LINE-1 hypomethylation, increased retrotransposition and tumor-specific insertion in upper gastrointestinal cancer.

The long interspersed nuclear element-1 (LINE-1) retrotransposons are a major family of mobile genetic elements, comprising approximately 17% of the human genome. The methylation state of LINE-1 is often used as an indicator of global DNA methylation levels and it regulates the retrotransposition and somatic insertion of the genetic element. We have previously reported the significant relationship between LINE-1 hypomethylation and poor prognosis in upper gastrointestinal (GI) cancers. However, the causal relationships between LINE-1 hypomethylation, retrotransposition, and tumor-specific insertion in upper GI cancers remain unknown. We used bisulfite-pyrosequencing and quantitative real-time PCR to verify LINE-1 methylation and copy number in tissue samples of 101 patients with esophageal and 103 patients with gastric cancer. Furthermore, we analyzed the LINE-1 retrotransposition profile with an originally developed L1Hs-seq. In tumor samples, LINE-1 methylation levels were significantly lower than non-tumor controls, while LINE-1 copy numbers were markedly increased. As such, there was a significant inverse correlation between the LINE-1 methylation level and copy number in tumor tissues, with lower LINE-1 methylation levels corresponding to higher LINE-1 copy numbers. Of particular importance is that somatic LINE-1 insertions were more numerous in tumor than normal tissues. Furthermore, we observed that LINE-1 was inserted evenly across all chromosomes, and most often within genomic regions associated with tumor-suppressive genes. LINE-1 hypomethylation in upper GI cancers is related to increased LINE-1 retrotransposition and tumor-specific insertion events, which may collectively contribute to the acquisition of aggressive tumor features through the inactivation of tumor-suppressive genes.

Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism.

Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca(2+) responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.

Exploration of cell type-specific somatic mutations in schizophrenia and the impact of maternal immune activation on the somatic mutation profile in the brain.

AIM: Schizophrenia (SZ) is a severe psychiatric disorder caused by the interaction of genetic and environmental factors. Although somatic mutations that occur in the brain after fertilization may play an important role in the cause of SZ, their frequencies and patterns in the brains of patients and related animal models have not been well studied. This study aimed to find somatic mutations related to the pathophysiology of SZ. METHODS: We performed whole-exome sequencing (WES) of neuronal and nonneuronal nuclei isolated from the postmortem prefrontal cortex of patients with SZ (n = 10) and controls (n = 10). After detecting somatic mutations, we explored the similarities and differences in shared common mutations between two cell types and cell type-specific mutations. We also performed WES of prefrontal cortex samples from an animal model of SZ based on maternal immune activation (MIA) and explored the possible impact of MIA on the patterns of somatic mutations. RESULTS: We did not find quantitative differences in somatic mutations but found higher variant allele fractions of neuron-specific mutations in patients with SZ. In the mouse model, we found a larger variation in the number of somatic mutations in the offspring of MIA mice, with the occurrence of somatic mutations in neurodevelopment-related genes. CONCLUSION: Somatic mutations occurring at an earlier stage of brain cell differentiation toward neurons may be important for the cause of SZ. MIA may affect somatic mutation profiles in the brain.

[FOLFIRI plus RAM Therapy in Later Line of Unresectable Colorectal Cancer].

FOLFIRI plus ramucirumab(RAM)therapy has been reported to be effective and safe in the RAISE trial as second-line treatment for unresectable colorectal cancer. It is hypothesized that RAM may be effective in patients with PD treated with FOLFIRI plus bevacizumab(Bev)due to different mechanism of action from that of Bev, which is also an angiogenesis inhibitor. From January 2017 to December 2021, we conducted a retrospective study of 6 patients who had PD with 5-FU, oxaliplatin, irinotecan, or Bev as first or second-line treatment at our institution and who received FOLFIRI plus RAM in later line treatment. The 6 cases consisted of 3 patients in the third-line treatment, 1 patient in the fourth-line treatment, and 2 patients in the sixth-line treatment. The anti-tumor effect was PD in all cases in the third-line and fourth-line treatment, but the 2 patients of sixth-line treatment were controlled diseases.

