Nivolumab receptor occupancy on effector regulatory T cells predicts clinical benefit.

Immune checkpoint inhibitor discovery represents a turning point in cancer treatment. However, the response rates of solid tumors remain ~10%-30%; consequently, prognostic and immune-related adverse event (irAE) predictors are being explored. The programmed cell death protein 1 (PD-1) receptor occupancy (RO) of PD-1 inhibitors depends on the number of peripheral blood lymphocytes and their PD-1 expression levels, suggesting that the RO may be related to efficacy and adverse events. As PD-1 inhibition affects each T-cell subset differently, the RO of each cell population must be characterized. However, relevant data have not been reported, and the prognostic relevance of this parameter is not known. In this study, we aimed to clarify the association between the nivolumab RO in each T-cell population and patient prognosis and reveal the development of irAEs in nivolumab-treated patients. Thirty-two patients were included in the study, and the mean follow-up period was 364 days. The nivolumab RO on effector regulatory T cells (eTregs) was significantly lower in the group that presented clinical benefits, and a significant negative association was observed between PD-1 occupancy on eTregs and all-cause mortality. The results suggest that the nivolumab RO on eTregs may be a prognostic factor in PD-1 inhibitor therapy, implying that the inhibition of PD-1/PD-ligand 1 (PD-L1) signaling on eTregs may attenuate antitumor effects.

Butyricimonas is a key gut microbiome component for predicting postoperative recurrence of esophageal cancer.

BACKGROUND: Recently, intestinal bacteria have attracted attention as factors affecting the prognosis of patients with cancer. However, the intestinal microbiome is composed of several hundred types of bacteria, necessitating the development of an analytical method that can allow the use of this information as a highly accurate biomarker. In this study, we investigated whether the preoperative intestinal bacterial profile in patients with esophageal cancer who underwent surgery after preoperative chemotherapy could be used as a biomarker of postoperative recurrence of esophageal cancer. METHODS: We determined the gut microbiome of the patients using 16S rRNA metagenome sequencing, followed by statistical analysis. Simultaneously, we performed a machine learning analysis using a random forest model with hyperparameter tuning and compared the data obtained. RESULTS: Statistical and machine learning analyses revealed two common bacterial genera, Butyricimonas and Actinomyces, which were abundant in cases with recurrent esophageal cancer. Butyricimonas primarily produces butyrate, whereas Actinomyces are oral bacteria whose function in the gut is unknown. CONCLUSION: Our results indicate that Butyricimonas spp. may be a biomarker of postoperative recurrence of esophageal cancer. Although the extent of the involvement of these bacteria in immune regulation remains unknown, future research should investigate their presence in other pathological conditions. Such research could potentially lead to a better understanding of the immunological impact of these bacteria on patients with cancer and their application as biomarkers.

Structural Dynamics of Amyloid-ß Protofibrils and Actions of Anti-Amyloid-ß Antibodies as Observed by High-Speed Atomic Force Microscopy.

Amyloid-ß (Aß) aggregation intermediates, including oligomers and protofibrils (PFs), have attracted attention as neurotoxic aggregates in Alzheimer's disease. However, due to the complexity of the aggregation pathway, the structural dynamics of aggregation intermediates and how drugs act on them have not been clarified. Here we used high-speed atomic force microscopy to observe the structural dynamics of Aß42 PF at the single-molecule level and the effect of lecanemab, an anti-Aß PF antibody with the positive results from Phase 3 Clarity AD. PF was found to be a curved nodal structure with stable binding angle between individual nodes. PF was also a dynamic structure that associates with other PF molecules and undergoes intramolecular cleavage. Lecanemab remained stable in binding to PFs and to globular oligomers, inhibiting the formation of large aggregates. These results provide direct evidence for a mechanism by which antibody drugs interfere with the Aß aggregation process.

The Curcumin Derivative GT863 Protects Cell Membranes in Cytotoxicity by Aß Oligomers.

