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The relationship between health status at birth and short-term health has been established; however, the relationship with long-term health remains unclear, particularly in Japan. This study investigates the effect of birth weight on child development using data from the Longitudinal Survey of Newborns in the twenty-firstst Century—a nationwide birth cohort study conducted by the Ministry of Health, Labour and Welfare. We employ twin fixed-effects estimation to examine the effects of birth weight on physical development, using measures including weight, height, percentage of overweight indexes, and hospitalization, with a focus on how the effects vary with age up to 12 years. The results show that for all ages, lower birth weight negatively affects body size but does not affect probability of hospitalization or overweight/underweight status, indicating a limited impact. However, lower birth weight shows larger adverse effects on body size and the probability of hospitalization when the sample is limited to birth weight

Genomic analysis revealed that the vaccine seed lot of Mycobacterium bovis bacillus Calmette-Guerin (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 1β (IL-1β), 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.

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-β/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.

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.

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 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 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.

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.

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.

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.

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 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(por1tub2tub1)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.

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.

We analyzed the effects of the Kampo medicine "Dai-kenchu-to" (DKT) on clinical aspects in colorectal surgery.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.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.The DKT might have the favorable influences on postoperative bowel movement and systemic inflammatory reaction, and induce the better postoperative course.

This retrospective report evaluated the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) for life threatening patients with unresectable hepatic metastases.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.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.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 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.

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.

症例は54歳，男性．臍周囲痛，嘔吐を主訴に来院した．腹部CTで十二指腸下行脚より連続し，膵頭側に突出する2cm大の低吸収域とその背側に後腹膜気腫を認めた．十二指腸憩室穿孔を疑い手術を施行した．Kocherの授動を行うと十二指腸下行脚～水平脚の背側に膿瘍を認めた．憩室は視触診上は不明であり，後腹膜ドレナージを行った．術後に施行した十二指腸造影では下行脚内側に1cm大の憩室が描出され，腹部CTの所見と一致し，十二指腸憩室穿孔と診断した．腹部CTにより術前診断が可能であった十二指腸下行脚の憩室穿孔の1手術例を経験したので報告する．

結腸癌手術における閉鎖式持続吸引ドレーンの使用経験について報告する．対象は閉鎖式持続吸引ドレーン（J-VACドレナージシステム）を用いた結腸癌202例．腹腔内合併症に対するドレーンの役割，ドレーン排液量と腹腔内合併症との関連，ドレーン留置の有害事象について検討した．腹腔内合併症に対するドレーンの役割では，縫合不全，腹腔内膿瘍，術後出血のいずれにおいても治療的意義は少なかった．排液量との関連では，腹腔内膿瘍，腸閉塞は4POD以降に排液が多く（後半型），縫合不全，術後出血は3PODまでに排液が多い（前半型）傾向がみられ，合併症により排液パターンが異なった．ドレーン留置に起因する有害事象として，ドレーン部の感染を４例（2.0％）認めたがいずれも軽微で，組織の吸い込みや挫滅，抜去時の組織脱出はなく，本ドレナージシステムは忍容可能であった．本ドレナージシステムは腹腔内合併症に対する予防的あるいは治療的意義は少なく，診断的意義に限られると思われるが，大きな有害事象もなく，排液量に着目することで合併症の早期発見の一助となることが示唆された．

原発不明未分化腺癌の再燃に対し，サイトケラチン染色を参照して化学療法を施行し，寛解，再燃を繰り返し長期生存している１例を報告する．症例は63歳，女性．盲腸腫瘍が疑われ当科に入院，回盲部嚢胞性腫瘍とDouglas窩に多発する結節性病変を認め，手術（回盲部切除術，大網切除術，子宮全摘出術，両側付属器切除術，低位前方切除術）を施行した．病理組織検査では未分化腺癌で，CK7+/CK20－から卵巣，子宮内膜由来と考えたが，これらの臓器に原発病変はなく，原発不明未分化腺癌と診断した．術後６カ月で腹腔内に再燃し，卵巣癌に準じてTJ療法を施行してCRを得た．その後２回の再燃に対して同療法でいずれもCRが得られ，術後６年近く経過した現在，維持療法は行わず経過観察している．本症例ではTJ療法が奏効したが，CR後から再燃までの間に補助療法や維持療法は行っておらず，このような症例に対する治療方針は今後の検討課題と考えている．

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.

We analyzed immune nutritional factors that affected the incidence of SSI in rectal cancer surgery.A total of 103 patients who underwent rectal cancer resection were enrolled in this retrospective study. The risk factors (DM, BMI18.5, ≥25.0, PNI≤40, G/L2, CONUT≥2, mGPS D) for SSI (Grade≥Ⅱ) were analyzed.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.As a risk factor for SSI after rectal cancer surgery, PNI≤40 and mGPS were risk factors.

