Contribution of aldehyde oxidase to methotrexate-induced hepatotoxicity: In Vitro and pharmacoepidemiological approaches.

BACKGROUND: Methotrexate (MTX) is partially metabolized by aldehyde oxidase (AOX) in the liver and its clinical impact remains unclear. In this study, we aimed to demonstrate how AOX contributes to MTX-induced hepatotoxicity in vitro and clarify the relationship between concomitant AOX inhibitor use and MTX-associated liver injury development using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: We assessed intracellular MTX accumulation and cytotoxicity using HepG2 cells. We used the FAERS database to detect reporting odds ratio (ROR)-based MTX-related hepatotoxicity event signals. RESULTS: AOX inhibition by AOX inhibitor raloxifene and siRNA increased the MTX accumulation in HepG2 cells and enhanced the MTX-induced cell viability reduction. In the FAERS analysis, the ROR for MTX-related hepatotoxicity increased with non-overlap of 95% confidence interval when co-administered with drugs with higher Imax, u (maximum unbound plasma concentration)/IC50 (half-maximal inhibitory concentration for inhibition of AOX) calculated based on reported pharmacokinetic data. CONCLUSION: AOX inhibition contributed to MTX accumulation in the liver, resulting in increased hepatotoxicity. Our study raises concerns regarding MTX-related hepatotoxicity when co-administered with drugs that possibly inhibit AOX activity at clinical concentrations.

Relationship between umami taste acuity with sweet or bitter taste acuity and food selection in Japanese women university students.

BACKGROUND AND OBJECTIVES: Although there are many studies on the umami receptor and its signaling pathway, literature on the effect of umami taste acuity on dietary choices in healthy subjects is limited. The current study aims to clarify the relationship between umami taste acuity with sweet or bitter taste acuity, food preference and intake. METHODS AND STUDY DESIGN: Forty-two healthy Japanese female university students were enrolled. The acuity for umami, sweet, and bitter tastes was evaluated using the filter-paper disc method. The study population was divided into 32 umami normal tasters and 10 hypo-tasters based on the taste acuity at the posterior part of the tongue using monosodium glutamate. RESULTS: Umami hypo-tasters exhibited a significantly lower sensitivity to sweet tastes than normal tasters. However, the sensitivity to bitter taste was comparable between the two groups. Food preference was examined by the food preference checklist consisted of 81 food items. Among them, umami tasters preferred shellfish, tomato, carrot, milk, low fat milk, cheese, dried shiitake, and kombu significantly more than umami hypo-tasters did. A self-reported food frequency questionnaire revealed no significant differences in the intake of calories and three macronutrients between the two groups; however, umami tasters were found to eat more seaweeds and less sugar than umami hypo-tasters. CONCLUSIONS: These data together may indicate the possibility that umami taste acuity has an effect on a dietary life. Therefore, training umami taste acuity from early childhood is important for a healthy diet later in life.

Percutaneous transesophageal gastro-tubing for management of gastric leakage after sleeve gastrectomy.

Gastric leakage is a challenging complication of sleeve gastrectomy. Multimodal approaches, including drainage, clipping, and stenting of the leak, are occasionally insufficient. We report successful management of refractory gastric leakage using percutaneous transesophageal gastro-tubing (PTEG). Drainage and stenting proved inadequate for treating sleeve leakage near the esophagogastric junction in two patients. PTEG was finally performed, and enteral feeding was started on the following day. The patients were discharged within 1 week. The PTEG-tube was removed after confirming oral food intake. Both patients continue to do well without recurrence. PTEG was developed for patients who are unsuitable for percutaneous endoscopic gastrostomy. PTEG provides decompression and permits enteral feeding in patients refractory to other endoscopic treatments. PTEG is an option for managing intractable sleeve leakage without surgery.

Efficacy and tolerability of controlled-release oxycodone for oxaliplatin-induced peripheral neuropathy and the extension of FOLFOX therapy in advanced colorectal cancer patients.

