Risk factors for peristomal skin disorders associated with temporary ileostomy construction.

PURPOSE: Skin disorders are the most common stoma-related complications after temporary diverting loop ileostomy with proctectomy. The aim of the present study was to investigate risk factors for skin disorders associated with temporary ileostomy construction. METHODS: A total of 185 consecutive patients who underwent curative proctectomy with temporary diverting loop ileostomy for rectal malignancies at a single comprehensive cancer center between 2013 and 2018 were collected and analyzed. RESULTS: The most frequent stoma-related complications were skin disorders (n = 62, 33.5%), followed by mucocutaneous separation (n = 38, 20.5%) and high-output stoma (n = 34, 18.4%). Patients with skin disorders had a higher median body mass index (BMI; 22.4 vs. 21.3 kg/m2, P = 0.002) and lower stoma height (16 vs. 20 mm, P < 0.001) than those without skin disorders. According to a multivariable logistic regression analysis, independent predictors of skin disorders included overweight (median BMI ≥ 25 kg/m2 [odds ratio = 3.6, 95% confidence interval: 1.5-8.6], P = 0.004) and lower stomal height (median stoma height < 20 mm [odds ratio = 3.2, 95% confidence interval: 1.6-6.3], P < 0.001). CONCLUSION: Overweight and lower stoma height are correlated with the presence of skin disorders. Construction of a well-elevated stoma can reduce skin disorders associated with temporary ileostomy construction.

Tegafur and 5-fluorouracil levels in tears and changes in tear volume in long-term users of the oral anticancer drug S-1.

Eye problems are an adverse reaction sometimes found in chemotherapy. Although not life-threatening, they can reduce patients' quality of life. The highest incidence of eye problems is reported for the combination anticancer drug S-1 (tegafur-gimeracil-oteracil), and methods to prevent or treat the eye problems caused by this drug are presently lacking. To determine early detection methods and treatment for adverse ocular reactions, we measured changes in tear volume and levels of tegafur (FT) and 5-fluorouracil (5-FU), an active metabolite of FT, in the tears of patients with long-term use of S-1. A total of 11 patients receiving S-1 monotherapy as adjuvant chemotherapy after gastric cancer surgery were included. Tear volume and FT and 5-FU levels in tears were measured by liquid chromatography with tandem mass spectrometry during a maximum of 8 treatment cycles (48 weeks). For analysis, patients were divided into two groups: "watering eyes" (n=6, complaints of watering eyes at least once during the treatment period) and "no watering eyes" (n=5, no complaints of watering eyes). Both groups exhibited increased FT and 5-FU levels in tears upon initiation of S-1 treatment, and levels rapidly decreased upon discontinuation. Our findings suggest a relationship between FT level in tears and tear volume in patients with long-term S-1 use. The symptom of watering eyes may thus be linked to FT level in tears.

Surgical Strategy for Rectovaginal Fistula After Colorectal Anastomosis at a High-volume Cancer Center According to Image Type and Colonoscopy Findings.

BACKGROUND/AIM: The reported incidence of rectovaginal fistula is very low. Although some case reports have described surgical procedures, no systematic approach to the treatment of rectovaginal fistula according to diagnostic image and colonoscopy findings has been proposed. We present a comprehensive surgical strategy for rectovaginal fistula after colorectal anastomosis according to diagnostic image and colonoscopy findings. PATIENTS AND METHODS: This retrospective study included 11 patients who developed rectovaginal fistula after colorectal anastomosis. Rectovaginal fistula was classified into 4 types according to contrast enema images and colonoscopy findings, i.e., "Alone type", "Dead space type", "Anastomotic stricture type", and "Dead space and Anastomotic stricture type". The surgical strategies were "Diversion (Stoma)", "Percutaneous drainage", "Anastomotic stricture type", "Endoscopic balloon dilation", "Curettage of foreign bodies", "Simple full-thickness closure", "Split-thickness closure", "Pedicled flaps packing", and "Reanastomosis". The surgical strategy appropriate for each rectovaginal fistula type was investigated. RESULTS: Among "Alone type" cases, 5 (71.4%) healed with "only Diversion (Stoma)". "Alone type" cases (n=11) and all other cases (n=4) healed with "only Diversion (Stoma)" (n=5) or any other method (n=6) (p=0.022). CONCLUSION: For treatment of rectovaginal fistula after colorectal anastomosis, less invasive treatment approaches should be attempted first.

