The emerging emetogenicity of trifluridine/tipiracil (TAS­102) from patient self-reporting: a multicenter, prospective, observational study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001). METHODS: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0. RESULTS: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%. CONCLUSIONS: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment.

Factors Affecting the Comprehension of Outpatients Receiving Cancer Chemotherapy.

Pharmaceutical consultation targeting outpatients at the Fujita Health University Hospital (Japan) provides support to patients undergoing anticancer drug treatment. This study aimed to explore factors that affect the comprehension of cancer chemotherapy among outpatients who received cancer treatment at our hospital. A questionnaire survey was conducted, and comprehension was scored on a scale of 1-5 (1, no comprehension; 5, full comprehension). When factors other than age and sex [the influence of which on comprehension has been reported in previous reports] were noted, differences in comprehension between the questionnaire items were comparatively analyzed according to the presence/absence of the relevant factors. Overall, 536 patients were included. Age (<70 years) and pharmacist interventions were identified as factors contributing to a comprehension score. The levels of comprehension regarding the name of the cancer chemotherapy, content/schedule of the treatment, purposes of the prescribed drugs, and objectives of blood tests were significantly higher in the group that received the pharmaceutical interventions; conversely, the level of comprehension for the self-management of adverse events was significantly lower in this group than in the group that did not receive any pharmaceutical interventions. Age and interventions by the pharmacist affected the comprehension of cancer chemotherapy by patients.

The Influence of Intervening on the Pharmaceutical Consultation Targeting Outpatients with Advanced Non-small Cell Lung Cancer Receiving Erlotinib Treatment.

Erlotinib is used to treat advanced non-small-cell lung cancer (NSCLC), the common serious adverse events are skin disorders. The dose intensity of erlotinib should be maintained as much as possible by an appropriate control of adverse events in order to maintain its efficacy. Therefore, the management of these adverse events related to skin disorders would enable a continuous erlotinib treatment without interruption and dose reduction. This study assessed the effect of pharmaceutical consultation in outpatients who received erlotinib. Participants included patients with NSCLC who received erlotinib therapy for more than 6 months between December 2007 and March 2019. The participants were divided into two groups: the intervention group that included patients who received pharmaceutical consultation targeting outpatients by a pharmacist and the nonintervention group that included patients who did not. We retrospectively investigated patient characteristics, treatment regimens, and treatment efficacy. We included a total of 33 patients (18 and 15 patients in the nonintervention and intervention groups, respectively) in this study. The intervention group had a significantly higher median relative dose intensity (RDI) of erlotinib than the nonintervention group (p = 0.0437). In addition, the pharmaceutical consultation targeting outpatients was identified as a factor contributing to the maintenance of RDI ≥90% (p = 0.0269). The present study indicated that there was improvement in RDI with pharmaceutical consultation targeting outpatients with advanced NSCLC.

Risk factors for cancer-associated thrombosis in patients undergoing treatment with immune checkpoint inhibitors.

Purpose Anticancer agents are known to increase cancer-associated thrombosis (CAT) onset. CAT onset rate is reported to be 1.92% in cisplatin-based therapy, 6.1% in paclitaxel plus ramucirumab combination therapy, and 11.9% in bevacizumab monotherapy. Because immune checkpoint inhibitors (ICIs) cause a sudden increase in T cell number, an association between administration of these drugs and increase in CAT incidence is likely. However, the extent to which ICI administration affects CAT incidence remains unclear. Further, risk factors for CAT incidence have not yet been identified. The present study investigated CAT incidence and associated risk factors in patients receiving ICI. Methods Patients administered nivolumab or pembrolizumab at Fujita Health University Hospital from April 2017 to March 2018 were enrolled. We collected retrospective data regarding age, sex, cancer type, BMI, medical history, laboratory data at treatment initiation, medications, and computed tomography (CT) interpretations from electronic medical records. Results We identified 122 eligible participants from 135 patients receiving nivolumab or pembrolizumab. Ten patients (8.2%) developed CAT. A history of venous thromboembolism (VTE) or arterial thromboembolism (ATE) was a risk factor for CAT incidence (odds ratio: 6.36, P = 0.039). A history of heart disease may be a risk factor for CAT incidence (odds ratio 6.56, P = 0.052). Significantly higher usage of antiplatelet and anticoagulant therapy was noted in patients who developed CAT (60%) than in those who did not (13.4%, p < 0.01). Conclusion High (8.2%) CAT incidence during ICI administration suggested that ICI is not associated with a lower blood clot risk than other anticancer agents investigated in previous studies. For patients with VTE, ATE, or heart disease history, it is crucial to consider the possibility of CAT even with antiplatelet therapy.