[A Case Report-A Successful Case of Distal Pancreatectomy with En Bloc Celiac Axis Resection for Locally Advanced Pancreatic Cancer with an Aberrant Right Hepatic Artery].

In cases of pancreatic cancer with anatomical variations of the hepatic artery, it is important to evaluate the hemodynamics of each case for surgical indication. We report the case of a 68-year-old man with locally advanced pancreatic cancer and an aberrant right hepatic artery who underwent distal pancreatectomy with celiac axis resection(DP-CAR). He was admitted to our institute due to abdominal discomfort. A CT scan showed pancreatic cancer invading the common hepatic artery. He underwent chemoradiotherapy with a diagnosis of locally advanced pancreatic cancer. After the tumor downstaging, we performed DP-CAR, which included a gastroduodenal artery and a proper hepatic artery resection. Even though delayed gastric emptying was observed after the operation, he was discharged on postoperative day 36.

Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder.

Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors are collectively associated with the etiology of BD, the underlying molecular mechanisms, particularly how environmental factors affect the brain, remain largely unknown. We performed promoter-wide DNA methylation analysis of neuronal and nonneuronal nuclei in the prefrontal cortex of patients with BD (N = 34) and controls (N = 35). We found decreased DNA methylation at promoters in both cell types in the BD patients. Gene Ontology (GO) analysis of differentially methylated region (DMR)-associated genes revealed enrichment of molecular motor-related genes in neurons, chemokines in both cell types, and ion channel- and transporter-related genes in nonneurons. Detailed GO analysis further revealed that growth cone- and dendrite-related genes, including NTRK2 and GRIN1, were hypermethylated in neurons of BD patients. To assess the effect of medication, neuroblastoma cells were cultured under therapeutic concentrations of three mood stabilizers. We observed that up to 37.9% of DMRs detected in BD overlapped with mood stabilizer-induced DMRs. Interestingly, mood stabilizer-induced DMRs showed the opposite direction of changes in DMRs, suggesting the therapeutic effects of mood stabilizers. Among the DMRs, 12 overlapped with loci identified in a genome-wide association study (GWAS) of BD. We also found significant enrichment of neuronal DMRs in the loci reported in another GWAS of BD. Finally, we performed qPCR of DNA methylation-related genes and found that DNMT3B was overexpressed in BD. The cell-type-specific DMRs identified in this study will be useful for understanding the pathophysiology of BD.

Comparison of clinical outcomes of single-incision versus multi-port laparoscopic surgery for descending colon cancer: a propensity score-matched analysis.

BACKGROUND: The clinical impact of single-incision laparoscopic surgery (SILS) for descending colon cancer (DCC) is unclear. The aim of this study was to evaluate the clinical outcomes of SILS for DCC compared with multi-port laparoscopic surgery (MPLS). METHODS: We retrospectively analyzed 137 consecutive patients with stage I-III DCC who underwent SILS or MPLS at two high-volume multidisciplinary tertiary hospitals between April 2008 and December 2018, using propensity score-matched analysis. RESULTS: After propensity score-matching, we enrolled 88 patients (n = 44 in each group). SILS was successful in 97.7% of the matched cohort. Compared with the MPLS group, the SILS group showed significantly less blood loss and a greater number of harvested lymph nodes. Morbidity rates were similar between groups. Recurrence pattern did not differ between groups. No significant differences were found between groups in terms of 3-year disease-free and overall survivals. CONCLUSION: SILS appears safe and feasible and can provide satisfactory oncological outcomes for patients with DCC.

Comparison of clinical outcomes of single-incision versus multi-port laparoscopic surgery for rectosigmoid or upper rectal cancer.

