Association between iron status markers and kidney outcome in patients with chronic kidney disease.

Several studies conducted in patients with various stages of chronic kidney disease (CKD) have investigated the association of iron status markers, such as transferrin saturation (TSAT) and serum ferritin, with kidney outcomes. However, the associations were inconsistent and remain strongly debated. Therefore, we aimed to investigate whether TSAT and serum ferritin levels were associated with kidney outcome in such a population. In this study, 890 patients who were admitted for the evaluation of and education for CKD were prospectively followed. Primary kidney outcome was a composite of doubling of serum creatinine, end-stage kidney disease, or death due to kidney failure. Participants were divided into quartiles (Q1-Q4) according to TSAT or serum ferritin levels. During a median follow-up period of 2.8 years, kidney events occurred in 358 patients. In the multivariable Cox analyses, compared with Q3 of TSAT, the hazard ratios (95% confidence intervals) for Q1, Q2, and Q4 were 1.20 (0.87, 1.66), 1.38 (1.01, 1.87), and 1.14 (0.82, 1.59), respectively. Compared with Q2 of serum ferritin, lower and higher quartiles had a significantly increased risk for kidney outcome; hazard ratios (95% confidence intervals) for Q1, Q3, and Q4 were 1.64 (1.18, 2.27), 1.71 (1.24, 2.37), and 1.52 (1.10, 2.10), respectively. A Fine-Gray model with death before kidney events as a competing risk showed results similar to the above. In CKD, lower and higher ferritin levels were independent risk factors for kidney disease progression.

[A Case of Rectal Cancer in Which Total Pelvic Organ Excision Could Be Avoided by TNT Therapy and Robotic Surgery].

The patient is a 50s year old man. He visited his local doctor with complaints of anal pain and bloody stools, and a rectal examination revealed a tumor on the anterior wall of the rectal canal. CT imaging showed tumors invading the prostate, urethra, and anorectal muscles, and a 3 mm-sized nodule was found in the lungs. The patient was diagnosed as cT4bN1M1a, Stage Ⅳ, and total neoadjuvant chemotherapy was planned as preoperative treatment. The 5 Gy×5 times radiation therapy followed by 5 courses of CAPOX plus BEV as preoperative chemotherapy and CAPOX. CAPOX was administered. After completion of treatment, the colonoscopy showed PR, and MRI showed clear boundary between the prostate and tumor but invasion into the anorectal muscles; CT showed no lung metastasis, and preoperative diagnosis was ycT4bN0M0, ycStage Ⅱ. Robotic-assisted rectal amputation and left lateral lymph node dissection were performed under general anesthesia. Pathologically, the patient was diagnosed as ycT4bN0M0, Stage Ⅱ, and the efficacy was determined as TRG 1(AJCC). Vertical dissection was negative and radical resection was possible.

[A Case of Rectal Cancer with Enlarged Lateral Lymph Nodes Treated with Total Neoadjuvant Therapy and Robotic Surgery].

A 70s woman with advanced rectal cancer(AV 3 cm, type 2)was diagnosed as cT3N2M1a, Stage Ⅳ(UICC, TNM 8th) and underwent total neoadjuvant therapy(TNT)consisted of preoperative 5 Gy×5 short course RT followed by 5 courses of CAPOX plus BEV and CAPOX. Post-treatment endoscopy revealed nearCR, MRI failed to identify the primary tumor, and the mesenteric and lateral lymph node enlargement had disappeared. The patient underwent robot-assisted low anterior resection, bilateral lymph node dissection, and temporary ileal colostomy. Postoperative pathological findings were ypT0N0M0, Stage 0, and the efficacy evaluation was TRG 0(AJCC)with no residual tumor including lateral lymph nodes. The patient was discharged on the 16th day without any postoperative complications and is currently alive 6 months postoperatively without recurrence.

[A Case of Locally Advanced Sigmoid Colon Cancer Invading the Urinary Bladder Treated with Neoadjuvant Chemotherapy and Robot Assisted Urinary Bladder-Conserving Surgery].

