Faster surgery initiation in oral cancer patients during the COVID-19 pandemic in Osaka, Japan.

BACKGROUND: We investigated the impact of the COVID-19 pandemic on oral cancer (OC), comparing diagnosis and number of pre-operative days in the diagnosis of OC in 2019 (pre-COVID-19) and that in 2020 (during the COVID-19 pandemic). METHODS: Using data from a cancer registry-based study on the impact of COVID-19 on cancer care in Osaka (CanReCO), we collected details of sex, age, residential area, cancer site, date of diagnosis, clinical stage at first treatment and number of pre-operative days in OC patients. RESULTS: A total of 1470 OC cases were registered. Incidence of OC before and during COVID-19 was 814 and 656 cases, respectively. During the first wave of the pandemic (March to May 2020), incidence was about half that in the same period in 2019 (2019; n = 271, 2020; n = 145). Number of pre-operative days (median number of days between the first hospital visit and surgery date) was significantly shorter during the COVID-19 year (24.5 days) than in the pre-COVID-19 year (28 days, p = 0.0015). CONCLUSIONS: Incidence of OC during the COVID-19 pandemic was lower than in pre-COVID-19. Despite disruption in the healthcare system, the number of pre-operative days for OC cases was shorter during the pandemic.

Clinical evidence that a dysregulated master neural network modulator may aid in diagnosing schizophrenia.

There are no validated biomarkers for schizophrenia (SCZ), a disorder linked to neural network dysfunction. We demonstrate that collapsin response mediator protein-2 (CRMP2), a master regulator of cytoskeleton and, hence, neural circuitry, may form the basis for a biomarker because its activity is uniquely imbalanced in SCZ patients. CRMP2's activity depends upon its phosphorylation state. While an equilibrium between inactive (phosphorylated) and active (nonphosphorylated) CRMP2 is present in unaffected individuals, we show that SCZ patients are characterized by excess active CRMP2. We examined CRMP2 levels first in postmortem brains (correlated with neuronal morphometrics) and then, because CRMP2 is expressed in lymphocytes as well, in the peripheral blood of SCZ patients versus age-matched unaffected controls. In the brains and, more starkly, in the lymphocytes of SCZ patients <40 y old, we observed that nonphosphorylated CRMP2 was higher than in controls, while phosphorylated CRMP2 remained unchanged from control. In the brain, these changes were associated with dendritic structural abnormalities. The abundance of active CRMP2 with insufficient opposing inactive p-CRMP2 yielded a unique lowering of the p-CRMP2:CRMP2 ratio in SCZ patients, implying a disruption in the normal equilibrium between active and inactive CRMP2. These clinical data suggest that measuring CRMP2 and p-CRMP2 in peripheral blood might reflect intracerebral processes and suggest a rapid, minimally invasive, sensitive, and specific adjunctive diagnostic aid for early SCZ: increased CRMP2 or a decreased p-CRMP2:CRMP2 ratio may help cinch the diagnosis in a newly presenting young patient suspected of SCZ (versus such mimics as mania in bipolar disorder, where the ratio is high).

Cementum is key to periodontal tissue regeneration: A review on apatite microstructures for creation of novel cementum-based dental implants.

The cementum is the outermost layer of hard tissue covering the dentin within the root portion of the teeth. It is the only hard tissue with a specialized structure and function that forms a part of both the teeth and periodontal tissue. As such, cementum is believed to be critical for periodontal tissue regeneration. In this review, we discuss the function and histological structure of the cementum to promote crystal engineering with a biochemical approach in cementum regenerative medicine. We review the microstructure of enamel and bone while discussing the mechanism underlying apatite crystal formation to infer the morphology of cementum apatite crystals and their complex structure with collagen fibers. Finally, the limitations of the current dental implant treatments in clinical practice are explored from the perspective of periodontal tissue regeneration. We anticipate the possibility of advancing periodontal tissue regenerative medicine via cementum regeneration using a combination of material science and biochemical methods.

