prepubertal and postpubertal-type teratoma.
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http://dx.doi.org/10.14989/ActaUrolJap_67_10_471DOI Listing
October 2021

Surgical Strategy for Directional Deep Brain Stimulation.

Neurol Med Chir (Tokyo) 2022 Jan 29;62(1):1-12. Epub 2021 Oct 29.

Department of Neurosurgery, Brain Research Institute, Niigata University.

Deep brain stimulation (DBS) is a well-established treatment for drug-resistant involuntary movements. However, the conventional quadripole cylindrical lead creates electrical fields in all directions, and the resulting spread to adjacent eloquent structures may induce unintended effects. Novel directional leads have therefore been designed to allow directional stimulation (DS). Directional leads have the advantage of widening the therapeutic window (TW), compensating for slight misplacement of the lead and requiring less electrical power to provide the same effect as a cylindrical lead. Conversely, the increase in the number of contacts from four to eight and the addition of directional elements has made stimulation programming more complex. For these reasons, new treatment strategies are required to allow effective directional DBS. During lead implantation, the directional segment should be placed in a "sweet spot," and the orientation of the directional segment is important for programming. Trial-and-error testing of a large number of contacts is unnecessary, and efficient and systematic execution of the programmed procedure is desirable. Recent improvements in imaging technologies have enabled image-guided programming. In the future, optimal stimulations are expected to be programmed by directional recording of local field potentials.
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http://dx.doi.org/10.2176/nmc.ra.2021-0214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8754682PMC
January 2022

The Association Between Hot Flashes and Renal Dysfunction After Androgen Deprivation Therapy With Radiotherapy in Japanese Patients With High-risk Prostate Cancer.

In Vivo 2021 Nov-Dec;35(6):3489-3493

Department of Urology, Teikyo University Chiba Medical Center, Chiba, Japan.

Background/aim: We investigated the changes in and characteristics of renal function in Japanese patients with high-risk prostate cancer (PCa) who underwent radiotherapy and long-term androgen deprivation therapy (ADT), including those seen after the ADT was discontinued.

Patients And Methods: Among 60 patients who were pathologically diagnosed with PCa and received ADT for 24 months and radiotherapy, 36 patients who underwent treatment for stage B or C PCa were eligible. We assessed renal function using the estimated glomerular filtration rate (eGFR) and investigated the rate of change in the eGFR (ΔeGFR) during and after ADT. Univariate and multivariate logistic analyses were carried out to identify clinical factors that were significantly associated with renal dysfunction at 36 months.

Results: The incidence of renal dysfunction at 36 months was 75% (27/36). Multivariate analysis showed that the presence/absence of HF was an independent predictor of renal dysfunction at 36 months.

Conclusion: Renal function tended to recover after ADT was received for 24 months and subsequently discontinued. The presence/absence of HF represents new and meaningful information for patients receiving ADT, and high-risk PCa patients prior to ADT.
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http://dx.doi.org/10.21873/invivo.12650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627764PMC
October 2021

Long-term seizure outcomes in patients with hypothalamic hamartoma treated by stereotactic radiofrequency thermocoagulation.

Epilepsia 2021 Nov 20;62(11):2697-2706. Epub 2021 Sep 20.

Department of Neurosurgery, Niigata Seiro Hospital, Niigata, Japan.

Objective: To investigate long-term seizure outcomes in patients with hypothalamic hamartoma (HH) following stereotactic radiofrequency thermocoagulation (SRT).

Methods: A total of 131 patients with HH who underwent SRT and were followed for at least three years after the last SRT were enrolled. Seizure outcomes were evaluated for gelastic seizures (GS) and other types of seizures (nGS) separately using the International League Against Epilepsy classification. Classes 1 and 2 were considered seizure-free. Kaplan-Meier survival analyses were used to estimate the proportion remaining seizure-free after the first and last SRTs. Risk factors relating to outcomes were analyzed by log-rank tests and a multivariate Cox proportional hazards model.

Results: Reoperation was performed in 34 patients (26.2%). Median total follow-up was 61 (range, 36-202) months. Seizure freedom was obtained in 116 patients (88.6%) for GS and 85 of 108 patients (78.7%) for nGS at the last follow-up. Mean GS-free survival times improved from after the first (64.1 [95%CI 57.3-70.9] months) to after the last SRT (80.2 [95%CI 75.7-84.8] months). About 90% of GS recurrences after the first SRT were found within 6 months, though a few patients recurred more than 2 years after the first SRT. On the other hand, mean nGS-free survival times after the first and last SRTs were not different between after the first SRT (84.4 [95%CI 73.0-90.7] months) and after the last SRT (83.1 [95%CI 74.1-92.0] months). There was no factor related to GS outcomes, but the significant factor for nGS-free survival after the last SRT was multiple previous treatments (p=0.01, hazard ratio=15.65, 95%CI 1.79-137.16).

Significance: The last SRT was almost equivalent to achieving complete disconnection of HHs from the hypothalamus according to our strategy. Considering the epileptogenic network, GS outcomes depend on complete disconnection, whereas nGS outcomes are not affected by surgical factors but independency of secondary epileptogenesis.
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http://dx.doi.org/10.1111/epi.17071DOI Listing
November 2021

Renal Function Improves After the Discontinuation of Androgen Deprivation Therapy in Japanese Patients With Prostate Cancer.

Anticancer Res 2021 Sep 1;41(9):4443-4446. Epub 2021 Sep 1.

Department of Urology, Teikyo University Chiba Medical Center, Chiba, Japan.

