Accelerated epigenetic aging in alcohol dependence.

Alcohol dependence poses a global health threat associated with aging and reduced life expectancy. Recently, aging research through deoxyribonucleic acid (DNA) methylation has gained attention. New epigenetic clocks have been developed; however, no study has investigated GrimAge components, GrimAge2 components and DunedinPACE in patients with alcohol dependence. In this study, we aimed to perform epigenetic clock analysis to evaluate epigenetic age acceleration and DNA methylation-based age-predictive components in patients with alcohol dependence and controls. We utilized publicly available DNA methylation data (GSE98876) for our analysis. Additionally, we compared the values of the same items before and after the patients underwent a treatment program. The dataset comprised 23 controls and 24 patients. We observed that DunedinPACE accelerated more in patients with alcohol dependence. AgeAccelGrim and AgeAccelGrim2 decelerated more after the treatment program than before, and beta-2-microglobulin and Cystatin C decreased after the treatment program than before. These findings are crucial as they affect the cranial nerve area, potentially contributing to cognitive dysfunction and psychiatric symptoms in patients with alcohol dependence.

Clinical benefits of tomosynthesis-guided vacuum assisted breast biopsy: a comparison with stereotactic vacuum assisted biopsy.

BACKGROUND: Tomosynthesis-guided vacuum assisted breast biopsy (3D-VAB) has been used increasingly. The aim of our study is to compare the clinical effectiveness of 3D-VAB and stereotactic vacuum assisted biopsy (2D-VAB) on the number of tissue cores containing targeted calcifications and on the procedure time. METHODS: Consecutive 87 women who underwent biopsy at our hospital from April 2020 to March 2022 for calcifications mammographically suspicious of malignancy were included in this study: 57 patients with 3D-VAB and 30 patients with 2D-VAB. RESULTS: Grouped or clustered calcified lesions were found in 39 and 21 patients among the 3D-VAB group and the 2D-VAB group, respectively. The mean number of tissue cores per biopsy containing targeted calcifications from the grouped or clustered calcified lesions was 3 and 2.3 specimens for the 3D-VAB group and for the 2D-VAB group, respectively. The mean procedure time for grouped or clustered calcifications was significantly shorter in the 3D-VAB group than in the 2D-VAB group (16.5 min vs. 27.4 min, P < 0.01). Comparing the procedure time between 3D-VAB and 2D-VAB based on calcification category, 3D-VAB had significantly shorter procedure time than 2D-VAB for both category 3 and category 4 calcification. For all patients, the mean procedure time was 18.1 min for the 3D-VAB group and 27.7 min for the 2D-VAB, thus being significantly shorter with 3D-VAB than 2D-VAB (P < 0.01). CONCLUSION: Our study demonstrated that the clinical effectiveness of 3D-VAB is superior to that of 2D-VAB and that the significant reduction in examination time with 3D-VAB is expected to benefit patients.

Epigenetic clock analysis reveals increased plasma cystatin C levels based on DNA methylation in major depressive disorder.

Major depressive disorder (MDD) is a common mental illness and a major public health concern worldwide. Depression is associated with epigenetic changes that regulate gene expression, and analyzing these changes may help elucidate the pathophysiology of MDD. Genome-wide DNA methylation (DNAm) profiles can function as 'epigenetic clocks' that can help estimate biological aging. Here, we assessed biological aging in patients with MDD using various DNAm-based indicators of epigenetic aging. We used a publicly available dataset containing data obtained from the whole blood samples of MDD patients (n = 489) and controls (n = 210). We analyzed five epigenetic clocks (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge) and DNAm-based telomere length (DNAmTL). We also investigated seven DNAm-based age-predictive plasma proteins (including cystatin C) and smoking status, which are components of GrimAge. Following adjustment for confounding factors such as age and sex, patients with MDD showed no significant difference in epigenetic clocks and DNAmTL. However, DNAm-based plasma cystatin C levels were significantly higher in patients with MDD than controls. Our findings revealed specific DNAm changes predicting plasma cystatin C levels in MDD. These findings may help elucidate the pathophysiology of MDD, leading to the development of new biomarkers and medications.