Incidence of second primary cancers among survivors of childhood cancer: A population-based study, Osaka, Japan, 1975-2015.

Second primary cancer (SPC) is one of the most life-threatening late effects of childhood cancers. We investigated the incidence and survival outcomes of SPC in childhood cancer patients in Japan. Data were obtained from the population-based Osaka Cancer Registry. Individuals diagnosed with cancer at age 0-14 years during 1975-2014 and survived 2 months or longer were followed through December 2015. The risk of developing SPC was assessed with standardized incidence ratio (SIR), excess absolute risk (EAR, per 100,000 person-years), and cumulative incidence. Multivariable Poisson regression analysis was carried out to assess relative risks of SPC by treatment method. Survival analysis was undertaken using the Kaplan-Meier method. Of 7229 childhood cancer survivors, 101 (1.4%) developed SPC after a median of 11.6 years. Overall SIR was 5.0, which corresponded with 84.3 EAR. The cumulative incidence was 0.9%, 2.1%, and 3.4% at 10, 20, and 30 years, respectively. Among all SPCs, the type that contributed most to the overall burden was cancers in the central nervous system (EAR = 28.0) followed by digestive system (EAR = 15.1), thyroid (EAR = 8.3), and bones and joints (EAR = 7.8); median latency ranged from 2.0 years (lymphomas) to 26.6 years (skin cancers). Patients treated with radiotherapy alone were at a 2.58-fold increased risk of developing SPC compared to those who received neither chemotherapy nor radiotherapy. Among patients who developed SPCs, 5-year and 10-year survival probabilities after SPC diagnosis were 61.7% and 52.0%, respectively. Risk-based long-term follow-up planning is essential to inform survivorship care and help reduce the burden of SPCs in childhood cancer survivors.

Patterns of staging, treatment, and mortality in gastric, colorectal, and lung cancer among older adults with and without preexisting dementia: a Japanese multicentre cohort study.

BACKGROUND: Little is known about dementia's impact on patterns of diagnosis, treatment, and outcomes in cancer patients. This study aimed to elucidate the differences in cancer staging, treatment, and mortality in older cancer patients with and without preexisting dementia. METHODS: Using cancer registry data and administrative data from 30 hospitals in Japan, this multicentre retrospective cohort study examined patients aged 65-99 years who were newly diagnosed with gastric, colorectal, or lung cancer in 2014-2015. Dementia status (none, mild, and moderate-to-severe) at the time of cancer diagnosis was extracted from clinical summaries in administrative data, and set as the exposure of interest. We constructed multivariable logistic regression models to analyse cancer staging and treatment, and multivariable Cox regression models to analyse three-year survival. RESULTS: Among gastric (n = 6016), colorectal (n = 7257), and lung (n = 4502) cancer patients, 5.1%, 5.8%, and 6.4% had dementia, respectively. Patients with dementia were more likely to receive unstaged and advanced-stage cancer diagnoses; less likely to undergo tumour resection for stage I, II, and III gastric cancer and for stage I and II lung cancer; less likely to receive pharmacotherapy for stage III and IV lung cancer; more likely to undergo tumour resection for all-stage colorectal cancer; and more likely to die within three years of cancer diagnosis. The effects of moderate-to-severe dementia were greater than those of mild dementia, with the exception of tumour resection for colorectal cancer. CONCLUSION: Older cancer patients with preexisting dementia are less likely to receive standard cancer treatment and more likely to experience poorer outcomes. Clinicians should be aware of these risks, and would benefit from standardised guidelines to aid their decision-making in diagnosing and treating these patients.

Mental health in Japanese children during school closures due to the COVID-19.