Background: Androgen deprivation therapy (ADT) is one of the most effective treatments for advanced prostate cancer (PCa). However, it has been reported that the use of ADT is significantly associated with an increased risk of acute kidney injury (AKI) among patients with newly diagnosed non-metastatic PCa. We investigated changes in renal function that occurred in Japanese patients with PCa after ADT was discontinued.

Patients And Methods: Among 121 patients who underwent prostate biopsies, were pathologically diagnosed with PCa, and received ADT for ≥6 months at our Institution between 2009 and 2014, 60 patients who underwent radiotherapy for stage B or C PCa were eligible for inclusion in this retrospective study. Renal function was assessed using the estimated glomerular filtration rate (eGFR) before treatment and at 1, 3, 6, 9, and 12 months after the initiation of ADT and the rate of change in the eGFR (ΔeGFR) during ADT and after the discontinuation of ADT was investigated. We divided patients into two groups: Group 1 received ADT for 6 months, and group 2 received ADT for 12 months. Age; ΔeGFR; prostate-specific antigen, testosterone and hemoglobin levels; clinical stage; Gleason score; comorbidities; body mass index; heart rate; and the cardiothoracic ratio were analyzed.

Results: A total of 60 patients (group 1: n=23, group 2: n=37) were analyzed. The Gleason score of group 2 was higher than that of group 1 (p=0.0011). Regarding clinical stage, group 1 had more patients with stage B disease, and group 2 had more with stage C (p<0.0001). The eGFR decreased with the duration of ADT treatment. At 12 months, renal function had started to recover in group 1, while it had continued to decrease in group 2.

Conclusion: Discontinuation of ADT tended to result in improvements in renal function. Furthermore, this study indicated that renal dysfunction caused by 6 months of ADT is transient. Normalization of the serum testosterone level seen after the discontinuation of ADT may be associated with improvements in renal function. Thus, intermittent ADT may be a useful treatment for PCa, as it would help to preserve renal function.
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http://dx.doi.org/10.21873/anticanres.15252DOI Listing
September 2021

Overlapping Features in Kawasaki Disease-Related Arthritis and Systemic-Onset Juvenile Idiopathic Arthritis: A Nationwide Study in Japan.

Front Pediatr 2021 20;9:597458. Epub 2021 Jul 20.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Arthritis may occur after the diagnosis of Kawasaki disease (KD). Most cases are self-limiting; however, some patients require prolonged treatment. To characterize KD-related arthritis, 14 patients who required arthritis treatment within 30 days after the diagnosis of KD were recruited from the 23rd KD survey in Japan. Twenty-six additional patients were included from our tertiary center and literature review cohorts. The estimated prevalence of KD-related arthritis in Japan was 48 per 100,000 KD patients. Patients with KD-related arthritis had an older age at onset (52 vs. 28 months, = 0.002) and higher rate of intravenous immunoglobulin (IVIG) resistance in comparison to those without arthritis (86 vs. 17%, < 0.001). Among 40 patients, 18 had arthritis in the acute phase KD (continued fever-onset type) and 22 did in the convalescent phase (interval fever-onset type). Both showed a similar rate of complete KD or IVIG response. Interval-type patients required biologics for arthritis control less frequently (5 vs. 39%, = 0.02) and had a higher 2-year off-treatment rate (100 vs. 43%, = 0.009) than continued-type ones. Interval-types showed lower serum ferritin and interleukin-18 levels than continued-types. When continued-types were grouped according to whether or not they required biologics ( = 7 and = 11, respectively), the former subgroup had higher ferritin and interleukin-18 levels ( = 0.01 and 0.02, respectively). A canonical discriminant analysis differentiated interval-type from continued-type with the combination of age, time to arthritis, and the ferritin and matrix metalloproteinase-3 levels. Arthritis requiring treatment is a rare complication of KD. KD-associated arthritis includes interval-type (KD-reactive) and continued-type (true systemic-onset juvenile idiopathic arthritis [JIA] requiring biologics), and overlapping arthritis, suggesting the pathophysiological continuity of autoinflammation between KD and JIA.
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http://dx.doi.org/10.3389/fped.2021.597458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329333PMC
July 2021

Association Between Albumin-Bilirubin Score at Admission and In-Hospital Mortality in Patients with Acute Heart Failure.

Int Heart J 2021 Jul 17;62(4):829-836. Epub 2021 Jul 17.

Department of Cardiovascular Medicine, Sassa General Hospital.

Liver dysfunction is one of the most recognized complications in patients with acute heart failure (HF) and therefore a liver function score may be useful for risk-stratification in those patients. Recently, the albumin-bilirubin (ALBI) score was developed as a new model to assess liver function in liver disease. We explored the association between the ALBI score at admission and in-hospital mortality in patients with acute HF.We enrolled 262 patients (median age, 86 years, 137 males) who were admitted to our hospital for treatment of acute HF. The following data were recorded: vital signs, laboratory data including B-type natriuretic peptide (BNP) level, echocardiographic data at admission, demographic and clinical characteristics, and treatment and prognostic information. The Get With the Guidelines-Heart Failure (GWTG-HF) risk score was calculated as an established risk model for each patient. The primary outcome was all-cause in-hospital mortality.During hospitalization, 37 patients (14.1%) died. The in-hospital mortality rate was significantly higher in patients with ALBI scores > -2.25 compared with patients with ALBI scores ≤ -2.25 (21.1% versus 4.5%, respectively; P = 0.0001). Multivariate analysis revealed that the GWTG-HF score (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.08-1.25, P < 0.0001), BNP level (OR 1.0007, 95% CI 1.0003-1.001, P = 0.0003) and ALBI score (OR 6.0, 95% CI 1.8-19.6, P = 0.0017) were independently associated with in-hospital mortality.Our results indicated that the ALBI score was independently associated with in-hospital mortality in patients hospitalized for acute HF.
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http://dx.doi.org/10.1536/ihj.21-080DOI Listing
July 2021

Action-at-a-distance mutations at 5'-GpA-3' sites induced by oxidised guanine in WRN-knockdown cells.

