Maximum carotid intima-media thickness and NT-pro BNP in association with retinal vein occlusion.

The purpose is to clarify the relationship between patients with retinal vein occlusion (RVO), maximal intima-media complex thickness (Max IMT), and N-terminal pro-brain natriuretic peptide (NT-proBNP), which is useful in assessing atherosclerosis. This was a retrospective observation, single center study. The patients were 86 RVO patients (male: female = 43:43, mean age 63.3 years), 25 with central retinal vein occlusion (CRVO) and 61 with branch retinal vein occlusion (BRVO), classified as ≧50 years old and <50 years old, Max IMT≧1.1 and less, NT-pro BNP≧55 and less. Results showed that Max IMT ≧1.1 was significantly more common in both the CRVO and BRVO groups at ≧50 years, and NT-pro BNP ≧55 was significantly more common in the CRVO group. Max IMT≧1.1 was seen in 80% of the BRVO group and in 85% of patients aged ≧50 years. Sixty-eight percent of patients in the CRVO group had Max IMT≧1.1, but none of those < 50 years had Max IMT≧1.1. Forty-eight percent of RVO patients had NT-pro BNP≧55, and significantly more patients had Max IMT≧1.1 than those who did not have NT-pro BNP more than 55 (p = 0.02). Multiple regression analysis with Max IMT as the dependent variable showed that age and NT-pro BNP were significantly associated with RVO (p = 0.015, 0.022). RVO patients were more likely to have a Max IMT≧1.1, which was associated with atherosclerosis. Max IMT and NT-pro BNP were also associated with RVO patients, so NT-pro BNP may be a marker of RVO.

METTL23 mutation alters histone H3R17 methylation in normal-tension glaucoma.

Normal-tension glaucoma (NTG) is a heterogeneous disease characterized by retinal ganglion cell (RGC) death leading to cupping of the optic nerve head and visual field loss at normal intraocular pressure (IOP). The pathogenesis of NTG remains unclear. Here, we describe a single nucleotide mutation in exon 2 of the methyltransferase-like 23 (METTL23) gene identified in 3 generations of a Japanese family with NTG. This mutation caused METTL23 mRNA aberrant splicing, which abolished normal protein production and altered subcellular localization. Mettl23-knock-in (Mettl23+/G and Mettl23G/G) and -knockout (Mettl23+/- and Mettl23-/-) mice developed a glaucoma phenotype without elevated IOP. METTL23 is a histone arginine methyltransferase expressed in murine and macaque RGCs. However, the novel mutation reduced METTL23 expression in RGCs of Mettl23G/G mice, which recapitulated both clinical and biological phenotypes. Moreover, our findings demonstrated that METTL23 catalyzed the dimethylation of H3R17 in the retina and was required for the transcription of pS2, an estrogen receptor α target gene that was critical for RGC homeostasis through the negative regulation of NF-κB-mediated TNF-α and IL-1ß feedback. These findings suggest an etiologic role of METTL23 in NTG with tissue-specific pathology.

Comparative Study of the Susceptibility to Oxidative Stress between Two Types of Mycobacterium bovis BCG Tokyo 172.

