Risk factors for febrile neutropenia in neoadjuvant docetaxel, cisplatin, and 5-fluorouracil chemotherapy for esophageal cancer.

PURPOSE: The aim of the present study was to evaluate the incidence and explore the risk factors of febrile neutropenia (FN) in patients with esophageal cancer receiving neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy in real-world settings. METHODS: We retrospectively reviewed clinical data of 128 consecutive patients with esophageal cancer. Specifically, these patients underwent neoadjuvant DCF chemotherapy with prophylactic antibiotic administration at our institution between July 2009 and January 2015. Two FN-related endpoints were set as follows: definite FN (dFN) defined as grade 4 neutropenia at the onset of fever and clinically suspected FN (csFN), which included both patients with dFN and patients without grade 4 neutropenia but with deteriorating grade 3 neutropenia at the onset of fever who were clinically diagnosed with FN for which they underwent treatment. The risk factors for dFN and csFN were evaluated based on patients' characteristics. RESULTS: A total of 72 (56.3%) patients developed grade 3 or grade 4 neutropenia and 26 (20.3%) developed csFN including 14 (10.9%) with dFN. Multivariate analysis revealed that older age (OR 3.57, CI 1.27-10.1, P = 0.016) and living alone (OR 5.17, 95% CI 1.26-21.3, P = 0.023) were statistically significant risk factors for csFN development. As to dFN, no statistically significant risk factors were identified. CONCLUSIONS: Older age and living alone are significant risk factors for developing FN, and thus, particularly for patients with risk factors for FN, G-CSF should be considered instead of prophylactic antibiotics with careful observation.

Evaluation of community pharmacist ability to ensure the safe use of oral anticancer agents: a nationwide survey in Japan.

OBJECTIVES: A recent study of community pharmacists in Canada reported that they required additional education. We conducted a survey of community pharmacists to evaluate the adequacy of education and training in oral anticancer agents in Japan. METHODS: Between May and June 2014, community pharmacists were asked to complete a questionnaire by using two different survey strategies, one online and one via postal mail. RESULTS: Three hundred community pharmacists responded to an online survey and 283 community pharmacists responded to a mailed survey. Only 6-10% of respondents felt that they had received adequate education in oncology or oral chemotherapy. Although 81% of Japanese pharmacists had attended at least one continuing education event related to oncology in the past 2 years, only 54% felt comfortable dispensing oral anticancer agents and only 40% felt comfortable educating patients about oral chemotherapy. In a multivariate analysis, confidence in educating patients about oral chemotherapy was associated with an understanding of chemotherapy cycles and doses (odds ratio = 4.89, 95% confidence interval [2.53-9.45]) and the number of continuing education events they had attended (odds ratio = 1.67, 95% confidence interval [1.35-2.08]). CONCLUSIONS: This is the first report to evaluate whether community pharmacists are equipped to ensure the safe use of oral anticancer agents in Japan. The results are similar to those previously reported for Canadian pharmacists, namely a low rate of positive responses for education in oncology and oral chemotherapy, demonstrating a similar need for additional education and training in oral chemotherapy.

Chemotherapy regimen checks performed by pharmacists contribute to safe administration of chemotherapy.

Background Computerized provider order entry (CPOE) has been developed and implemented within cancer center hospitals nationwide in Japan. To ensure that high-quality services are routinely provided by oncology pharmacists, this study was designed to evaluate the interventions through reviewing the orders that are generated by CPOE. Methods The objective of this retrospective chart review was to evaluate how pharmacists contributed to safe cancer treatment using paper-based pharmacy records. Data were collected from a total of 35,062 chemotherapy regimens for 18,515 outpatients between January and December 2013. Results Of these 35,062 chemotherapy regimens, the rate of pharmacists' interventions was 1.1% ( n = 408). Among them, 53.1% (217/408) of the chemotherapy prescriptions were modified due to pharmacist interventions. The reasons for interventions included "changes in the chemotherapy regimen were unclear" in 49.5%, "physicians' prescription errors" (22.0%), "pharmacist suggestions to improve chemotherapy" (15.1%), and "finding differences between physicians' chemotherapy records and their chemotherapy prescriptions" (13.2%). The top three reasons for the 217 prescription modifications due to pharmacist interventions were "finding prescription errors" (34.5%), "reasons for change in the chemotherapy regimen were unclear" (32.7%), and "finding differences between physicians' chemotherapy records and their chemotherapy prescriptions" (28.5%). Conclusion The computer could not evaluate chemotherapy protocols or adjust doses of anticancer medicines according to patients' conditions. Therefore, oncology pharmacists should continue to ensure safe and appropriate administration of cancer chemotherapy.