BACKGROUND: Single-incision laparoscopic surgery (SILS) for rectal cancer is technically challenging, and its clinical impact is unclear. The aim of this study was to evaluate clinical outcomes of SILS for rectal cancer compared with multi-port laparoscopic surgery (MPLS). PATIENTS AND METHODS: We retrospectively analyzed 357 consecutive patients with stage I-III rectal cancer located in the rectosigmoid or upper rectum who underwent SILS or MPLS between January 2012 and December 2016, using propensity score-matched analysis. RESULTS: After propensity score-matching, we enrolled 204 patients (n = 102 per group). Before matching, significant group-dependent differences were observed in tumor location (p < 0.001). After matching, preoperative clinical factors were similar between groups. SILS was successful in 73.5% of cases, an additional port was required in 23.5%, and 2.9% were converted to open surgery. Compared to the MPLS group, the SILS group showed shorter operative time (192 vs. 211 min, p = 0.015) and shorter postoperative hospital stay (9 vs. 11 days, p = 0.038). Other operative factors and morbidity rates did not differ significantly between groups. The number of harvested lymph nodes was smaller in the SILS group (24) than in the MPLS group (27, p = 0.008). Postoperative recurrence did not differ between groups, either before or after matching. No significant differences in 3-year disease-free, 3-year local recurrence-free, or 5-year overall survival were found between groups. CONCLUSIONS: SILS is safe, is feasible, and offers satisfactory oncological outcomes in selected patients with rectosigmoid or upper rectal cancer.

Laparoscopic-assisted disinvagination and polypectomy for multiple intussusceptions induced by small intestinal polyps in patients with Peutz-Jeghers syndrome: a case report.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a very rare autosomal dominant genetic disorder characterized by hamartomatous polyps in the gastrointestinal tract and hyperpigmentation of the lips, hands, and feet. The hamartomatous polyps in the small intestine often cause intussusception and bleeding. CASE PRESENTATION: A 62-year-old male was hospitalized for treatment of deep vein thrombosis and pulmonary embolism. In the small intestine, computed tomography showed three small polyps with intussusceptions. Since the patient had gastrointestinal polyposis and pigmentation of his lips, fingers, and toes, he was diagnosed with PJS. After an inferior vena cava filter was placed, he underwent laparoscopic-assisted surgery. The polyps causing intussusception were resected as far as possible without intestinal resection, since they had caused progressive anemia and might cause intestinal obstruction in the future. The patient was discharged from the hospital on postoperative day 9 without complications. CONCLUSIONS: Laparoscopic-assisted disinvagination and polypectomy is a useful, minimally invasive treatment for multiple intussusceptions caused by small intestinal polyps in patients with PJS.

[Effect of Endoscopic Resection on Prognosis in T1b Colorectal Cancer].

With the advancement of endoscopic resection(ER)of colorectal cancer, surgical resection after ER has been increasing. This study evaluated the effects of initial ER on short- and long-term outcomes in T1b colorectal cancer. This retrospective cohort study enrolled patients with pathological T1b colorectal cancer who underwent colorectal surgical resection between 2008 and 2018. A total of 239 eligible patients were divided into 2 groups: patients initially treated using surgical resection with lymph node dissection(LND)(surgery alone, n=142)and patients treated using initial ER and additional surgical resection with LND(surgery after ER, n=97). No significant differences were observed in short-term outcomes(ie, operative time, blood loss, or postoperative complications)or the long-term outcomes(ie, recurrence rate, overall survival rate, or recurrence free survival rate)between groups.

[A Case of Carcinomatous Meningitis from Gastric Cancer with Improvement of QOL by Ventriculoperitoneal Shunt].

In cases where carcinomatous meningitis leads to hydrocephalus and increases intracranial pressure, patients present with exacerbated pain and several neurological symptoms. It is reported that multidisciplinary therapy, including radiation therapy, drug therapy, and surgery, is performed for patients with carcinomatous meningitis; however, it is rarely successful. Ventriculoperitoneal shunting(V-P shunt)is a surgical intervention that might relieve the pain temporarily and improve the quality of life. VPS should be taken into consideration in line with patients' and their families' intentions since the overall survival is fairly short.

Syntenin-1 promotes colorectal cancer stem cell expansion and chemoresistance by regulating prostaglandin E2 receptor.

