Comparison of preventive effects of combined furosemide and mannitol versus single diuretics, furosemide or mannitol, on cisplatin-induced nephrotoxicity.

Cisplatin (CDDP)-induced nephrotoxicity is a common dose-limiting toxicity, and diuretics are often administered to prevent nephrotoxicity. However, the efficacy and optimal administration of diuretics in preventing CDDP-induced nephrotoxicity remain to be established. This study aimed to evaluate the efficacy of combining furosemide and mannitol to prevent CDDP-induced nephrotoxicity. This was a post-hoc analysis of pooled data from a multicenter, retrospective, observational study, including 396 patients who received one or two diuretics for CDDP-based chemotherapy, compared using propensity score matching. Multivariate logistic regression analyses were used to identify risk factors for nephrotoxicity. There was no significant difference in the incidence of nephrotoxicity between the two groups (22.2% vs. 28.3%, P = 0.416). Hypertension, CDDP dose ≥ 75 mg/m2, and no magnesium supplementation were identified as risk factors for nephrotoxicity, whereas the use of diuretics was not found to be a risk factor. The combination of furosemide and mannitol showed no advantage over a single diuretic in preventing CDDP-induced nephrotoxicity. The renal function of patients receiving CDDP-based chemotherapy (≥ 75 mg/m2) and that of those with hypertension should be carefully monitored. Magnesium supplementation is important for these patients.

Preventive effect of 20 mEq and 8 mEq magnesium supplementation on cisplatin-induced nephrotoxicity: a propensity score-matched analysis.

PURPOSE: The protective effect of magnesium (Mg) supplementation against cisplatin (CDDP)-induced nephrotoxicity has been widely described; however, the optimal dose of Mg supplementation is unclear. The aim of this study was to investigate whether 20 mEq of Mg supplementation is more effective than 8 mEq Mg in preventing CDDP-induced nephrotoxicity, as well as the associated risk factors, in cancer patients treated with CDDP-based chemotherapy. METHODS: Pooled data of 272 patients receiving 20 mEq or 8 mEq Mg supplementation to CDDP-based chemotherapy from a multicenter, retrospective, observational study were compared using propensity score matching. Separate multivariate logistic regression analyses were used to identify the risk factors for renal failure induced by each treatment dose. RESULTS: There was no significant difference in the incidence of nephrotoxicity between the 8 mEq and 20 mEq groups (P = 0.926). There was also no significant difference in the severity of nephrotoxicity, elevated serum creatinine levels, and decreased estimated creatinine clearance levels between the two groups. Cardiac disease and albumin levels were identified as independent risk factors for CDDP-induced nephrotoxicity. CONCLUSION: We did not find an advantage of 20 mEq over 8 mEq Mg supplementation in terms of a preventive effect against CDDP-induced nephrotoxicity. The optimal dose of Mg supplementation for the prevention of CDDP-induced nephrotoxicity remains unknown, and further studies are warranted.

Risk Factors for Cisplatin-Induced Nephrotoxicity: A Multicenter Retrospective Study.

INTRODUCTION: Cisplatin (CDDP)-induced nephrotoxicity is a concern in CDDP-based chemotherapy. The goal of this multicenter retrospective study was to identify potential risk factors for CDDP nephrotoxicity. METHODS: Clinical data were reviewed for 762 patients who underwent chemotherapy including CDDP ≥60 mg/m2 per day from Spring 2014 to September 2016. CDDP nephrotoxicity was defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events for acute kidney injury. Univariate and multivariate logistic regression analyses were performed to identify risk factors for CDDP nephrotoxicity. RESULTS: CDDP nephrotoxicity was observed in 165 patients (21.7%). Multivariate analysis showed a significantly higher rate of CDDP nephrotoxicity in patients with cardiac disease (odds ratio [OR]: 2.05, 95% confidence interval [CI]: 1.07-3.93, p = 0.03), hypertension (OR: 1.57, 95% CI: 1.06-2.32, p = 0.02), and high-dose CDDP therapy (OR: 2.15, 95% CI: 1.50-3.07, p < 0.01). Magnesium (Mg) supplementation (OR: 0.65, 95% CI: 0.45-0.93, p = 0.02) and diuretic use (OR: 0.22, 95% CI: 0.08-0.63, p < 0.01) were also independent risk factors for CDDP nephrotoxicity. CONCLUSIONS: Our results suggest that high-dose CDDP and comorbidities of cardiac disease and hypertension are independent risk factors for CDDP nephrotoxicity. Therefore, close monitoring of serum creatinine values during CDDP treatment is recommended for patients with these risk factors. In addition, Mg supplementation and administration of diuretics might be effective for prevention of CDDP nephrotoxicity.