Stability of lenalidomide suspension after preparation by a simple suspension method for enteral tube administration.

PURPOSE: A simple suspension method has been developed for tube administration, in which tablets (and capsules) are disintegrated in hot water (55℃) without grinding (or opening) them. In the present study, we evaluated the feasibility of this simple suspension method for the preparation of lenalidomide (Celgene, Summit, New Jersey and USA) suspension by testing the stability of this drug at 55℃ and its adsorbability on the tube. METHODS: We examined, by high-performance liquid chromatography, the time-dependent changes in the concentration of lenalidomide in suspensions of the drug prepared by the simple suspension method. The high-performance liquid chromatography analyses of lenalidomide were performed on Prominence LC-20AB/SPD-20 A (Shimadzu, Kyoto, Japan) with a ZORBAX SB-C18 RR analytical column (Agilent Technologies, Santa Clara, California, USA; particle size: 2.1 × 100 mm, 3.5 µm) at a flow rate of 0.4 mL/min. A solvent system consisting of 10 mM ammonium acetate (pH 7.0)/acetonitrile was used as the eluent and the eluate was detected by UV at 254 nm. RESULTS: Lenalidomide was confirmed to remain stable in hot water at 55℃ for 24 h in the prepared suspension by the simple suspension method, and more than 99% of the drug could be recovered from the suspension. In addition, 94.5-98.0% of the drug amount could pass through a percutaneous endoscopic gastrostomy tube. Lenalidomide was scarcely adsorbed on to the percutaneous endoscopic gastrostomy tube made of polyurethane or polyvinyl chloride. CONCLUSION: Lenalidomide was found to be stable even in hot water and was not adsorbed on to the percutaneous endoscopic gastrostomy tube.

Extracorporeal Shock Wave Therapy for Digital Ulcers of Systemic Sclerosis: A Phase 2 Pilot Study.

Patients with systemic sclerosis (SSc) often display Raynaud's phenomenon and digital skin ulcers. As these ulcers are not associated with autoimmune factors or abnormal coagulation, conventional immunosuppressive therapies, vasodilators, and anticoagulants are often ineffective. Here, we used extracorporeal shock wave therapy (ESWT) to treat these ulcers. Nine SSc patients with new digital ulcers, previously treated with at least one currently available vasodilator or anticoagulant were enrolled. One ESWT session consisted of 100 pulses at 0.08-0.25 mJ/mm(2) in 20 areas on both hands and 15 areas on both feet, totaling 7,000 pulses. Treatment was performed once per week for 9 weeks with observations over 20 weeks. Outcomes were evaluated according to the number and diameter of ulcers, Rodnan skin score, Health Assessment Questionnaire (HAQ), EuroQol 5 dimensions (EQ-5D), visual analog scale for pain, and the PainVision system. The surface skin temperature of all the fingers was measured using thermography. Ulcers showed signs of healing after one session, and their mean number decreased from 5.4 to 1.1 at 9 weeks. In particular, of the 18 large ulcers (> 5 mm) observed in 7 patients before the treatment, 10 disappeared and the rest became smaller; namely, the mean size decreased from 10.9 mm to 2.5 mm at 20 weeks. The average scores on the HAQ, EQ-5D, and PainVision system also improved. Treatment was minimally invasive and could be repeated without any adverse effects. ESWT may be added to standard treatments for indolent digital ulcers of SSc, as an effective and safe method.

[The Usefulness of Outpatient Pharmacy Services in Adjuvant Chemotherapy for Gastric Cancer].