Yokukansan Alleviates Cancer Pain by Suppressing Matrix Metalloproteinase-9 in a Mouse Bone Metastasis Model.

Bone cancer pain control is difficult because it includes various characteristics of pain such as nociceptic and neuropathic pain. In this study, we investigated the effect of yokukansan (YKS), one of the traditional Japanese herbal medicines, on cancer pain in mouse bone metastasis model. Oral administration of YKS significantly alleviated pain behavior measured by quantitative body weight bearing. Furthermore, the pain behavior was also significantly alleviated by intrathecal and intraperitoneal administration of matrix metalloproteinase- (MMP-) 9 inhibitor, but not of MMP-2 inhibitor. MMP-9 expression was significantly elevated in the bone tissue on day 3 after carcinoma cell injection and in the ipsilateral spinal cord on day 7, which was suppressed by YKS administration. Taken together, these results suggest that YKS alleviates cancer pain via suppressing MMP-9 expression in bone metastasis model in mice.

Proposal of a Scoring Scale to Estimate Risk of the Discontinuation of S-1 Adjuvant Monotherapy in Patients with Stage II to III Gastric Cancer: A Multi-Institutional Dataset Analysis.

BACKGROUND: Discontinuation of postoperative S-1 adjuvant monotherapy is a frequent problem in the management of patients with gastric cancer. METHODS: A total of 355 stage II/III gastric cancer patients who underwent gastrectomy and adjuvant S-1 were retrospectively analyzed using a multicenter dataset. We randomly assigned patients into either discovery or validation cohort in a 2:1 ratio. In the discovery cohort, 29 parameters were assessed as candidate factors to predict discontinuation of S-1 adjuvant within 6 months. A scoring system was designed using independent risk factors identified by the multivariate analysis. Reproducibility was tested in the validation cohort. RESULTS: Overall, 92 patients (25.9%) discontinued the treatment within 6 months because of adverse effects. Age, preoperative urea nitrogen (UN) and the preoperative albumin-to-bilirubin index (ALBI) showed the highest area under the curve (AUC) for the discontinuation of S-1 adjuvant within 6 months in each category: body status, blood tests and indices. In the multivariate analysis, age ≥ 64 years, preoperative UN ≥ 15.2 mg/dl and preoperative ALBI ≥ -0.265 were identified as independent risk factors. A scoring scale consisting of these three factors was developed for the prediction of drug discontinuation and demonstrated a greater AUC (0.728) than that of each of the three constituents. The time to treatment discontinuation decreased incrementally as the risk score increased. The reproducible findings were confirmed in the validation cohort. CONCLUSIONS: We identified risk factors and developed a scoring scale to predict S-1 adjuvant monotherapy discontinuation in patients with stage II/III gastric cancer.

Corrigendum to "Yokukansan Alleviates Cancer Pain by Suppressing Matrix Metalloproteinase-9 in a Mouse Bone Metastasis Model".

[This corrects the article DOI: 10.1155/2019/2956920.].

＜Editors' Choice＞ Efficacy of enteral nutrients containing ß-hydroxy-ß-methylbutyrate, glutamine, and arginine for the patients with anastomotic leakage after gastrectomy: study protocol of a multicenter phase II clinical trial.