Effect of Obesity on Hematotoxicity Induced by Carboplatin and Paclitaxel Combination Therapy in Patients with Gynecological Cancer.

Despite in vivo studies suggesting that obesity increases carboplatin (CBDCA) bone marrow toxicity, the American Society of Clinical Oncology recommends that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer. Accordingly, the present study retrospectively investigated the effect of body mass index (BMI) on bone marrow toxicity in patients with gynecological cancer who underwent paclitaxel and carboplatin (TC) therapy after eliminating the effect of the target area under the curve (AUC). Risk factors for CBDCA bone marrow toxicity were also identified. A total of 110 patients with primary gynecological cancer or gynecological cancer of unknown primary origin who underwent TC therapy with a target AUC of 5-6 were included herein. Patients with a BMI of ≥25 and <25 kg/m2 were assigned to the obesity and control groups, respectively, and evaluated according to changes in hematological test values (platelet, white blood cell, and hemoglobin counts) starting from initial TC therapy administration until 21 d after the second treatment course. The obesity group had a significantly higher thrombocytopenia rate than the control group. Risk factors for thrombocytopenia ≥ grade 2 included BMI ≥25 kg/m2. Among patients with primary gynecological cancer or gynecological cancer of unknown primary origin who had a BMI of ≥25 kg/m2, those receiving CBDCA may be at increased risk for thrombocytopenia ≥ grade 2 when the dosage is calculated using the Calvert formula with the creatinine clearance level.

Standardized volumetric plaque quantification and characterization from coronary CT angiography: a head-to-head comparison with invasive intravascular ultrasound.

OBJECTIVES: We sought to evaluate the accuracy of standardized total plaque volume (TPV) measurement and low-density non-calcified plaque (LDNCP) assessment from coronary CT angiography (CTA) in comparison with intravascular ultrasound (IVUS). METHODS: We analyzed 118 plaques without extensive calcifications from 77 consecutive patients who underwent CTA prior to IVUS. CTA TPV was measured with semi-automated software comparing both scan-specific (automatically derived from scan) and fixed attenuation thresholds. From CTA, %LDNCP was calculated voxels below multiple LDNCP thresholds (30, 45, 60, 75, and 90 Hounsfield units [HU]) within the plaque. On IVUS, the lipid-rich component was identified by echo attenuation, and its size was measured using attenuation score (summed score ∕ analysis length) based on attenuation arc (1 = < 90°; 2 = 90-180°; 3 = 180-270°; 4 = 270-360°) every 1 mm. RESULTS: TPV was highly correlated between CTA using scan-specific thresholds and IVUS (r = 0.943, p < 0.001), with no significant difference (2.6 mm3, p = 0.270). These relationships persisted for calcification patterns (maximal IVUS calcium arc of 0°, < 90°, or ≥ 90°). The fixed thresholds underestimated TPV (- 22.0 mm3, p < 0.001) and had an inferior correlation with IVUS (p < 0.001) compared with scan-specific thresholds. A 45-HU cutoff yielded the best diagnostic performance for identification of lipid-rich component, with an area under the curve of 0.878 vs. 0.840 for < 30 HU (p = 0.023), and corresponding %LDNCP resulted in the strongest correlation with the lipid-rich component size (r = 0.691, p < 0.001). CONCLUSIONS: Standardized noninvasive plaque quantification from CTA using scan-specific thresholds correlates highly with IVUS. Use of a < 45-HU threshold for LDNCP quantification improves lipid-rich plaque assessment from CTA. KEY POINTS: • Standardized scan-specific threshold-based plaque quantification from coronary CT angiography provides an accurate total plaque volume measurement compared with intravascular ultrasound. • Attenuation histogram-based low-density non-calcified plaque quantification can improve lipid-rich plaque assessment from coronary CT angiography.

Effect of L-Leucine Therapy on Hematopoietic Function in Elderly Myelodysplastic Syndrome Patients.