In Alzheimer's disease (AD), accumulation of amyloid ß-protein (Aß) is one of the major mechanisms causing neuronal cell damage. Disruption of cell membranes by Aß has been hypothesized to be the important event associated with neurotoxicity in AD. Curcumin has been shown to reduce Aß-induced toxicity; however, due to its low bioavailability, clinical trials showed no remarkable effect on cognitive function. As a result, GT863, a derivative of curcumin with higher bioavailability, was synthesized. The purpose of this study is to clarify the mechanism of the protective action of GT863 against the neurotoxicity of highly toxic Aß oligomers (Aßo), which include high-molecular-weight (HMW) Aßo, mainly composed of protofibrils in human neuroblastoma SH-SY5Y cells, focusing on the cell membrane. The effect of GT863 (1 µM) on Aßo-induced membrane damage was assessed by phospholipid peroxidation of the membrane, membrane fluidity, membrane phase state, membrane potential, membrane resistance, and changes in intracellular Ca2+ ([Ca2+]i). GT863 inhibited the Aßo-induced increase in plasma-membrane phospholipid peroxidation, decreased membrane fluidity and resistance, and decreased excessive [Ca2+]i influx, showing cytoprotective effects. The effects of GT863 on cell membranes may contribute in part to its neuroprotective effects against Aßo-induced toxicity. GT863 may be developed as a prophylactic agent for AD by targeting inhibition of membrane disruption caused by Aßo exposure.

Effects of Quinolinate-Induced Lesion of the Medial Prefrontal Cortex on Prefrontal and Striatal Concentrations of D-Serine in the Rat.

D-Serine has been shown to play an important role in the expression and control of a variety of brain functions by acting as the endogenous coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDAR), at least, in the forebrain. To obtain further insight into the still debatable cellular localization of the D-amino acid, we have examined the effects of the selective destruction of the neuronal cell bodies by quinolinate on the tissue or extracellular D-serine concentrations in the medial prefrontal cortex of the rat. A local quinolinate infusion into the bilateral medial prefrontal cortex produced a cortical lesion with a marked (- 65%) and non-significant alteration (- 5%) in the cortical and striatal tissue D-serine concentrations, respectively, 7 days post-infusion. In vivo microdialysis experiments in the right prefrontal lesion site 9 days after the quinolinate application revealed that the basal extracellular D-serine levels were also dramatically reduced (- 64%). A prominent reduction in the tissue levels of GABA in the interneurons of the prefrontal cortex (- 78%) without significant changes in those in the striatum (+ 12%) verified that a major lesion part was confined to the cortical portion. The lack of a significant influence of the prefrontal quinolinate lesion on its dopamine concentrations in the mesocortical dopamine projections suggests that the nerve terminals and axons in the lesion site may be spared. These findings are consistent with the perikarya-selective nature of the present quinolinate-induced lesion and further support the view that neuronal cell bodies of intrinsic neurons in the prefrontal cortical region contain substantial amounts of D-serine, which may sustain the basal extracellular concentrations of D-serine.

Combined Treatment with Curcumin and Ferulic Acid Suppressed the Aß-Induced Neurotoxicity More than Curcumin and Ferulic Acid Alone.

Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive cognitive decline. Several effective natural components have been identified for the treatment of AD. However, it is difficult to obtain conclusive evidence on the safety and effectiveness of natural components, because a variety of factors are associated with the progression of AD pathology. We hypothesized that a therapeutic effect could be achieved by combining multiple ingredients with different efficacies. The purpose of this study was thus to evaluate a combination treatment of curcumin (Cur) and ferulic acid (FA) for amyloid-ß (Aß)-induced neuronal cytotoxicity. The effect of Cur or FA on Aß aggregation using thioflavin T assay was confirmed to be inhibited in a concentration-dependent manner by Cur single or Cur + FA combination treatment. The effects of Cur + FA on the cytotoxicity of human neuroblastoma (SH-SY5Y) cells induced by Aß exposure were an increase in cell viability, a decrease in ROS and mitochondrial ROS, and repair of membrane damage. Combination treatment showed an overall higher protective effect than treatment with Cur or FA alone. These results suggest that the combined action mechanisms of Cur and FA may be effective in preventing and suppressing the progression of AD.

The Sympathetic Nervous System Contributes to the Establishment of Pre-Metastatic Pulmonary Microenvironments.