BACKGROUND: The protein syntenin-1 is expressed by a variety of cell types, and is upregulated in various malignancies, including melanoma, breast cancer and glioma. Although the mechanism by which elevated syntenin-1 expression contributes to cancer has been described, the exact pathway has not been elucidated. METHODS: To investigate the involvement of syntenin-1 in colorectal cancer (CRC), we performed immunohistochemical analysis of 139 CRC surgical specimens. We also examined syntenin-1 knockdown in CRC cell lines. RESULTS: High syntenin-1 expression was associated with less differentiated histologic grade and poor prognosis, and was an independent prognostic indicator in CRC. Syntenin-1 knockdown in CRC cells reduced the presence of cancer stem cells (CSCs), oxaliplatin chemoresistance and migration. DNA microarray analysis and quantitative real-time polymerase chain reaction showed decreased prostaglandin E2 receptor 2 (PTGER2) expression in syntenin-1-knockdown cells. PTGER2 knockdown in CRC cells yielded the same phenotype as syntenin-1 knockdown. Celecoxib, which has anti-inflammatory effects by targeting cyclooxygenase-2, reduced CSCs and decreased chemoresistance, while prostaglandin E2 (PGE2) had the opposite effect. CONCLUSIONS: Our findings suggested that syntenin-1 enhanced CSC expansion, oxaliplatin chemoresistance and migration capability through regulation of PTGER2 expression. Syntenin-1 may be a promising new prognostic factor and target for anti-cancer therapies.

Somatic mutations in the human brain: implications for psychiatric research.

Psychiatric disorders such as schizophrenia and bipolar disorder are caused by complex gene-environment interactions. While recent advances in genomic technologies have enabled the identification of several risk variants for psychiatric conditions, including single-nucleotide variants and copy-number variations, these factors can explain only a portion of the liability to these disorders. Although non-inherited factors had previously been attributed to environmental causes, recent genomic analyses have demonstrated that de novo mutations are among the main non-inherited risk factors for several psychiatric conditions. Somatic mutations in the brain may also explain how stochastic developmental events and environmental insults confer risk for a psychiatric disorder following fertilization. Here, we review evidence regarding somatic mutations in the brains of individuals with and without neuropsychiatric diseases. We further discuss the potential biological mechanisms underlying somatic mutations in the brain as well as the technical issues associated with the detection of somatic mutations in psychiatric research.

[Nodular Lymphocyte-Predominant Hodgkin Lymphoma(NLPHL)Which Originate from the Mesentery-A Series of Two Cases].

Nodular lymphocyte-predominant Hodgkin lymphoma(NLPHL)is a subtype of Hodgkin lymphoma. It is uncommon in Japan, and only a few cases of NLPHL originating from the mesentery have been reported. Most patients with NLPHL present in the early stage, but some patients have malignancy at initial presentation. We should perform staging laparotomy for the diagnosis and treatment of cases in which a lymph node biopsy is difficult.

[Case Series of the TAS-102 plus Bevacizumab(Bev)Combination Therapy in Unresectable Advanced Colorectal Cancer].

A phase-Ⅱtrial of TAS-102 plus bevacizumab(Bev)combination therapy showed a progression-free survival(PFS)of 3.7-4.6 months. Here, we report 12 cases of unresectable advanced recurrent colorectal cancer treated with TAS-102 plus Bev therapy at our hospital between June 2017 and February 2020. The median PFS was 6 months(2-12). Adverse events greater than Grade 3 were neutropenia(33.3%), febrile neutropenia(8.3%), thrombocytopenia(8.3%), and vomiting (8.3%). The frequency of non-hematotoxicity was low. In conclusion, the TAS-102 plus Bev therapy may be a useful option for the late-line treatment of unresectable advanced recurrent colorectal cancer.

[Launching Robot-Assisted Laparoscopic Surgery for Rectal Cancer in Our Hospital-Short-Term Results].

Robot-assisted laparoscopic surgery(RALS)for rectal cancer has been covered by National Health Insurance in Japan since April 2018. We launched RALS in our hospital in October 2019 and now report the short-term results(up to January 2020). Altogether, 15 consecutive patients(12 men, 3 women: median age 70 years)with rectal cancer underwent RALS during that period. For the first 2 cases, we performed RALS under the instruction of an experienced proctor from another institution. Among the 15 patients, 6 underwent high anterior resection and 9 low anterior resection. Median operating time was 358 min, median intraoperative blood loss was 0 mL, and there were no apparent intraoperative complications. Median postoperative length of hospital stay was 13 days, and only 1 patient developed a high-grade complication(Clavien-Dindo Grade Ⅲb)postoperatively. Hence, RALS for rectal cancer was launched successfully in our institution.