Patients with myelodysplastic syndrome (MDS) often require blood transfusion and anticancer therapy; however, elderly patients are intolerant to the associated side effects of anticancer therapy. Because L-leucine can be used to treat Diamond-Blackfan anemia, which is caused by defects in ribosomal protein (RP) genes, resulting in increased in vivo hemoglobin synthesis, it is possible that some MDS patients who have aberrations in their RP genes could also be effectively treated with L-leucine. In the present study, we investigated the effects of L-leucine on hematopoietic function (reticulocyte count), red blood cell count, and hemoglobin level in MDS patients. We administered L-leucine (1.8 g, twice daily, 3 d/week) with oral vitamin B6 supplements to a final cohort of eight MDS patients for 15 (interquartile range: 11-18) weeks. We assessed the patients at 10 ± 2 weeks after therapy initiation. Only the absolute reticulocyte count was affected, improving in 6/8 (75%) patients. The median absolute reticulocyte count was 3.5 × 104 (range: 2.7-6.4 × 104) cells/µL, an increase of 0.5 × 104 (range: 0.2-0.7 × 104) cells/µL. At 10 weeks, there was only one case of an improved hemoglobin level. Non-hematological adverse events of grade 3 were observed one raised triglycerides. These data suggest that L-leucine has little effect on MDS. However, it may contribute to the recovery of hematopoietic function, futher study be desired.

Transcriptional profile of ethylene glycol monomethyl ether-induced testicular toxicity in rats.

To clarify the molecular mechanism of ethylene glycol monomethyl ether (EGME)-induced testicular toxicity, the potential for EGME-related changes in transcript levels of genes including spermatocyte-specific genes was evaluated in the testis of rats given single dosing of EGME at 200, 600, or 2000 mg/kg. Furthermore, the contribution of decreased testicular testosterone on EGME-induced spermatocyte toxicity was investigated by comparing to transcriptional profile due to a testosterone synthesis inhibitor, ketoconazole (KET), at 30 or 300 mg/kg. EGME at 600 mg/kg or more dose-dependently caused testicular toxicity characterized by degeneration and necrosis of spermatocytes at stage VII-XIV seminiferous tubules. The spermatocyte injury was well correlated with decreased spermatocyte-specific gene expression. Analysis of upstream regulators by the Ingenuity Pathways Analysis system suggested that up-regulation of oxidative stress, protein kinase activation, and histone acetylation was involved in EGME-induced spermatocyte toxicity. Interestingly, KET decreased testicular testosterone to a similar extent compared to the EGME treatment, but KET at up to 300 mg/kg did not show any histopathological abnormality or change in the expression of spermatocyte-specific genes. These results suggested that the decreased testicular testosterone have little impact on EGME-induced spermatocyte injury. In contrast, KET showed trends toward increases in Hsd3b2 and Hsd17b2 mRNAs, presumably resulting from inhibition of androgen synthesis. Transcriptome analysis clearly demonstrated the differential effects of EGME and KET on androgen synthesis. In conclusion, EGME caused spermatocyte toxicity correlated with decreased expression of spermatocyte-specific genes. Furthermore, oxidative stress, protein kinase activation, and histone acetylation were suggested to be involved in EGME-induced testicular toxicity.

Influence of R-CHOP Therapy on Immune System Restoration in Patients with B-Cell Lymphoma.

OBJECTIVE: To assess the immunosuppressive effect of R-CHOP in patients with B-cell lymphoma at 2 years. METHODS: Parameters of humoral and cell-mediated immunity were assessed in 89 patients with diffuse large B-cell lymphoma or follicular lymphoma before and after 6-8 cycles of R-CHOP-14 or R-CHOP-21 regimen. RESULTS: Data on pre- and posttreatment serum IgG (sIgG) levels were available for all 89 patients, while the corresponding data on serum CD20+, CD3+, CD4+, and CD8+ lymphocyte counts were available in only 43. Median sIgG levels significantly decreased from 1,221 mg/dl (baseline) to 733 mg/dl (after chemotherapy) (p < 0.001). Although CD20+ and CD4+ cell counts decreased (p < 0.001), no significant effect of chemotherapy on CD3+ and CD8+ cell counts was observed. CD20+ cell counts were restored to baseline levels at the 12-month follow-up. sIgG levels and CD4+ cell counts were not completely restored at 24 months, indicating a sustained immunosuppressive effect of R-CHOP in these patients. The incidence of infections over the 2-year period was 16.3-23.6%. CONCLUSION: The immunosuppressive effect of R-CHOP in newly diagnosed cases of B-cell lymphoma tends to persist for >2 years, although sIgG levels were restored more quickly than CD4+ cell counts.