Genomic analysis revealed that the vaccine seed lot of Mycobacterium bovis bacillus Calmette-Guérin (BCG) Tokyo 172 contains two subclones (types I and II), but their phenotypic differences have not been elucidated. In this study, we compared the susceptibility of bacilli types I and II to oxidative stress in vitro and within host cells. Notably, the subclones displayed similar superoxide dismutase activity; however, foam height in the catalase test and lysate catalase/peroxidase activity were higher for type I bacilli than for type II bacilli. Additionally, type I bacilli were less susceptible to hydrogen peroxide (H2O2) than type II bacilli. After exposure to H2O2, antioxidative stress response genes katG, ahpC, sodA, and trxA were more strongly induced in type I bacilli than in type II bacilli. Further, we investigated cell survival in macrophages. Fewer type II bacilli were recovered than type I bacilli. However, in the presence of apocynin, a specific inhibitor of NADPH oxidase, type II recovery was greater than that of type I. The production of interleukin 1ß (IL-1ß), IL-12 p40, and tumor necrosis factor alpha (TNF-α) was higher in type I bacillus-infected macrophages than in type II bacillus-infected macrophages. The proportions of type I and type II bacilli in vaccine lots over 3 years (100 lots) were 97.6% ± 1.5% and 2.4% ± 1.5%, respectively. The study results illustrated that type I bacilli are more resistant to oxidative stress than type II bacilli. Overall, these findings provide important information in terms of the quality control and safety of BCG Tokyo 172 vaccine.IMPORTANCE This study revealed the difference of in vivo and in vitro antioxidative stress properties of BCG Tokyo 172 types I and II as one of the bacteriological characteristics. In particular, the bacilli exhibited differences in catalase/peroxidase activity, which could explain their different protective effects against infection. The differences correlated with survival in the host cell and the production of proinflammatory cytokines to protect against infection by Mycobacterium tuberculosis The proportion of bacilli types I and II in all commercial lots of BCG Tokyo 172 over 3 years (100 lots) was constant. The findings also highlighted the importance of analyzing their content for quality control during vaccine production.

Binding of Gtf2i-ß/δ transcription factors to the ARMS2 gene leads to increased circulating HTRA1 in AMD patients and in vitro.

The disease-initiating molecular events for age-related macular degeneration (AMD), a multifactorial retinal disease affecting many millions of elderly individuals worldwide, are still unknown. Of the over 30 risk and protective loci so far associated with AMD through whole genome-wide association studies (GWAS), the Age-Related Maculopathy Susceptibility 2 (ARMS2) gene locus represents one of the most highly associated risk regions for AMD. A unique insertion/deletion (in/del) sequence located immediately upstream of the High Temperature Requirement A1 (HTRA1) gene in this region confers high risk for AMD. Using electrophoretic mobility shift assay (EMSA), we identified that two Gtf2i-ß/δ transcription factor isoforms bind to the cis-element 5'- ATTAATAACC-3' contained in this in/del sequence. The binding of these transcription factors leads to enhanced upregulation of transcription of the secretory serine protease HTRA1 in transfected cells and AMD patient-derived induced pluripotent stem cells (iPSCs). Overexpression of Htra1 in mice using a CAG-promoter demonstrated increased blood concentration of Htra1 protein, caused upregulation of vascular endothelial growth factor (VEGF), and produced a choroidal neovascularization (CNV)-like phenotype. Finally, a comparison of 478 AMD patients to 481 healthy, age-matched controls from Japan, India, Australia, and the USA showed a statistically increased level of secreted HTRA1 blood concentration in AMD patients compared with age-matched controls. Taken together, these results suggest a common mechanism across ethnicities whereby increased systemic blood circulation of secreted serine protease HTRA1 leads to subsequent degradation of Bruch's membrane and eventual CNV in AMD.

KUS121, an ATP regulator, mitigates chorioretinal pathologies in animal models of age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness among elderly people. The appearance of drusen is a clinical manifestation and a harbinger of both exudative and atrophic AMD. Recently, antibody-based medicines have been used to treat the exudative type. However, they do not restore good vision in patients. Moreover, no effective treatment is available for atrophic AMD. We have created small chemicals (Kyoto University Substances; KUSs) that act as ATP regulators inside cells. In the present study, we examined the in vivo efficacy of KUS121 in C-C chemokine receptor type 2-deficient mice, a mouse model of AMD. Systemic administration of KUS121 prevented or reduced drusen-like lesions and endoplasmic reticulum stress, and then substantially mitigated chorioretinal pathologies with significant preservation of visual function. Additionally, we confirmed that long-term oral administration of KUS121 caused no systemic complications in drusen-affected monkeys. ATP regulation by KUSs may represent a novel strategy in the treatment of drusen and prevention of disease progression in AMD.

[A Case of Sigmoid Colon Cancer with Locally Advanced Infiltration Curatively Resected after CapeOX Therapy].