We report a case of 72s male with locally advanced sigmoid colon cancer. Colonoscopy revealed an advanced sigmoid colon cancer(AV 15 cm, type 2, semi-peripheral, deeper than T3). He was diagnosed as cT4bN2M0, cStage Ⅲc(Japanese Classification of Colorectal, appendiceal, and, Carcinoma, 9th edition), and was given chemotherapy as preoperative treatment. He was treated with CAPOX plus BEV as neoadjuvant chemotherapy. Preoperative diagnosis was ycT4bN0M0, ycStage Ⅱc. The robot assisted high anterior resection and partial bladder resection were performed. The bladder was sutured under robotic assistance. The residual bladder capacity was 100 mL. Postoperative diagnosis was ypT0N0M0, ypStage 0, TRG 0 (AJCC). We experienced a case of neoadjuvant chemotherapy for rectosigmoid colon cancer with bladder invasion, which resulted in pCR.

[A Case of Pathological Complete Response for MSI-High Locally Advanced Unresectable Transverse Colon Cancer Treated with Nivolumab plus Ipilimumab Combination Therapy].

74-year-old woman was diagnosed with locally advanced unresectable transverse colon cancer. She started CAPOX therapy as first-line therapy after ileostomy. After second course, MSI-high was detected, so nivolumab plus ipilimumab combination therapy was started as second-line therapy. After 4 courses of combination therapy, she was judged to be in partial response and surgery was performed. Histopathological diagnosis of the surgical specimen showed complete response, and she is still alive without recurrence 15 months after surgery.

[A Case of Response to Pembrolizmab in Unresectable MSI-High Transverse Colon Cancer].

A 80s man was diagnosed circulated type 2 colon cancer at the transverse colon, and pathological findings was adenocarcinoma( por1). Genomic findings were microsatellite instability-high(MSI-H), all RAS wild type and BRAFV600E mutated. Contrast-enhanced CT showed an enlarged lymph nodes(#221, #222, #223, #214)along the middle colic and superior mesenteric artery. Clinical diagnosis was a locally advanced unresectable transverse colon cancer, cT4aN3M1a(LYM), cStage Ⅳa. Drug therapy with pembrolizumab was prescribed. Six months later, contrast-enhanced CT and PET demonstrated remarkable shrinkage of the primary tumor and lymph nodes except 2 peri-colic enlarged lymph nodes. Primary lesion turned almost undetectable, however the biopsy demonstrated residual tumor. Two months later, CT showed that the residual lymph nodes had also disappeared.

Immune response to cytosolic DNA via intercellular receptor modulation in oral keratinocytes and fibroblasts.

OBJECTIVE: Double-strand (ds) DNA-enveloped viruses can cause oral infection. Our aim is to investigate whether oral mucosal cells participate in immune response against cytosolic dsDNA invasion. METHODS: We examined the response to transfected herpes simplex virus (HSV) dsDNA via intracellular receptors in oral keratinocytes (RT7) and fibroblasts (GT1), and the effect of TNF-α on those responses. RESULTS: Transfected dsDNA increased CXCL10 expression via NF-κB activation in both cell types, while those responses were inhibited by knockdown of RIG-I, an RNA sensor. Although IFI16, a DNA sensor, was expressed in the nuclei of both types, its knockdown decreased transfected dsDNA-induced CXCL10 expression in GT1 but not RT7 cells. IFI16 in GT1 cells was translocated into cytoplasm from nuclei, which was attributed to immune response to cytosolic dsDNA. TNF-α enhanced transfected dsDNA-induced CXCL10, and knockdown of IFI16 decreased TNF-α and dsDNA-driven CXCL10 expression in both RT7 and GT1 cells. Finally, the combination of TNF-α and transfected dsDNA resulted in translocation of IFI16 from nuclei to cytoplasm in RT7 cells. CONCLUSION: RIG-I and IFI16 in oral mucosal cells may play important roles in host immune response against DNA viral infection, while TNF-α contributes to development of an antiviral system via those intracellular receptors.

Association of aortic valve calcification with carotid artery lesions and peripheral artery disease in patients with chronic kidney disease: a cross-sectional study.