Emerging evidence suggests that neural activity contributes to tumor initiation and its acquisition of metastatic properties. More specifically, it has been reported that the sympathetic nervous system regulates tumor angiogenesis, tumor growth, and metastasis. The function of the sympathetic nervous system in primary tumors has been gradually elucidated. However, its functions in pre-metastatic environments and/or the preparation of metastatic environments far from the primary sites are still unknown. To investigate the role of the sympathetic nervous system in pre-metastatic environments, we performed chemical sympathectomy using 6-OHDA in mice and observed a decrease in lung metastasis by attenuating the recruitment of myeloid-derived suppressor cells. Furthermore, we note that neuro-immune cell interactions could be observed in tumor-bearing mouse lungs in conjunction with the decreased expression of Sema3A. These data indicate that the sympathetic nervous system contributes to the preparation of pre-metastatic microenvironments in the lungs, which are mediated by neuro-immune cell interactions.

Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis.

OBJECTIVES: To determine the expression of hepatocyte growth factor (HGF) in RA biological fluids, the role of HGF in monocyte migration and the therapeutic effect of the c-Met inhibitor savolitinib in an arthritis model mice. METHODS: HGF/c-Met expression in serum, SF and synovial tissues (STs) obtained from RA patients and controls, as well as RA fibroblast-like synoviocytes (FLSs), was evaluated by ELISA and immunostaining. To determine the function of HGF in RA SF, we preincubated RA SF with a neutralizing anti-HGF antibody and measured the chemotactic ability of a human acute monocytic leukaemia cell line (THP-1). Additionally, examinations were conducted of SKG mice treated with savolitinib for 4 weeks. RESULTS: HGF levels in serum from RA patients were significantly higher than those in the controls and were decreased by drug treatment for 24 weeks. Additionally, the HGF level in SF from RA patients was higher than that in SF from OA patients. HGF and c-Met expression was also noted in RA STs. Stimulation of RA FLSs with TNF-α increased HGF/c-Met expression in a concentration-dependent manner, and c-Met signal inhibition suppressed production of fractalkine/CX3CL1 and macrophage inflammatory protein-1α/CCL3. When HGF was removed by immunoprecipitation, migration of THP-1 in RA SF was suppressed. In SKG mice, savolitinib significantly suppressed ankle bone destruction on µCT, with an associated reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. CONCLUSION: HGF produced by inflammation in synovium of RA patients activates monocyte migration to synovium and promotes bone destruction via a chemotactic effect and enhanced chemokine production.

High molecular weight amyloid ß1-42 oligomers induce neurotoxicity via plasma membrane damage.

Amyloid ß-protein (Aß) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aß species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates amyloid oligomers in AD neuropathology, but the precise mechanisms are uncertain. We examined the mechanisms of neuronal dysfunction from HMW-Aß1-42 exposure by measuring membrane integrity, reactive oxygen species (ROS) generation, membrane lipid peroxidation, membrane fluidity, intracellular calcium regulation, passive membrane electrophysiological properties, and long-term potentiation (LTP). HMW-Aß1-42 disturbed membrane integrity by inducing ROS generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired LTP. The damaging effects of HMW-Aß1-42 were significantly greater than those of LMW-Aß1-42. Therapeutic reduction of HMW-Aß1-42 may prevent AD progression by ameliorating direct neuronal membrane damage.-Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe-Nakayama, T., Imamura, K., Inoue, H., Nakamura, S., Inoue, T., Kimura, A., Yano, S., Nishijo, H., Kiuchi, Y., Teplow, D. B., Ono, K. High molecular weight amyloid ß1-42 oligomers induce neurotoxicity via plasma membrane damage.

[Evaluation of the Benefits of Administering Hand Therapy to Patients with Chemotherapy-Induced Peripheral Neuropathy].

