Machine learning analysis of pathological images to predict 1-year progression-free survival of immunotherapy in patients with small-cell lung cancer.

BACKGROUND: In small-cell lung cancer (SCLC), the tumor immune microenvironment (TIME) could be a promising biomarker for immunotherapy, but objectively evaluating TIME remains challenging. Hence, we aimed to develop a predictive biomarker of immunotherapy efficacy through a machine learning analysis of the TIME. METHODS: We conducted a biomarker analysis in a prospective study of patients with extensive-stage SCLC who received chemoimmunotherapy as the first-line treatment. We trained a model to predict 1-year progression-free survival (PFS) using pathological images (H&E, programmed cell death-ligand 1 (PD-L1), and double immunohistochemical assay (cluster of differentiation 8 (CD8) and forkhead box P3 (FoxP3)) and patient information. The primary outcome was the mean area under the curve (AUC) of machine learning models in predicting the 1-year PFS. RESULTS: We analyzed 100,544 patches of pathological images from 78 patients. The mean AUC values of patient information, pathological image, and combined models were 0.789 (range 0.571-0.982), 0.782 (range 0.750-0.911), and 0.868 (range 0.786-0.929), respectively. The PFS was longer in the high efficacy group than in the low efficacy group in all three models (patient information model, HR 0.468, 95% CI 0.287 to 0.762; pathological image model, HR 0.334, 95% CI 0.117 to 0.628; combined model, HR 0.353, 95% CI 0.195 to 0.637). The machine learning analysis of the TIME had better accuracy than the human count evaluations (AUC of human count, CD8-positive lymphocyte: 0.681, FoxP3-positive lymphocytes: 0.626, PD-L1 score: 0.567). CONCLUSIONS: The spatial analysis of the TIME using machine learning predicted the immunotherapy efficacy in patients with SCLC, thus supporting its role as an immunotherapy biomarker.

The Role of Chorein Deficiency in Late Spermatogenesis.

VPS13A, also known as chorein, whose loss of function causes chorea-acanthocytosis (ChAc), is characterized by Huntington's-disease-like neurodegeneration and neuropsychiatric symptoms in addition to acanthocytosis in red blood cells. We previously reported that ChAc-model mice with a loss of chorein function exhibited male infertility, with asthenozoospermia and mitochondrial dysmorphology in the spermatozoa. Here, we report a novel aspect of chorein dysfunction in male fertility, particularly its role in spermatogenesis and mitochondrial integrity. An increase in anti-malondialdehyde antibody immunoreaction within the testes, predominantly observed at the advanced stages of sperm formation in chorein-deficient mice, suggests oxidative stress as a contributing factor to mitochondrial dysfunction and impaired sperm maturation. The chorein immunoreactivity in spermatids of wild-type mice accentuates its significance in sperm development. ChAc-model mice exhibit mitochondrial ultrastructural abnormalities, specifically during the late stages of sperm maturation, suggesting a critical timeframe for chorein's action in spermiogenesis. We observed an increase in TOM20 protein levels, indicative of disrupted mitochondrial import mechanisms. The concurrent decrease in metabolic enzymes such as IDH3A, LDHC, PGK2, and ACAT1 suggests a complex chorein-mediated metabolic network that is essential for sperm vitality. Additionally, heightened separation of cytoplasmic droplets from sperm highlights the potential membrane instability in chorein-deficient spermatozoa. Metabolomic profiling further suggests a compensatory metabolic shift, with elevated glycolytic and TCA-cycle substrates. Our findings suggest that chorein is involved in anti-ferroptosis and the maturation of mitochondrial morphology in the late stages of spermatogenesis, and its deficiency leads to asthenozoospermia characterized by membrane instability, abnormal cytosolic glycolysis, abnormal mitochondrial function, and a disrupted TCA cycle. Further analyses are required to unravel the molecular mechanisms that directly link these findings and to elucidate the role of chorein in spermatogenesis as well as its broader implications.

Development of a novel artificial intelligence algorithm to detect pulmonary nodules on chest radiography.