Outpatient pharmacy services were established since June 2009 for educating about the signs and symptoms that required treatment, explaining how to receive an emergency service, improving a patient's adherence, and managing side effects. In this study, we evaluated the usefulness of one of our outpatient pharmacy services, which aims to help patients receiving adjuvant chemotherapy including S-1 monotherapy for gastric cancer. In total, 34 and 80 patients received S-1 monotherapy without or with the intervention of outpatient pharmacy services, respectively; additionally, the median ages of the former and latter were 68 and 65 years, respectively. The treatment completion rates(82.4% versus 67.5%)were similar between the 2 groups(odds ratio[OR]: 0.45, 95% confidence interval[CI]: 0.16-1.21, p=0.106). Their emergency visit rates were 23.5% and 8.8%(OR: 0.31, 95% Cl: 0.10-0.94, p<0.05). Emergency hospitalization was required for 8.8% and 0% of the population from each group(OR: 0.00, 95% CI: not significant, p<0.05). We suggest that outpatient pharmacy services are useful because they are likely to improve a patient's safety.

[Efficacy of Ipragliflozin in Patients with Steroid-Induced Hyperglycemia during Cancer Chemotherapy].

Steroid is a key drug in cancer chemotherapy-induced emesis. However, it may sometimes cause inadequately controlled hyperglycemia. Ipragliflozin is a novel selective sodium-dependent glucose cotransporter 2 inhibitor of urinary glucose excretion. In this case, we controlled steroid-induced hyperglycemia by administering ipragliflozin. The case was a 47-year-old man who was diagnosed with Stage IV esophageal cancer (T3N2M1). He had type 2 diabetes. He was treated with cisplatin (70 mg/m2; day 1) and 5-FU (700 mg/m2; days 1-4) as radiochemotherapy. Intravenous infusion of dexamethasone (9.9 mg) was administered on day 1, followed by additional doses (6.6 mg) for 3 days, as one of the emetic therapies. He received intensive insulin therapy during the first course of chemotherapy, but had Grade 3 hyperglycemia regardless. For the next treatment course, we additionally administered ipragliflozin along with dexamethasone. As a result, the hyperglycemia subsided to Grade 2. These findings suggest that ipragliflozin suppresses steroid-induced hyperglycemia.

[Evaluation of Drug Interaction between S-1 and Warfarin].

Prolonged prothrombin time is observed in patients taking warfarin (WF) with a fluoropyrimidine, such as S-1. When WF is combined with S-1, the prothrombin time-international normalized ratio (PT-INR) and dose adjustment of WF should be closely monitored. To date, no clinical data have been reported in terms of the relation between temporal variation of PT-INR and its therapeutic range. In this study, we retrospectively collected patients' clinical data including PT-INR. We identified 21 patients receiving WF therapy before the start of S-1 treatment. Patient characteristics were male/female: 18/3, median age: 69 (range 48-81) years old, cancer of gastric/lung/pancreatic/other: 8/5/4/4, and history of deep vein thrombosis (DVT)/atrial fibrillation (AF)/cerebral infarction (CI)/other: 11/6/2/2. The PT-INR of 16 patients exceeded normal upper limits after taking S-1 with WF. The median time to exceed the PT-INR upper therapeutic range is 25 (range 3-77) days. Patients receiving WF anticoagulant therapy concomitant with S-1 should have their PT-INR closely monitored and WF doses adjusted accordingly.

Autophagy plays a protective role as an anti-oxidant system in human T cells and represents a novel strategy for induction of T-cell apoptosis.

Autophagy is an intracellular degradation system that plays an important role in T-cell survival. However, the precise mechanism linking autophagy and cell death in primary human T cells is unclear because methods for monitoring autophagy in small numbers of primary human cells remain controversial. We established a novel method for assessing autophagy in activated human T cells using a retroviral GFP-LC3 expression system. We found that autophagy was induced after TCR stimulation and that autophagy-defective naïve CD4(+) T cells were susceptible to apoptosis through the intrinsic apoptotic pathway. Enhanced apoptosis of autophagy-defective T cells resulted from accumulation of ROS due to impaired mitophagy. We also demonstrated that effector memory CD4(+) T cells had lower autophagic activity than naïve CD4(+) T cells, which contributed to their enhanced apoptosis due to increased ROS. Moreover, blocking autophagy increased intracellular mitochondrial volume and ROS levels in activated T cells. These results suggest a protective role of autophagy as an anti-oxidant system in activated human T cells. The combination of an autophagy blocker and a mitochondrial electron transport chain inhibitor has a synergistic effect on T-cell death, which could be a novel strategy for induction of T-cell apoptosis.