Taxanes, which are used to treat breast cancer, damage the microtubules of normal nerve cells, causing numbness of the fingers related to chemotherapy-induced peripheral neuropathy(CIPN); therefore, effective methods for reducing numbness are needed. In 2017, it was reported that physical stimuli related to massage improved finger blood flow volumes, contributing to the regeneration of damaged nerves. We developed a method of hand therapy for breast cancer patients complaining of numbness related to anticancer drug administration, and examined its effects on numbness. Hand therapy was performed by a single therapist who received lectures at the Sophia Phytotherapy College, which is accredited by the Japan Handcare Association. The fingertips to wrist, ankle, metacarpal bones, palm, and elbow were massaged using the bilateral arms/fingers for 15minutes. We investigated the influences of daily living status(Support Team Assessment Sched- ule-Japan: STAS-J), age, body mass index(BMI), severity/site of numbness, type of numbness, type of drug, duration of breast cancer, duration of numbness, and presence or absence of lymph node dissection, and evaluated the severity of numbness using a 10-cm Visual Analog Scale(VAS). The study included 51 breast cancer patients complaining of numbness of the fingers, with a mean age of 59 years. In patients with relatively mild numbness(STAS-J 1), the VAS scores before and after hand therapy were 4.7±1.8 and 1.9±1.3, respectively, showing a marked decrease. In STAS-J 2 patients, the values were 4.9 ±1.4 and 2.1±1.3, respectively, also showing a marked decrease. Thus, this hand therapy reduced numbness in mild- and moderate-status patients. Statistical comparisons were performed between the STAS-J 1/2(mild/moderate numbness)and STAS-J 3/4(severe numbness)groups. Although the severity of numbness was not correlated with age, BMI, type of drug, lymph node dissection, or duration of breast cancer, the proportion of patients with a B1-year history of numbness was significantly larger in the STAS-J 1/2 group. The most frequent site of numbness was from the proximal interphalangeal joints to the fingertips. Concerning the severity of numbness, many patients complained of severe numbness, as represented by that after sitting straight. These results suggest that this hand therapy is effective for reducing numbness in patients receiving taxanes and complaining of mild to moderate numbness.

Hepcidin-25/erythroferrone ratio predicts improvement of anaemia in haemodialysis patients treated with ferric citrate hydrate.

BACKGROUND/AIMS: Hepcidin-25 (HEP-25) and erythroferrone (ERFE) are key regulators of iron homeostasis. Correlations among serum ferritin, ERFE and HEP-25 levels and improvements in anaemia have not been evaluated after administration of ferric citrate hydrate (FCH). METHODS: This retrospective observational study investigated 24 patients on haemodialysis with both anaemia (haemoglobin (Hb) < 12 g/dL) and hyperphosphatemia (inorganic phosphorus ≥6 mg/dL). The patients who were administered FCH (1500 mg/day) for 12 consecutive weeks and 12 control patients who were administered a phosphate binder other than FCH were included. Correlations among Hb, HEP-25 and ERFE levels were studied. We then stratified the FCH group into two subgroups using the median baseline values of ferritin, HEP-25, ERFE and HEP-25/ERFE ratio to predict whether these markers could serve as prognostic indicators in the treatment of anaemia. RESULTS: In the FCH group, Hb, transferrin saturation, ferritin, HEP-25 and ERFE levels were all significantly increased, while inorganic phosphorus levels, dosage of erythropoietin-stimulating agent, and erythropoietin resistance index were all significantly decreased after drug administration. A significant inverse correlation was apparent between Hb and HEP-25 levels, and a significant positive correlation was seen between Hb and ERFE levels. A significant inverse correlation was found between HEP-25 and serum ERFE levels. Compared with the high HEP-25/ERFE ratio group, only the low HEP-25/ERFE ratio group exhibited significantly increased Hb levels at 12 weeks. CONCLUSION: HEP-25/ERFE ratio could be a novel prognostic marker for increases in Hb levels following FCH administration.

Efficient High-Throughput Screening by Endoplasmic Reticulum Ca2+ Measurement to Identify Inhibitors of Ryanodine Receptor Ca2+-Release Channels.