BACKGROUND: In this study, we aimed to develop a novel artificial intelligence (AI) algorithm to support pulmonary nodule detection, which will enable physicians to efficiently interpret chest radiographs for lung cancer diagnosis. METHODS: We analyzed chest X-ray images obtained from a health examination center in Fukushima and the National Institutes of Health (NIH) Chest X-ray 14 dataset. We categorized these data into two types: type A included both Fukushima and NIH datasets, and type B included only the Fukushima dataset. We also demonstrated pulmonary nodules in the form of a heatmap display on each chest radiograph and calculated the positive probability score as an index value. RESULTS: Our novel AI algorithms had a receiver operating characteristic (ROC) area under the curve (AUC) of 0.74, a sensitivity of 0.75, and a specificity of 0.60 for the type A dataset. For the type B dataset, the respective values were 0.79, 0.72, and 0.74. The algorithms in both the type A and B datasets were superior to the accuracy of radiologists and similar to previous studies. CONCLUSIONS: The proprietary AI algorithms had a similar accuracy for interpreting chest radiographs when compared with previous studies and radiologists. Especially, we could train a high quality AI algorithm, even with our small type B data set. However, further studies are needed to improve and further validate the accuracy of our AI algorithm.

Aging-Related Catatonia with Reversible Dopamine Transporter Dysfunction in Females with Depressive Symptoms: A Case Series.

OBJECTIVES: The authors describe five depressive patients with initially decreased striatal accumulation of dopamine transporter (DAT) single-photon emission computed tomography (SPECT), which improved in parallel with clinical symptoms. METHODS: Patients who exhibited decreased striatal accumulation and recovery of DATSPECT were identified among patients with the symptoms of depression. Their clinical and neuroimaging data were reviewed. RESULTS: Five patients were identified. All patients were presenile or senile women who presented with catatonia subsequent to symptoms of depression that remitted with treatment. DAT-SPECT showed a decreased striatal accumulation in all patients, which increased after treatment. Two patients had met the diagnostic criteria of probable dementia with Lewy bodies (DLB), but no longer did so after their symptoms improved. CONCLUSIONS: Reversible DAT dysfunction observed in this study suggests that reversible impairment of dopaminergic transmission in the striatum partly underlies catatonia. Careful consideration should be given to diagnosing DLB in patients with decreased DAT-SPECT accumulation, especially when catatonia is present.

Association of auditory Charles Bonnet syndrome with increased blood flow in the nondominant Brodmann area 22.

Aim: Auditory Charles Bonnet syndrome (aCBS) is characterized by musical hallucinations (MHs) that accompany acquired hearing impairments. This hallucination is the acoustic perception of music, sounds, or songs in the absence of an outside stimulus, and it may be associated with hyperactivity of the superior temporal lobes. Some studies have reported the possibility of improving MH with antiepileptics. To elucidate in detail the brain regions responsible for aCBS, we analyzed the regions that changed functionally after treatment. Methods: Before and after treatment with carbamazepine (four cases), clonazepam (one case), and a hearing aid (one case), cerebral perfusion single-photon emission computed tomography (SPECT) and the Auditory Hallucination Rating Scale (AHRS) were applied to six patients with hearing-loss-associated MHs. Results: Cerebral blood flow analysis using SPECT revealed hyperperfusion in Brodmann area (BA) 22-the posterior region of the superior temporal gyrus-in the nondominant hemisphere in all six patients in the pretreatment phase. After treatment, the hyperperfusion region improved in all patients. The area percentages with hyperperfusion in the nondominant BA22 were strongly positively correlated with the AHRS score. Conclusion: The results suggest that aCBS, which was treatable with antiepileptics or hearing aids, was involved in hyperexcitement in BA22, and that MH strength was correlated with degree of excitement.

Predicting postpartum depression by evaluating temperament during pregnancy.

AIM: The purpose of this study was to investigate premorbid temperaments to predict postpartum depression in pregnant women with no previous psychiatric history and to clarify the correlation between postpartum depression and the factors included in the Postpartum Depression Predictors Inventory-Revised (PDPI-R) and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Auto questionnaire (TEMPS-A)/Munich Personality Test (MPT). METHODS: A total of 170 eligible pregnant women filled out both questionnaires, the first between the 8th and 23rd week of gestation, and the latter between the 34th and 38th week of gestation. Participants filled out The Edinburgh Postnatal Depression Scale (EPDS) one month postpartum to measure for postpartum depression symptoms. All participants delivered full-term healthy babies. RESULTS: Seventeen (10%) women met the criteria for postpartum depression with a score of 9 or higher on the EDPS. The factors significantly related to developing postpartum depression were schizoid and melancholic temperament on the TEMPS-A/MPT and marital dissatisfaction on the PDPI-R. The total score on the PDPI-R was significantly correlated with depressive, cyclothymic, irritable, and anxious temperaments on the TEMPS-A/MPT. A lack of social support on the PDPI-R was significantly correlated with depressive, irritable, and anxious temperaments on the TEMPS-A/MPT. CONCLUSION: The findings suggest that postpartum depression may be related to schizoid and melancholic temperaments and marital dissatisfaction. The hyperthymic temperament was identified as a significant predictor in preventing PPD. Careful observation during puerperium is recommended if a pregnant woman is likely to have these temperaments or psychological conditions. Temperament evaluation should be done during pregnancy as a form of postpartum depression screening.