Comparison between 5-day aprepitant and single-dose fosaprepitant meglumine for preventing nausea and vomiting induced by cisplatin-based chemotherapy.

PURPOSE: We aimed to compare the preventive effect of 5-day administration of aprepitant with single administration of fosaprepitant meglumine against nausea and vomiting symptoms due to highly emetogenic chemotherapy regimens comprising cisplatin (CDDP). METHODS: Subjects were inpatients who underwent chemotherapy for gastric cancer, esophageal cancer, lung cancer, or head and neck cancer with a regimen comprising 60 mg/m(2) or higher dose of CDDP. In this randomised, open-label, controlled study, the subjects were assigned to a group given aprepitant for 5 days or a group given a single administration of fosaprepitant meglumine. The nausea and vomiting symptoms that emerged within 7 days after the first CDDP administration were investigated with a questionnaire form; the results were compared between the two groups. Risk factors affecting nausea and vomiting symptoms were also investigated. RESULTS: Of the 101 patients enrolled, 93 patients were included (48 in the 5-day aprepitant group and 45 in the single fosaprepitant meglumine group). No significant intergroup differences in the complete response rate or the complete control rate were found over the entire period. The nausea score tended to increase from day 3 in both groups, but no significant intergroup difference was observed. Furthermore, the investigation of risk factors affecting moderate or severe nausea symptoms indicated that the fosaprepitant meglumine administration was not a risk factor. CONCLUSIONS: Single administration of fosaprepitant meglumine was not inferior to 5-day administration of aprepitant for preventing acute and delayed nausea and vomiting symptoms occurring after administration of CDDP (60 mg/m(2) or higher).

Effect of Liver Dysfunction on S-1 Therapy Induced Adverse Effects: A Retrospective Cohort Study.

BACKGROUND/AIM: Renal dysfunction necessitates S-1 dose reduction. However, decreased dihydropyrimidine dehydrogenase (DPD) activity may lead to adverse events due to 5-FU. The guidelines provided by pharmaceutical companies state that total bilirubin (T-Bil) should be ≤upper limit of normal (ULN)×1.5 as a reference value for safely taking S-1. Nevertheless, the relationship between the degree of liver dysfunction and S-1 dose reduction has not been clearly established. PATIENTS AND METHODS: This study focused on patients who received S-1 monotherapy for various types of cancer. The primary outcome was defined as the variation between blood sampling results on the test day and the subsequent test. The variation data were categorized based on the difference in T-Bil: Low T-Bil group (≤2.25) and High T-Bil group (>2.25). RESULTS: The number of patients that underwent S-1 monotherapy was 883 and the running number was 7,511; Low T-Bil group included 7,245 and High T-Bil group included 266. Examination of the effect of the T-Bil Group on clinical outcomes revealed a correlation with red blood cell (RBC) count, platelet (PLT) count, and T-Bil level. When the impact of the interaction between the T-Bil Group and any of the clinical outcomes, such as the RBC count, PLT count, and T-Bil level, was determined, each outcome showed a significant decrease in the High T-Bil group compared with the Low T-Bil group. CONCLUSION: S-1 administration in patients with liver dysfunction accompanied by elevated T-Bil levels may cause thrombocytopenia.

Prediction Model for Severe Thrombocytopenia Induced by Gemcitabine Plus Cisplatin Combination Therapy in Patients with Urothelial Cancer.