Anastomotic leakage is a major cause of prolonged hospitalization after gastrectomy and sometimes leads to fatal complications, such as abdominal abscess and sepsis. Arginine, glutamine, and ß-hydroxy-ß-methylbutyrate (HMB) are indispensable for biosynthesis of collagen, which plays an important role in the process of wound healing. However, treatment effects of amino acid supplements containing HMB on the healing process of anastomotic leakage after gastrectomy remain unclear. We designed an open-label, multicenter, phase II clinical trial to evaluate the therapeutic efficacy of an enteral amino acid supplement consisting of arginine, glutamine, and HMB (Abound, Abbott Japan Co., Ltd., Tokyo, Japan) in patients with anastomotic leakage after gastrectomy. Patients who are diagnosed with anastomotic leakage within 14 days after gastrectomy are eligible for this trial and the target sample size is 20. A pack of Abound is administered twice a day for 2 weeks. The primary objective of this clinical trial is to determine the length of time between diagnosis and cure of anastomotic leakage. The secondary endpoints include the safety of Abound, duration of drainage placement and fasting, postoperative hospital stay, surgical procedure, and blood test data. Variables are compared between enrolled patients and a historical control consisting of 20 patients who underwent gastrectomy between 2004 and 2016 at Nagoya University Hospital. We herein describe the study design and the concept in this protocol paper.

Changes in tear volume and ocular symptoms of patients receiving oral anticancer drug S-1.

BACKGROUND: Most eye disorders are not fatal but may deteriorate the quality of life of a patient. The eye disorder that is most frequently reported in the cancer chemotherapy is associated with the combination of tegafur/gimeracil/potassium oxonate (S-1). However, preventive methods or treatment methods for the eye disorder have not yet been established. This study aimed to determine changes in tear volume and subjective ocular symptoms during the treatment period in patients receiving S-1 monotherapy for early detection of adverse effects in the eye and establishment of its treatment methods. METHODS: This study included eleven patients receiving S-1 monotherapy as a postoperative adjuvant chemotherapy for gastric cancer. Six subjective ocular symptoms including watering eyes were evaluated and changes in tear volume measured by the Schirmer's test in patients receiving S-1 during the treatment period. In the present study, the patients were divided into "no watering eyes" (patients not experienced watering eyes) group and "watering eyes" (patients experienced watering eyes even once) group. RESULTS: Six out of eleven patients developed watering eyes after receiving S-1 monotherapy. Among these, the earliest onset occurred on the 2nd week after oral administration. Watering eyes and eye discharge were highly related in patients having a trouble in daily life due to the decreased QOL. Changes in tear volume in the "watering eyes" group significantly increased compared to the "no watering eyes" group during the treatment period, especially when the patients had no subjective symptom of the increased tear volume. CONCLUSIONS: It is essential to prevent eye disorders including watering eyes as an adverse effect of S-1 administration. The present study recommends that the tear volume should be periodically measured using Schirmer's test, and the patient should be interviewed regarding the subjective ocular symptoms for the early detection of watering eyes caused by S-1 administration. If the tear volume can not be measured periodically, medical staffs should pay attention to the patient with eye discharge.

Adjuvant capecitabine plus oxaliplatin after D2 gastrectomy in Japanese patients with gastric cancer: a phase II study.

BACKGROUND: Adjuvant chemotherapy with XELOX (capecitabine plus oxaliplatin) has been shown to be beneficial following resection of gastric cancer in South Korean, Chinese, and Taiwanese patients. This phase II study (J-CLASSIC-PII) was undertaken to evaluate the feasibility of XELOX in Japanese patients with resected gastric cancer. METHODS: Patients with stage II or III gastric cancer who underwent curative D2 gastrectomy received adjuvant XELOX (eight 3-week cycles of oral capecitabine, 1000 mg/m2 twice daily on days 1-14, plus intravenous oxaliplatin 130 mg/m2 on day 1). The primary endpoint was dose intensity. Secondary endpoints were safety, proportion of patients completing treatment, and 1-year disease-free survival (DFS) rate. RESULTS: One hundred patients were enrolled, 76 of whom completed the study as planned. The mean dose intensity was 67.2 % (95 % CI, 61.9-72.5 %) for capecitabine and 73.4 % (95 % CI, 68.4-78.4 %) for oxaliplatin, which were higher than the predefined age-adjusted threshold values of 63.4 % and 69.4 %, respectively, and the study therefore met its primary endpoint. The 1-year DFS rate was 86 % (95 % CI, 77-91 %). No new safety signals were identified. CONCLUSIONS: The feasibility of adjuvant XELOX in Japanese patients with resected gastric cancer is similar to that observed in South Korean, Chinese, and Taiwanese patients in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study. Based on findings from this study and the CLASSIC study, the XELOX regimen can be considered an adjuvant treatment option for Japanese gastric cancer patients who have undergone curative resection.