BACKGROUND: Changes in relationships, sleep rhythms, and physical activity caused by school closures instituted to curb the spread of COVID-19 influenced children's mental health. We explored changes in children's daily life and effects on their mental health during school closures. METHODS: Participants included elementary and junior high school students 9 years of age and older seen in the outpatient clinic during school closures and were required to complete the Japanese version of WHO Five Well-Being Index (WHO-5-J). The results were compared with those of students seen after schools reopened. RESULTS: Participants included 78 students in the school closure group and 113 in the school reopening group. Although those in the closure group devoted more time to family and sleep, their sleep rhythms, eating habits, and physical activities were disrupted. Although there were no significant differences between the two groups in total WHO-5-J scores, single WHO-5-J items such as activity and vigor and interest were significantly worse and rest was significantly better in the school closure group. CONCLUSION: Although school closures resulted in elementary and junior high school students spending more time with family and sleeping, their sleep rhythms, eating habits, and physical activities were disrupted. As the children's living environment changed, they felt less active and vigorous and had difficulty finding things that interested them. However, their sleep improved and overall, the number of children with potential mental health problems did not change.

Evaluating the mental health of children in a local hospital outpatient clinic.

BACKGROUND: The 30-item Questionnaire for Triage and Assessment (QTA30) is a standardized triage and assessment tool for assessing pediatric psychosomatic disorders. It is estimated that one in 10 children in Japan experience difficulties in their school life. Using the QTA30 we evaluated mental health in children at an outpatient clinic in a local hospital. METHODS: All elementary and junior high school students (≥9 years) who visited our institution between December 1 2019 and March 31 2020 were asked to complete the QTA30. RESULT: A total of 372 children responded. Half of the children with a psychosomatic disorder and 9% of children with other chronic disorders were suspected to have poor mental health. Suspected poor mental health was associated with higher odds of female gender (odds ratio [OR]: 1.89, 95% confidence interval [CI]: 1.07-3.39), junior high school students (OR: 3.73, 95% CI: 2.11-6.73), and not enjoying exercise (OR: 2.13, 95% CI: 1.16-3.9). The mean ± standard deviation total QTA30 score was significantly worse in children with psychosomatic disorders (38.0 ± 19.1) among children with other chronic diseases; however, only the score in children with central precocious puberty (27.4 ± 13.7) showed no difference. CONCLUSION: Based on our survey, the percentage of children suspected to have mental health problems manifesting as non-psychosomatic chronic disorders was similar to the proportion of children suspected to experience difficulties with their school life. Pediatricians should carefully consider the possibility of mental health problems when children are seen in regular visits to the outpatient clinic.

Potential for Drug Repositioning of Midazolam for Dentin Regeneration.

Drug repositioning promises the advantages of reducing costs and expediting approvalschedules. An induction of the anesthetic and sedative drug; midazolam (MDZ), regulatesinhibitory neurotransmitters in the vertebrate nervous system. In this study we show the potentialfor drug repositioning of MDZ for dentin regeneration. A porcine dental pulp-derived cell line(PPU-7) that we established was cultured in MDZ-only, the combination of MDZ with bonemorphogenetic protein 2, and the combination of MDZ with transforming growth factor-beta 1. Thedifferentiation of PPU-7 into odontoblasts was investigated at the cell biological and genetic level.Mineralized nodules formed in PPU-7 were characterized at the protein and crystal engineeringlevels. The MDZ-only treatment enhanced the alkaline phosphatase activity and mRNA levels ofodontoblast differentiation marker genes, and precipitated nodule formation containing a dentinspecificprotein (dentin phosphoprotein). The nodules consisted of randomly orientedhydroxyapatite nanorods and nanoparticles. The morphology, orientation, and chemicalcomposition of the hydroxyapatite crystals were similar to those of hydroxyapatite that hadtransformed from amorphous calcium phosphate nanoparticles, as well as the hydroxyapatite inhuman molar dentin. Our investigation showed that a combination of MDZ and PPU-7 cellspossesses high potential of drug repositioning for dentin regeneration.

[Case of Hyperammonemia Induced by High-Dose Fluorouracil].