A 68-year-old man presented with malaise and abdominal swelling.Lower gastrointestinal endoscopy revealed a type 2 circumferential sigmoid colon cancer.Computed tomography suggested the cancer infiltrating bladder and abdominal wall with abscess.Because of locally advanced infiltration, the patient was treated with capecitabine plus oxaliplatin(CapeOX) plus bevacizumab therapy after loop-colostomy.After 2 courses of chemotherapy, a CT revealed tumor reduction and increased abscess, which was punctured drainage.After 4 courses of chemotherapy, a CT revealed abscess reduction, we tried to operation.Sigmoidectomy with combined resection of abdominal wall and bladder total hysterectomy and fascia lata grafting were performed.The pathological diagnosis was tub1, T4b, ly2, v2, PN0, N0, M0, Stage II, pR0, Grade I a.We reported a case of curative resection of locally advanced sigmoid colon cancer treated with combined resection of bladder and abdominal wall after CapeOX therapy.

[A Case of a Bulky Axillary Ectopic Breast Cancer Which Successfully Resected after Chemotherapy(Docetaxel)].

A 78-year-old woman presented with a right axillary mass.With an incisional biopsy a diagnosis of invasive ductal carcinoma was achieved.In the whole body search, any primary focus including the breast was unclear, advanced occult breast cancer with supraclavicular lymph node metastases was diagnosed.Administration of 3 courses of docetaxel achieved disappearance of supraclavicular lymph node and reduction of an axillary mass.Right axillary lymph node dissection could be successfully performed.Pathological report showed a right ectopic cancer with right axillary lymph node metastases.The patient has been well without any relapse for 3 years.

[Prolonged Survival Achieved with Surgical Resection and Multidisciplinary Therapy for Acinar Cell Carcinoma of the Pancreas with Liver Metastases].

We report 2 cases of prolonged survival achieved with surgical resection and multidisciplinary therapy for acinar cell carcinoma of the pancreas with liver metastases.Case 1: The patient was a 55-year-old woman.She presented with upper right abdominal pain and anemia.We diagnosed a tumor originating from the pancreas and multiple liver metastases.To avoid death caused by bleeding from the tumor, we performed pancreaticoduodenectomy and right-hemi hepatectomy, and a rapid diagnosis of acinar cell carcinoma of the pancreas was confirmed intraoperatively.After the hospital discharge, we administered hepatic intra-arterial chemotherapy and performed microwave ablation for the remnant liver metastases.Additionally, systemic chemotherapy with gemcitabine was administered; however, multiple metastases of the lung and liver became uncontrollable and she died 2 and half years postoperatively.Case 2: The patient was a 42-year-old woman.Through a medical checkup, gastric varix and elevated tumor markers were detected.The examination revealed a tumor at the tail of the pancreas and liver metastasis.We performed distal pancreatomy and partial liver resection.The pathological diagnosis was acinar cell carcinoma and liver metastasis.We administered adjuvant chemotherapy by using gemcitabine and achieved 5 years of relapse-free survival.The prognosis of ACC is better than that for PDAC.However, prognosis of unresectable cases is still unfavorable.Therapeutic strategies including aggressive surgical resection for metastatic ACC are worthy of consideration.

Significance of optineurin mutations in glaucoma and other diseases.

Glaucoma is one of the leading causes of bilateral blindness, affecting nearly 57 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells and is often associated with intraocular pressure (IOP). Normal tension glaucoma (NTG), marked by normal IOP but progressive glaucoma, is incompletely understood. In 2002, Sarfarazi et al. identified FIP-2 gene mutations responsible for hereditary NTG, renaming this gene "optineurin" (OPTN). Further investigations by multiple groups worldwide showed that OPTN is involved in several critical cellular functions, such as NF-κB regulation, autophagy, and vesicle transport. Recently, OPTN mutations were found to cause amyotrophic lateral sclerosis (ALS). Surprisingly, a mutation in the OPTN interacting protein, i.e., the duplication of TANK binding protein 1 (TBK1) gene, also can cause both NTG and ALS. These phenotypically distinct neuronal diseases are now merging into one common pathological mechanism by these two genes. TBK1 inhibition has emerged as a potential therapy for NTG. In this manuscript, we focus on the OPTN E50K mutation, the most common mutation for NTG, to describe the molecular mechanism of NTG by expressing a mutant Optn gene in cells and genetically modified mice. Patient iPS cells were developed and differentiated into neural cells to observe abnormal behavior and the impact of the E50K mutation. These in vitro studies were further extended to identify the inhibitors BX795 and amlexanox, which have the potential to reverse the disease-causing phenomenon in patient's neural cells. Here we show for the first time that amlexanox protects RGCs in Optn E50K knock-in mice.