Denoising PET images for proton therapy using a residual U-net.

The use of proton therapy has the advantage of high dose concentration as it is possible to concentrate the dose on the tumor while suppressing damage to the surrounding normal organs. However, the range uncertainty significantly affects the actual dose distribution in the vicinity of the proton range, limiting the benefit of proton therapy for reducing the dose to normal organs. By measuring the annihilation gamma rays from the produced positron emitters, it is possible to obtain a proton induced positron emission tomography (pPET) image according to the irradiation region of the proton beam. Smoothing with a Gaussian filter is generally used to denoise PET images; however, this approach lowers the spatial resolution. Furthermore, other conventional smoothing processing methods may deteriorate the steep region of the pPET images. In this study, we proposed a denoising method based on a Residual U-Net for pPET images. We conducted the Monte Carlo simulation and irradiation experiment on a human phantom to obtain pPET data. The accuracy of the range estimation and the image similarity were evaluated for pPET images using the Residual U-Net, a Gaussian filter, a median filter, the block-matching and 3D-filtering (BM3D), and a total variation (TV) filter. Usage of the Residual U-Net yielded effective results corresponding to the range estimation; however, the results of peak-signal-to-noise ratio were identical to those for the Gaussian filter, median filter, BM3D, and TV filter. The proposed method can contribute to improving the accuracy of treatment verification and shortening the PET measurement time.

Positional cloning and comprehensive mutation analysis identified a novel KDM2B mutation in a Japanese family with minor malformations, intellectual disability, and schizophrenia.

The importance of epigenetic control in the development of the central nervous system has recently been attracting attention. Methylation patterns of lysine 4 and lysine 36 in histone H3 (H3K4 and H3K36) in the central nervous system are highly conserved among species. Numerous complications of body malformations and neuropsychiatric disorders are due to abnormal histone H3 methylation modifiers. In this study, we analyzed a Japanese family with a dominant inheritance of symptoms including Marfan syndrome-like minor physical anomalies (MPAs), intellectual disability, and schizophrenia (SCZ). We performed positional cloning for this family using a single nucleotide polymorphism (SNP) array and whole-exome sequencing, which revealed a missense coding strand mutation (rs1555289644, NM_032590.4: c.2173G>A, p.A725T) in exon 15 on the plant homeodomain of the KDM2B gene as a possible cause of the disease in the family. The exome sequencing revealed that within the coding region, only a point mutation in KDM2B was present in the region with the highest logarithm of odds score of 2.41 resulting from whole genome linkage analysis. Haplotype analysis revealed co-segregation with four affected family members (IV-9, III-4, IV-5, and IV-8). Lymphoblastoid cell lines from the proband with this mutation showed approximately halved KDM2B expression in comparison with healthy controls. KDM2B acts as an H3K4 and H3K36 histone demethylase. Our findings suggest that haploinsufficiency of KDM2B in the process of development, like other H3K4 and H3K36 methylation modifiers, may have caused MPAs, intellectual disability, and SCZ in this Japanese family.

Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by the recurrence of depressive and manic episodes. Its heritability is high, and many linkage and association studies have been performed. Although various linkage regions and candidate genes have been reported, few have shown sufficient reproducibility, and none have identified the pathogenic genes based on the results of the linkage analysis. To find functional variants that are expected to be rare and have strong genetic effects, we recruited ten healthy individuals, two individuals with unknown status, and six patients with BD or recurrent major depressive disorder (MDD) from a Japanese family consisting of 21 members. We performed a genome-wide linkage analysis using a 100K single-nucleotide polymorphism (SNP) array and microsatellite markers to narrow linkage regions within this family. Subsequently, we performed whole-exome sequencing for two patients with BD to identify genetic mutations in the narrowed linkage regions. Then, we performed co-segregation analysis for DNA variants obtained from the results of the exome sequencing. Finally, we identified a rare heterozygous mutation in exon 31 of DOCK5 (c.3170A>G, p.E1057G). Convergent functional genomics analysis revealed that DOCK5 was listed as one of the biomarkers for mood state and suicidality. Although DOCK5 is still a functionally unknown gene, our findings highlight the possibility of a pathological relationship between BD and DOCK5.

DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.

Extension of the ML-EM algorithm for dose estimation using PET in proton therapy: application to an inhomogeneous target.