Genetic mutations in ryanodine receptors (RyRs), Ca2+-release channels in the sarcoplasmic reticulum essential for muscle contractions, cause various skeletal muscle and cardiac diseases. Because the main underlying mechanism of the pathogenesis is overactive Ca2+ release by gain-of-function of the RyR channel, inhibition of RyRs is expected to be a promising treatment of these diseases. Here, to identify inhibitors specific to skeletal muscle type 1 RyR (RyR1), we developed a novel high-throughput screening (HTS) platform using time-lapse fluorescence measurement of Ca2+ concentrations in the endoplasmic reticulum (ER) ([Ca2+]ER). Because expression of RyR1 carrying disease-associated mutation reduces [Ca2+]ER in HEK293 cells through Ca2+ leakage from RyR1 channels, specific drugs that inhibit RyR1 will increase [Ca2+]ER by preventing such Ca2+ leakage. RyR1 carrying the R2163C mutation and R-CEPIA1er, a genetically encoded ER Ca2+ indicator, were stably expressed in HEK293 cells, and time-lapse fluorescence was measured using a fluorometer. False positives were effectively excluded by using cells expressing wild-type (WT) RyR1. By screening 1535 compounds in a library of well characterized drugs, we successfully identified four compounds that significantly increased [Ca2+]ER They include dantrolene, a known RyR1 inhibitor, and three structurally different compounds: oxolinic acid, 9-aminoacridine, and alexidine. All the hit compounds, except for oxolinic acid, inhibited [3H]ryanodine binding of WT and mutant RyR1. Interestingly, they showed different dose dependencies and isoform specificities. The highly quantitative nature and good correlation with the channel activity validated this HTS platform by [Ca2+]ER measurement to explore drugs for RyR-related diseases.

Lack of correlation between the costs of anticancer drugs and clinical benefits in Japan.

Both overall survival (OS) and progression-free survival (PFS) are primary endpoints of phase III studies of new anticancer drugs. Medical care expenditures, especially oncology drug prices, are rapidly increasing; however, the impact of oncology drug prices on OS and PFS is unclear. We analyzed the relationship between oncology drug prices and clinical outcomes in Japan. The costs of a full course or 1 year of treatment were estimated on the basis of the latest National Health Insurance Drug Price Standards, and the relationship between costs and improvements in OS or PFS obtained with each drug were analyzed. Cost-effectiveness was compared between new-class drugs and next-in-class drugs. We then developed a simple model for estimating the costs required to prolong OS and PFS by 1 day and used this model to compare cost-effectiveness. Drug costs were not significantly related to treatment outcomes in terms of PFS or OS. There was no significant difference in the median cost between novel drugs and the next-in-class drugs (P = 0.39). The oncology drug cost required to prolong PFS by 1 day was more expensive than the drug cost required for prolong OS by 1 day. Prices of oncology drugs should be decided on the basis of actual clinical benefits for cancer patients, and the drug price evaluation process should be disclosed in Japan.

Biological effects of anti-RANKL antibody administration in pregnant mice and their newborns.

Denosumab, a fully human monoclonal antibody that neutralizes receptor activator of nuclear factor-κB ligand (RANKL) and blocks osteoclast differentiation, has received approval in Japan for use as an anti-resorptive drug for osteoporosis and skeletal-related events (SREs) in patients with solid cancer. Denosumab is contraindicated during pregnancy, though the effects of blocking RANKL activity on pregnant mothers and their newborns are unclear. We used mice to investigate the effects of an anti-RANKL antibody on maternal and newborn health. Mothers injected with the anti-RANKL antibody had increased bone mass as compared with the controls, while osteoclast number and the level of tartrate-resistant acid phosphatase (TRAP) in serum were increased at the end of pregnancy. Newborn mice exposed to the antibody in utero were normally born, but showed increased bone mass and died within 48 h after birth. None of the newborns were found to have milk in their stomachs, suggesting that they died due to a maternal defect in lactation. Consistent with this, anti-RANKL antibody-injected mothers displayed impaired mammary gland development. However, fostering by healthy surrogate mothers rescued only 33% of the antibody-exposed newborns, suggesting that neonatal mortality was due, at least in part, to an intrinsic defect in the newborns. Our findings show that anti-RANKL antibody administration during pregnancy results in not only an undesirable increase in bone mass, but also has harmful effects on newborn survival.