A case of hyperammonemia induced by chemotherapy, including high-dose fluorouracil(5-FU), for advanced unresectable large intestinal cancer has been reported. This case involved an 81-year-old female who was diagnosed with pT4bcN2M1 (multiple hepatic metastases; stage Ⅳ; KRAS: mutant)after emergency surgery for sigmoid colon cancer and diffuse peritonitis. Post-operation, the 4 courses of mFOLFOX6 plus Bmab therapy was started for advanced unresectable recurrent large intestinal cancer; 48 hours later, she developed consciousness disorder(JCS Ⅲ-300). The disorder promptly disappeared after discontinuation of high-dose 5-FU. Because high-dose 5-FU was inferred to be the main cause of hyperammonemia, XELOX plus Bmab therapy was started as a post-treatment. She did not develop hyperammonemia; therefore, 8 courses were administered. The patient is being followed-up now.

[SENSITIZATION PATTERN FOR INHALED AND FOOD ALLERGENS IN JAPANESE RECURRENT WHEEZERS UNDER 60 MONTHS OF AGE].

BACKGROUND: Allergen sensitization differs according to countries and regions. Understanding the characteristics of allergen sensitization in one's own country is useful for the treatment of patients with allergic diseases. Recently, Japanese cedar pollen (JCP) sensitization is increasing in young Japanese children. Therefore, we evaluated allergen sensitization patterns in under 60-month-old Japanese recurrent wheezers using multiple allergen tests. METHODS: Allergen tests for 204 Japanese recurrent wheezers between April 2010 and April 2016 were reviewed. Children were divided into 10 groups by age, in 6-month intervals, from 0 months and analyzed by age group. RESULTS: Seventy five percent of children were diagnosed as bronchial asthma. Children under 12-months showed sensitization to food allergens, such as egg white (13.3%) and cow's milk (3.3%), and no sensitization to inhaled allergens. However, house dust mite (HDM) and JCP sensitization increased significantly in children 1 to 2 year of age (HDM; 7.7-32.1%, JCP; 3.9-17.9%) and both sensitization increased to most frequent in children over 36 months of age. JCP sensitization was also frequently detected in children with HDM sensitization (47.1%). CONCLUSION: Sensitization to inhaled allergens was significantly increased in Japanese recurrent wheezers over 12 months of age and sensitization to HDM and JCP increased to most frequent over 36 months of age. JCP sensitization was established from early childhood and detected frequently in Japanese recurrent wheezers under 60 months of age. These characteristics are the same with HDM sensitization.

Decitabine inhibits tumor cell proliferation and up-regulates e-cadherin expression in Epstein-Barr virus-associated gastric cancer.

The present study investigated the effect of a DNA demethylating agent, decitabine, against Epstein-Barr virus-associated gastric cancer (EBVaGC). Decitabine inhibited cell growth and induced G2/M arrest and apoptosis in EBVaGC cell lines. The expression of E-cadherin was up-regulated and cell motility was significantly inhibited in the cells treated with decitabine. The promoter regions of p73 and RUNX3 were demethylated, and their expression was up-regulated by decitabine. They enhanced the transcription of p21, which induced G2/M arrest and apoptosis through down-regulation of c-Myc. Decitabine also induced the expression of BZLF1 in SNU719. Induction of EBV lytic infection was an alternative way to cause apoptosis of the host cells. This study is the first report to reveal the effectiveness of a demethylating agent in inhibiting tumor cell proliferation and up-regulation of E-cadherin in EBVaGC. J. Med. Virol. 89:508-517, 2017. © 2016 Wiley Periodicals, Inc.

Perirhinal accumulation of neuronal alpha-synuclein in a multiple system atrophy patient with dementia.