In vivo two-photon imaging of structural dynamics in the spinal dorsal horn in an inflammatory pain model.

Two-photon microscopy imaging has recently been applied to the brain to clarify functional and structural synaptic plasticity in adult neural circuits. Whereas the pain system in the spinal cord is phylogenetically primitive and easily exhibits behavioral changes such as hyperalgesia in response to inflammation, the structural dynamics of dendrites has not been analysed in the spinal cord mainly due to tissue movements associated with breathing and heart beats. Here we present experimental procedures to prepare the spinal cord sufficiently to follow morphological changes of neuronal processes in vivo by using two-photon microscopy and transgenic mice expressing fluorescent protein specific to the nervous system. Structural changes such as the formation of spine-like structures and swelling of dendrites were observed in the spinal dorsal horn within 30 min after the multiple-site injections of complete Freund's adjuvant (a chemical irritant) to a leg, and these changes continued for 5 h. Both AMPA and N-methyl-D-aspartate receptor antagonists, and gabapentin, a presynaptic Ca(2+) channel blocker, completely suppressed the inflammation-induced structural changes in the dendrites in the spinal dorsal horn. The present study first demonstrated by in vivo two-photon microscopy imaging that structural synaptic plasticity occurred in the spinal dorsal horn immediately after the injection of complete Freund's adjuvant and may be involved in inflammatory pain. Furthermore, acute inflammation-associated structural changes in the spinal dorsal horn were shown to be mediated by glutamate receptor activation.

A comparison of multimodality treatment: two or four courses of paclitaxel plus cisplatin or S-1 plus cisplatin followed by surgery for locally advanced gastric cancer, a randomized Phase II trial (COMPASS).

This randomized Phase II trial compares neoadjuvant chemotherapy of two or four courses of S-1 (1 M tegafur-0.4 M gimestat-1 M ostat potassium) plus cisplatin or paclitaxel plus cisplatin by a two-by-two factorial design for patients with macroscopically resectable locally advanced gastric cancer. The primary endpoint is the 3-year overall survival. The sample size is 60-80 in a total for two hypotheses of the superiority of four courses to two courses and the superiority of paclitaxel plus cisplatin to S-1 plus cisplatin. In both arms, S-1 is strongly recommended post-operatively for at least 6 months but no adjuvant chemotherapy is permitted other than S-1 until recurrence. This trial could appraise more suitable cycles and regimen as neoadjuvant chemotherapy for gastric cancer.

A synthetic kainoid, (2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid (PSPA-1) serves as a novel anti-allodynic agent for neuropathic pain.