Risk factors for delayed chemotherapy-induced nausea and vomiting with low-emetic-risk chemotherapy: a prospective, observational, multicenter study.

PURPOSE: Improvement in the control of delayed chemotherapy-induced nausea and vomiting (CINV) is needed. There is limited information on antiemetic prophylaxis for patients undergoing low-emetic-risk chemotherapy (LEC), and the optimal antiemetic treatment is not well understood. Therefore, we analyzed the risk factors for delayed CINV to aid in the development of individualized treatments. PATIENTS AND METHODS: This prospective multicenter study was conducted in 13 hospitals and included patients with solid cancers undergoing LEC. A total of 222 patients were enrolled between September 2013 and November 2014. The participants completed a daily diary for 5 days after the commencement of the first cycle of LEC to describe the daily incidence of CINV (yes/no). Furthermore, the participants described the severity of nausea and the amount of food intake with the help of VAS. RESULTS: Two hundred and ten patients provided their data that were analyzed using multivariate logistic regression to examine the risk factors for delayed CINV. History of CINV, Eastern Cooperative Oncology Group performance status score ≥1, acute CINV, and single-day antiemetic prophylaxis were identified as independent risk factors for delayed CINV. CONCLUSION: The current use of antiemetic prophylaxis according to the recommended guideline appears to effectively control delayed CINV in patients undergoing LEC. Therefore, patients with the abovementioned risk factors should be carefully observed, and their treatment should be adjusted according to their symptoms. The use of multiple-day dexamethasone may be beneficial for those patients who develop acute CINV, especially when it is accompanied by anorexia.

A prospective, observational, multicenter study on risk factors and prophylaxis for low emetic risk chemotherapy-induced nausea and vomiting.

PURPOSE: The incidence of and the risk factors for nausea and vomiting in patients undergoing low emetic risk chemotherapy (LEC) are unclear. The aim of the study was to provide information on these topics by performing a multicenter, observational, prospective study. METHODS: The study consisted of patients who were administered first-time LEC that was consistent or inconsistent with current guidelines. Using the visual analog scale, patients recorded their daily food intake and the occurrence and severity of nausea over a 5-day treatment period. RESULTS: The overall incidence of chemotherapy-induced nausea and vomiting did not differ significantly between patients undergoing guideline-consistent (n = 89) or guideline-inconsistent (n = 121) prophylaxis (30.3 vs. 22.3%, respectively; P = 0.19). Logistic regression analysis identified a history of nausea and LEC other than taxanes as independent risk factors associated with nausea and vomiting in patients undergoing LEC. The mean daily visual analog scale scores for nausea severity and a decrease in food intake were <25 mm throughout the entire observation period. CONCLUSIONS: Guideline-consistent prophylaxis appeared to control nausea and vomiting effectively in patients undergoing LEC. However, patients with a history of nausea and receiving LEC other than taxanes should be carefully observed and treatment should be adjusted according to their symptoms.

Cerebral blood flow and metabolism associated with cerebral microbleeds in small vessel disease.