BACKGROUND: Chemotherapy-induced thrombocytopenia is often a use-limiting adverse reaction to gemcitabine and cisplatin (GC) combination chemotherapy, reducing therapeutic intensity, and, in some cases, requiring platelet transfusion. OBJECTIVE: A retrospective cohort study was conducted on patients with urothelial cancer at the initiation of GC combination therapy and the objective was to develop a prediction model for the incidence of severe thrombocytopenia using machine learning. METHODS: We performed receiver operating characteristic analysis to determine the cut-off values of the associated factors. Multivariate analyses were conducted to identify risk factors associated with the occurrence of severe thrombocytopenia. The prediction model was constructed from an ensemble model and gradient-boosted decision trees to estimate the risk of an outcome using the risk factors associated with the occurrence of severe thrombocytopenia. RESULTS: Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×104/µL) [odds ratio 7.19, p < 0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, p = 0.03], lymphocyte count ≤ 1.458 (×103/µL) [odds ratio 2.47, p = 0.02], and dose of gemcitabine ≥ 775.245 (mg/m2) [odds ratio 4.00, p < 0.01] were risk factors of severe thrombocytopenia. The performance of the prediction model using these associated factors was high (area under the curve 0.76, accuracy 0.82, precision 0.68, recall 0.50, and F-measure 0.58). CONCLUSIONS: Platelet count, hemoglobin level, lymphocyte count, and gemcitabine dose contributed to the development of a novel prediction model to identify the incidence of GC-induced severe thrombocytopenia.

Angptl3 regulates lipid metabolism in mice.

The KK obese mouse is moderately obese and has abnormally high levels of plasma insulin (hyperinsulinemia), glucose (hyperglycemia) and lipids (hyperlipidemia). In one strain (KK/San), we observed abnormally low plasma lipid levels (hypolipidemia). This mutant phenotype is inherited recessively as a mendelian trait. Here we report the mapping of the hypolipidemia (hypl) locus to the middle of chromosome 4 and positional cloning of the autosomal recessive mutation responsible for the hypolipidemia. The hypl locus encodes a unique angiopoietin-like lipoprotein modulator, which we named Allm1. It is identical to angiopoietin-like protein 3, encoded by Angptl3, and has a highly conserved counterpart in humans. Overexpression of Angptl3 or intravenous injection of the purified protein in KK/San mice elicited an increase in circulating plasma lipid levels. This increase was also observed in C57BL/6J normal mice. Taken together, these data suggest that Angptl3 regulates lipid metabolism in animals.

Changes in mouse liver protein glutathionylation after acetaminophen exposure.

The role of protein glutathionylation in acetaminophen (APAP)-induced liver injury was investigated in this study. A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase and aspartate aminotransferase levels and liver necrosis in a dose-dependent manner. The ratio of GSH to GSSG was decreased in a dose-dependent manner, suggesting that APAP produced a more oxidizing environment within the liver. Despite the increased oxidation state, the level of global protein glutathionylation was decreased at 1 h and continued to decline through 24 h. Immunohistochemical localization of glutathionylated proteins showed a complex dynamic change in the lobule zonation of glutathionylated proteins. At 1 h after APAP exposure, the level of glutathionylation decreased in the single layer of hepatocytes around the central veins but increased mildly in the remaining centrilobular hepatocytes. This increase correlated with the immunohistochemical localization of APAP covalently bound to protein. Thereafter, the level of glutathionylation decreased dramatically over time in the centrilobular regions with major decreases observed at 6 and 24 h. Despite the overall decreased glutathionylation, a layer of cells lying between the undamaged periportal region and the damaged centrilobular hepatocytes exhibited high levels of glutathionylation at 3 and 6 h in all samples and in some 24-h samples that had milder injury. These temporal and zonal pattern changes in protein glutathionylation after APAP exposure indicate that protein glutathionylation may play a role in protein homeostasis during APAP-induced hepatocellular injury.

Early Palliative Care Improves Overall Survival in Patients With Lymphoma: A Single-institution Retrospective Study.