In spite of prominent progress in basic pain research, neuropathic pain remains a significant medical problem, because it is often poorly relieved by conventional analgesics. Thus this situation encourages us to make more sophisticated efforts toward the discovery of new analgesics. We previously showed that i.t. administration of acromelic acid-A (ACRO-A), a Japanese mushroom poison, provoked prominent tactile pain (allodynia) at an extremely low dose of 1 fg/mouse. In the present study we synthesized ACRO-A analogues (2S,3R,4R)-3-carboxymethyl-4-phenoxypyrrolidine-2-carboxylic acid (POPA-2) and (2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid (PSPA-1) chemically and examined their ability to induce allodynia in conscious mice. Whereas POPA-2 induced allodynia at extremely low doses from 1 to 100 fg/mouse, similar to ACRO-A, PSPA-1 did not induce allodynia; rather, it inhibited the ACRO-A-induced allodynia with an ID(50) value (95% confidence limits) of 2.19 fg/mouse (0.04-31.8 fg/mouse). Furthermore, PSPA-1 relieved neuropathic pain produced by L5 spinal nerve transection on day 7 after the operation in a dose-dependent manner from 1 to 100 pg/mouse. In contrast, it did not affect thermal or mechanical nociception or inflammatory pain. PSPA-1 reduced the increase in neuronal nitric oxide synthase activity in the spinal cord of neuropathic pain mice assessed by NADPH-diaphorase histochemistry and blocked the allodynia induced by N-methyl-d-aspartate. These results demonstrate that PSPA-1 may represent a novel class of anti-allodynic agents for neuropathic pain acting by blocking the glutamate-nitric oxide pathway.

Analgesic effect of extracts of Chinese medicinal herbs Moutan cortex and Coicis semen on neuropathic pain in mice.

Neuropathic pain arising from peripheral nerve injury is a clinical disorder characterized by a combination of spontaneous pain, hyperalgesia and tactile pain (allodynia), and remains a significant clinical problem since it is often poorly relieved by conventional analgesics. To seek an analgesic compound(s) in Chinese herbs, we examined the effect of seven Chinese herbs that are routinely prescribed for pain management in two neuropathic pain models: allodynia induced by intrathecal administration of prostaglandin F2alpha (PGF2alpha) and by selective L5 spinal nerve transection. The extracts of Moutan cortex and Coicis semen dose-dependently alleviated the PGF2alpha-induced allodynia by oral administration 1 h before intrathecal injection of PGF2alpha. When orally administrated every day for 7 days, these extracts attenuated neuropathic pain in the ipsilateral side, but not in the contralateral side, day 7 after L5 spinal nerve transection. The increase in NADPH diaphorase activity in the spinal cord associated with neuropathic pain was also blocked by these extracts. These results suggest that Moutan cortex and Coicis semen contain substances effective in neuropathic pain.

Characterization of the isoforms of MOVO zinc finger protein, a mouse homologue of Drosophila Ovo, as transcription factors.

We previously described two isoforms (MOVO-A and -B) of a novel zinc finger protein MOVO, a mouse homologue of Drosophila Ovo protein. Here, we isolated cDNA encoding the third isoform MOVO-C, which had a transactivation domain and zinc finger domain, but lacked an N-terminal potential repression domain that was present in MOVO-A. Three isoform mRNAs were expressed highly in mouse testis and also in the ovary at lower levels. The structural analyses of the isolated Movo gene and mRNAs demonstrated that three different Movo transcripts were differentially processed to generate three isoforms. Major mRNA species encoded MOVO-B with a zinc finger domain alone, and minor mRNA species encoded MOVO-A (potential repressor) and MOVO-C (potential activator). To assign MOVO to a transcriptional factor, we characterized DNA-binding and transactivation properties. Random oligonucleotide selection, electrophoretic mobility shift assay and footprinting indicated that MOVO bound to the sequence, 5'-G(G/C/T)GGGGG-3'. These motifs were found in the 5'-flanking regions of Movo and other testis-specific genes. Nuclear proteins binding to this motif were detected in mouse testis, and the expression of MOVO mRNA was restricted in spermatocytes. The luciferase assay demonstrated that MOVO-C activated Movo promoter and MOVO-A repressed it, but MOVO-B had no effects. Mutated MOVO-binding motifs in the Movo promoter reduced the luciferase activity. All the isoforms had no effects on SV40 promoter without MOVO-binding motifs. MOVO-A partially rescued oogenesis of a Drosophila ovo mutant. These results suggest that MOVO isoforms are transcription factors to regulate genes carrying the MOVO-binding motifs in the testis.

Acute and late effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic acid.