OBJECTIVE: Cerebral microbleeds (CMBs), probably reflecting microangiopathy, have not yet sufficiently been examined in association with cerebral blood flow (CBF) and metabolism. We investigated the relationships between CMBs, and CBF and metabolism in symptomatic small vessel disease. METHODS: We enrolled 22 patients with symptomatic small vessel disease without severe stenosis (>50 %) in major cerebral arteries. Volumes of white matter lesions (WMLs) and number of CMBs were assessed on images of fluid-attenuated inversion recovery and gradient-echo T2*-weighted magnetic resonance imaging, respectively. Patients were divided into two groups according to the median number of CMBs (group I <5, n = 10; group II ≥5, n = 12). Parametric images of CBF, cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction and cerebral blood volume were estimated using positron emission tomography and (15)O-labeled gases. The functional values in the cortex-subcortex, basal ganglia, and centrum semiovale were compared between the two groups. RESULTS: Volumes of WMLs of group II were larger than those of group I (median: 38.4; range: 25.1-91.5 mL vs. median: 11.3; range: 4.2-73.4 mL, p = 0.01). In the centrum semiovale, the mean CBF of group II was significantly lower than that of group I (12.6 ± 2.6 vs. 15.6 ± 3.3 mL/100 g/min, p = 0.04). In the other regions, there were no significant differences in either CBF or CMRO2 between the two groups. CONCLUSIONS: Our study indicated that increases in the number of CMBs with larger volumes of WMLs were associated with cerebral ischemia in the deep white matter in patients with symptomatic small vessel disease.

Effect of Plasma Fibrinogen, High-Sensitive C-Reactive Protein, and Cigarette Smoking on Carotid Atherosclerosis: The Suita Study.

BACKGROUND: Few studies have reported on the association between inflammatory markers and atherosclerosis by smoking status. We investigated the effect of plasma levels of fibrinogen and high-sensitive C-reactive protein (hsCRP) on subclinical atherosclerosis stratified by smoking in a general urban population. METHODS: From participants of the Suita study without a history of cardiovascular diseases, a total of 2502 subjects (805 men, median age 64 years) who underwent carotid ultrasonography were enrolled. Subjects were divided into current smokers (n = 566) and never-smokers. Ex-smokers were not included in the study. Each group was subdivided according to the median levels of markers (plasma fibrinogen [2.99 g/L] and hsCRP [.51 mg/L]) and the smoking amounts. We compare the adjusted maximum and mean intima-media thickness (IMT). RESULTS: In men and women, maximum IMT and mean IMT of the high fibrinogen and high hsCRP (Fib(H)CRP(H)) with smoking were thicker than those of the low fibrinogen and low hsCRP (Fib(L)CRP(L)) without smoking, the Fib(L)CRP(L) with smoking, and the Fib(H)CRP(H) without smoking after adjusting for covariates. The Fib(L)CRP(L) with smoking had thicker IMTs than the Fib(L)CRP(L) without smoking. There was a dose-dependent smoking effect on IMT in men. These trends were similar in age 60, 65, and 70. CONCLUSIONS: Plasma fibrinogen and hsCRP levels were related to multivariate-adjusted IMT, and smoking was associated with IMT in men. The combination of plasma fibrinogen and hsCRP levels could be a potential marker on subclinical carotid atherosclerosis in urban people.

Subsequent vascular events after ischemic stroke: the Japan Statin Treatment Against Recurrent Stroke-Longitudinal.