Epigenetic clock analysis and increased plasminogen activator inhibitor-1 in high-functioning autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by impaired social communication and behavioral problems. An increased risk of premature mortality has been observed in individuals with ASD. Therefore, we hypothesized that biological aging is accelerated in individuals with ASD. Recently, several studies have established genome-wide DNA methylation (DNAm) profiles as 'epigenetic clocks' that can estimate biological aging. In addition, ASD has been associated with differential DNAm patterns. METHODS: We used two independent datasets from blood samples consisting of adult patients with high-functioning ASD and controls: the 1st cohort (38 ASD cases and 31 controls) and the 2nd cohort (6 ASD cases and 10 controls). We explored well-studied epigenetic clocks such as HorvathAge, HannumAge, SkinBloodAge, PhenoAge, GrimAge, and DNAm-based telomere length (DNAmTL). In addition, we investigated seven DNAm-based age-related plasma proteins, including plasminogen activator inhibitor-1 (PAI-1), and smoking status, which are the components of GrimAge. RESULTS: Compared to controls, individuals with ASD in the 1st cohort, but not in the 2nd cohort, exhibited a trend for increased GrimAge acceleration and a significant increase of PAI-1 levels. A meta-analysis showed significantly increased PAI-1 levels in individuals with ASD compared to controls. CONCLUSION: Our findings suggest there is no epigenetic age acceleration in the blood of individuals with ASD. However, this study provides novel evidence regarding increased plasma PAI-1 levels in individuals with high-functioning ASD. These findings suggest PAI-1 may be a biomarker for high-functioning ASD, however, larger studies based on epigenetic clocks and PAI-1 will be necessary to confirm these findings.

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

PHLDA1 expression in ulcerative colitis: A potential role in the management of dysplasia.

Pleckstrin homology-like domain, family A, member 1 (PHLDA1) is a protein involved in cell proliferation, adhesion and migration in colon cancer. In normal large intestinal mucosa, this protein is expressed only in the crypts. By contrast, its expression in adenomas and cancers of the large intestine is spread throughout the glandular ducts, and it has been reported that PHLDA1 may be involved in the process of carcinogenesis. PHLDA1 may also be involved in the pathogenesis of ulcerative colitis (UC). The expression levels of PHLDA1 in tissues from patients with UC were analyzed using immunohistochemistry, and its relationship with the development of UC-associated colorectal cancer (UC-CRC) was examined. Overall, tissue samples from 143 lesions (90 colitis lesions, 39 dysplastic lesions and 14 UC-CRC lesions) were prepared from excised specimens of 49 patients with UC who underwent surgery in Tokyo Medical and Dental University Hospital between January 2004 and December 2017. Subsequently, immunostaining for PHLDA1 was performed. PHLDA1 expression was evaluated in UC-CRC and dysplastic tissues within the entire lesion area on the slide and in colitis over the area of the accompanying duct. The cytoplasmic staining intensity was classified into four levels, and the expression score (0-2 points) was calculated. The median PHLDA1 expression score was 0.295 for colitis, 0.607 for dysplasia and 0.865 for UC-CRC. The dysplasia expression score was significantly higher than the colitis score (P<0.001), while the UC-CRC expression score was significantly higher than the dysplasia score (P=0.003). The expression levels of PHLDA1 in UC cases were higher in colitis, followed by dysplasia and UC-CRC, which suggested that this protein may be involved in the carcinogenesis of UC-CRC. In addition, PHLDA1 immunostaining may help in the diagnosis of dysplasia, which is a type of precancerous lesion.

The effectiveness of plasma miR-33a-5p as a predictive biomarker for the efficacy of colorectal cancer chemotherapy.