Resveratrol derivative-rich melinjo (Gnetum gnemon L.) seed extract improves obesity and survival of C57BL/6 mice fed a high-fat diet.

Melinjo (Gnetum gnemon L.) seed extracts (MSEs) are rich in resveratrol dimers (gnemonoside A, C, D, gnetin C), trans-resveratrol, and other resveratrol derivatives. trans-Resveratrol is a widely studied caloric restriction mimetic. In mice fed a high-fat diet (HFD), trans-resveratrol protects against obesity, type 2 diabetes, and premature death. Here, treatment of HFD-fed mice with 2.0% MSE significantly reduced body weight gain (p < 0.001), blood insulin (p < 0.01), and HOMA-IR (p < 0.05) after 8 weeks compared with untreated HFD-fed mice. Additionally, 0.2% MSE treatment of HFD-fed mice significantly improved physiological activity (p < 0.05) at 18 months of age and reduced risk of death due to HFD by 25% (hazard ratio = 0.75, p = 0.036). These data show that MSE can improve several aspects of metabolic syndrome and survival in mice and may have health benefits as a dietary supplement.

[Information provided by pharmacists regarding the effective timing of the coadministration of first-generation serotonin receptor antagonists and dexamethasone for chemotherapy-induced nausea and vomiting in patients receiving Doxorubicin and cyclophosphamide chemotherapy for breast cancer - the second report].

In this report, we highly recommend the coadministration of first-generation serotonin receptor antagonists, dexamethasone, and aprepitant for chemotherapy-associated nausea and vomiting in patients with breast cancer receiving doxorubicin and cyclophosphamide (AC) chemotherapy. Aprepitant has an advantage of high efficacy rates for the treatment of nausea and vomiting; its disadvantages include the high cost and interactions with other drugs. Herein, we report the information provided by pharmacists regarding the effective timing of the coadministration of first-generation serotonin receptor antagonists and dexamethasone for nausea and vomiting in patients receiving AC chemotherapy for breast cancer. The primary end point was the proportion of patients who achieved a complete response (CR; no emesis or use of rescue therapy)in cycle 1 after receiving AC chemotherapy. A total of 46 patients were enrolled in this study between November 2010 and December 2011. The overall rate of CR (0-120 hours) was 85%. The rates of acute (0-24 hours) and delayed (24-120 hours)CR were 85% and 93%, respectively. These findings suggest that the information provided by pharmacists regarding the effective timing of the coadministration of first-generation serotonin receptor antagonists and dexamethasone is effective in patients who cannot be administered with aprepitant.

A novel autoantibody against ephrin type B receptor 2 in acute necrotizing encephalopathy.

Acute necrotizing encephalopathy (ANE) is characterized by symmetrical brain necrosis, suggested to be due to breakdown of the blood-brain barrier (BBB). We experienced a rare case of ANE complicated with systemic lupus erythematosus (SLE), and found that the patient's serum (V10-5) had binding activity to human umbilical vein endothelial cells (HUVECs). By SARF (Serological identification system for Autoantigens using a Retroviral vector and Flow cytometry) method using V10-5 IgG, a clone bound to V10-5 IgG was isolated. This cell clone was integrated with cDNA identical to EphB2, which plays critical roles in neuronal cells and endothelial cells. HUVECs and human brain microvascular endothelial cells expressed EphB2 and the V10-5 IgG bound specifically to EphB2-transfected cells. Anti-EphB2 antibody was not detected in other SLE patients without ANE. In this report, we identified EphB2 as a novel autoantigen, and anti-EphB2 antibody may define a novel group of brain disorders. Anti-EphB2 antibody can interfere not only with endothelial cells including those of the BBB (acting as an anti-endothelial cell antibody), but also neuronal cells (acting as an anti-neuronal antibody) if the BBB has been breached. Future studies should determine the clinical prevalence and specificity of anti-EphB2 antibody, and the molecular mechanisms by which anti-EphB2 antibody mediates neuronal and vascular pathological lesions.