BACKGROUND: We undertook a multicenter cohort observational study to investigate the frequency and type of subsequent vascular events after an ischemic stroke and to compare the rates of vascular events between patients with and without hyperlipidemia. METHODS: This nationwide study was conducted in 19 hospitals participating in the Japan Standard Stroke Registry Study. We enrolled ischemic stroke patients, including those with a transient ischemic attack, who had not experienced any vascular events before enrollment after their ischemic stroke events. Each subject was observed prospectively from September 1, 2003, to October 1, 2005, or until a primary end point or death. Primary end points included subsequent fatal or nonfatal vascular events: stroke, angina pectoris, acute myocardial infarction, aortic aneurysm, or arteriosclerosis obliterans. RESULTS: A total of 449 patients (mean age, 67.6 years; 64.8% men) were enrolled in this study. Of the 41 vascular events observed during follow-up, 40 were stroke. The median observation period was 568 days. We found that patients with hyperlipidemia had a significantly higher rate of vascular events compared with those without hyperlipidemia according to the Kaplan-Meier method and the log-rank test (P = .013). Hyperlipidemia significantly increased the risk of vascular events (hazard ratio, 2.169 [1.125-4.312]; P = .021) according to the Cox proportional hazard model after adjusting for confounding factors (age, sex, days from ischemic stroke until enrollment, smoking habits, and daily drinking habits). CONCLUSIONS: This study demonstrated that stroke was the most common subsequent vascular event after ischemic stroke; the study also indicated that hyperlipidemia could be a risk factor for subsequent vascular events after ischemic stroke.

Stroke education using an animated cartoon and a manga for junior high school students.

BACKGROUND: We investigated whether junior high school students could be educated regarding stroke with an animated cartoon and a Manga that we produced for the purpose of dissemination of this knowledge. METHODS: We produced a 10-minute animated cartoon and a Manga that provided information regarding stroke risk factors, stroke signs and symptoms, and awareness to immediately contact emergent medical service (EMS) on identification of stroke signs and symptoms. From December 2011 to March 2012, 493 students in 15 classes of the first grade (age 12-13 years) of 3 junior high schools were enrolled in the study. Each subject watched the animated cartoon and read the Manga; this was referred to as "training." Lessons about stroke were not given. Questionnaires on stroke knowledge were evaluated at baseline, immediately after the training, and 3 months after the training. RESULTS: The proportion of correct answers given immediately after the training was higher for all questions, except those related to arrhythmia, compared with baseline. Percentage of correct answers given at 3 months was higher than that at baseline in questions related to facial palsy (75% versus 33%), speech disturbance (91% versus 60%), hemiplegia (79% versus 52%), numbness of 1 side (58% versus 51%), calling for EMS (90% versus 85%), alcohol intake (96% versus 72%), and smoking (69% versus 54%). At 3 months after the training, 56% of students answered the FAST (facial droop, arm weakness, speech disturbance, time to call for EMS) mnemonic correctly. CONCLUSIONS: Stroke education using these teaching aids of the animated cartoon and the Manga improved stroke knowledge in junior high school students.

Stroke education program of act FAST for junior high school students and their parents.

BACKGROUND: We produced a stroke education program using the FAST (facial droop, arm weakness, speech disturbance, time to call an ambulance) mnemonic. AIMS: The aim of this study is to examine efficacy of our education program for junior high school students and their parents. METHODS: One hundred ninety students of 3 junior high schools (aged 12-13 years) and their parents were enrolled. Students received a 45-minute lesson of stroke enlightenment using the FAST mnemonic. Enlightenment items, such as a magnet poster, were distributed. Parents were educated indirectly from their child. Surveys of stroke knowledge were examined at baseline, immediately after the lesson, and at 3 months after the lesson. RESULTS: For the students, correct answers at 3 months were significantly higher than those at baseline in questions of facial palsy (98% versus 33%), speech disturbance (98% versus 54%), numbness on one side (64% versus 42%), weakness on one side (80% versus 51%), calling an ambulance (88% versus 60%), alcohol drinking (85% versus 65%), smoking (70% versus 43%), dyslipidemia (58% versus 46%), hyperglycemia (59% versus 48%), and obesity (47% versus 23%). At 3 months, the parents answered more correctly questions of facial palsy (93% versus 66%), calling an ambulance (95% versus 88%), and alcohol drinking (65% versus 51%) than at baseline. At 3 months, 96% of students and 78% of parents answered the FAST mnemonic correctly. CONCLUSIONS: Our stroke education program improved stroke knowledge, especially the FAST message, for junior high school students and their parents.