Effect of clonazepam and clonidine on primary sleep bruxism: a double-blind, crossover, placebo-controlled trial.

The aim of this study was to assess the acute effects of clonazepam and clonidine on rhythmic masticatory muscle activity in young adults with primary sleep bruxism, as well as accompanying effects on sleep architecture and cardiac activity. This study used a double-blind, crossover, placebo-controlled design. Polysomnography was performed on 19 subjects [nine men and 10 women; mean age (±SE): 25.4 ± 2.7 years] for 5 nights. The first 2 nights were used for the habituation and diagnosis of sleep bruxism. The other 3 nights were randomly assigned for clonazepam (1.0 mg), clonidine (0.15 mg) or placebo (all administered 30 min before bedtime). Sleep, oromotor activity and cardiac activity variables were assessed and compared among the three drug conditions. Clonidine significantly reduced the median percentage of time spent in the rapid eye movement sleep stage compared with placebo and clonazepam. The number of rhythmic masticatory muscle activity episodes was reduced with clonidine by >30% compared with placebo and clonazepam. The reduction of rhythmic masticatory muscle activity index by clonidine was associated with an increase of mean RR intervals (slower heart rate) during quiet sleep periods and during a 70-s period before the onset of rhythmic masticatory muscle activity episodes. However, no changes in cardiac activity variables were observed for clonazepam. In young adults with primary sleep bruxism, clonidine was significantly more effective in suppressing sleep bruxism than clonazepam. The acute effects of clonidine on rhythmic masticatory muscle activity episodes may be mediated by suppression of autonomic nervous system activity and non-rapid eye movement-rapid eye movement sleep processes.

Inhibitory Effect of Oxethazaine on Midazolam Metabolism in Rats.

There have been few reports concerning to the drug-drug interactions (DDIs) with OTC drugs although an increase in the use of OTC drugs in recent years. This current study was conducted to clarify the DDIs through CYP3A inhibition by oxethazaine (OXZ), an antacid available as an OTC drug. Midazolam (MDZ) was used as a probe drug for CYP3A activity. In an in vivo study, a single oral dose of OXZ (50 mg/kg) was administered to rats 30, 60, or 120 min before oral MDZ administration (15 mg/kg). Serum concentrations of MDZ were analyzed by HPLC, and its pharmacokinetic parameters were compared with a water-treated control group. The inhibitory effect of OXZ on MDZ 1'-hydroxylation (MDZ 1'-OH) activity was investigated in vitro using rat liver and intestinal microsomes. Pretreatment of OXZ 120 min before MDZ administration significantly increased the area under the serum concentration-time curve (AUC0-∞) of MDZ six-fold compared to the control group without a change in elimination half-life (t1/2). In contrast, OXZ pretreatment 30 or 60 min before MDZ administration did not show any remarkable change in MDZ pharmacokinetic parameters. The in vitro study showed that OXZ inhibited MDZ 1'-OH activity in a concentration-dependent manner both in liver and intestinal microsomes. These results suggested that OXZ increases serum MDZ concentration presumably by the inhibition of liver and/or intestinal CYP3A activity. OXZ was predicted to cause the DDIs mediated by CYP3A inhibition, although this effect depended on the dose interval.

Inhibitory Effects of Gastrointestinal Drugs on CYP Activities in Human Liver Microsomes.

OTC drugs have an important role in self-medication. However, the pharmacokinetic properties of some OTC drugs have not been fully investigated and reports concerning their drug interactions are insufficient. Several gastrointestinal drugs are available as OTC drugs. Because of their pharmacological properties, these drugs are often used concomitantly with other drugs. Therefore, it is important to predict the possible drug interactions among these drugs. In the current study, we investigated the inhibitory effects of five gastrointestinal drugs, namely loperamide, oxethazaine, papaverine, pirenzepine, and trimebutine, on CYP activities in human liver microsomes. Furthermore, we calculated the ratio of the intrinsic clearance of each CYP substrate in the presence or absence of the gastrointestinal drugs. The possibility of drug interactions in vivo was predicted by cut-off criteria. CYP3A4 activity was markedly inhibited by trimebutine, papaverine, and oxethazaine. Their inhibitory properties were competitive and the Ki values were 6.56, 12.8, and 3.08 µM, respectively. Alternative R values of CYP3A4 exceeded the cut-off level. These results suggested that drug interactions mediated by CYP3A4 may occur during treatment with these gastrointestinal drugs, necessitating the confirmation of the clinical significance of these drug interactions to prevent unexpected adverse effects.

