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.

[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.

[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 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.

[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.

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.

[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.

Hyperbaric pressure and increased susceptibility to glutamate toxicity in retinal ganglion cells in vitro.

PURPOSE: To investigate the effect of hyperbaric pressure on purified retinal ganglion cells (RGCs) and the additive effect of hyperbaric pressure on glutamate-induced RGC death. METHODS: An RGC primary culture from 8-day-old Wistar rats was prepared and cultured in a hyperbaric chamber. The RGC survival rate under various pressure conditions and with 5 or 25 µM of glutamate stimulation was determined and compared with that of RGCs under isobaric conditions. First, RGCs were cultured at atmospheric pressure (0 mmHg) and under hyperbaric pressure (+30 and +90 mmHg, with pressure fluctuations varying from 0 to +30 or +60 mmHg). Next, RGCs were cultured at +15, +30, and +90 mmHg with the addition of 5 or 25 µM of glutamate. The effects of N-Methyl-D-aspartic acid (NMDA) and 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid (AMPA)/kainate receptor antagonists, MK-801, and 6,7-dinitroquinoxaline-2,3-dione (DNQX), on cell survival were assessed. Additionally, types of cell death and the induction of Bcl-2-associated X protein (BAX) leading to apoptosis were studied under hyperbaric pressure conditions and/or with 5 µM of glutamate. RESULTS: RGC death was not induced under increasing or fluctuating pressure conditions. RGC death was induced by 25 µM of glutamate and increased as pressure increased. RGC death was not induced by 5 µM of glutamate but was induced by and increased with increasing pressure. MK-801 and DNQX significantly reduced glutamate-induced RGC death, and DNQX was more effective than MK-801. Under hyperbaric pressure conditions, the addition of 5 µM of glutamate resulted in the induction of apoptosis and BAX, which did not occur under hyperbaric pressure conditions or with the addition of glutamate alone. CONCLUSION: In a rat RGC culture, hyperbaric pressure alone did not induce RGC death but increased RGC susceptibility to glutamate toxicity, which may be of relevance to ocular diseases with pressure-induced RGC death.

Liquid tissue adhesive, subcuticular suture and subcutaneous closed suction drain for wound closure as measures for wound infection in a colorectal cancer surgery with stoma creation.

BACKGROUND/AIMS: 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. METHODOLOGY: 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. RESULTS: 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. CONCLUSIONS: Our several changes of wound closure including tissue adhesive, subcuticular suture and subcuticular closed suction drainage reduced incisional SSI.

Incidence and risk factors for incisional hernia after open surgery for colorectal cancer.

BACKGROUND/AIMS: 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. METHODOLOGY: One hundred sixty seven patients with open abdominal surgery for colorectal cancer were analyzed retrospectively. RESULTS: 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). CONCLUSIONS: Obesity, lower median incision and malnutrition might seem to relate to the incisional hernia after colorectal cancer surgery.

[Onodera's prognostic nutritional index(PNI)and the modified Glasgow Prognostic Score(mGPS)in colorectal cancer surgery].

UNLABELLED: We evaluated the significance of the prognostic nutritional index(PNI)and modified Glasgow Prognostic Score(mGPS)in colorectal cancer resection. METHODS: We classified 165 patients undergoing colorectal cancer excision according to PNI(>40 [n=141]and ≤40[n=24])and mGPS (A/B[n=95], C[n=44], and D [n=26]). We examined the incidence of postoperative complications, postoperative hospital stay, and survival. RESULTS: Both indices were associated with all complications, surgical site infection(SSI), and med ian postoperative hospital stay. RI was only associated with the mGPS, whereas a long postoperative hospital stay was associated with the PNI alone. Both indices showed a relationship with survival for each clinical stage. CONCLUSION: Both PNI and mGPS were useful clinical indices for patients undergoing colorectal cancer resection.

[Two cases of intrapelvic recurrence after radical resection of rectal cancer, treated with carbon ion radiotherapy].

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.

[Successful resection of recurrent lesions in a patient with ovarian torsion diagnosed with rectal cancer].

We report the successful resection of recurrent tumors, including brain metastasis, in a patient with StageIV rectal cancer. A 29-year-old female patient was admitted with lower abdominal pain to the gynecological department in April 2005. The patient underwent emergency surgery following the diagnosis of left ovarian torsion. She was transferred to the Department of Surgery with suspected rectal cancer based on a pathological diagnosis of a Krukenberg's tumor. She underwent surgery for local advanced cancer using high anterior resection, hysterectomy, right oophorectomy, partial ileal resection, and appendectomy. In September 2007, she underwent very low anterior resection for an anastomotic recurrence. The patient then received 6 courses of modified 5-fluorouracil Leucovorin oxaliplatin (mFOLFOX6) as adjuvant chemotherapy. In March 2009, left paresis was observed. She underwent tumor resection and g-knife radiosurgery for brain metastasis in the right temporal lobe. In December 2009, metastasis in the right rectal muscle was resected following diagnosis by computed tomography (CT). In September 2013, she underwent further surgical resection of a tumor recurrence in the right rectal muscle. The pathological diagnosis of each resected tumor was metastatic rectal cancer. The patient has been disease-free since the last operation.