Preserved acetazolamide reactivity in lacunar patients with severe white-matter lesions: 15O-labeled gas and H2O positron emission tomography studies.

Limited evidence exists on the relationships between severity of white-matter lesions (WMLs) and cerebral hemodynamics in patients without major cerebral artery disease. To examine changes of cerebral blood flow (CBF), oxygen metabolism, and vascular reserve capacity associated with severity of WML in patients with lacunar stroke, we used a positron emission tomography (PET). Eighteen lacunar patients were divided into two groups according to the severity of WMLs, assessed by Fazekas classification; grades 0 to 1 as mild WML group and grades 2 to 3 as severe WML group. Rapid dual autoradiography was performed with (15)O-labeled gas-PET followed by (15)O-labeled water-PET with acetazolamide (ACZ) challenge. Compared with the mild WML group, the severe WML group showed lower CBF (20.6±4.4 versus 29.9±8.2 mL/100 g per minute, P=0.008), higher oxygen extraction fraction (OEF) (55.2±7.4 versus 46.7±5.3%, P=0.013), and lower cerebral metabolic rate of oxygen (CMRO(2)) (1.95±0.41 versus 2.44±0.42 mL/100 g per minute, P=0.025) in the centrum semiovale. There were no significant differences in the ACZ reactivity between the two groups (48.6±22.6% versus 42.5±17.2%, P=0.524). Lacunar patients with severe WMLs exhibited reduced CBF and CMRO(2), and increased OEF in the centrum semiovale. The ACZ reactivity was preserved in both patients with severe and mild WMLs in each site of the brain.

Gene and protein analysis of brain derived neurotrophic factor expression in relation to neurological recovery induced by an enriched environment in a rat stroke model.

Although an enriched environment enhances functional recovery after ischemic stroke, the mechanism underlying this effect remains unclear. We previously reported that brain derived neurotrophic factor (BDNF) gene expression decreased in rats housed in an enriched environment for 4 weeks compared to those housed in a standard cage for the same period. To further clarify the relationship between the decrease in BDNF and functional recovery, we investigated the effects of differential 2-week housing conditions on the mRNA of BDNF and protein levels of proBDNF and mature BDNF (matBDNF). After transient occlusion of the right middle cerebral artery of male Sprague-Dawley rats, we divided the rats into two groups: (1) an enriched group housed multiply in large cages equipped with toys, and (2) a standard group housed alone in small cages without toys. Behavioral tests before and after 2-week differential housing showed better neurological recovery in the enriched group than in the standard group. Synaptophysin immunostaining demonstrated that the density of synapses in the peri-infarct area was increased in the enriched group compared to the standard group, while infarct volumes were not significantly different. Real-time reverse transcription polymerase chain reaction, Western blotting and immunostaining all revealed no significant difference between the groups. The present results suggest that functional recovery cannot be ascribed to an increase in matBDNF or a decrease in proBDNF but rather to other underlying mechanisms.

Medial medullary infarction identified by diffusion-weighted magnetic resonance imaging.

OBJECTIVE: To elucidate the frequency and clinical profiles of patients with medial medullary infarction (MMI) identified by diffusion-weighted MRI (DWI). METHODS: We assessed the frequency, radiological findings, etiology and clinical features of MMI detected by DWI from our single-center registry of acute ischemic patients. RESULTS: Thirty patients (1.5% of 2,014 with ischemic stroke) had MMI, including isolated unilateral MMI in 26 patients. Lesions were located by DWI in the rostral medulla of 25 patients (83%). Culprit infarcts that were undetectable by DWI in 6 (38%) of 16 patients who were assessed within 24 h after onset were later confirmed as MMI. The major etiological mechanism was small artery occlusion (SAO; 19 patients) and the median initial National Institutes of Health Stroke Scale score was 4 (interquartile range: 3-4.75). The most frequent symptom was contralateral hemiparesis (27 patients). None of the patients fulfilled the classical Dejerine Triad. Twenty-two patients (73%) had a modified Rankin Scale score of ≤2 at 3 months. A patient developed transient ischemic attack within 3 months; none developed recurrent stroke. CONCLUSIONS: Rostral medullary infarction with mild neurological deficits resulting from SAO is relatively frequent. Because emergency DWI within 24 h could not detect MMI in one third of the patients, this type of infarction could be misdiagnosed as capsular/pontine lacunae or other neurological disorders.