Several chemotherapeutic options are available for patients with metastatic colorectal cancer (mCRC), making it important to individualize treatment regimens. Individualization requires the clinical application of biomarkers for regimen selection, which is presently insufficient. miRNAs serve an important role in the control of biological processes in several types of cancer, acting as plasma biomarkers. The current study aimed to evaluate novel plasma microRNAs for predicting chemo-resistance in chemotherapy for patients with colorectal cancer (CRC) by employing a Toray 3D-Gene microRNA array-based approach, which compared plasma content before and during treatment. Specific miRNAs that acted as biomarkers of the fluoropyrimidine (FP) + oxaliplatin (OX) + bevacizumab (BEV) regime, a common first-line treatment for mCRC, were searched. The plasma samples of 110 patients with mCRC who had received the FP+OX+BEV regimen were subjected to microarray analyses using the 3D-Gene miRNA microarray platform, after which miRNAs levels were quantified via reverse transcription- quantitative PCR. Patients exhibiting complete response, partial response (PR) and reduced stable disease (SD) were defined as responders. Patients with extended SD and progression disease (PD) were defined as non-responders. Following microarray analysis, miR-33a-5p was selected as the candidate miRNA as it was upregulated in non-responder plasma samples. The expression of miR-33a-5p was upregulated in the non-responders (n=15) compared with the responders (n=95) (P=0.032). The high expression group demonstrated significantly poor progression-free survival (P<0.01). To evaluate whether miR-33a-5p can serve as a marker of chemo-resistance, miR-33a-5p expression levels were assessed at the following three time-points: Pre-point (before chemotherapy); PR-point (3-months after chemotherapy began); and PD-point (the time at which recurrence or progression was recorded). The results revealed that expression levels were significantly increased at the PD-point when compared with that at the pre-point (P=0.024). The current study determined that the miR-33a-5p expression level in the plasma may serve as a predictive marker of efficacy and as a biomarker of chemo-resistance.

The feasibility of circulating tumor DNA analysis as a marker of recurrence in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has a poorer prognosis than other breast cancer subtypes; therefore, identifying markers of early recurrence is important. The present study aimed to establish a liquid biopsy protocol for droplet digital PCR-based detection of frequently mutated genes in patients with TNBC. Tumor DNA from 36 patients with TNBC who relapsed within 2 years after surgical resection was retrospectively analyzed. Somatic mutational profiles were evaluated using targeted sequencing to identify frequently mutated genes and genes associated with molecularly targeted therapies. The association between genetic alterations and associated protein phosphorylation was investigated using immunohistochemical analysis. Recurrent hot spot mutations in the plasma were monitored over time. Mutation-specific probes were used to successfully detect mutations in the blood samples of patients who were positive for PIK3CA H1047R and AKT1 E17K mutations. Somatic mutations in AKT1 (14.9%) and PIK3CA (25.5%) were frequently identified in the data. Robust phosphorylation of AKT and S6RP was more common in tumors with PIK3CA H1047R and AKT1 E17K mutational background than in tumors with wild-type PIK3CA and AKT1. In conclusion, the present study evaluated a high-sensitivity detection system for frequently mutated genes that was also applicable for cell-free DNA. The PI3K/AKT pathway was revealed to be activated in patients harboring PIK3CA H1047R and AKT1 E17K mutations; therefore, the PI3K/AKT pathway may be a promising candidate for targeted therapy in these patients.

Potential Molecular Cross Talk Among CCR5 Pathway Predicts Regorafenib Responsiveness in Metastatic Colorectal Cancer Patients.

BACKGROUND: Genetic variants in the CCL5/CCR5 pathway have been shown to predict regorafenib efficacy in patients with metastatic colorectal cancer (mCRC). This study investigated the biological role of CCL4 and CCL3 gene polymorphisms in patients with refractory mCRC treated using regorafenib. PATIENTS AND METHODS: We analyzed the genomic DNA extracted from mCRC patients receiving regorafenib. Serum factor levels at baseline, day 21, and progressive disease (PD) were measured using ELISA. RESULTS: Decreased CCL4 levels at day 21 or increased CCL3 levels at PD were associated with better clinical outcomes. In patients with any CCL5 rs2280789 G allele, CCL3 significantly increased between BL and day 21 compared with the A/A variant (72.7% vs. 23.1%, p=0.006), but CCL4 decreased (31.8% vs. 69.2%, p=0.043). CONCLUSION: Increased CCL3 and decreased CCL4 seen in specific genotypes may serve as potential biomarkers of regorafenib in mCRC patients.

Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer.

Colorectal cancer (CRC) can be classified into subtypes based on gene expression signatures. Patients with stage III enterocyte subtype of the CRC Assigner classifier have been shown to benefit from oxaliplatin adjuvant therapy. Here, we investigated whether single nucleotide polymorphisms (SNPs) in two enterocyte subtype-related genes, MS4A12 and CDX2, could predict the efficacy of oxaliplatin in first-line treatment for patients with metastatic CRC (mCRC). Three cohorts of patients were included: a discovery cohort receiving FOLFOX ± bevacizumab (BEV) (n = 146), a validation cohort receiving FOLFOXIRI + BEV (n = 230), and a control cohort receiving FOLFIRI + BEV (n = 228). SNPs were analyzed by PCR-based direct sequencing. In the discovery cohort, MS4A12 rs4939378 and CDX2 rs3812863 were identified as potential markers of efficacy. In the validation cohort, any G allele of MS4A12 rs4939378 was associated with longer progression-free survival (PFS) than the A/A variant in both univariate analysis (12.4 vs. 10.9 months, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49-0.99, P = 0.033) and multivariable analysis (HR 0.65, 95%CI 0.44-0.97, P = 0.035) in patients expressing wild-type KRAS, but not mutant KRAS. In contrast, longer PFS was observed for patients expressing the CDX2 rs3812863 G/G variant than any A allele in univariate analysis (32.3 vs. 10.3 months, HR 0.39, 95%CI 0.19-0.81, P = 0.004) only in patients expressing mutant KRAS. These findings were not observed in the control cohort. Thus, MS4A12 and CDX2 SNPs may have utility as predictive biomarkers of response to oxaliplatin-based treatment in mCRC patients.

ELF3 Overexpression as Prognostic Biomarker for Recurrence of Stage II Colorectal Cancer.

BACKGROUND/AIM: Adjuvant chemotherapy for high-risk Stage II colorectal cancer (CRC) is weakly recommended; however, no consensus exists on "high-risk" definition. Prognostic biomarker identification is important for selecting patients with poor prognosis who may benefit from adjuvant chemotherapy. MATERIALS AND METHODS: Using Microarray data analyses, ELF3 was identified as a candidate gene highly expressed in Stage II CRC with distant recurrences. ELF3 mRNA expression in 168 Stage II CRC patients was subjected to quantitative RT-PCR analysis and ELF3 protein expression in 185 patients was quantified by immunohistochemical analysis. The relationship between mRNA and protein expression levels and patient characteristics were also investigated. RESULTS: The overall recurrence rate and relapse-free survival were significantly poorer in the ELF3 high-expression than the low-expression group at the mRNA and protein levels. High ELF3 mRNA and protein expression levels were independent poor prognostic factors. CONCLUSION: High ELF3 expression was associated with recurrence of Stage II.

Epigenetic Clock Analysis in Children With Fetal Alcohol Spectrum Disorder.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is characterized by severe clinical impairment, considerable social burden, and high mortality and morbidity, which are due to various malformations, sepsis, and cancer. As >50% of deaths from FASD occur during the first year of life, we hypothesized that there is the acceleration of biological aging in FASD. Several recent studies have established genome-wide DNA methylation (DNAm) profiles as "epigenetic clocks" that can estimate biological aging, and FASD has been associated with differential DNAm patterns. Therefore, we tested this hypothesis using epigenetic clocks. METHODS: We investigated 5 DNAm-based measures of epigenetic age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge) and telomere length (DNAmTL) using 4 independent publicly available DNAm datasets; 2 datasets were derived from buccal epithelium, and the other 2 datasets were derived from peripheral blood. RESULTS: Compared with controls, children with FASD exhibited an acceleration of GrimAge in 1 buccal and 2 blood datasets. No significant difference was found in other DNAm ages and DNAmTL. Meta-analyses showed a significant acceleration of GrimAge in the blood samples but not in the buccal samples. CONCLUSIONS: This study provides novel evidence regarding accelerated epigenetic aging in children with FASD.

Role of enterocyte-specific gene polymorphisms in response to adjuvant treatment for stage III colorectal cancer.