We report two cases of intrapelvic recurrence after radical resection of rectal cancer, which were successfully treated with Carbon Ion Radiotherapy (C-ion RT). The first case is of a 71-year-old man who underwent abdominoperineal resection (APR) with D2 lymphadenectomy for rectal cancer in December 2010, followed by adjuvant chemotherapy with S-1 plus oxaliplatin. The patient was diagnosed with a recurrence on the left pelvic wall in August 2012, and underwent C-ion RT (73.6 Gray equivalent) for this lesion in October 2012. Three months after this treatment, the lesion had regressed significantly, as ascertained by computed tomography (CT). He remains alive with no signs of recurrence. The second case is of a 63-year-old man who underwent APR with D3 lymphadenectomy for rectal cancer, followed by adjuvant chemotherapy with uraciltegafur ( UFT). The patient was diagnosed with a recurrence on the right pelvic wall in January 2013, and underwent C-ion RT (73.6 Gray equivalent) for this lesion in March 2013. Three months after this treatment, the lesion reduced significantly, and the patient is alive with no signs of recurrence. Although the long-term outcomes need to be assessed, C-ion RT could be a safe and effective therapy.

To confirm the incidence and risk factors of incisional hernia after colorectal cancer surgery, we analyzed the clinical data including the surveillance computed tomography (CT) examination.One hundred sixty seven patients with open abdominal surgery for colorectal cancer were analyzed retrospectively.Incisional hernia was recognized in 27 cases (16.2%), and occurred at median 7 (1-21) months after surgery. Multivariate analysis showed the risk factors for incisional hernia were female (p=0.0014), distal colon and rectal cancer (p=0.0038), high body mass index (p=0.0055) and lower serum albumin (p=0.0081).Obesity, lower median incision and malnutrition might seem to relate to the incisional hernia after colorectal cancer surgery.

Stoma creation is one of the risk factors for the incisional surgical site infection (SSI) which can develop the patient's pain in a colorectal surgery.We performed the subcuticular suture with subcutaneous negative pressure drainage and sealing with liquid tissue adhesive for the prevention of wound infection at the stoma creation.A total of 72 patients between January 2006 and December 2012 were retrospectively analyzed. Up to December 2008, the wound closure was performed by the percutaneous transdermal interrupted suture with monofilament nylon sutures (conventional procedure). From January 2009, the 10-Fr silastic flexible drains were placed at the subcutaneous space and subcuticular suture using a monofilament absorption string was performed. A liquid tissue adhesive was used to seal the skin wound (revised procedure). There was no difference between the conventional group and the revised group in age and gender. Risk factors in two groups were not found the significant difference except diabetes mellitus. Incisional SSI was observed in 23 patients out of 72 patients (31.9%). There was no significant difference in incidence in clinicopathological factors. Only the revised procedure of wound closure significantly decreased 13.8% of incisional SSI rate from 44.2% in the conventional procedure.Our several changes of wound closure including tissue adhesive, subcuticular suture and subcuticular closed suction drainage reduced incisional SSI.

The cytotoxic regimens and bevacizumab (Bev) or anti-EGFR antibody are used for metastatic colorectal cancer (mCRC) that can expect conversion therapy. In this paper, we would present our practical data including the response, survival and toxicity of the capecitabine plus oxaliplatin (CAPEOX) with Bev for mCRC that cannot expect conversion therapy.Nineteen patients with mCRC who were treated with CAPEOX with Bev were enrolled. All the patients had the disseminated hepatic, lung, peritoneal metastases or distant lymph node metastasis assessed as no possibility of R0 resection.The median age was 66 (45-85) years old. Target lesion was liver and lung in 9 patients, peritoneum in 5 patients and distant lymph node in 3 patients. CAPEOX with Bev therapy was administered for a median of 8.0 cycles (range, 4-21 cycles). In the 16 evaluable cases, there were no patient with complete response (CR), 9 patients with partial response (PR), 6 with stable disease (SD), and 1 with progressive disease. The objective response rate (CR plus PR) was 56.3%, and disease control rate (CR, PR plus SD) was 93.8%. The median TTP was 9.3 months and the median OS was 21.1 months. No patients treated with surgery even though the good responses were obtained. No severe hematologic adverse toxicities were observed except only one case with grade 3 platelet decrease. Nonhematologic grade 3 events were observed totally 8 patients including 3 for peripheral neuropathy, 2 for bilirubin, and 1 for nausea/vomiting, amylase and stomatitis.We obtained the quite good results of CAPEOX plus Bev as the first-line treatment practically. This regimen might be useful for mCRC that cannot expect conversion therapy.

Case1: A 63-year-old woman with diarrhea and hematochezia was diagnosed as having rectal cancer invading the pelvis. Six courses of the 5-fluorouracil, leucovorin, and oxaliplatin( mFOLFOX6) plus panitumumab regimen were administered after sigmoid colostomy, following which low anterior resection was performed. Since the 6 courses of mFOLFOX6 were administered postoperatively, no evidence of recurrence has been observed for 18 months. Case2: A 52-year-old man with high fever and abdominal pain was diagnosed as having rectal cancer invading the bladder with a vesicorectal fistula. After transverse colostomy and 6 courses of mFOLFOX6 plus panitumumab, high anterior resection with partial cystectomy was performed. Since the 8 courses of capecitabine plus oxaliplatin (XELOX) were administered postoperatively, no evidence of recurrence has been observed for 12 months. Although no consensus has been reached pertaining to the use of neoadjuvant chemotherapy for the treatment of colorectal cancer, we could, in this study, demonstrate the efficacy of neoadjuvant chemotherapy with panitumumab for the treatment of locally advanced colorectal cancer.