Mutagenesis 2021 10;36(5):349-357

Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.

G:C sites distant from 8-oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine) are frequently mutated when the lesion-bearing plasmid DNA is replicated in human cells with reduced Werner syndrome (WRN) protein. To detect the untargeted mutations preferentially, the oxidised guanine base was placed downstream of the reporter supF gene and the plasmid DNA was introduced into WRN-knockdown cells. The total mutant frequency seemed higher in the WRN-knockdown cells as compared to the control cells. Mutation analyses revealed that substitution mutations occurred at the G:C pairs of 5'-GpA-3'/5'-TpC-3' sites, the preferred sequence for the apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3 (APOBEC3)-family cytosine deaminases, in the supF gene in both control and knockdown cells. These mutations were observed more frequently at G sites than C sites on the DNA strand where the GO base was originally located. This tendency was promoted by the knockdown of the WRN protein. The present results imply the possible involvement of APOBEC3-family cytosine deaminases in the action-at-a-distance (untargeted) mutations at G:C (or G) sites induced by GO and in cancer initiation by oxidative stress.
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http://dx.doi.org/10.1093/mutage/geab027DOI Listing
October 2021

Elucidation of Novel -Regulatory Elements and Promoter Structures Involved in Iron Excess Response Mechanisms in Rice Using a Bioinformatics Approach.

Front Plant Sci 2021 2;12:660303. Epub 2021 Jun 2.

Faculty of Bioresource Sciences, Department of Biological Production, Akita Prefectural University, Akita, Japan.

Iron (Fe) excess is a major constraint on crop production in flooded acidic soils, particularly in rice cultivation. Under Fe excess, plants activate a complex mechanism and network regulating Fe exclusion by roots and isolation in various tissues. In rice, the transcription factors and -regulatory elements (CREs) that regulate Fe excess response mechanisms remain largely elusive. We previously reported comprehensive microarray analyses of several rice tissues in response to various levels of Fe excess stress. In this study, we further explored novel CREs and promoter structures in rice using bioinformatics approaches with this microarray data. We first performed network analyses to predict Fe excess-related CREs through the categorization of the gene expression patterns of Fe excess-responsive transcriptional regulons, and found four major expression clusters: Fe storage type, Fe chelator type, Fe uptake type, and WRKY and other co-expression type. Next, we explored CREs within these four clusters of gene expression types using a machine-learning method called microarray-associated motif analyzer (MAMA), which we previously established. Through a comprehensive bioinformatics approach, we identified a total of 560 CRE candidates extracted by MAMA analyses and 42 important conserved sequences of CREs directly related to the Fe excess response in various rice tissues. We explored several novel -elements as candidate Fe excess CREs including GCWGCWGC, CGACACGC, and Myb binding-like motifs. Based on the presence or absence of candidate CREs using MAMA and known PLACE CREs, we found that the Boruta-XGBoost model explained expression patterns with high accuracy of about 83%. Enriched sequences of both novel MAMA CREs and known PLACE CREs led to high accuracy expression patterns. We also found new roles of known CREs in the Fe excess response, including the DCEp2 motif, IDEF1-, Zinc Finger-, WRKY-, Myb-, AP2/ERF-, MADS- box-, bZIP and bHLH- binding sequence-containing motifs among Fe excess-responsive genes. In addition, we built a molecular model and promoter structures regulating Fe excess-responsive genes based on new finding CREs. Together, our findings about Fe excess-related CREs and conserved sequences will provide a comprehensive resource for discovery of genes and transcription factors involved in Fe excess-responsive pathways, clarification of the Fe excess response mechanism in rice, and future application of the promoter sequences to produce genotypes tolerant of Fe excess.
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http://dx.doi.org/10.3389/fpls.2021.660303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207140PMC
June 2021

Changes in prognostic nutritional index during hospitalization and outcomes in patients with acute heart failure.

Heart Vessels 2022 Jan 15;37(1):61-68. Epub 2021 Jun 15.

Department of Cardiovascular Medicine, Sassa General Hospital, 4-24-15, Tanashicho, Nishi Tokyo-City, Tokyo, 188-0011, Japan.

Although the prognostic nutritional index (PNI) is reported as a prognosticator in patients with heart failure (HF), that is evaluated usually on one occasion, and any changes in PNI during hospitalization are not considered. This study aimed to assess between changes in the PNI during hospitalization and outcomes in patients with acute HF. We enrolled 141 patients (median age, 84 years, 75 male) admitted to our hospital for the treatment of acute HF. The PNI was calculated on admission and at discharge based on the original report. According to the PNI change during hospitalization, patients were classified as either improved (PNI at discharge ≥ PNI on admission) or deteriorated (PNI at discharge < PNI on admission). Primary outcomes were all-cause death or unplanned hospitalization due to HF within the first year. Forty-nine events occurred (19 deaths, 30 HF hospitalizations). The event-free survival rate determined by Kaplan-Meier analysis was significantly higher in patients in the improved group (log-rank test, P < 0.0001), regardless of the PNI value on admission. Multivariate analysis showed that younger age (HR 1.06, 95% CI 1.01-1.11, P = 0.016), higher body mass index (HR 0.90, 95% CI 0.82-0.98, P = 0.021) and the PNI in the improved group (HR 0.30, 95% CI 0.14-0.57, P = 0.0006) were independently associated with favorable outcomes. In conclusion, changes in nutritional status during hospitalization, evaluated using the PNI on admission and at discharge, were independently associated with 1-year outcomes in patients with acute HF.
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http://dx.doi.org/10.1007/s00380-021-01888-xDOI Listing
January 2022

Validation of the Effectiveness of Neutrophil-to-lymphocyte Ratio (NLR) as a Predictive Factor in Patients Undergoing Prostate Biopsy With Prostate Specific Antigen (PSA) Between 4.0 and 10.0 ng/ml.