OBJECTIVES: The enterocyte subtype of colorectal cancer (CRC) responds favorably to oxaliplatin-based adjuvant treatment for stage III CRC. We examined the clinical significance of single-nucleotide polymorphisms (SNPs) in enterocyte-related genes MS4A12 and CDX2 in response to adjuvant treatment for stage III CRC. PATIENTS AND METHODS: A total of 350 patients with stage III CRC were included: 274 received adjuvant treatment with surgical resection (discovery cohort) and 76 received surgery alone (control cohort). In the discovery cohort, 68 patients received FOLFOX and 206 received oral fluoropyrimidine. SNPs were analyzed by PCR-based direct sequencing. RESULTS: In the discovery cohort, the MS4A12 rs4939378 G/G variant was associated with lower 5-year survival than any A allele [70% vs. 90%, univariate: hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.03-5.06, P = 0.035; multivariate: HR 2.58, 95% CI 1.15-5.76, P = 0.021]. Patients with the CDX2 rs3812863 G/G variant had better overall survival than those with any A allele, although this was not significant in multivariate analysis (5 year-survival: 95% vs. 82%, univariate: HR 0.34, 95% CI 0.12-0.97, P = 0.034; multivariate: HR 0.39, 95% CI 0.13-1.11, P = 0.078). The SNPs did not show significant association with overall survival in the control cohort, and significant interaction was observed between MS4A12 genotypes and groups (P = 0.007). CONCLUSIONS: Our findings suggest that MS4A12 and CDX2 gene polymorphisms may predict outcome in stage III CRC. However, the clinical significance of SNPs for response to oxaliplatin may differ by tumor stage.

A polymorphism in the cachexia-associated gene INHBA predicts efficacy of regorafenib in patients with refractory metastatic colorectal cancer.

Activin/myostatin signaling has a critical role not only in cachexia but also in tumor angiogenesis. Cachexia is a frequent complication among patients with advanced cancer and heavily pretreated patients. We aimed to evaluate the prognostic significance of cachexia-associated genetic variants in refractory metastatic colorectal cancer (mCRC) patients treated with regorafenib. Associations between twelve single nucleotide polymorphisms in 8 genes (INHBA, MSTN, ALK4, TGFBR1, ALK7, ACVR2B, SMAD2, FOXO3) and clinical outcome were evaluated in mCRC patients of three cohorts: a discovery cohort of 150 patients receiving regorafenib, a validation cohort of 80 patients receiving regorafenib and a control cohort of 128 receiving TAS-102. In the discovery cohort, patients with any G variant in FOXO3 rs12212067 had a significantly lower response rate (P = 0.031) and overall survival (OS) than those with a T/T in univariate analysis (4.5 vs. 7.6 months, hazard ratio [HR] = 1.63, 95% confidence interval [CI] = 1.09-2.46, P = 0.012). Among female patients, those with any G variant in INHBA rs2237432 had a significantly longer OS than those with an A/A in both univariate (7.6 vs. 4.3 months, HR = 0.57, 95%CI = 0.34-0.95, P = 0.021) and multivariable (HR = 0.53, 95%CI = 0.29-0.94, adjusted P = 0.031) analysis. This association was confirmed in female patients of the validation cohort, though without statistical significance (P = 0.059). Conversely, female patients with any G allele in the control group receiving TAS-102 did not show a longer OS. This was the first study evaluating the associations between polymorphisms in cachexia-associated genes and outcomes in refractory mCRC patients treated with regorafenib. Further studies should be conducted to confirm these associations.

A new monitoring tool CLIP test for progression of oxaliplatin-induced peripheral neuropathy: A multicenter prospective study.