Positron emission tomography (PET) has been used for in vivo treatment verification, mainly for range verification, in proton therapy. Evaluating the direct dose from PET measurements remains challenging; however, it is highly desirable from a clinical perspective. In this study, a method for estimating the dose distribution from the positron emitter distributions was developed using the maximum likelihood expectation maximization algorithm. The 1D spatial relationship between positron emitter distributions and a dose distribution in an inhomogeneous target was inputted into the system matrix based on a filter framework. In contrast, spatial resolution of the PET system and total variation regularization (as prior knowledge for dose distribution) were considered in the 3D image-space. The dose estimation was demonstrated using Monte Carlo simulated PET activity distributions with substantial noise in a head and neck phantom. This mimicked the single field irradiation of the spread-out Bragg peak beams at clinical dose levels. Besides the simple implementation of the algorithm, this strategy achieved a high-speed calculation (30 s for a 3D dose estimation) and accurate dose and range estimations (less than 10% and 2 mm errors at 1-σ values, respectively). The proposed method could be key for using PET for in vivo dose monitoring.

Sleep Disorders in Four Patients With Myotonic Dystrophy Type 1.

Sleep disturbances such as excessive daytime sleepiness, central and obstructive sleep apneas, restless legs syndrome, and rapid eye movement sleep dysregulation are prominent in patients with myotonic dystrophy type 1 (DM1). Mild intellectual deficits presented in many patients with DM1. In addition, psychosocial issues caused by neuropsychiatric symptoms are a clinical problem. We herein present the cases of four DM1 patients with sleep disturbances and neuropsychiatric symptoms in the preceding stage of clinically significant muscle symptoms. One of the cases exhibited a sleep disorder and neuropsychiatric symptoms before electromyography showed myotonic discharge, suggesting that careful follow-up is also important. Patients 1 and 2 were first referred to our department due to daytime sleepiness. Patients 3 and 4 were objectively suffering from daytime sleepiness of which they were not subjectively aware of. Patients 1, 3, and 4 obtained high apnea-hypopnea index (AHI) scores, which reflected central and/or obstructive apnea, whereas patient 2 had an AHI score of zero. The daytime cerebrospinal fluid (CSF) orexin levels of all patients ranged from the normal lower limit to low, although they were not as low as those observed in narcolepsy with typical cataplexy. Neuropsychological tests of patients 1 and 2 showed frontal lobe dysfunction. Patients 3 and 4 were diagnosed with mild intellectual disability and autism spectrum disorder, respectively. All patients exhibited indifference toward their own symptoms, which may have resulted from the cognitive decline caused by DM1. Based on family history and/or neurological findings such as myotonia, we suspected DM1 as the cause of their sleep disturbances. Molecular analysis using the triplet repeat-primed polymerase chain reaction (TP PCR) method and Southern blotting, which provided a genetic confirmation of the diagnosis of DM1, were performed. These clinical features of sleep disturbances were unrelated to the length of CTG repeats and are caused by unknown molecular mechanisms. Clinicians should take into account that multisystem involvement in DM1 is hugely variable, and thus, a disabling sleep disorder could overshadow muscle impairment in DM1 patients.

A PRIMPOL mutation and variants in multiple genes may contribute to phenotypes in a familial case with chronic progressive external ophthalmoplegia symptoms.

Chronic progressive external ophthalmoplegia (CPEO) is one of the most common mitochondrial disorders. It is characterized by bilateral, slowly progressing loss of extraocular muscle mobility, orbicularis oculi weakness, ptosis, and other neuromuscular symptoms, which are caused by the accumulation of multiple mitochondrial DNA (mtDNA) deletions. Many mutations in different nuclear genes, such as POLG1, POLG2, ANT1, and others, have been described as causing autosomal-inherited CPEO with multiple mtDNA deletions. Most causative genes are involved in mtDNA replication impairment. Here, we report a family with CPEO-like symptoms characterized by multiple muscle mtDNA deletions, ptosis, diabetes, hearing loss, mental retardation, and emotional instability. We performed genetic analyses to identify nuclear gene mutations in the family. DNA from the proband was analyzed by whole-exome sequencing. In addition to possible pathogenic mutations, rare variants were prioritized for gene-functional phenotype interpretation. We found possible pathogenetic mutations in the PRIMPOL, BRCA1, CPT2, and GJB2 genes, and functional polymorphisms in the CARD8, and MEFV genes. Multiple functional polymorphisms and possible pathogenic mutations may contribute to mitochondrial-disease-like phenotypes in a composite manner.

Discriminating chorea-acanthocytosis from Huntington's disease with single-case voxel-based morphometry analysis.