We examined the association of the physical, nutritional, and immune status with adverse events in patients treated with mFOLFOX6 adjuvant chemotherapy after colorectal cancer surgery.This study included 17 patients, 7 male and 10 female. The median age was 62( range, 32-75) years. The median number of treatment cycles was 12 (range, 4-12). Age, performance status( PS), body mass index( BMI),serum albumin level( Alb),Onodera's prognostic nutritional index( PNI), controlling nutritional status( CONUT),Glasgow prognostic score( GPS),the granulocyte/lymphocyte ratio( G/L),neutrophil count, and the total lymphocyte count( TLC) were evaluated with regard to the nutrition and immunity status of the host before chemotherapy. The incidents of toxicity of greater than Grade 2 severity, excluding gastrointestinal events or gastrointestinal toxicities, were analyzed to determine the correlation with host status.Any toxicities and toxicities without digestive symptoms were observed in 11 patients( 64.7%),and the number of incidents was significantly increased in patients with a PNI of45. Gastrointestinal toxicities were observed in 4 patients (23.5%), but there were no significant correlations with any of the factors investigated.Toxicities are observed to a greater extent in patients with a PNI of45 during adjuvant chemotherapy. These findings suggest that nutritional support may be required to safely administer mFOLFOX6 adjuvant chemotherapy.

Purpose This study was conducted to investigate the effect of flavonoids, a major family of antioxidants contained in foods, on retinal ganglion cell (RGC) death induced by hypoxia, excessive glutamate levels, and oxidative stress. Moreover, to assess the structure-activity relationships of flavonoids, three types of flavonoids with different numbers of hydroxyl groups and varieties of sugar chains were studied. Methods Three kinds of flavonoids—nicotiflorin, rutin, and quercitrin—were used. The death of neonatal rat purified RGCs was induced by hypoxic conditions (5% O2, 5% CO2, 37 °C) for 12 h, 25 µM glutamate over three days, or oxidative stress by depleting antioxidants from the medium for 24 h. RGC survival rates were calculated under each condition and compared with vehicle cultures. Modification of cell death signaling after stress-induced apoptosis and necrosis by flavonoids was assessed using caspase-3 and calpain immunoreactivity assays. Results Under hypoxic and glutamate stress, both nicotiflorin and rutin significantly increased the RGC survival rate at 1 nM or higher, while quercitrin increased it at 100 nM or higher. Under oxidative stress, nicotiflorin, rutin, and quercitrin also significantly increased the RGC survival rate at 1 nM, 0.1 nM, and 100 nM or higher, respectively. Rutin significantly inhibited the induction of caspase-3 under both hypoxia and excessive glutamate stress, as well as blocking the induction of calpain during oxidative stress. Conclusions Nicotiflorin and rutin showed neuroprotective effects on hypoxia-, glutamate- or oxidative stress–induced RGC death at concentrations of 1 nM or higher. The presence of a specific sugar side chain (rutinoside) may enhance neuroprotective activity.

PURPOSE We determined the function of ARMS2 and HtrA1 in the choroid and retina using transgenic (Tg) mice and evaluated the effects of mainstream cigarette smoke on these mice. METHODS The chicken actin promoter (CAG) was used to drive mouse HtrA1, human ARMS2, and ARMS2 (A69S) expression in the entire body of a mouse for one year. Fundus observations were performed with a Spectralis HRA+ optical coherence tomograph (OCT). Eyes were sectioned, stained with hematoxylin and eosin (H&E), and analyzed with immunohistochemistry. Mice were exposed to cigarette smoke for 30 min/d, 5 d/wk for 12 weeks using a mainstream smoking chamber (INH06-CIGR02A, MIPS). After 12 weeks, fundus observations and pathological analyses were performed. RESULTS Approximately 18.2% of 12-month-old HtrA1 Tg mice exhibited choroidal neovascularization (CNV) by OCT and positive immunostaining with anti-CD31 and anti-fibronectin antibodies. Furthermore, elastic van Gieson (EVG) staining showed Bruch's membrane damage in HtrA1 Tg mice. No retinal changes were observed in ARMS2 and ARMS2 (A69S) Tg mice. A total of 12 weeks of exposure to mainstream cigarette smoke led to CNV rates of 7.7% for wild type (Wt) mice and 20% for HtrA1 Tg mice, but had no effect on ARMS2 Tg mice. In addition, abnormal deposits were observed between photoreceptor cells and the RPE in an HtrA1 Tg mouse exposed to mainstream cigarette smoke. CONCLUSIONS The HtrA1 overexpression and mainstream cigarette smoke can independently lead to CNV. The HtrA1 gene is a strong risk factor for wet AMD, but not all of the HtrA1 Tg mice developed CNV, suggesting that CNV development depends on multiple risk factors.