INTRODUCTION: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse events that can limit a patient's quality of life during/after chemotherapy. However, no appropriate methods have been established yet for monitoring the risk of progression of OIPN. METHODS: A simple assessment tool using gem clips, the CLIP test, was established and its performance in predicting the risk of progression to ≥grade 2 peripheral sensory neuropathy (CTCAE ver. 4.0) was investigated in patients receiving chemotherapy with oxaliplatin. RESULTS: Among 101 patients included in this study, 71 patients developed CTCAE ≥grade 1 peripheral neuropathy (grade 1, n = 67; grade 2, n = 4) at a median of 63 (range, 14-259) days after the start of treatment. Of the 67 patients with grade 1 peripheral neuropathy, 17 showed progression to ≥grade 2 neuropathy after a median interval of 84 (range, 21-246) days. Of these patients, 27 showed a positive result of the CLIP test at a median of 91 (range, 14-224) days, excluding one patient who already showed a positive result of the test at the baseline. Therefore, the risk ratio for the development of CTCAE ≥grade 2 peripheral neuropathy was 8.3 in the patients who showed a positive result on the CLIP test. Multivariate analysis confirmed that a positive results on the CLIP test was significantly correlated with the risk of future development of CTCAE ≥grade 2 peripheral neuropathy (odds ratio, 9.37; P = 0.002). CONCLUSION: A positive result on the CLIP test predict is predictive of the risk of progression of OIPN during chemotherapy with oxaliplatin.

Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial.

BACKGROUND: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes RPA2 and GTF2H1 are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether RPA2 and GTF2H1 SNPs predict the efficacy of oxaliplatin in metastatic CRC (mCRC) patients. PATIENTS AND METHODS: Genomic DNA was extracted from blood samples from 457 patients with mCRC enrolled in the TRIBE trial, which compared first-line FOLFOXIRI plus bevacizumab (BEV) (n = 230, discovery cohort) and first-line FOLFIRI plus BEV (n = 227, control cohort). SNPs were analyzed by PCR-based direct sequencing. RESULTS: In the FOLFOXIRI + BEV-treated cohort expressing wild-type KRAS, progression-free survival (PFS) was shorter for the RPA2 rs7356 C/C variant subgroup than the any T allele subgroup in univariate analysis (9.1 versus 13.3 months respectively, hazard ratio (HR) 2.32, 95% confidence interval (CI): 1.07-5.03, p = 0.020) and this remained significant in multivariable analysis (HR 2.97, 95%CI: 1.27-6.94, p = 0.012). A similar trend was observed for overall survival. In contrast, patients expressing mutant RAS and RPA2 rs7356 C/C variant had longer PFS with FOLFOXIRI + BEV than with FOLFIRI + BEV (12.1 versus 7.6 months, HR 0.23, 95%CI: 0.09-0.62, p = 0.002) but no superiority of FOLFOXIRI + BEV was observed for the RAS mutant, RPA2 rs7356 any T variant subgroup (11.7 versus 9.6 months, HR 0.77, 95%CI: 0.56-1.07, p = 0.12) or the RAS wild-type, RPA2 rs7356 C/C variant subgroup. CONCLUSION: RPA2 SNPs may serve as predictive and prognostic markers of oxaliplatin responsiveness in a RAS status-dependent manner in mCRC patients receiving FOLFOXIRI + BEV.

Photodynamic Diagnosis for Pleural Disseminated Lesions of Lung Cancer Using a Combination of 5-Aminolevulinic Acid and Autofluorescence Observation System.

PURPOSE: We developed a diagnostic method for pleural disseminated lesions of lung cancer using a combination of 5-aminolevulinic acid (5ALA) and autofluorescence observation system. We utilized a phenomenon in which externally ingested 5ALA is metabolized to protoporphyrin IX, a precursor of heme, which remains inside malignant cells and emits red fluorescence of approximately 630 nm. The diagnosis was made employing an observation system based on autofluorescence emitted from normal tissues that we have investigated. METHODS: Between January 2017 and April 2019, we examined 82 lung cancer patients with suspected pleural invasion. We orally administered 5ALA (20 mg/m2) to the patients 4 hours before surgery, and malignant pleural lesions were thoracoscopically visualized using the autofluorescence observation system. RESULTS: (1) Pleural disseminated lesions were observed in six patients. Of these lesions, two were not detected by usual white light inspection, and the use of this method enabled the diagnosis of disseminated lesions. (2) Regarding the diagnosis of lung cancer pleural invasion to estimate the risk of pleural dissemination, if limited to adenocarcinoma, the sensitivity was 93.9%; specificity, 74.3%; positive predictive value, 60.8%; and negative predictive value, 96.2%. CONCLUSION: This method may facilitate the detection of minute disseminated lesions that are difficult to detect by usual inspection. In addition, the degree of pleural invasion may be diagnosed to evaluate the need for limited resection such as segmentectomy.