[A Study of Gemctabine plus Nab-Paclitaxel Therapy for Advanced Local Progressive Pancreatic Cancer].

We studied the significance of gemcitabine plus nab-paclitaxel(GnP)therapy for locally progressive pancreatic cancer. We enrolled 10 patients with local progression without distant metastasis. We used GnP therapy for the ablative borderline resectable(BR)and unresectable(UR)cases based on images that followed NCCN pancreatic cancer treatment guidelines. In 1 case of resectable(R)pancreatic cancer, the tumor was located in the pancreas body but we determined that surgery was impossible because of the underlying disease detected on imaging analysis. The 10 cases involved R(n=1), UR(n=5), and BR(n=4). Treatment toxicities were reported in all cases. We withheld treatment in the R case because of toxicities. The objective response rate was 40%, and the tumor control rate was 70% with CR 0, PR 4, SD 3, and PD 2. Resection was possible in 5 cases. The response rate to the GnP therapy was 40%, with a tumor control rate of 70%, allowing excision of 50%. We believe GnP therapy is feasible for operative resistant cases.

[A Case of Advanced Gastric Cancer with a Pathological Complete Response after Neoadjuvant Chemotherapy(S-1/Oxaliplatin)].

A 63-year-old man was seen by his family doctor for epigastric distress, and he was referred to our hospital with a diagnosis of gastric cancer. Upper gastrointestinal endoscopy revealed type 3 gastric cancer(por1>tub2>tub1)at the lesser curvature of the stomach. Computed tomography suggested thickening of the wall of the stomach at the lesser curvature and bulky lymph node swelling. After a diagnosis of cT4a cN2M0, cStage III B advanced gastric cancer, we treated him with neoadjuvant chemotherapy consisting of 3 courses of SOX(oxaliplatin 100mg/m / 2 on day 1, S-1 120mg/day on day 1-14, followed by 7 days of rest). After the chemotherapy, because the primary tumor and lymph nodes were reduced, we performed distal gastrectomy with D2 lymph node dissection. Histopathological examination revealed no residual cancer cells, indicating a pathological complete response(Grade 3). We report a case of advanced gastric cancer with a pathological complete response after neoadjuvant chemotherapy.

[A Case of Hemodialysis Patients with Resected Synchronous Multiple Metastases from Colorectal Cancer Successfully Treated with CapeOX Therapy].

A 65-year-old man had been receiving hemodialysis for chronic renal failure. We diagnosed colonic ileus with transverse colon cancer and synchronous multiple liver metastases(liver segments 4 and 6)based on symptoms of abdominal pain and distension. After stent placement in the region of the colonic stenosis, left hemicolectomy was performed for transverse colon cancer. After surgery, the patient received capecitabine plus oxaliplatin(CapeOX)therapy. The dose of capecitabine was 1,250mg/m2, and the dose of oxaliplatin was 70 mg/m2 until the second course, after which it was increased to 100 mg/m2 for the third course. Peripheral neuropathy(Grade 1)was the only adverse event observed. After 6 courses of treatment, the size of the liver metastases and the levels of tumor markers had reduced. For control of liver metastases, partial hepatectomy (liver segments 4 and 6)was performed. We report this case with a review of the literature.

[Combination Chemotherapy Using Oxaliplatin plus S-1 for Well-Advanced Gastric Cancer].