BACKGROUND: The oxaliplatin-based regimen FOLFOX is widely used to treat patients with advanced colorectal cancer (CRC). However, dose-limiting toxicity after continuous oxaliplatin administration can lead to peripheral neuropathy. Several agents, including opioids, that have been employed to treat oxaliplatin-induced peripheral neuropathy (OIPN) have been examined in clinical settings regarding their protective and therapeutic effects. However, the pharmacotherapy of these agents has not yet been established. Therefore, we investigated the efficacy and tolerability of oxycodone for OIPN and subsequently with FOLFOX therapy in CRC patients. METHODS: This was a single-center retrospective study of 64 CRC patients who underwent FOLFOX therapy at the Toho University Sakura Medical Center (Sakura, Japan). Controlled-release (CR) oxycodone was concomitantly administered to 29 patients (OXY group), whereas the additional 35 patients (non-OXY group) were not given oxycodone during the FOLFOX treatment course. The incidence and severity of OIPN and the number of FOLFOX cycles were measured and compared between the two groups. Neurological toxicities were assessed according to the Common Terminology Criteria for Advanced Events, version 3.0. RESULTS: All study patients had OIPN. Most patients experienced grade 1 or 2 sensory neuropathy. Grade 3 sensory neuropathy was observed in two patients in the non-OXY group. All patients in the OXY group completed the scheduled FOLFOX therapy, whereas FOLFOX therapy was discontinued in ten patients in the non-OXY group due to severe peripheral neuropathy. The median numbers of FOLFOX cycles in the OXY and non-OXY groups were 13 (range, 6-46) and 7 (range, 2-18), respectively (P < 0.05). The median cumulative oxaliplatin doses were 1072.3 mg/m(2) (range, 408.7-3385.3 mg/m(2)) in the OXY group and 483.0 mg/m(2) (range 76.2-1414.1 mg/m(2)) in the non-OXY group (P < 0.05). CONCLUSIONS: Our findings indicate that CR oxycodone might attenuate the severity of OIPN and extend the use of FOLFOX therapy.

Tumor-like growth of giant inflammatory polyposis in a patient with ulcerative colitis.

We report a unique case of giant obstructing inflammatory polyposis associated with ulcerative colitis (UC). A 25-year-old Japanese man with an UC history of 2 years and 6 months was referred to our institution because of diarrhea and melena. His computed tomography scan showed marked dilation of the transverse and descending colon; therefore, we performed total colectomy. Macroscopic evaluation of the excised specimen indicated constricting lesions with giant polyposis in the transverse and descending colon. The polyposis consisted of narrow worm- or noodle-like polyps that bridged over the irregular ulcers. Histologic evaluation of the excised specimen indicated transmural inflammation with a thickened proper muscular layer overlaid with inflammatory polyposis. Based on these data, a diagnosis of giant inflammatory polyposis should be considered in patients who have had UC. Although giant inflammatory polyposis is considered benign, surgical treatment may be indicated to avoid serious complications.

Association between genetic polymorphisms of the ß1-adrenergic receptor and sensitivity to pain and fentanyl in patients undergoing painful cosmetic surgery.

Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. The adrenergic system is reportedly involved in the mechanisms of pain and analgesia. Here, we focused on one of the adrenergic receptor genes, ADRB1, and analyzed the influence of single-nucleotide polymorphisms (SNPs) in the ADRB1 gene on individual differences in pain and analgesic sensitivity. We examined associations between pain and fentanyl sensitivity and the two SNPs, A145G and G1165C, in the human ADRB1 gene in 216 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. The patients who carried the A-allele of the A145G SNP were more sensitive to cold pressor- induced pain than those who did not carry this allele, especially in male patients. The analgesic effect was significantly less in females who carried the G-allele of the G1165C SNP than the females who did not carry the G-allele. The haplotype analysis revealed a significant decrease in 24-h postoperative fentanyl use in female 145A/1165C haplotype carriers. These results suggest that SNPs in the ADRB1 gene are associated with individual differences in pain and analgesic sensitivity, and analyzing these SNPs may promote personalized pain treatment in the future.

Triple-negative breast cancer and poly(ADP-ribose) polymerase inhibitors.

Recent gene profiling studies have identified at least 5 major subtypes of breast cancer, including normal type, luminal A type, luminal B type, human epidermal growth factor receptor (HER)-2 positive type, and basal-like type. Triple-negative breast cancer (TNBC), showing no or low expressions of estrogen receptor (ER), progesterone receptor (PgR), and HER2, considered important clinical biomarkers, accounts for 10% to 20% of all breast cancers. Hormonal therapy and molecular targeted therapy are not indicated for the management of TNBC, resulting in poor outcomes. Because TNBC lacks clear-cut therapeutic targets, effective treatment strategies remain to be established. However, TNBC is known to share similar biologic characteristics with basal-like type breast cancer and is often accompanied by loss of functional BRCA, a gene-modifying enzyme. Breast cancer with BRCA1 or BRCA2 mutations is accompanied by activation of the enzyme poly(ADP-ribose) polymerase (PARP). PARP, a DNA base-excision repair enzyme, is known to play a central role in gene repair, along with BRCA. Because some breast cancers with BRCA1 or BRCA2 mutations are TNBC, the suppression of PARP has attracted attention as a new treatment strategy for TNBC. In this article, we review the clinical characteristics of TNBC, discuss problems in treatment, and briefly summarize the international development status of PARP inhibitors.