Acute Dose-Response Effectiveness of Combined Catechins and Chlorogenic Acids on Postprandial Glycemic Responses in Healthy Men: Results from Two Randomized Studies.

Epidemiologic studies show that the risk of diabetes can be reduced by ingesting green tea or coffee. Previous studies have shown that simultaneously taking green tea catechins (GTC) and coffee chlorogenic acid (CCA) alters postprandial gastrointestinal hormones secretion and improves insulin sensitivity. However, there is no evidence on the acute effects of GTC and CCA on incretin and blood glucose, and on the respective dose of polyphenols. In this randomized, double-blind, placebo-controlled crossover study, we examined the effective dose of GTC and CCA on postprandial glucose, insulin, and incretin responses to a high-fat and high-carbohydrate cookie meal containing 75 g of glucose in healthy men. Study 1 (n = 18) evaluated two doses of GTC (270 or 540 mg) containing a fixed dose of CCA (270 mg) with 113 mg of caffeine and a placebo (0 mg GTC and 0 mg CCA) with 112 mg of caffeine. Study 2 (n = 18) evaluated two doses of CCA (150 or 300 mg) containing a fixed dose of GTC (540 mg) and a placebo with 99 mg of caffeine. The single combined ingestion of GTC and CCA significantly altered the incretin response and suppressed glucose and insulin levels. These findings suggest that the effective minimum dose is 540 mg of GTC and 150 mg of CCA.

Indirect CRISPR screening with photoconversion revealed key factors of drug resistance with cell-cell interactions.

Comprehensive screenings to clarify indirect cell-cell interactions, such as those in the tumor microenvironment, especially comprehensive assessments of supporting cells' effects, are challenging. Therefore, in this study, indirect CRISPR screening for drug resistance with cell-cell interactions was invented. The photoconvertible fluorescent protein Dendra2 was inducted to supporting cells and explored the drug resistance responsible factors of supporting cells with CRISPR screenings. Random mutated supporting cells co-cultured with leukemic cells induced drug resistance with cell-cell interactions. Supporting cells responsible for drug resistance were isolated with green-to-red photoconversion, and 39 candidate genes were identified. Knocking out C9orf89, MAGI2, MLPH, or RHBDD2 in supporting cells reduced the ratio of apoptosis of cancer cells. In addition, the low expression of RHBDD2 in supporting cells, specifically fibroblasts, of clinical pancreatic cancer showed a shortened prognosis, and a negative correlation with CXCL12 was observed. Indirect CRISPR screening was established to isolate the responsible elements of cell-cell interactions. This screening method could reveal unknown mechanisms in all kinds of cell-cell interactions by revealing live phenotype-inducible cells, and it could be a platform for discovering new targets of drugs for conventional chemotherapies.

Association between breath methane concentration and visceral fat area: a population-based cross-sectional study.

High visceral fat area (VFA) is a stronger predictor of cardiovascular disease and overall mortality, compared with body mass index (BMI) and waist circumference (WC). Recent reports demonstrate that obesity is related to breath gas, which is produced by the intestinal microflora. However, these studies define obesity using BMI, not VFA. In this population-based cross-sectional study, we investigated the relationship between breath gases (methane and hydrogen) and both VFA and BMI. A total of 1033 participants (62% women; age [mean ± standard deviation] 54.4 ± 14.9 years) in the 2015 Iwaki Health Promotion Project in Japan were enrolled in the study. Breath samples were collected using a breath bag and analyzed by gas chromatography. VFA was measured using a visceral fat meter. The proportion of methanogenic bacteria to total intestinal microbiota was measured by polymerase chain reaction and 16S rRNA gene sequencing analysis. Our analysis revealed a significant association between high VFA and low breath methane, even after adjusting for confounding factors (B = -0.024 and P = 0.004). To identify the association between breath methane and VFA in participants with methane-producing bacteria in their intestinal microflora, participants were divided into two groups based on the presence or absence of methanogenic bacteria in their stool. The Methanogen + group was further divided into two subgroups with breath methane higher (Methane-UP) or lower (Methane-LO) than the median breath methane concentration. VFA was significantly lower in the Methane-UP group than in the Methane-LO group. In participants with methanogenic bacteria, breath methane concentration might be an independent biomarker of visceral fat accumulation.