BACKGROUND/AIM: Early palliative care (EPC) intervention in patients with solid tumors can provide many benefits. However, studies on patients with hematological malignancies are limited, and there is no data on patients with lymphoma. We conducted a preliminary retrospective survey of palliative care (PC) intervention in patients with lymphoma to clarify the effect of EPC on overall survival (OS). PATIENTS AND METHODS: The first palliative care consultation (PC1) was retrospectively reviewed from medical records in Japan. Patients with lymphoma requiring inpatient PC at our institution from January 2012 to December 2018 were recruited. We conducted receiver operating characteristic (ROC) analysis; patients were divided into two groups (early and delayed), and the survival periods and palliative care team (PCT) referral details were compared. RESULTS: The analysis included 77 patients with lymphoma [median age, 71 (64-79)] years. The median period to PC1 from the initial diagnosis was 395 (180-1,086) days. ROC analysis revealed an optimal PC intervention timing of 140 days. OS was significantly longer in the early group than that in the delayed group. The most common counseling details for the PCT were symptom relief and palliative care transfer (36.8% and 35.2%, respectively). CONCLUSION: This real-world evaluation of PC intervention for inpatients with lymphoma revealed that PC intervention was provided at approximately 13 months following initial diagnosis. EPC intervention from diagnosis to 140 days may improve OS in patients with lymphoma; however further large-scale studies are required to verify this finding.

Correlation between serum albumin and serum zinc in malignant lymphoma.

Objectives: Zinc (Zn) is a cofactor for more than 200 enzymes within the human body. Zn deficiency can result in cell-mediated immune dysfunction. Furthermore, serum Zn levels have been reported to be associated with nutritional status, but this association has not been clarified in malignant lymphoma. This study aimed to examine the deficiency of serum Zn levels and clarify the factors that are correlated with serum Zn in malignant lymphoma. Methods: Initial malignant lymphoma was diagnosed in patients at Fujita Health University Hospital between April 2011 and March 2019. Based on the serum Zn levels, the study population was divided into "deficient" and "low or normal". For the serum Zn levels of patients undergoing pre-chemotherapy, laboratory parameters and nutritional factors were included. We compared these factors between the abovementioned two groups, and the serum Zn levels with its correlation factors were investigated. Results: A total of 77 patients (Deficient group, n=20 and Low or Normal group, n=57) were enrolled. Histology, hemoglobin, serum albumin levels, Glasgow Prognostic Score (GPS), neutrophile-lymphocyte ratio (NLR), prognostic nutrition index (PNI) and Controlling Nutritional Status (CONUT) were significantly different between the two groups. Of these parameters, only serum albumin level was significantly associated with serum Zn level (p=0.0024; estimated regression coefficient, 9.51; adjusted coefficient of determination, 0.28). Conclusions: Poor nutritional status at the initial diagnosis may have affected Zn deficiency in initial malignant lymphoma.

Hepatic transcriptome and proteome responses against diethyl maleate-induced glutathione depletion in the rat.

Hepatic transcriptome and proteome responses against glutathione depletion were investigated by Affymetrix GeneChip Microarray and 2-dimensional gel electrophoresis (2D-DIGE), followed by MALDI-TOF-MS analysis and utilizing a glutathione-depleted rat model treated with diethyl maleate (DEM). Hepatic glutathione content decreased to 1.29 µmol/g liver (25.5% compared to control) after DEM treatment, and there were no apparent hepatotoxic signs estimated by blood chemistry examinations. A total of 247 and 213 annotated gene probe sets exhibited greater than twofold up- and down-regulation compared with controls, respectively. The up-regulated gene list contained a number of glutathione depletion-responsive genes reported previously, such as Trib3, Srxn1, Myc, Asns, Igfbp1, Txnrd1, or Hmox1, suggesting that these genes are robust mRNA biomarkers for evaluating hepatic glutathione depletion. In the 2D-DIGE analysis, proteins for a total of 361 spots were identified by MALDI-TOF-MS analysis. Of the identified proteins, 5 and 14 proteins showed up- and down-regulation, respectively. Some proteins exhibited differential expression in the protein level but not in the mRNA level, including L-FABP, MAWDBP, aldo-keto reductase family 1 member A1, catalase and ATP synthase subunit beta, suggesting that these proteins would be potential protein biomarkers for evaluating glutathione depletion. Moreover, up-regulation of FABP1 protein along with up-regulation of PPARα-regulated gene transcripts (i.e., Acot2 and Acot4) is indicative of PPARα activation, which may contribute to hepatocellular protection against glutathione depletion-induced oxidative stress. The up-regulation of L-FABP1 was detected by proteome data but not by transcriptome data, demonstrating the advantage of utilizing transcriptomics and proteomics combination to investigate glutathione depletion-induced molecular dynamics.

Effects of 5-mg dose of olanzapine for breakthrough nausea and vomiting in patients receiving carboplatin-based chemotherapy: a prospective trial.