In Vivo 2021 May-Jun;35(3):1641-1646

Department of Urology, Teikyo University Chiba Medical Center, Chiba, Japan.

Background/aim: This study aimed to access the effectiveness of serum neutrophil-to-lymphocyte ratio (NLR) in patients undergoing prostate needle biopsy with a prostate specific antigen (PSA) between 4.0 and 10.0 ng/ml.

Patients And Methods: A total of 633 cases were eligible. We evaluated several factors including age, PSA, PSA-density (PSAD), platelet-to-lymphocyte ratio (PLR) and NLR in the presence or absence of prostate cancer (PCa), retrospectively. We evaluated statistically the associations between each factor and pathological findings or Gleason score.

Results: A total of 201 were evaluated in this study. Regarding the presence or absence of prostate cancer, there were statistically significant differences in age, PSA levels, PSAD, the PLR and NLR. The mean NLR value of the patients with PCa was significantly lower compared to the entire cohort. Multivariate analysis showed that age, PSAD, and NLR were independent risk factors predicting PCa.

Conclusion: For patients having a PSA between 4.0 and 10.0 ng/ml, NLR was a predicting factor of PCa prior to prostate needle biopsy and an effective biomarker and useful tool for avoiding unnecessary biopsies.
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http://dx.doi.org/10.21873/invivo.12422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193316PMC
June 2021

High Serum Alkaline Phosphatase Flare after First-Line Androgen Deprivation Therapy Predicts Poor Prognosis in Metastatic Prostate Cancer Patients Treated with Second-Generation Androgen Receptor Targeted Therapy.

Prostate Cancer 2021 8;2021:5574067. Epub 2021 Apr 8.

Department of Urology, Teikyo University Chiba Medical Center, Ichihara, Japan.

Objectives: To determine whether an alkaline phosphatase (ALP) flare after androgen deprivation therapy (ADT) is associated with the treatment response in castration-resistant prostate cancer (CRPC) and predicts the prognosis of metastatic prostate cancer (PCa) patients.

Methods: One hundred and nineteen patients diagnosed with metastatic PCa between 2008 and 2017 were retrospectively studied. The ALP flare ratio was calculated as the ratio of ALP levels 1 month after beginning ADT to ALP levels at diagnosis. The association of the ALP flare ratio with the prostate-specific antigen (PSA) response to CRPC treatment (second-generation androgen receptor targeted therapy (ART) or docetaxel), time to CRPC, and overall survival (OS) were investigated.

Results: The time to CRPC and OS was significantly longer in patients with an ALP flare ratio less than 1.33 compared to a ratio more than 1.33. No difference in PSA response was seen regarding the ALP flare ratio in both ART and docetaxel treatment. Second-generation ART-treated patients with a low ALP flare ratio showed longer OS than those with a higher ALP flare ratio (=0.0367). However, no difference was seen between a high and low ALP flare ratio (=0.8054) in docetaxel-treated patients. The ALP flare ratio was the most significant prognostic factor for OS ( < 0.0001).

Conclusions: A higher ALP flare ratio after first-line ADT was a significant prognostic factor in metastatic PCa, especially in patients treated with second-generation ART for CRPC. Chemotherapy for patients with a higher ALP flare ratio 1 month after induction of ADT may be a clinically relevant decision.
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http://dx.doi.org/10.1155/2021/5574067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052161PMC
April 2021

Development of a mugineic acid family phytosiderophore analog as an iron fertilizer.

Nat Commun 2021 03 10;12(1):1558. Epub 2021 Mar 10.

Department of Pharmaceutical Sciences, Tokushima University, Tokushima, Japan.

Iron (Fe) is an essential nutrient, but is poorly bioavailable because of its low solubility in alkaline soils; this leads to reduced agricultural productivity. To overcome this problem, we first showed that the soil application of synthetic 2'-deoxymugineic acid, a natural phytosiderophore from the Poaceae, can recover Fe deficiency in rice grown in calcareous soil. However, the high cost and poor stability of synthetic 2'-deoxymugineic acid preclude its agricultural use. In this work, we develop a more stable and less expensive analog, proline-2'-deoxymugineic acid, and demonstrate its practical synthesis and transport of its Fe-chelated form across the plasma membrane by Fe(III)•2'-deoxymugineic acid transporters. Possibility of its use as an iron fertilizer on alkaline soils is supported by promotion of rice growth in a calcareous soil by soil application of metal free proline-2'-deoxymugineic acid.
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http://dx.doi.org/10.1038/s41467-021-21837-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946895PMC
March 2021

A case of congenital single testis with testicular cancer patient and azoospermia who was able to collect spermatozoa with ipsilateral Onco-TESE.

Clin Case Rep 2021 Jan 23;9(1):535-539. Epub 2020 Nov 23.

Department of Urology Ladies Clinic Kitahama Osaka Japan.

Onco-TESE is a useful strategy for cancer patients with a congenital single testis who wish to preserve their fertility.
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http://dx.doi.org/10.1002/ccr3.3576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813069PMC
January 2021

False-positive I-metaiodobenzylguanidine scan in a patient with renal cell carcinoma: A case of chromophobe renal cell carcinoma oncocytic variant with a complicated clinical course.

IJU Case Rep 2021 Jan 24;4(1):39-42. Epub 2020 Oct 24.