We report the case of a 79-year-old Japanese woman who developed cerebellar ataxia followed by rigidity, dysautonomia and cognitive disorders, and was thus clinically diagnosed as having possible MSA with dementia. Neuropathological findings demonstrated not only olivopontocerebellar and striatonigral degeneration with frequent glial cytoplasmic inclusions (GCIs), but also degenerative changes in the parahippocampal region, accentuated in the anterior portion of perirhinal cortex, where neuronal cytoplasmic inclusions (NCIs) and NFTs were numerous while GCIs were limited. NCIs were frequent in the deep layer, whereas NFTs were more frequent in superficial cortical layers. Other hippocampal subregions including subiculum, dentate fascia and cornu ammonis were minimally involved. NCIs in the perirhinal cortex showed intense argyrophilia with the Campbell-Switzer silver impregnation method, but not argyrophilic with the Gallyas method. Most neuronal alpha-synuclein aggregates in dendrosomatic fraction formed globular/tadpole-like, and ultrastructurally comprised granular-coated fine fibrils 12-24 nm in diameter. To the best of our knowledge, alpha-synuclein-related neuronal pathology localized in the perirhinal region without hippocampal involvement has not been previously reported in MSA, and may provide clues to elucidate how neuronal pathology evolves in the hippocampal/parahippocampal regions in MSA, particularly in cases with dementia.

A survey of palliative medicine education in Japan's undergraduate medical curriculum.

BACKGROUND: This study aimed to examine the status of undergraduate palliative care education among Japanese medical students using data from a survey conducted in 2015. METHODS: A questionnaire was originally developed, and the survey forms were sent to universities. The study's objectives, methods, disclosure of results, and anonymity were explained to participating universities in writing. Responses returned by the universities were considered to indicate consent to participate. Descriptive statistical methodology was employed. RESULTS: The response rate was 82.5% (66 of 80 medical faculties and colleges). Palliative care lectures were implemented in 98.5% of the institutions. Regarding lecture titles, "palliative medicine," "palliative care," and "terminal care" accounted for 42.4, 30.3, and 9.1% of the lectures, respectively. Teachers from the Department of Anesthesia, Palliative Care, and Psychiatry administered 51.5, 47.0, and 28.8% of lectures, respectively. Subjects of lectures included general palliative care (81.8%), pain management (87.9%), and symptom management (63.6%). Clinical clerkship on palliative care was a compulsory and non-compulsory course in 43.9 and 25.8% of the schools, respectively; 30.3% had no clinical clerkship curriculum. CONCLUSIONS: Undergraduate palliative care education is implemented in many Japanese universities. Clinical clerkship combined with participation in actual medical practice should be further improved by establishing a medical education certification system in compliance with the international standards.

The Role of Epigenetic Regulation in Epstein-Barr Virus-Associated Gastric Cancer.

The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma (EBVaGC), all tumor cells harbor the clonal EBV genome. The expression of latent EBV genes is strictly regulated through the methylation of EBV DNA. The methylation of viral DNA regulates the type of EBV latency, and methylation of the tumor suppressor genes is a key abnormality in EBVaGC. The methylation frequencies of several tumor suppressor genes and cell adhesion molecules are significantly higher in EBVaGC than in control cases. EBV-derived microRNAs repress translation from viral and host mRNAs. EBV regulates the expression of non-coding RNA in gastric carcinoma. With regard to the clinical application of demethylating agents against EBVaGC, we investigated the effects of decitabine against the EBVaGC cell lines. Decitabine inhibited the cell growth of EBVaGC cells. The promoter regions of p73 and Runt-related transcription factor 3(RUNX3) were demethylated, and their expression was upregulated by the treatment. We review the role of epigenetic regulation in the development and maintenance of EBVaGC and discuss the therapeutic application of DNA demethylating agents for EBVaGC.

Image quality of a novel light-emitting diode (LED)-illuminated colonoscope.