We studied the clinical efficacy of pre-operative combination chemotherapy using S-1 plus oxaliplatin for advanced gastric cancer. Four patients hadclinical Stage IV disease, 1 patient had clinical Stage III C disease, 2 patients had clinical Stage III B disease, and 1 patient had clinical Stage III A disease. The patients received 2-8 courses of oxaliplatin(130mg/m2)on day 1, andS -1 on days 1-14 every 3 weeks. The response rate was 56%(5 PR, 1 PD, and2 SD), andthe disease control rate was 88%. Toxicities were Grade 2 anemia, Grade 1 peripheral neuropathy, Grade 1 fatigue, and anorexia. Five of the 8 patients underwent R0 surgery after SOX chemotherapy, and no severe complications occurred. Histological responses were Grade 3 for 2 cases, Grade 2 for 2 cases, andGrad e 1a for 1 case. The SOX regimen showeda high objective tumor response, andis one of the promising regimens in the neoadjuvant setting for well-advanced gastric cancer.

[Immuno-Nutritional Factors Affecting the Incidence of Surgical Site Infection（SSI）after Rectal Cancer Surgery].

BACKGROUND: We analyzed immune nutritional factors that affected the incidence of SSI in rectal cancer surgery. METHOD: A total of 103 patients who underwent rectal cancer resection were enrolled in this retrospective study. The risk factors (DM, BMI<18.5, ≥25.0, PNI≤40, G/L>2, CONUT≥2, mGPS D) for SSI (Grade≥Ⅱ) were analyzed. RESULT: The factors that significantly affected SSI (in 13 cases) was PNI≤40 on univariate analysis. In the analysis adjusted by age and sex, mGPS D and PNI≤40 were significant factors. In the stepwise selection method, PNI≤40 was selected as an independent factor. CONCLUSION: As a risk factor for SSI after rectal cancer surgery, PNI≤40 and mGPS were risk factors.

[Short-Term Outcome of TAS-102 for Refractory Metastatic Colorectal Cancer].

We retrospectively analyzed 7 patients with refractory colorectal cancer treated with TAS-102 as salvage therapy. Subjects were 3 men and 4 women. The median age at initiation of TAS-102 was 71 years (range, 41-82 years). The number of target organs was 1 in 5 patients, 2 in 1 patient, and 3 in 1 patient. The median treatment courses were 2 courses (range, 1-6 courses). The reason for discontinuation was hematological toxicity in 1 patient, patients' wish in 3 patients, disease progression in 2 patients, and worsening of general condition in 1 patient. The median survival time since the first administration of TAS-102 was 9 months.

The Clinical Effects of Dai-kenchu-to on Postoperative Intestinal Movement and Inflammatory Reaction in Colorectal Surgery.

BACKGROUND/AIMS: We analyzed the effects of the Kampo medicine "Dai-kenchu-to" (DKT) on clinical aspects in colorectal surgery. METHODOLOGY: Total 122 patients who underwent colorectal cancer surgery were divided into a DKT group (n = 53) and a non-DKT group (n = 69). The differences of postoperative course and anti-inflammatory responses between those two groups were analyzed. RESULTS: The 53 out of 59 patients could completely take DKT. In the postoperative course, significant difference was observed in the first flatus day. In the anti-inflammatory effects, differences were observed in the heart rate (HR) of the 3rd POD. In the change between 1st POD and 3rd POD, HR in the DKT group was well controlled compared to the non-DKT group. In the patients who had over 37.5°C of body temperature in 1st POD (n = 53), inflammatory response of the DKT group was reduced compared to the non-DKT group. CONCLUSIONS: The DKT might have the favorable influences on postoperative bowel movement and systemic inflammatory reaction, and induce the better postoperative course.

Hepatic Arterial Infusion Chemotherapy for Life Threatening Patients due to Liver Metastases from Colorectal Cancer with Cetuximab.

BACKGROUND/AIMS: This retrospective report evaluated the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) for life threatening patients with unresectable hepatic metastases. METHODOLOGY: Seven life threatening patients with hepatic metastases who were treated with HAIC up to September 2011 were retrospectively analyzed. As HAIC regimen, 5-FU (1000mg/m2) was administered weekly via continuous 5-hour infusion using a continuous-infusion device. After improvement of liver dysfunction, cetuximab was administered simultaneously by the same dose of single administration. Treatment was repeated weekly until progression of hepatic lesion or discontinuity by unacceptable toxicity or patients' proposal. RESULTS: In 5 patients with hepatic metastasis related complaints, 3 patients improved after the initiation of HAIC. Three out of 4 patients with PS 2 or 3 were improved by the initiation of HAIC. The median OS was 9.5 months. No severe adverse toxicities and no treatment death related to HAIC were observed. The most severe non-hematologic adverse events were ALP in 3 patients, transaminase and bilirubin in 1 patient with grade 3. CONCLUSION: HAIC may be considered to perform when the hepatic metastases progress as life threatening status even though those are refractory to standard systemic chemotherapy.