Department of Urology Teikyo University Chiba Medical Center Ichihara Japan.

Introduction: I-metaiodobenzylguanidine scanning has high sensitivity and specificity for the diagnosis of tumors derived from sympathetic nerves or the adrenal medulla. We report the rare case of a I-metaiodobenzylguanidine false-positive renal cell carcinoma.

Case Presentation: The patient was referred to our hospital with an incidental left renal mass during evaluation for hypertension. An ovarian tumor and prominent ascites were also observed. Serum and urine catecholamine levels were high to suspect a catecholamine-producing tumor of the kidney. I-metaiodobenzylguanidine scintigraphy showed increased I-metaiodobenzylguanidine intake in the tumor. Laparoscopic radical left nephrectomy was performed. The pathologic diagnosis was an oncocytic variant of chromophobe renal cell carcinoma. No pheochromocytoma features were found.

Conclusion: We report the first case of a I-metaiodobenzylguanidine false-positive renal cell carcinoma. This case was diagnosed with primary aldosteronism and Meigs' syndrome, which made the clinical course more complicated.
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http://dx.doi.org/10.1002/iju5.12233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784746PMC
January 2021

Corrigendum: How Does Rice Defend Against Excess Iron?: Physiological and Molecular Mechanisms.

Front Plant Sci 2020 20;11:601527. Epub 2020 Nov 20.

Department of Biological Production, Faculty of Bioresource Sciences, Akita Prefectural University, Akita, Japan.

[This corrects the article DOI: 10.3389/fpls.2020.01102.].
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http://dx.doi.org/10.3389/fpls.2020.601527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714916PMC
November 2020

Location of emotional corticobulbar tract in the internal capsule.

J Neurol Sci 2021 01 21;420:117228. Epub 2020 Nov 21.

Department of Neurosurgery, Hypothalamic Hamartoma Center, National Hospital Organization, Nishiniigata Chuo Hospital, Niigata, Japan. Electronic address:

Emotional facial paresis (EFP) is a rare neurological symptom with intact volitional facial movement. The exact location of emotional corticobulbar tract remains unclear. EFP was frequently recognized following the surgery of stereotactic radiofrequency thermocoagulation for hypothalamic hamartoma in 84.5% of 58 patients. To examine our hypothesis that EFP might be caused by stereotactic trajectories passing through an area including the internal capsule (IC), topographical locations of trajectories were analyzed and compared between the EFP-positive group (n = 41) and the EFP-negative group (n = 8). In the EFP-positive group, multiple (2 to 5) trajectories focused within the genu of the IC in 31 (75.6%) cases, whereas a single trajectory passed through the genu in 8 (19.5%) cases. In the EFP-negative group, 6 (75.0%) of 8 patients had a single trajectory and only one patient had two trajectories passing through the genu of the IC. The ratio between multiple trajectories and a single trajectory relevant to the genu differed significantly between two groups (p < 0.01). The multiple trajectories focusing in the genu have high risks of EFP, whereas a single trajectory seemed to incidentally cause EFP. The results proved our hypothesis and provided a high probability that the emotional corticobulbar tract passes through the genu rather than anterior or posterior limbs of the IC. The location of the emotional corticobulbar tract is in the genu of the IC.
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http://dx.doi.org/10.1016/j.jns.2020.117228DOI Listing
January 2021

Significance of the electrophysiological border between hypothalamic hamartomas and the hypothalamus for the target of ablation surgery identified by intraoperative semimicrorecording.

Epilepsia 2020 12 21;61(12):2739-2747. Epub 2020 Oct 21.

Department of Neurosurgery, Niigata Seiro Hospital, Niigata, Japan.

Objective: Ablation surgery has become the first line of treatment for hypothalamic hamartomas (HHs). For effective treatment, optimum targeting of ablation is mandatory. The present study aimed to evaluate the correspondence between the electrophysiological features of HHs and morphological targeting by semimicrorecording during stereotactic radiofrequency thermocoagulation (SRT).

Methods: Eighty HH patients who underwent SRT were involved. Semimicrorecording was performed on the first trajectory. The distance from the center of the target at the morphological border (TMB) determined by magnetic resonance imaging, differences in discharge patterns, and area potentials (APs) were measured.

Results: The electrophysiological border (EB) between the HH and hypothalamus was detected by semimicrorecording in 73 (91.3%), AP increase (API) in the HH was detected in 31 (38.8%), and spike discharges (SDs) of the HH were detected in 56 patients (70.0%). Semimicrorecording showed significantly different APs among structures passing through the trajectory, except between API and SDs. The median distances from the center of the TMB to the EB, API, SDs, and AP decline were -3.50, -2.49, -1.38, and +2.00 mm, respectively.

Significance: The electrophysiological features of HHs were shown by semimicrorecording during SRT. The EB corresponded to the morphological border. The electrophysiologically active area of HHs was located near the border. Ablation surgery should focus on disconnection at the border between the HH and the hypothalamus to maximize its effectiveness, as well as to reduce complications.
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http://dx.doi.org/10.1111/epi.16730DOI Listing
December 2020

A Distinct Feature of T Cell Subpopulations in a Patient with CHARGE Syndrome and Omenn Syndrome.

J Clin Immunol 2021 01 6;41(1):233-237. Epub 2020 Oct 6.

Department of Human Genetics, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.

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http://dx.doi.org/10.1007/s10875-020-00875-7DOI Listing
January 2021

How Does Rice Defend Against Excess Iron?: Physiological and Molecular Mechanisms.

Front Plant Sci 2020 7;11:1102. Epub 2020 Aug 7.

Department of Biological Production, Faculty of Bioresource Sciences, Akita Prefectural University, Akita, Japan.