BACKGROUND: Olanzapine 10 mg is recommended for breakthrough chemotherapy-induced nausea and vomiting. However, there is a possibility that 5 mg can be expected to be sufficiently effective. We aimed to investigate the efficacy and safety of olanzapine 5 mg for breakthrough chemotherapy-induced nausea and vomiting. METHODS: A single-arm prospective trial of olanzapine 5 mg every 24 h for 72 h was conducted to treat breakthrough chemotherapy-induced nausea and vomiting in patients receiving carboplatinbased chemotherapy. The primary endpoint was total control (i.e., no emesis, no nausea, and no rescue medications) over 72 h. The secondary endpoints were early efficacy using the nausea scores at 30, 60, and 120 min after taking olanzapine from baseline and adverse events. RESULTS: Among 84 potentially eligible patients, 19 patients who took olanzapine for breakthrough chemotherapy-induced nausea and vomiting were examined. The total control rate was 32% (95% CI: 13- 57%), 65% (95% CI: 38-89%), 65% (95% CI: 38-89%), and 29% (95% CI: 10-56%) during 2-24, 24-48, 48-72 h, and overall period, respectively. The nausea scale significantly reduced after 30 min (P=0.0078), and the scale had been reduced by 67% from the baseline after 60 min. The adverse event of somnolence of any grade was observed in 13 (68%) patients, 6 (32%) of whom had grade 2 and 1 (5%) grade 3 somnolence. CONCLUSIONS: Olanzapine 5 mg did not show the expected effect on the complete disappearance of breakthrough chemotherapy-induced nausea and vomiting within 24 h.

Identification of genes related to heart failure using global gene expression profiling of human failing myocardium.

Although various management methods have been developed for heart failure, it is necessary to investigate the diagnostic or therapeutic targets of heart failure. Accordingly, we have developed different approaches for managing heart failure by using conventional microarray analyses. We analyzed gene expression profiles of myocardial samples from 12 patients with heart failure and constructed datasets of heart failure-associated genes using clinical parameters such as pulmonary artery pressure (PAP) and ejection fraction (EF). From these 12 genes, we selected four genes with high expression levels in the heart, and examined their novelty by performing a literature-based search. In addition, we included four G-protein-coupled receptor (GPCR)-encoding genes, three enzyme-encoding genes, and one ion-channel protein-encoding gene to identify a drug target for heart failure using in silico microarray database. After the in vitro functional screening using adenovirus transfections of 12 genes into rat cardiomyocytes, we generated gene-targeting mice of five candidate genes, namely, MYLK3, GPR37L1, GPR35, MMP23, and NBC1. The results revealed that systolic blood pressure differed significantly between GPR35-KO and GPR35-WT mice as well as between GPR37L1-Tg and GPR37L1-KO mice. Further, the heart weight/body weight ratio between MYLK3-Tg and MYLK3-WT mice and between GPR37L1-Tg and GPR37L1-KO mice differed significantly. Hence, microarray analysis combined with clinical parameters can be an effective method to identify novel therapeutic targets for the prevention or management of heart failure.

A highly Li(+)-selective glass optode based on fluorescence ratiometry.

This paper presents the preparation and characterization of a single-excitation, dual-emission ratiometric optical Li(+)-sensing device using a newly designed and synthesized highly Li(+)-selective fluoroionophore (KBL-01) carrying 14-crown-4 ether with tetramethyl and benzene blocking subunits as Li(+)-binding site and boron-dipyrromethene as fluorophore. The indicator dye was covalently immobilized on the surface of a porous glass support having a large internal surface area using a silane-coupling agent. The resulting Li(+)-selective glass optode shows dual fluorescence emission response in pseudo-serum at varying Li(+) concentrations, allowing ratiometric signal processing. The obtained signal is independent of the presence of possibly interfering cations (Na(+), K(+), Mg(2+) and Ca(2+)) and pH. The sensor response was found to be reversible within the Li(+) concentration range from 10(-4) to 10(-1) M, and showed good repeatability and light stability. The plots of the ratiometric signal versus the Li(+) concentrations in spiked real human serum go along with the response curve in pseudo-serum. These results indicate that the novel Li(+)-selective glass optode can be employed as a Li(+)-sensing device with high durability, sensitivity and accuracy for medical analyses.