Glucose Response during the Night Is Suppressed by Wheat Albumin in Healthy Participants: A Randomized Controlled Trial.

Postprandial blood glucose excursions are important for achieving optimal glycemic control. In normal-weight individuals, glucose tolerance is diminished in the evening compared to glucose tolerance in the morning. Wheat albumin (WA) has the potential to suppress the postprandial glucose response with a relatively small dose, compared to the dose required when using dietary fiber. In the present study, the effect of WA on glycemic control during the night was investigated after a late evening meal. A randomly assigned crossover trial involving a single oral ingestion in healthy male participants was performed in a double-blind placebo-controlled manner. The participants ingested the placebo (PL) tablets or the WA (1.5 g)-containing tablets 3 min before an evening meal at 22:00 hour, and blood samples were drawn during the night until 07:00 hour using an intravenous cannula. The participants slept from 00:30 hour to 06:30 hour. Glucose response, as a primary outcome during the night, was suppressed significantly by the WA treatment compared to the PL treatment, but the insulin response was not. Plasma glucose-dependent insulinotropic polypeptide concentration during the night was lowered significantly by the WA treatment compared to the PL treatment. In conclusion, WA may be a useful food constituent for glycemic control during the night.

Wheat Albumin Increases the Ratio of Fat to Carbohydrate Oxidation during the Night in Healthy Participants: A Randomized Controlled Trial.

Not only are energy expenditure (EE) and the respiratory quotient (RQ) parameters of the energy nutrient utilization and energy balance, they are also related to the development of obesity. In this study, post-meal night-time energy metabolism was investigated following the oral ingestion of wheat albumin (WA) with a late evening meal. A randomly assigned, double-blind, placebo-controlled crossover trial for a single oral ingestion in healthy participants was completed. The participants ingested the placebo (PL) or WA (1.5 g) containing tablets 3 minutes before the late evening meal at 22:00 hour, and energy metabolism was measured using a whole-room indirect calorie meter until wake-up. The participants were in bed from 00:00 hour until 06:30 hour. Twenty healthy participants completed the trial and were included in the analyses. Night-time RQ and carbohydrate oxidation were significantly lower following the WA treatment as compared with the PL treatment. Although the total EE was not significantly different between treatments, postprandial fat oxidation was significantly higher following the WA treatment as compared with the PL treatment. In conclusion, WA has the potential to shift the energy balance to a higher ratio of fat to carbohydrate oxidation during the night.

Association between Nutrients and Visceral Fat in Healthy Japanese Adults: A 2-Year Longitudinal Study Brief Title: Micronutrients Associated with Visceral Fat Accumulation.

: High visceral fat area (VFA) is a stronger predictor of cardiovascular disease and overall mortality than body mass index or waist circumference. VFA may be decreased by proper dietary habits. Although previous epidemiologic studies demonstrated an association between nutritional components or foodstuffs and VFA, only the associations of a few nutrients, such as dietary fiber and calcium, are reported. We performed a comprehensive 2-year longitudinal study in more than 624 healthy people and analyzed 33 micronutrients to investigate nutrients that contribute to changes in visceral fat. Our analyses revealed that "macronutrients" and "micronutrients" were "mutual confounders". Therefore, when evaluating the association between VFA and micronutrients, associations were adjusted by macronutrients. The ingestion of 7 nutrients: soluble dietary fiber, manganese, potassium, magnesium, vitamin K, folic acid, and pantothenic acid, which are abundant components in vegetable diets, was significantly inversely correlated with a change in VFA. Additionally, a change in the ingestion of one nutrient, monounsaturated fat, was significantly positively correlated with a change in VFA. These associations were independent of body mass index and waist circumference. Thus, a predominantly vegetable diet may decrease VFA. In addition, adjusting the intake of macronutrients might help to clarify the association of micronutrients with VFA.