Intersigmoid hernia: Report of a case.

A 28-year-old man with no previous history of abdominal surgery presented at a local hospital with abdominal pain. He was diagnosed to have an intestinal obstruction and was treated conservatively. However, the symptoms persisted, and he was thereafter referred to this hospital. Plain abdominal radiographs demonstrated small-bowel gas. A computed tomographic scan of the abdomen disclosed wall thickening of an edematous, fluid-filled ileum. An exploratory laparotomy was performed to determine the cause of the intestinal obstruction. The ileum had herniated into the intersigmoid fossa, 100 cm proximal to the ileocecal valve, and the patient was diagnosed to have an intersigmoid hernia. Since the incarcerated portion of the small bowel was viable, reduction of the hernia and closure of the defect in the sigmoid mesocolon were performed. The postoperative course was uneventful. A sigmoid mesocolon hernia is an uncommon condition. This report presents a case of intersigmoid hernia and a review of 60 cases of sigmoid mesocolon hernia reported in Japan.

[Ten cases of advanced gastro-intestinal cancer that required preoperative dosage of PSK].

We examined ten convalescent cases of local progression digestive organ cancer, which required a radical operation after a 2-week administration of preoperative dosage of PSK. Because adjuvant chemotherapy was performed for all of the cases, 3 out of 5 advanced gastric cancer patients and 4 out of 5 advanced colorectal cancer patients had more than 5-year survival. We might be effective in controlling a host immune compromise for the lap art period, which was our aim, how long preoperative PSK dosage has contributed for the extension of survival duration. We also examined the influence of the dosage in this study in preoperational of PSK, which gave a host immune compromise by the operational aggression so far, and we reported it as well.

[Regulation of perioperative immunological changes following laparotomy--effects of PSK on surgical stress].

Immune responses have been reported to decline following surgical stress, leading to an increased susceptibility to infection or to the growth of tumors. We report that preoperative treatment with PSK can inhibit the decline of immunocompetence during the perioperative period. BALB/c mice were laparotomized, and then the abdomens were closed. The concentrations of IL-6 and of IFN-gamma and IL-4 were measured. PSK treatment controlled the stress induced elevation. It was lower in the group with surgical stress than in the cultures derived from the non-treated group. The IFN-gamma concentration in the group with PSK was significantly higher than the level in the group with surgical stress alone. The IL-4 concentration was significantly lower in the surgical stress group than the control group. However, the concentration tended to be higher in the surgical stress + PSK treatment group than the group with surgical stress alone. The IFN-gamma/IL-4 ratio in the group with surgical stress was lower than the ratio in the non-treated group. The ratio in the group with PSK treatment was significantly higher than the ratio in the group with surgical stress alone. These results suggest that PSK restores the abnormality of the biological responses induced by surgical stress and corrects the reduced Th1/Th2 cytokine balance to a normal level.

Fournier's gangrene progressing from the buttocks to the scrotum following a perianal abscess.

We describe a case of gas-producing infection following a perianal abscess. A 61-year-old man was admitted to our hospital complaining of perineal pain and was found to have a perianal abscess. He was diabetic but had not received treatment for the disease. Although the perianal abscess was drained and antibiotic treatment started, severe swelling of the scrotum, with crepitation, redness, and partial necrosis progressed rapidly. Computed tomography revealed subcutaneous gas formation in the scrotum. A culture study revealed Clostridium, Enterococcus, and numerous other types of bacteria. The patient was diagnosed with Fournier's gangrene caused by infection with Clostridium in combination with other species of bacteria. The infection was refractory to drainage and antibiotic therapy. Thus, repeated extensive debridement of all necrotic tissue in the scrotum was required until healthy granulation was present in the wound. Our case shows that, in patients with Fournier's gangrene caused by infection with Clostridium in combination with other species of bacteria, the mainstay of treatment should be open drainage and aggressive surgical debridement of all necrotic tissue, followed by broad-spectrum antibiotic therapy.