Prognostic Index for Survival in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Third-Generation Agents.

We retrospectively evaluated clinical data from patients with advanced non-small-cell lung cancer (NSCLC) treated with third-generation chemotherapy agents prior to treatment, to determine a reliable method for predicting prognosis in such patients. We analyzed 100 patients who received third-generation agents (paclitaxel, docetaxel, gemcitabine, irinotecan, and vinorelbine) for the treatment of advanced NSCLC. Factors significantly related to prognosis were evaluated using the Cox regression model, and the prognostic index (PI) was determined by combining these factors. The mean follow-up duration was 12.6 months (0.2-67.0 months). Multivariate analysis identified pleural effusion, absolute neutrophil count (ANC), and C-reactive protein (CRP) level as significant factors that independently contribute to prognosis in patients with advanced NSCLC treated with third-generation agents (p < 0.05). The PI was calculated using these 3 factors, according to the following formula: PI = 0.581 × pleural effusion + 0.125 × ANC + 0.105 × CRP. The death rate in the group with the highest PI scores was significantly higher than in the group with the lowest scores (p < 0.001). Pleural effusion, ANC, and CRP level were the most important factors that contributed to prognosis following chemotherapy with third-generation agents in patients with advanced NSCLC. The PI is suggested to be an appropriate index to predict the prognosis of patients with NSCLC.

Vitamin E-Coated Dialyzer Inhibits Oxidative Stress.

AIM: To examine the effects of vitamin E-coated dialyzer on oxidative stress in vitro. METHODS: A dialyzer with a synthetic polymer membrane (APS-11SA) and vitamin E-coated dialyzer (VPS-11SA) were connected to a blood tubing line, and U937 cells were circulated in the device. The circulating fluid was collected at 1, 2, 5, 10, 25, and 50 cycles, which are estimated numbers of passes through the dialyzer. Intracellular reactive oxygen species (ROS) production, malondialdehyde (MDA), and Cu/Zn-superoxide dismutase (SOD) were quantified. RESULTS: Intracellular ROS production was increased in the first cycle by APS-11SA and was decreased throughout the experiment by VPS-11SA. Intracellular ROS production in the VPS-11SA device was lower, and MDA levels were decreased. MDA levels were lower during VPS-11SA processing than during APS-11SA processing. Cu/Zn-SOD levels remained unchanged. CONCLUSION: Our results highlight anti-oxidative-stress effects of a vitamin E-coated dialyzer.

Practical prognostic index for survival in patients with unresectable pancreatic cancer treated with gemcitabine or S-1.

BACKGROUND/AIMS: We performed this retrospective cohort study to identify prognostic factors for unresectable pancreatic cancer treated with current standard therapy using gemcitabine (GEM) or S-1 and to stratify patients prior to treatment using a prognostic index (PI). METHODOLOGY: We analyzed 182 patients with unresectable pancreatic cancer, who had received GEM or S-1 as first-line chemotherapy. Factors that contributed to the prognosis were identified by univariate and multivariate analysis using a Cox proportional hazards model. The PI was constructed using the factors identified in the multivariate analysis. RESULTS: By multivariate analysis, performance status (PS), stage, and absolute neutrophil count (ANC) were identified as factors that independently contributed to the prognosis of unresectable pancreatic cancer (P < 0.05). The hazard ratios were 1.69, 3.33, and 1.18, respectively. In addition, PI was calculated using these three factors. Patients were classified into three groups according to the PI values. A significant difference was observed among the survival curves of these three groups (P < 0.05). CONCLUSIONS: We identified three prognostic factors in the population after the introduction of S-1, and have created a simple and useful PI. This index demonstrates the ability to accurately classify advanced pancreatic cancer patients before the start of treatment.