Low levels of plasma soluble receptor for advanced glycation end products are associated with severe leukoaraiosis in acute stroke patients.

A secreted isoform of the receptor for advanced glycation end products (RAGE), soluble RAGE (sRAGE), can neutralize the adverse effects of RAGE signaling by acting as a decoy. RAGE signaling contributes to the development of diabetic microangiopathy, however few studies have addressed pivotal roles of RAGE signaling in acute stroke. We examined plasma sRAGE levels associated with clinical features in acute stroke patients. Plasma sRAGE was measured in 482 patients (318 men; mean age 71 years) admitted within three days of stroke onset. Median values of sRAGE were significantly different among stroke subtypes (p=0.001); 1010 pg/ml in atherothrombotic infarction, 933 pg/ml in lacunar, 1280pg/ml in cardioembolic infarction, 1050 pg/ml in other types of infarctions, and 943 pg/ml in primary intracerebral hemorrhage. Severe leukoaraiosis on brain MR images, high NIHSS scores on admission, cigarette smoking, and normal estimated glomerular filtration rate were significantly associated with low sRAGE levels (p<0.05). The low level of sRAGE was associated with severe leukoaraiosis, reflecting long-standing presence of hypertensive angiopathy. Kidneys play a role in the removal of sRAGE. RAGE signaling can contribute to the deterioration of neuronal damage under severe leukoaraiosis, result in a high NIHSS score on admission in acute stroke patients, especially those with smoking habits.

Aggravation of hemorrhagic transformation by early intraarterial infusion of low-dose vascular endothelial growth factor after transient focal cerebral ischemia in rats.

Vascular endothelial growth factor (VEGF) is a unique growth factor associated with angiogenesis, vascular permeability, and neuroprotection. The aim of this study was to observe the effects of early intraarterial infusion of low-dose VEGF on ischemia/reperfusion injury after transient focal cerebral ischemia in rats. Male Sprague-Dawley rats were subjected to 2 h of focal ischemia by middle cerebral artery occlusion. After the 2 h ischemia, the rats were infused with 0.3 microg/kg of VEGF (n = 15), or the vehicle as a control (n = 15), via the reperfused internal carotid artery. The brains were collected after a 1 h, 6 h, or 72 h reperfused period. Severity of ischemic cellular injury, serum extravasation, hemorrhagic transformation, and matrix metalloproteinase (MMP)-2 and -9 expressions were compared between the VEGF-treated and control groups. No significant difference in the extent of ischemic cellular injury and serum extravasation was observed between the two groups. However, vessel numbers with hemorrhagic transformation were significantly greater in the VEGF-treated group than in the control group after the 72 h reperfusion (9.4 +/- 1.6 versus 2.6 +/- 1.5; P = 0.028). The severity of hemorrhagic transformation was not correlated with the extent of ischemic cellular injury or serum extravasation. MMP-2 and -9 expressions were not enhanced in the VEGF-treated group compared with the control group. These results suggest that exogenous VEGF administered intravascularly at a very early point in reperfusion aggravates hemorrhagic transformation. The aggravated hemorrhagic transformation does not seem to depend on the enlargement of ischemic cellular injury, serum extravasation, or overexpressions of MMP-2 and -9.