[The Significance of Primary Tumor Resection in Unresectable Stage â £ Colorectal Cancer].

The significance of primary tumor resection for unresectable Stage Ⅳcolorectal cancer is controversial. In the present study, we examined cases of unresectable Stage Ⅳ colorectal cancer treated in our department. The subjects were 78 patients with unresectable Stage Ⅳ colorectal cancer who received either resection of the primary tumor, intensive chemotherapy, or both, between 2006 and 2012. The patients were divided into 2 groups: the group that received primary tumor resection (67 patients) and the non-resection group (11 patients). No differences were noted between a history of primary tumor resection and various clinicopathological factors, but the prognoses in the primary tumor resection group were favorable. The subjects were divided into 3 groups based on the selection of primary tumor resection and chemotherapy. The median survival time was 21.6 months, 11.8 months, and 8.1 months for patients who underwent chemotherapy after primary tumor resection (52 patients), patients who received primary tumor resection only (15 patients), and patients who received only chemotherapy (11 patients), respectively. The prognoses of patients who received primary tumor resection were favorable in comparison with those who received only chemotherapy. The results of the present study suggest the possibility that primary tumor resection can improve the prognoses of patients who have unresectable Stage Ⅳ colorectal cancer.

[A Case of Peritoneal Metastasis in Which Colostomy Was Useful for Restenosis after Stenting].

We report a case of restenosis after performing stenting twice for ileus caused by peritoneal dissemination that occurred after surgery for sigmoid colon cancer, in which colostomy was performed to improve the patient's QOL. The patient was a 58-year-old woman who underwent sigmoidectomy for sigmoid colon cancer. She presented with a peritoneal recurrence 3 times, and the third surgery was a non-curative resection. Chemotherapy was administered but was discontinued because of severe adverse events, and the patient was followed up with the best supportive care. An anastomotic stricture occurred 4 years after the initial surgery, and despite performing stenting twice, stenosis occurred 3 times within a few months. The third stenosis occurred shortly after the second episode, and colostomy was therefore performed. The patient died from cancer 4 months after colostomy without having another episode of stenosis. Although stenting is effective for patients with malignant colon stenosis, colostomy appears to be more effective for repeated post-stenting stenosis, when the patient is in an eligible general condition.

HTRA1 Overexpression Induces the Exudative Form of Age-related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness in the elderly. The dry form is more common and accounts for about 85-90% of AMD patients in US, while Japanese AMD patients predominantly progress to wet-form or polypoidal choroidal vasculopathy (PCV). Recent studies have shown HTRA1, a serine protease gene, as major risk factor for wet form AMD (De Wan et al., Science 2006). Furthermore, we reported that the Japanese typical wet form AMD patients showed significant association with ARMS2/HTRA1 (Goto, Akahori et al., JOBDI 2009). The purpose of this study is to elucidate the function of ARMS2/HTRA1 gene promoter in wet-form AMD patients. The promoter sequence experiment showed that a great number of AMD patients had specific indel mutation in 3.8 kb upstream of HTRA1 gene. 2-3-fold increase of promoter activity was observed in indel HTRA1 promoter compared to control sequence (Iejima et al., JBC 2015). Furthermore, we created transgenic mice ubiquitously overexpressing mouse HtrA1 using the chicken act in promoter, continuous induction of HtrA1 in vivo was shown to lead to CNV, similar to wet AMD patients (Nakayama, Iejima et al., IOVS 2014). These results suggest that human HTRA1 expression is enhanced by AMD specific indel mutation in the promoter region of HTRA1 gene, and this enhanced HTRA1 may be concerned with induce retinal neovasucularization.