Iron (Fe) is an essential nutrient for all living organisms but can lead to cytotoxicity when present in excess. Fe toxicity often occurs in rice grown in submerged paddy fields with low pH, leading dramatical increases in ferrous ion concentration, disrupting cell homeostasis and impairing growth and yield. However, the underlying molecular mechanisms of Fe toxicity response and tolerance in plants are not well characterized yet. Microarray and genome-wide association analyses have shown that rice employs four defense systems to regulate Fe homeostasis under Fe excess. In defense 1, Fe excess tolerance is implemented by Fe exclusion as a result of suppression of genes involved in Fe uptake and translocation such as , , , , , , , , , and . The Fe-binding ubiquitin ligase, HRZ, is a key regulator that represses Fe uptake genes in response to Fe excess in rice. In defense 2, rice retains Fe in the root system rather than transporting it to shoots. In defense 3, rice compartmentalizes Fe in the shoot. In defense 2 and 3, the vacuolar Fe transporter , Fe storage protein ferritin, and the nicotinamine synthase mediate the isolation or detoxification of excess Fe. In defense 4, rice detoxifies the ROS produced within the plant body in response to excess Fe. Some transcription factors, variants, p450-family proteins, and , , and are implicated in defense 4. These knowledge will facilitate the breeding of tolerant crops with increased productivity in low-pH, Fe-excess soils.
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http://dx.doi.org/10.3389/fpls.2020.01102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426474PMC
August 2020

Clinical outcomes of microdissection testicular sperm extraction and intracytoplasmic sperm injection in Japanese men with Y chromosome microdeletions.

Reprod Med Biol 2020 Apr 13;19(2):158-163. Epub 2020 Jan 13.

Sendai ART Clinic Miyagi Japan.

Purpose: We investigated the clinical results of Japanese men with Y chromosome microdeletions.

Methods: This study retrospectively examined 2163 azoospermic or severe oligozoospermic patients. We investigated the frequency of azoospermia factor (AZF) deletions and sperm retrieval rate (SRR) by microTESE in patients with these deletions, then analyzed the ICSI outcomes.

Results: Azoospermia factor deletions were found in 201 patients. SRR was significantly higher than that of the control group (74.0% vs 20.4%,  < .001). Thirty-three couples underwent ICSI using testicular spermatozoa retrieved by microTESE, and eight couples underwent ICSI using ejaculatory spermatozoa. The fertilization rate and clinical pregnancy rate per embryo transfer cycle were significantly higher in the ejaculatory group than that of the testicular group (66.4% vs 43.7%,  < .001, 53.3% vs 24.7%,  = .03, respectively). When compared with the control group, the fertilization rate was significantly lower in the testicular group with AZFc microdeletions (43.7% vs 53.6%,  < .001).

Conclusions: Our study highlights that although microTESE in azoospermic men with AZFc microdeletions led to a higher SRR, ICSI outcomes of these men were worse than that of men without AZF deletions, even if testicular spermatozoa were retrieved.
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http://dx.doi.org/10.1002/rmb2.12317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138942PMC
April 2020

Repeat stereotactic radiofrequency thermocoagulation in patients with hypothalamic hamartoma and seizure recurrence.

Epilepsia Open 2020 Mar 18;5(1):107-120. Epub 2020 Jan 18.

Department of Functional Neurosurgery National Hospital Organization Nishiniigata Chuo Hospital Niigata Japan.

Objective: To evaluate the feasibility of repeat stereotactic radiofrequency thermocoagulation (re-SRT) for patients with hypothalamic hamartoma (HH) and to clarify clinical and surgical factors for seizure outcomes.

Methods: Hypothalamic hamartoma patients with gelastic seizures (GSs) who underwent SRT were retrospectively reviewed. Seizure outcomes were evaluated separately for GS and other types of seizures (non-GS). Surgical complications were compared between re-SRT and first SRT. Clinical and surgical factors related to both seizure recurrences after first SRT and final seizure outcomes were analyzed.

Results: Participants comprised 150 patients (92 males; median age at surgery, 8 years; range, 1.7-50 years). Of those, 122 (81.3%) had non-GS. Forty-three patients (28.7%) underwent re-SRT. Freedom from GS was achieved by first SRT in 103 patients (68.7%), second SRT in 30/40 (67.5%), third SRT in 3/10 (30.0%), and fourth SRT in 2/3 (66.7%). Finally, 135 patients (90.0%) became GS-free. Ninety patients (73.8%) achieved non-GS freedom, with first SRT in all except one case. Transient complications were more frequent with first SRT (118/150, 78.7%) than re-SRT (35/56, 62.5%), whereas persistent complications were more frequent with re-SRT (7/56, 12.5%) than with first SRT (3/150, 2.0%). Multivariate analyses revealed only younger age at surgery (≤1 year) as related to GS recurrence after first SRT, with no variables affecting final GS outcomes. Meanwhile, seizure type (tonic seizure), intellectual disability, and genetic syndromes were significant factors for both non-GS recurrence and final outcomes. Multiple previous treatments were significantly related to final non-GS outcomes as well. Size and subtype of HH and surgical factors were unrelated to seizure outcomes.

Significance: Repeat stereotactic radiofrequency thermocoagulation provides potential opportunities to achieve freedom from recurrent GS, albeit with increased risks of persistent complications. Non-GS and intellectual disability could offer early surgical indications, and repeated ineffective treatments should be avoided.
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http://dx.doi.org/10.1002/epi4.12378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049799PMC
March 2020

Enhancement of Iron Acquisition in Rice by the Mugineic Acid Synthase Gene With Ferric Iron Reductase Gene and Confers Tolerance in Submerged and Nonsubmerged Calcareous Soils.