BACKGROUND: Patients with chronic kidney disease (CKD) reportedly have a high prevalence of aortic valve calcification (AVC). In population-based studies, AVC is considered a manifestation of systemic atherosclerosis. The association of AVC with atherosclerotic lesions has not been fully investigated in predialysis patients. The present study was performed to determine whether carotid artery lesions and peripheral artery disease (PAD) are associated with AVC in patients with CKD not on dialysis. METHODS: In total, 749 patients were included in this cross-sectional study. AVC was evaluated using echocardiography. Carotid artery lesions including carotid artery plaque (CAP) and PAD were simultaneously examined in each patient. A logistic regression analysis was applied to determine the factors associated with AVC. RESULTS: AVC, CAP, and PAD were found in 201, 583, and 123 patients, respectively. In the multivariable analyses adjusted for covariates including the estimated glomerular filtration rate and makers of mineral metabolism (serum calcium, serum phosphorus, parathyroid hormone, 1,25-dihydroxyvitamin D, and fibroblast growth factor 23), AVC was significantly associated with the presence of CAP [odds ratio (OR), 3.37; 95% confidence interval (CI), 1.43-7.95], the presence of PAD (OR, 1.76; 95% CI, 1.10-2.81), the CAP score (per 1.0-point increase) (OR, 1.06; 95% CI, 1.02-1.11), and the ankle-brachial blood pressure index (per 0.1-point increase) (OR, 0.83; 95% CI, 0.72-0.95). CONCLUSIONS: AVC was associated with atherosclerotic lesions independent of kidney function and mineral metabolism. We consider that this association between AVC and atherosclerosis might reflect the burden of shared atherosclerotic risk factors.

Declining interest in general surgical training - Challenging misconceptions and improving access at undergraduate level.

BACKGROUND: In recent years, general surgery has faced a decline in applicants for postgraduate training. The St. George's Surgical Society hosted a national surgical conference with an aim to explore the reasons for the decline and to investigate the effectiveness of a one-day intervention on students' perceptions of general surgery and surgical skills. MATERIALS AND METHODS: The conference took place on 20th January 2018 at St. George's, University of London. During the conference, medical students received lectures on "careers in surgery" and small-group workshops introducing students to simulation-based laparoscopic machines. Delegates were invited to complete before and after questionnaires looking at various domains; (1) Perceptions of general surgery, (2) Simulation skills, and (3) Usefulness of the day. RESULTS: There were significant impacts on student perceptions of the speciality such as increases in the views that "general surgery contained the opportunities for personal and professional development" (26%, p = 0.04), and of "general surgery as a rewarding speciality" (26%, p = 0.05). There were also negative changes such as an increase in the perception that "general surgery is female unfriendly" (+32%, p = 0.01). There were positive findings in all aspects relating to the use of laparoscopic simulation. DISCUSSION: The challenges faced in improving access to general surgery has been highlighted. More importantly the benefits of a one day intervention in addressing misconceptions and improving knowledge was seen. This study also shows the benefits of simulation teaching in the undergraduate curriculum. CONCLUSION: The intervention has improved the perceptions on general surgery, surgical skills and knowledge and provided a platform for engaging students and clinicians.

Preoperative oral health care reduces postoperative inflammation and complications in oral cancer patients.

The records of 70 patients with oral cancer who were treated at a single institution between 2008 and 2014 were reviewed. The body temperature, white blood cell count, and C-reactive protein (CRP) levels were compared between those who had received preoperative oral care (oral care group) and those who had not received any (non-oral care group). When the patients were divided into those who underwent minimally invasive surgery and those who underwent severely invasive surgery, the mean CRP level in the early postoperative period was lower in the oral care group as compared with the non-oral care group in those who underwent minimally invasive surgery as well as those who underwent severely invasive surgery. However, the mean CRP level was most evidently reduced in the severely invasive group on days 1 and 3-5. However, no significant differences were observed with regard to the percentage of postoperative infectious complications (for example, surgical site infection, anastomotic leak and pneumonia) between the oral care (13.6%) and non-oral care (20.8%) groups, though a reduced prevalence of postoperative complications following preoperative oral care was noted. The results of the present study suggest that preoperative oral care can decrease inflammation during the early postoperative stage in patients with oral cancer who undergo severely invasive surgery.