BACKGROUND AND PURPOSE: Chorea-acanthocytosis is clinically difficult to distinguish from Huntington's disease because these disorders have similar symptoms and MR imaging findings. We evaluated the usefulness of single-case voxel-based morphometry (VBM) analysis for differentiating the two diseases as well as VBM analysis. MATERIALS AND METHODS: We examined five genetically proven chorea-acanthocytosis patients and 11 Huntington's disease patients to detect differences in the gray and white matter atrophic pattern by using single-case VBM analysis in each patient and their clinical findings. We also evaluated VBM analysis for a group comparison in both disease and control groups. RESULTS: The single-case VBM analysis results demonstrated a gray matter volume loss in caudate nucleus in all 16 patients. A characteristic symmetrical white matter volume loss was detected in globus pallidus, putamen, and thalamus on both sides in all the chorea-acanthocytosis patients, but this pattern of atrophy was not seen in any of the Huntington's disease patients. With the VBM analysis, a significant gray matter volume loss was noted in caudate nucleus on both sides in chorea-acanthocytosis patients compared with Huntington's disease patients, and a more extensive white matter volume loss around the basal ganglia and thalamus was observed in chorea-acanthocytosis patients compared to Huntington's disease patients, consistent with the single-case VBM analysis results. Genetic testing identified two novel pathogenic mutations, exon 1 c.16_22delGTGGTCG and exon 55 c.7736-7739delGAGA in a chorea-acanthocytosis patient. CONCLUSIONS: Single-case VBM analysis may be useful to differentiate chorea-acanthocytosis from Huntington's disease with a focus on white matter atrophy.

A patient with McLeod syndrome showing involvement of the central sensorimotor tracts for the legs.

BACKGROUND: McLeod syndrome is a rare X-linked recessive acanthocytosis associated with neurological manifestations including progressive chorea, cognitive impairment, psychiatric disturbances, seizures, and sensorimotor axonal polyneuropathy. However, no studies have investigated the functioning of central sensorimotor tracts in patients with McLeod syndrome. CASE PRESENTATION: A 66-year-old man had experienced slowly progressive chorea and gait disturbance due to lower limb muscle weakness since his early fifties. Blood examinations showed erythrocyte acanthocytosis and the reduction of Kell antigens in red blood cells. Brain magnetic resonance imaging showed atrophy of the bilateral caudate nuclei and putamen. The diagnosis of McLeod syndrome was confirmed by the presence of a mutation of the XK gene on the X chromosome. Somatosensory-evoked potential and transcranial magnetic stimulation studies demonstrated that the central sensory and motor conduction times were abnormally prolonged for the lower extremity but normal for the upper extremity. CONCLUSIONS: This is the first report of the involvement of the central sensorimotor tracts for the legs in a patient with McLeod syndrome. The clinical neurophysiological technique revealed the central sensorimotor tracts involvements clinically masked by neuropathy.

Working Memory-Related Prefrontal Hemodynamic Responses in University Students: A Correlation Study of Subjective Well-Being and Lifestyle Habits.

Identification of social risk factors and the promotion of stress coping mechanisms and mental resilience are topics of interest in the field of mental health. The relationships between risk- or tolerability-associated factors and task-related hemodynamic responses in the prefrontal cortex (PFC) in adolescents may have important implications for mental health challenges. The purpose of this study was to investigate the relationship between task-related PFC hemodynamic activities and subjective well-being or lifestyle habits using wearable near-infrared spectroscopy (NIRS). In this study, after sample refinement to reduce heterogeneity, 20 university students were included in verbal working memory (VWM) task analyses and 21 were included in spatial working memory (SWM) task analyses. The task-related hemodynamic responses were detected using wearable NIRS. To assess the risk- or tolerability-associated factors, the levels of positive and negative affect were assessed using the Subjective Well-Being Inventory (SUBI) and lifestyle habits (such as gaming) were evaluated using a nine-item questionnaire. There was a positive correlation between SUBI positive affect and VWM task-related oxy-hemoglobin signal changes in the right dorsolateral PFC (DLPFC), underlining the significance of subjective well-being as an important independent emotional domain and suggesting the possibility of the differential objective evaluations of subjective well-being in the right PFC. Negative correlations between PFC activities during both VWM and SWM tasks at the left DLPFC and the number of game playing days in 1 week were also statistically significant, suggesting the presence of modality-non-specific hemodynamic regulation by habitual game playing. Each correlation was still robust after the elimination of major confounding impacts. Although further replication studies are warranted to confirm these preliminary results, this investigation of the relationship between task-related PFC hemodynamic activities and emotional domains or lifestyle habits might have clinical significance with regard to primary prevention of mental health issues in university students. To our knowledge, this is the first demonstration of these relationships with the use of wearable NIRS, which enables measurement under near natural conditions and is easy to use in schools or workplaces.