BACKGROUND AND STUDY AIMS: Light-emitting diodes (LEDs) are used widely for their high luminous efficiency and durability. We developed a novel prototype high definition endoscope with white LEDs and evaluated the image quality it produced against a commercial endoscope with conventional light source. PATIENTS AND METHODS: The specifications of both colonoscopes were identical, except for the LED light source at the tip of the prototype. We examined 20 patients with rectal or sigmoid colon lesions and the image quality was evaluated in 40 images (one image from the LED colonoscope and one from the conventional colonoscope for each lesion) by three endoscopists. We additionally evaluated the 17 videos recorded with the LED colonoscope that were available. Image quality, mucosal and vascular color, and luminous distribution and intensity were scored on a 5-point scale. RESULTS: The mean score for vascular color given by one evaluator was significantly higher using the LED colonoscope than using the conventional colonoscope. The mean scores for mucosal color and luminous intensity from another evaluator were significantly lower with the LED colonoscope than with the conventional colonoscope. There were no significant differences in the luminous distribution scores for any of the evaluators. The image quality of the videos was evaluated as being similar with both colonoscopes. CONCLUSIONS: Image quality from the LED and conventional colonoscopes were similar, although the luminous intensity of the LEDs is inferior to that of the conventional light source at the present time.

Endoscopic Resection is Infeasible for Early Gastric Cancers with Undifferentiated Components.

BACKGROUND/AIMS: Aim of this study is to find subgroup of early gastric cancer with lymph node metastasis for which successive further surgical operation is needed after endoscopic resection. METHODOLOGY: A total of 559 lesions of early gastric cancer, which had undergone curative gastrectomy, were enrolled in this study. We retrospectively investigated 10 clinicopathological factors predictive of lymph node metastasis by univariate and multivariate analysis. We showed the frequency of lymph node metastasis of subgroups in combination of independent factors selected by multivariate analysis. RESULTS: Lymph node metastases were detected in 57 lesions (10.2%). Univariate analysis revealed that lesion size > 30 mm, undifferentiated components, sm massive invasion, lymphatic invasion and venous invasion were factors significantly correlated with lymph node metastasis. By multivariate analysis, risk factors for lymph node metastasis were lesion size > 30 mm, undifferentiated components, sm massive invasion, and lymphatic invasion, with odds ratios of 2.17, 2.30, 5.88 and 8.24, respectively. In lesions with undifferentiated components, LNM were found in all subgroups. CONCLUSIONS: When we treat early gastric cancers contained undifferentiated components, even if they are predominantly differentiated-type intramucosal lesions, an additional surgical procedure should be considered or careful follow-up is required.

Nanoscale osseointegration of zirconia evaluated from the interfacial structure between ceria-stabilized tetragonal zirconia and cell-induced hydroxyapatite.

BACKGROUND: The osseointegration of zirconia implants has been evaluated based on their implant fixture bonding with the alveolar bone at the optical microscopic level. Achieving nano-level bonding between zirconia and bone apatite is crucial for superior osseointegration; however, only a few studies have investigated nanoscale bonding. This review outlines zirconia osseointegration, including surface modification, and presents an evaluation of nanoscale zirconia-apatite bonding and its structure. HIGHLIGHT: Assuming osseointegration, the cells produced calcium salts on a ceria-stabilized zirconia substrate. We analyzed the interface between calcium salts and zirconia substrates using transmission electron microscopy and found that 1) the cell-induced calcium salts were bone-like apatite and 2) direct nanoscale bonding was observed between the bone-like apatite and zirconia crystals without any special modifications of the zirconia surface. CONCLUSION: Structural affinity exists between bone apatite and zirconia crystals. Apatite formation can be induced by the zirconia surface. Zirconia bonds directly with apatite, indicating superior osseointegration in vivo.

Identification of genes specifically methylated in Epstein-Barr virus-associated gastric carcinomas.