Purification, gene cloning, and characterization of γ-butyrobetainyl CoA synthetase from Agrobacterium sp. 525a.

The report is the first of purification, overproduction, and characterization of a unique γ-butyrobetainyl CoA synthetase from soil-isolated Agrobacterium sp. 525a. The primary structure of the enzyme shares 70-95% identity with those of ATP-dependent microbial acyl-CoA synthetases of the Rhizobiaceae family. As distinctive characteristics of the enzyme of this study, ADP was released in the catalytic reaction process, whereas many acyl CoA synthetases are annotated as an AMP-forming enzyme. The apparent Km values for γ-butyrobetaine, CoA, and ATP were, respectively, 0.69, 0.02, and 0.24 mM.

Expression and function of RIG-I in oral keratinocytes and fibroblasts.

BACKGROUND: Innate immune response by oral mucosal cells may be the first line of host defense against viral infection. Retinoic acid-inducible gene-I (RIG-I) recognizes viral dsRNA in the cytoplasm, and RIG-I-mediated signaling regulates antiviral type I IFN, and inflammatory chemokine production. Here, we tested the hypothesis that oral mucosal cell participation in host defense against viral infection via RIG-I. METHODS: RIG-I expression was detected in immortalized oral keratinocytes (RT7), oral fibroblasts (GT1) using and RT-PCR and immunohistochemistry. RT7 and GT1 were exposed to dsRNA virus mimic Poly I:C-LMW/LyoVec (PLV). Expression of IFN-ß and CXCL10 via RIG-I was examined by Real-time RT-PCR and ELISA. Phosphorylation of IRF3 and STAT1 were detected by western blotting. RESULTS: RT7 and GT1 constitutively expressed RIG-I in the cytoplasm. Furthermore, PLV increased IFN-ß and CXCL10 productions in both RT7 and GT1 via RIG-I concurrent with phosphorylation of IRF3 and STAT1. PLV-induced CXCL10 production was attenuated by neutralization of IFN-ß and blocking of IFN-α/ß receptor (IFNAR), indicating primal IFN-ß production via the RIG-I-IRF3 axis, which eventually induces CXCL10 production via the IFNAR -STAT1 axis. CONCLUSION: We propose that RIG-I in oral keratinocytes and fibroblasts may cumulatively develop host-defense mechanisms against viral infection in oral mucosa.

Toll-like receptor (TLR) expression and TLR­mediated interleukin-8 production by human submandibular gland epithelial cells.

Toll-like receptor (TLR) family members are pattern recognition receptors that are essential in the activation of innate and adaptive immune responses. Submandibular gland epithelial cells (SMGCs) may recognize microbial components through TLRs and be involved in the development of inflammatory reactions in the submandibular glands. Therefore, the functional expression of TLRs in SMGCs was investigated in the present study. The mRNA expression of TLRs in SMGC and whole submandibular tissues was determined by RT-PCR. Subsequently, the effects of various TLR agonists and tumor necrosis factor alpha (TNF-α) on IL-8 production were examined using an ELISA. SMGCs, as well as whole submandibular tissues, expressed TLR1-10 mRNA. Furthermore, interleukin (IL)-8 production in SMGCs was increased by Pam3CSK4 (TLR1/2 agonist), poly I:C (TLR3 agonist), E. coli lipopolysaccharide (LPS; TLR4 agonist), flagellin (TLR5 agonist) and macrophage­activating lipopeptide (MALP)-2 (TLR2/6 agonist) treatments in a dose­dependent manner, whereas administration of either imiquimod (TLR7 agonist) or CpG-oligodeoxynucletide (TLR9 agonist) exerted no evident effect. Pam3CSK4, poly I:C, LPS, flagellin and MALP-2 also enhanced TNF­α­induced IL-8 production in SMGCs. These findings suggest that innate immune responses against microbial components result in the development of TNF-α-mediated autoimmune inflammatory disease in the submandibular glands.

[Tolerability of XELOX in postoperative adjuvant chemotherapy for colorectal cancer].