Front Plant Sci 2019 18;10:1179. Epub 2019 Oct 18.

Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan.

Iron (Fe) is an essential micronutrient for plants. Plants encounter Fe deficiency when grown in calcareous soil with low Fe availability, leading to reduced crop yield and agricultural problem. Rice acquires Fe from the soil Strategy I-related system (ferrous ion uptake by OsIRT1) and Strategy II system (ferric ion uptake by chelation). However, rice plants have a weak ability in Fe(III) reduction and phytosiderophore secretion. We previously produced an Fe deficiency-tolerant rice harboring promoter- (for higher Fe(III) reductase ability) and a promoter- (for higher phytosiderophore secretion). In this study, we produced a new Fe deficiency-tolerant rice by the additional introduction of a barley genome fragment with and (named as IRI lines) for further enhancement in Strategy II phytosiderophore productivity and better growth performance in various environments. Our results show that an enhanced tolerance was observed in introduced line at the early growth stage, introduced line in the late stage, and RI line in all stages among five types of cultivation method. Moreover, we demonstrated that new IRI rice lines exhibited enhanced tolerance to Fe deficiency compared to nontransgenic (NT) rice and rice lines harboring the overexpressing or the fragment under submerged calcareous soil. The yields of IRI lines were ninefold higher than the NT line. Furthermore, under Fe-limited nonsubmerged calcareous soil condition (a new cultivation condition), IRI lines also conferred enhanced tolerance than NT, lines introducing only the promoter- or overexpressing , and lines harboring both. Our results demonstrate that further enhancement of the Strategy II Fe uptake system by the mugineic acid synthase gene in addition to Fe uptake by enhanced ferric Fe reduction and phytosiderophore production in rice contributes Fe deficiency tolerance and broaden its utility in calcareous soil cultivation under paddy or nonpaddy field conditions.
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http://dx.doi.org/10.3389/fpls.2019.01179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813920PMC
October 2019

Surgical strategy for focal cortical dysplasia based on the analysis of the spike onset and peak zones on magnetoencephalography.

J Neurosurg 2019 Oct 4:1-13. Epub 2019 Oct 4.

1Department of Functional Neurosurgery, National Hospital Organization, Nishiniigata Chuo Hospital, Niigata.

Objective: The aim of this study was to elucidate the surgical strategy for focal cortical dysplasia (FCD) based on the interictal analysis on magnetoencephalography (MEG). For this purpose, the correlation between the spike onset zone (Sp-OZ) and the spike peak zone (Sp-PZ) on MEG was evaluated to clarify the differences in the Sp-OZ and its correlation with Sp-PZ in FCD subtypes to develop an appropriate surgical strategy.

Methods: Forty-one FCD patients (n = 17 type I, n = 13 type IIa, and n = 11 type IIb) were included. The Sp-OZ was identified by the summation of gradient magnetic-field topography (GMFT) magnitudes at interictal MEG spike onset, and Sp-PZ was defined as the distribution of the equivalent current dipole (ECD) at spike peak. Correlations between Sp-OZ and Sp-PZ distributions were evaluated and compared with clinical factors and seizure outcomes retrospectively.

Results: Good seizure outcomes (Engel class I) were obtained significantly more often in patients with FCD type IIb (10/11, 90.9%) than those with type IIa (4/13, 30.8%; p = 0.003) and type I (6/17, 35.3%; p = 0.004). The Sp-OZ was significantly smaller (1 or 2 gyri) in type IIb (10, 90.9%) than in type IIa (4, 30.8%; p = 0.003) or type I (9, 53.0%; p = 0.036). Concordant correlations between the Sp-OZ and Sp-PZ were significantly more frequent in type IIb (7, 63.6%) than in type IIa (1, 7.7%; p = 0.015) or type I (1, 5.8%; p = 0.004). Complete resection of the Sp-OZ achieved significantly better seizure outcomes (Engel class I: 9/10, 90%) than incomplete resection (11/31, 35.5%) (p = 0.003). In contrast, complete resection of the Sp-PZ showed no significant difference in good seizure outcomes (9/13, 69.2%) compared with incomplete resection (11/28, 39.3%).

Conclusions: The Sp-OZ detected by MEG using GMFT and its correlation with Sp-PZ were related to FCD subtypes. A discordant distribution between Sp-OZ and Sp-PZ in type I and IIa FCD indicated an extensive epileptogenic zone and a complex epileptic network. Type IIb showed a restricted epileptogenic zone with the smaller Sp-OZ and concordance between Sp-OZ and Sp-PZ. Complete resection of the Sp-OZ provided significantly better seizure outcomes than incomplete resection. Complete resection of the Sp-PZ was not related to seizure outcomes. There was a definite difference in the epileptogenic zone among FCD subtypes; hence, an individual surgical strategy taking into account the correlation between the Sp-OZ and Sp-PZ should be considered.
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http://dx.doi.org/10.3171/2019.6.JNS191058DOI Listing
October 2019

Genetic deletion of Ca3.2 T-type calcium channels abolishes HS-dependent somatic and visceral pain signaling in C57BL/6 mice.

J Pharmacol Sci 2019 Jul 30;140(3):310-312. Epub 2019 Jul 30.

Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan. Electronic address:

We tested whether genetic deletion of Ca3.2 T-type Ca channels abolishes hydrogen sulfide (HS)-mediated pain signals in mice. In Ca3.2-expressing HEK293 cells, NaS, an HS donor, at 100 μM clearly increased Ba currents, as assessed by whole-cell patch-clamp recordings. In wild-type C57BL/6 mice, intraplantar and intracolonic administration of NaS evoked mechanical allodynia and visceral nociceptive behavior, respectively, which were abolished by TTA-A2, a T-type Ca channel blocker. In Ca3.2-knockout mice of a C57BL/6 background, NaS caused neither somatic allodynia nor colonic nociception. Our study thus provides definitive evidence for an essential role of Ca3.2 in HS-dependent somatic and colonic pain.
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http://dx.doi.org/10.1016/j.jphs.2019.07.010DOI Listing
July 2019

Noninvasive evaluation of testicular function by measuring oxygen saturation of scrotal-testicular tissue.

Reprod Biol 2019 Sep 9;19(3):299-302. Epub 2019 Aug 9.

Tawara IVF Clinic, 2-20, Izumi-cho, Suruga-ku Shizuoka-shi, Shizuoka, 422-8066, Japan; Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu-shi, Shizuoka, 431-3192, Japan.

We conducted a single-center cross-sectional study to determine whether scrotal-testicular tissue oxygen saturation (S-T StO) measured by finger-mounted near-infrared spectroscopy is useful for the evaluation of testicular function. S-T StO was significantly higher in patients with nonobstructive azoospermia (NOA, p< 0.05), and showed a positive correlation with luteinizing hormone levels (LH) even in participants without NOA (r = 0.34, p< 0.05), suggesting that elevated S-T StO is associated with a reduction in testicular function.
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http://dx.doi.org/10.1016/j.repbio.2019.07.006DOI Listing
September 2019

Nicotianamine Synthesis by Is Important for Mitigating Iron Excess Stress in Rice.

Front Plant Sci 2019 4;10:660. Epub 2019 Jun 4.

Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan.

Iron (Fe) toxicity in plants causes tissue damage and cellular homeostasis disorders, thereby affecting plant growth and development. Nicotianamine (NA) is a ubiquitous chelator of metal cations and is responsible for metal homeostasis. Rice has three NA synthase () genes, of which the expression of and but not of is strongly induced in response to Fe deficiency. Recently, we found that expression is strongly induced with excess Fe in most rice tissues, particularly old leaves, suggesting that it may play a vital role under excess Fe conditions. However, the mechanism by which responds to excess Fe in rice remains poorly understood. In this study, we clarified the physiological response of expression to excess Fe and the role of NA synthesis in this condition. Promoter analyses revealed that was widely expressed in roots, especially in vascular bundle, epidermis, exodermis, stem, and old leaf tissues under Fe excess compared to control plants. Nicotianamine and deoxymugineic acid (DMA; a type of phytosiderophore synthesized by Strategy II species) were present in roots and shoots under Fe excess likewise under control conditions. In addition, knockout plants were sensitive to excess Fe, exhibiting inferior growth, reduced dry weight, severer leaf bronzing, and greater Fe accumulation in their leaves than non-transformants with excess Fe. We also observed that NA-overproducing rice was tolerant of excess Fe. These results show that NA synthesized by under Fe excess condition is to mitigate excess Fe whereas NA synthesized by and under normal Fe condition is to enhance Fe translocation, suggesting the different roles and functions of the NA existence between these two conditions. Overall, these findings suggest that rice synthesizes NA with under Fe excess in roots and shoots, and that NA and DMA within the plant body are important for mitigating excess Fe stress and alleviating other metal deficiencies in rice. This report will be important for the development of tolerant rice adapted to Fe-contaminated soils.
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http://dx.doi.org/10.3389/fpls.2019.00660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558524PMC
June 2019

Pathogenic variants of , , and associated with hypothalamic hamartoma.

Neurology 2019 07 13;93(3):e237-e251. Epub 2019 Jun 13.

From the Departments of Human Genetics (A.F., S. Mitsuhashi, T.M., A.T., S. Miyatake, N. Miyake, N. Matsumoto) and Neurosurgery (M.S.), Yokohama City University Graduate School of Medicine; Departments of Functional Neurosurgery (T.H., H. Shirozu, H.M., M.F., S.K.) and Child Neurology (J.T.), Epilepsy Center, National Hospital Organization Nishiniigata Chuo Hospital Niigata, Japan; Department of Pediatrics and Neurology (M.S.), Wayne State University, Children's Hospital of Michigan, Detroit Medical Center; Department of Pediatrics (M.K.), Showa University School of Medicine, Tokyo; Department of Biochemistry (M.N., H. Saitsu), Hamamatsu University School of Medicine; and Clinical Research Institute (Y.T.), Kanagawa Children's Medical Center, Yokohama, Japan.

Objective: Intensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH).

Methods: Thirty-eight individuals with HH were investigated by whole exome sequencing, target capture-based deep sequencing, or single nucleotide polymorphism (SNP) array using DNA extracted from blood leukocytes or HH samples.

Results: We identified a germline variant of , which encodes a ciliary protein, and 2 somatic variants of , which forms part of the RAS/mitogen-activated protein kinase (MAPK) pathway, as well as variants in known genes associated with HH. An SNP array identified (among 3 patients) one germline copy-neutral loss of heterozygosity (cnLOH) at 6p22.3-p21.31 and 2 somatic cnLOH; one at 11q12.2-q25 that included , which encodes a ciliary motor protein, and the other at 17p13.3-p11.2. A germline heterozygous variant and an identical somatic variant of arising from cnLOH at 11q12.2-q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of ). Furthermore, a combination of a germline and a somatic variant was detected in another patient.

Conclusions: Overall, our cohort identified germline/somatic alterations in 34% (13/38) of patients with HH. Disruption of the Shh signaling pathway associated with cilia or the RAS/MAPK pathway may lead to the development of HH.
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http://dx.doi.org/10.1212/WNL.0000000000007774DOI Listing
July 2019
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