[A Case of Slow-Growing Intrahepatic Cholangiocarcinoma after Resection of Gastric Cancer].

An 83-year-old woman was given a diagnosis of gastric cancer and received distal gastrectomy 9 years ago. Three years later, CT revealed a tumor measuring 13 mm in diameter in hepatic segment 7. She was followed for 5 years, and the size of the tumor did not change. Eight years later after gastrectomy, the tumor size slightly enlarged to 17 mm, and biopsy revealed adenocarcinoma. The patient underwent liver resection of segment 7. The pathological diagnosis was well differentiated intrahepatic cholangiocarcinoma(ICC). No sign of recurrence has been found during a 1-year. This case, in which the patient was followed for 5 years before curative surgical treatment, is significant, because it demonstrates the slow-growing nature of ICC.

Correction to: Safety of Single-Site Laparoscopic Surgery Requiring Perioperative Heparinization in Colorectal Cancer: Propensity Score-Matched Analysis.

In the original article, Yuichiro Doki's first and last names are transposed. The author's name is correct as reflected here.

Safety of Single-Site Laparoscopic Surgery Requiring Perioperative Heparinization in Colorectal Cancer: Propensity Score-Matched Analysis.

BACKGROUND: We assessed the feasibility and safety of single-site laparoscopic surgery for patients with colorectal cancer who required perioperative heparinization. METHODS: This retrospective study reviewed the medical records of 390 patients who underwent single-site laparoscopic surgery for colorectal cancer from January 2010 to December 2016. Antithrombotic drugs were stopped preoperatively and heparin was administered according to the operative risk of each patient, based on consultation with the cardiologist physician or neurosurgeon. Propensity score modeling was utilized to adjust for baseline characteristics. RESULTS: Of 390 patients, 29 were treated with standard bridging intravenous heparin therapy. Propensity matching identified 119 patients: 22 patients in the heparinization group and 97 in the control group. The matched groups were not significantly different in operation times, bleeding volumes, or conversion rate. The mean postoperative hospital stay was 17.9 days in the heparinization group and 9.5 days in the control group (p = 0.034). Postoperative bleeding was observed in 4 patients (18.2%) in the heparinization group and 11 patients (11.4%) in the control group (p = 0.646), while other complications were similar in the two study groups (p = 0.502). Of these other complications, thromboembolic events were observed in two patients in the heparinization group and one patient in the control group. CONCLUSIONS: We found that single-site laparoscopic surgery for colorectal cancer with heparinization was feasible and safe. Heparinization did not increase the risk of postoperative bleeding complications, but postoperative hospital stay was prolonged.

DNA Methylation Profiling in a Neuroblastoma Cell Line Exposed to the Antipsychotic Perospirone.

INTRODUCTION: Accumulating evidence suggests the importance of epigenetic changes in the brain induced by antipsychotic drugs. However, due to the lack of systematic investigation, their effects on epigenetic status remain largely unclear. During the course of examining the epigenetic effects of antipsychotics, we here focused on perospirone, an atypical antipsychotic drug mainly used in Japan. METHODS: Genomic DNA was obtained from human neuroblastoma cells exposed to 2 different doses of perospirone. Comprehensive DNA methylation analysis was performed using the Infinium HumanMethylation450 BeadChip. RESULTS: Of about 470,000 probes, perospirone exposure changed DNA methylation at 4098 probes. These probes were enriched to genes for neural development. Probes showing hypermethylation were mainly found at gene body and intergenic regions, whereas those that showed hypomethylation were located near promoter regions. Additionally, DNA methylation changes were found in the probes for dopamine receptor 2 and serotonin receptor (HTR) 2A and HTR1A, which are the pharmacological targets of atypical antipsychotics. DISCUSSION: Our comprehensive DNA methylation analyses will contribute to a better understanding of detailed pharmacological actions of perospirone.