A regimen of capecitabine plus oxaliplatin(XELOX)has become one of the standard postoperative adjuvant chemotherapies for colon cancer. However, few tolerability studies have been conducted in Japan. In this study, we retrospectively examined treatment continuation and the adverse events that occurred during 8 courses of postoperative adjuvant chemotherapy with XELOX in 21 patients with colorectal cancer who had undergone curative resection. The completion rate for 8 courses of treatment with XELOX was 71.4%, while the median relative dose intensities of capecitabine and oxaliplatin were 85.0% and 75.0%, respectively. Although the incidence of subsequent Grade 3 or higher hand-foot syndrome was 14.3%, the rate of peripheral neuropathy was 0%. Our hospital had a high rate of XELOX treatment continuation, suggesting that XELOX adjuvant chemotherapy would be well tolerated in clinical practice as well.

[A case of metachronous triple cancer treated with a multimodal approach including surgical resection].

We report a patient with metachronous triple cancer of the hypopharynx, esophagus, and tongue. A 37-year-old man with hypopharyngeal cancer underwent hypopharyngolaryngectomy and cervical lymphadenectomy in 1999. Submental lymphadenectomy following adjuvant radiotherapy was performed for lymph node recurrence in 2000. The patient then underwent esophagectomy for esophageal cancer in 2004. Subsequently, the patient underwent 2 partial resections and 1 subtotal resection of the tongue for tongue cancer in 2005, 2007, and 2008, respectively. The pathological findings for each cancer were squamous cell carcinoma. Two rounds of radiotherapy were performed for bone metastasis of the esophageal cancer and for the local recurrence of the tongue cancer. A total of 7 lines of chemotherapy, including superselective arterial infusion chemotherapy, were administered to treat the recurrences. The patient died in 2013, but he showed long-term survival of 13 years from the first operation owing to the multimodality treatment.

[Chemotherapy for gastric cancer patients over 75 years of age].

PURPOSE: The efficacy of chemotherapy for advanced or recurrent gastric cancer in patients who were aged over 75 years was investigated. MATERIALS AND METHODS: Progression free survival (PFS) and overall survival (OS) of advanced gastric cancer patients who received first-line chemotherapy with TS-1 plus cisplatin or TS-1 in our hospital from 2009 to 2013 were determined. The patients were divided into two groups: H and L. H group patients were aged over 75 years, and L group patients were aged less than 75 years. RESULTS: Median PFS and median OS of patients in the H and L groups who received TS-1 plus cisplatin chemotherapy were not significantly different. PFS was 77[range, 13-211] days and 139[range, 53-211]days for the H and L groups, respectively(p=0.141), while OS was 523[range, 22-1,030] days and 402 [range, 322-623] days, respectively (p=0.620). Similarly, median PFS and median OS of patients who received TS-1 chemotherapy were not significantly different between the H and L groups. PFS was 103[range, 51-156]days and 152.5[range, 85-278]days for the H and L groups, respectively (p=0.230), while OS was 414 [range, 224-714]days and 605[range, 452-1,077] days, respectively ( p=0.1337). CONCLUSION: PFS and OS were not significantly different in younger patients with advanced gastric cancer who received TS-1 plus cisplatin or TS-1 chemotherapy compared to that in similarly treated elderly patients with advanced gastric cancer.

[A case of advanced gastric cancer successfully treated with second-line chemotherapy followed by curative conversion gastrectomy].

We report a case of advanced gastric cancer that was successfully treated with second-line chemotherapy followed by curative conversion gastrectomy. The patient was a 71-year-old man. Endoscopic examination revealed a type 3 gastric cancer in the lower third of the stomach. Abdominal computed tomography (CT) revealed multiple lymph node metastases and metastasis to the peritoneal cavity. The clinical diagnosis was cT4N3aP1H0M1(LYM), cStage IV. The patient was treated with S-1 (80 mg/m² on days 1-28, every 6 weeks [q6w]) in November 2009. Temporarily, both the size of the primary lesion and the swelling of the lymph nodes were markedly reduced. However, after 10 courses of chemotherapy, the primary lesion was found to be enlarged again. The patient was then treated with S-1(80 mg/m², on days 1-14, every 6 weeks [q3w]) plus CPT- 11 (150 mg/m² on day 1, q3w) as the second-line chemotherapy. After 8 courses, an abdominal CT showed no peritoneal or lymph node metastases, but gastric endoscopy revealed the presence of a residual primary lesion. After staging laparoscopy, distal gastrectomy with D2 lymphadenectomy was performed. The histological diagnosis was ypT3 (SS) N1M0, Stage IIB. Analysis of the histological features of the primary tumor and peritoneal metastases resulted in their classifications as Grade 1a and Grade 3, respectively. After surgery, there were no serious adverse events. The patient has been in good health without recurrence for over 3 years after surgery.