1. Ingestion of a poisonous mushroom Clitocybe acromelalga is known to cause severe tactile pain (allodynia) in the extremities for a month and acromelic acid (ACRO), a kainate analogue isolated from the mushroom, produces selective damage of interneurons of the rat lower spinal cord when injected either systemically or intrathecally. Since ACRO has two isomers, ACRO-A and ACRO-B, here we examined their acute and late effects on induction of allodynia. 2. Intrathecal administration of ACRO-A and ACRO-B provoked marked allodynia by the first stimulus 5 min after injection, which lasted over the 50-min experimental period. Dose-dependency of the acute effect of ACRO-A on induction of allodynia showed a bell-shaped pattern from 50 ag x kg(-1) to 0.5 pg x kg(-1) and the maximum effect was observed at 50 fg x kg(-1). On the other hand, ACRO-B induced allodynia in a dose-dependent manner from 50 pg x kg(-1) to 50 ng x kg(-1). 3. N-methyl-d-aspartate (NMDA) receptor antagonists and Joro spider toxin, a Ca(2+)-permeable AMPA receptor antagonist, inhibited the allodynia induced by ACRO-A, but not by ACRO-B. However, other AMPA/kainate antagonists did not affect the allodynia induced by ACRO. 4. Whereas no neuronal damage was observed in the spinal cord in ACRO-A-treated mice, induction of allodynia by ACRO-A (50 fg x kg(-1)) and ACRO-B (50 ng x kg(-1)) was selectively lost 1 week after i.t. injection of a sublethal dose of ACRO-A (50 ng x kg(-1)) or ACRO-B (250 ng x kg(-1)). Higher doses of ACRO-A, however, could evoke allodynia dose-dependently from 50 pg x kg(-1) to 500 ng x kg(-1) in the ACRO-A-treated mice. The allodynia induced by ACRO-A (500 ng x kg(-1)) was not inhibited by Joro spider toxin or NMDA receptor antagonists. These properties of the late allodynia induced by ACRO-A were quite similar to those of the acute allodynia induced by ACRO-B. 5. ACRO-A could increase [Ca(2+)](i) in the deeper laminae, rather than in the superficial laminae, of the spinal cord. This increase was not blocked by the AMPA-preferring antagonist GYKI52466 and Joro spider toxin. 6. Taken together, these results demonstrate the stereospecificity of ACRO for the induction of allodynia and suggest the presence of a receptor specific to ACRO.

Characterization of N-methyl-D-aspartate receptor subunits involved in acute ammonia toxicity.

Rapid administration of large doses of ammonia leads to death of animals, which is largely prevented by pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists. The present study focuses on a subunit(s) of NMDA receptor involved in ammonia-induced death by use of NMDA receptor GluRepsilon subunit-deficient (GluRepsilon(-/-)) mice and the selective GluRepsilon2 antagonist CP-101,606. Acute ammonia intoxication was induced in mice (eight per group) by a single intraperitoneal (i.p.) injection of ammonium chloride. Appearance of neurological deteriorations depended on the doses of ammonium chloride injected. While wild-type, GluRepsilon1(-/-), GluRepsilon4(-/-), and GluRepsilon1(-/-)/epsilon4(-/-) mice all died by ammonium chloride at 12 mmol/kg during the first tonic convulsions, two of eight GluRepsilon3(-/-) mice survived. Pretreatment of wild-type mice with CP-101,606 prevented two mice from ammonia-induced death. Pretreatment of GluRepsilon3(-/-) mice with CP-101,606 prevented the death of three mice and prolonged the time of death of non-survivors. Similarly, the neuronal form of nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI) as well as the nonselective NOS inhibitor L-NMMA, but not the inducible NOS inhibitor 1400W, partially prevented the death of mice and prolonged the period of death. Furthermore, ammonium chloride prolonged the increase in intracellular free Ca2+ concentration ([Ca2+]i) and subsequent NO production induced by NMDA in the cerebellum. These results suggest that activation of NMDA receptor containing GluRepsilon2 and GluRepsilon3 subunits and following activation of neuronal NOS are involved in acute ammonia intoxication which leads to death of animals.