We studied the comprehensive DNA methylation status in the naturally derived gastric adenocarcinoma cell line SNU-719, which was infected with the Epstein-Barr virus (EBV) by methylated CpG island recovery on chip assay. To identify genes specifically methylated in EBV-associated gastric carcinomas (EBVaGC), we focused on seven genes, TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1, based on the results of methylated CpG island recovery on chip assay. We confirmed DNA methylation of the genes by methylation-specific PCR and bisulfite sequencing in SNU-719. The expression of the genes, except for BCL7A, was upregulated by a combination of 5-Aza-2'-deoxycytidine and trichostatin A treatment in SNU-719. After the treatment, unmethylated DNA became detectable in all seven genes by methylation-specific PCR. We verified DNA methylation of the genes in 75 primary gastric cancer tissues from 25 patients with EBVaGC and 50 EBV-negative patients who were controls. The methylation frequencies of TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1 were significantly higher in EBVaGC than in EBV-negative gastric carcinoma. We identified seven genes with promoter regions that were specifically methylated in EBVaGC. Inactivation of these genes may suppress their function as tumor suppressor genes or tumor-associated antigens and help to develop and maintain EBVaGC.

Role of DNA methylation in the development of Epstein-Barr virus-associated gastric carcinoma.

The frequencies of DNA methylation of certain tumor-related genes are higher in Epstein-Barr virus (EBV)-associated gastric carcinomas than in EBV-negative gastric carcinomas. EBV-associated gastric carcinomas have distinct clinicopathological features; however, there are no case-control studies comparing methylation frequency between EBV-associated gastric carcinomas and controls that have been adjusted according to the clinicopathological features of EBV-associated gastric carcinomas. This study evaluated 25 EBV-associated gastric carcinomas that were positive for EBV-encoded small RNA 1 (EBER-1) by in situ hybridization and 50 EBV-negative gastric carcinomas that were matched with the EBV-associated gastric carcinomas by age, sex, histology, depth of tumor invasion, and stage. Methylation status of 16 loci associated with tumor-related genes was analyzed by methylation-specific polymerase chain reaction (PCR) to identify genes in which DNA methylation specifically occurred in EBV-associated gastric carcinomas. Methylation frequencies of 12 of the 16 genes were higher in EBV-associated gastric carcinomas than in EBV-negative controls, and the frequency of methylation of 6 specific loci (MINT2, MINT31, p14, p16, p73, and RUNX3) was significantly higher in EBV-associated gastric carcinomas than in EBV-negative controls. There were no significant differences in the methylation frequencies of the other genes. The mean methylation index in EBV-associated gastric carcinomas was significantly higher than that in EBV-negative controls. DNA methylation of tumor suppressor genes that regulate the cell cycle and apoptosis specifically occurred in EBV-associated gastric carcinomas. Aberrant DNA methylation might lead to the development and progression of EBV-associated gastric carcinoma.

Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome.

BACKGROUND: Rituximab (RTX) is a promising option for treating childhood-onset steroid-dependent (SDNS), frequently relapsing (FRNS), and steroid-resistant (SRNS) nephrotic syndrome. METHODS: We retrospectively surveyed RTX treatment for these conditions to evaluate its indications, efficacy and adverse events. Questionnaires were sent to 141 hospitals in Japan. RESULTS: Seventy-four patients (52 SDNS; 3 FRNS; 19 SRNS) were treated with RTX because of resistance to various immunosuppressive agents. Most patients received a single administration of RTX (85%). Forty-one of 53 SDNS/FRNS (77%) and 5 of 17 SRNS (29%) patients successfully discontinued prednisolone (16 SDNS/FRNS and 6 SRNS achieved their first discontinuation since onset), and 17 out of 53 SDNS/FRNS patients (31%) discontinued cyclosporine. However, 28 of the 53 patients (51%) relapsed. Although immunosuppressive agents did not extend B cell depletion, relapses were significantly less if immunosuppressive agents were continued after RTX (P = 0.006; hazard ratio = 0.2). Among the SRNS patients, complete (n = 6) and partial remission (n = 6) were achieved. No life-threatening adverse events were experienced. CONCLUSIONS: Although this was a multi-center survey where treatment of nephrotic syndrome varied between centers, the steroid-sparing effect of RTX in SDNS/FRNS was excellent. If single administration of RTX is chosen, continuation of immunosuppressive agents is recommended for prevention of relapse.