Bone formation and osseointegration with titanium implant using granular- and block-type porous hydroxyapatite ceramics (IP-CHA).

The aim of the present study was to examine whether interconnected porous hydroxyapatite ceramics (IP-CHA) could be used as bone substitute for implant treatment in reconstructive surgery. We firstly assessed if surround of the titanium surface placed into granular or block-type IP-CHA can observe new bone formation in a rabbit bone defect model. Subsequently, osseointegration and stability of titanium implant inserted into block-type IP-CHA was investigated in a rabbit onlay graft model. Direct contact between new bone and the surface of the titanium in granular- or block-type IP-CHA was found in a rabbit bone defect. Further, new bone formation was found in direct contact with the implant surface in the block-type IP-CHA in an onlay graft model, and the implant stability quotient (ISQ) values were significantly increased after surgery. Therefore, IP-CHA may be a useful material for implant treatment in reconstructive surgery strategies.

[Study of tolerability of capecitabine in postoperative adjuvant chemotherapy in colon cancer].

OBJECTIVE: Based on the results of the X-ACT study, capecitabine has become one of the standard postoperative adjuvant chemotherapies for colon cancer. However, few studies of tolerability have been conducted in Japan. METHOD: In this study, we retrospectively examined treatment continuation, and the adverse events that occurred during eight courses of postoperative adjuvant chemotherapy with capecitabine, in 34 patients with colon cancer who had undergone curative resection. RESULT: The completion rate for eight courses of treatment with capecitabine was 79. 4%(27 of 34 subjects), the median relative dose intensity was 94. 4%(13% to 106%), and the proportion of subjects with relative dose intensity B 60% was 82. 4%(28 of 34 subjects). The following Grade 3 or higher adverse events were reported: hand-foot syndrome, in 11. 8%(4 of 34 subjects); mucositis oral, in 2. 9%(1 of 34 subjects); diarrhea, in 2. 9%(1 of 34 subjects); and glans penis ulcer, in 2. 9%(1 of 34 subjects). CONCLUSION: In our hospital, a high rate of capecitabine treatment continuation comparable to that reported in the X-ACT study was obtained, suggesting that capecitabine adjuvant chemotherapy would be well tolerated in clinical practice as well.

[Efficacy of capecitabine/cisplatin chemotherapy after failure of all conventional therapies in patients with advanced gastric cancer].

There is no standard therapy for advanced gastric cancer patients who had already failed treatment with major anti-cancer drugs including fluoropyrimidine, cisplatin, taxans, and irinotecan. We report the results of treatment with capecitabine and cisplatin(XP)after the failure of all other conventional therapies. A total of five advanced gastric cancer patients were treated. The median age was 59 years(range, 46-76); there were 3male and 2 female patients; performance status was 0/1/2: 2/2/ 1 patients, respectively. The median duration from start of first-line chemotherapy to XP was 653 days(range, 372-1,107). Three patients were treated after fourth-line therapy and two patients after fifth-line therapy. All of the patients had received S-1, cisplatin, irinotecan, paclitaxel, and docetaxel previously. Patients received 80mg/m2 of cisplatin intravenously on day 1, and 1,000mg/m2 of capecitabine orally twice a day from day 1 to day 14 followed by a 7-day rest period. Treatment courses were between 2 to 5. Median time to progression was 107 days. Median overall survival was 245 days. One PR and one SD were reported. All reported adverse events were manageable. XP is considered one of the effective regimens for advanced gastric cancer after all conventional therapies have failed.