[A Case of Pelvic Desmoid-Type Fibromatosis Treated by Radiation and Medication Therapies].

The treatment for desmoid-type fibromatosis involves surgical resection and medication therapy, but the standard treatment has not yet been established. In the West, the usefulness of radiation therapy has been reported. We encountered a patient with desmoid-type fibromatosis in the pelvis who was treated by radiation and medication therapies and achieved a good tumor reduction effect. The patient was a 70-year-old man. He had a 6-year history of pain in the right leg and had a palpable mass on the right side of the anus; he was admitted to our department. CT showed a 12×7×12 cm mass in the pelvis, and CT-guided needle biopsy revealed a desmoid-type fibromatosis. Because tumor exclusion resulted in obstruction of the rectum, radiation therapy(60 Gy in 30 Fr)was started after performing transverse colon colostomy; simultaneous medication therapy with a COX-2 inhibitor and the anti-allergic agent tranilast was administered. Cystic degeneration was observed 5 months after the end of radiation therapy, and after 12 months, the tumor volume had halved. Around 28 months after the end of radiation therapy, medication treatment has been continued with slow contraction.

[Perioperative Chemotherapies for Patients with Colorectal Liver Metastasis].

Perioperative chemotherapies are expected to improve prognosis of patients with colorectal liver metastasis(CRLM). In patients with a resectable CRLM, the adjuvant chemotherapy with 5-FU/LV effectively prolongs DFS or RFS. In patients with unresectable CRLM, a neoadjuvant chemotherapy with high response rate and high liver resection rate, such as FOLFOX(or CAPOX, SOX)plus bevacizumab, FOLFOX/FOLFIRI plus cetuximab, or FOLFOXIRI plus bevacizumab, could be an optimal regimen for the conversion therapy.

ATP and repetitive electric stimulation increases leukemia inhibitory factor expression in astrocytes: A potential role for astrocytes in the action mechanism of electroconvulsive therapy.

AIM: Electroconvulsive therapy (ECT) is effective for psychiatric disorders. However, its action mechanism remains unclear. We previously reported that transcription factor 7 (TCF7) was increased in patients successfully treated with ECT. TCF7 regulates Wnt pathway, which regulates adult hippocampal neurogenesis. Adult hippocampal neurogenesis is involved in the pathophysiology of psychiatric disorders. Astrocytes play a role in adult hippocampal neurogenesis via neurogenic factors. Of astrocyte-derived neurogenic factors, leukemia inhibitory factor (LIF) and fibroblast growth factor 2 (FGF2) activate Wnt pathway. In addition, adenosine triphosphate (ATP), released from excited neurons, activates astrocytes. Therefore, we hypothesized that ECT might increase LIF and/or FGF2 in astrocytes. To test this, we investigated the effects of ATP and electric stimulation (ES) on LIF and FGF2 expressions in astrocytes. METHODS: Astrocytes were derived from neonatal mouse forebrain and administered ATP and ES. The mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. Protein concentration was measured with ELISA. RESULTS: ATP increased LIF, but not FGF2, expression. Multiple ES, but not single, increased LIF expression. Knockdown of P2X2 receptor (P2X2R) attenuated ATP-induced increase of LIF mRNA expression. In contrast, P2X3 and P2X4 receptors intensified it. CONCLUSION: P2X2R may mediate ATP-induced LIF expression in astrocytes and multiple ES directly increases LIF expression in astrocytes. Therefore, both ATP/P2X2R and multiple ES-induced increases of LIF expression in astrocytes might mediate the efficacy of ECT on psychiatric disorders. Elucidating detailed mechanisms of ATP/P2X2R and multiple ES-induced LIF expression is expected to result in the identification of new therapeutic targets for psychiatric disorders.