Structure and Additive-free Transamidation of Planar N-Cyano Amides.

Although transamidation of amides generally requires metals, additives, or harsh conditions, we present here a facile transamidation of N-cyano amides with various amines at ambient temperature without any additive. N-cyano amides preferred the trans conformation and have a reduced double bond character revealed by crystal analysis. The DFT study indicates that the transamidation reaction proceeds through the direct attack of amine on the amide carbonyl since the LUMO (or LUMO+1) is located at the carbonyl moiety.

Predictive factors for postpartum glucose intolerance in women with gestational diabetes mellitus.

AIM: The aim of this prospective cohort study was to evaluate the risk factors for postpartum glucose intolerance (GI) in women with gestational diabetes mellitus (GDM). METHOD: A total of 140 women with GDM were enrolled. Of these, 115 underwent a 75-g oral glucose tolerance test (OGTT) at 12 weeks after delivery. Clinical factors and parameters in the antepartum 75-g OGTT associated with postpartum GI were evaluated by logistic regression analyses. RESULTS: Twenty-two (19.1%) of the 115 women with GDM developed postpartum GI. The univariate and multivariable logistic regression analyses revealed that low oral disposition index (DI) was a risk factor for postpartum GI (OR, 0.2; 95% CI, 0.04-0.7; p < 0.05), and that no clinical factors were associated with postpartum GI. CONCLUSIONS: Lower oral DI on the antepartum 75-g OGTT may be a useful marker for identifying GDM women who are at high risk for postpartum GI.

Exosome Degeneration in Mesenchymal Stem Cells Derived from Patients with Type 1 Diabetes Mellitus.

Type 1 diabetes mellitus is characterized by the destruction of pancreatic ß-cells and requires the regeneration of these destroyed pancreatic ß-cells for radical treatment. The degeneration of organelles in stem cells compromises stem cell quality; however, organelles in the mesenchymal stem cells of patients with type 1 diabetes mellitus have not been characterized previously. In this study, we use transmission electron microscopy to evaluate the degeneration of organelles in adipose-derived stem cells of patients with type 1 diabetes mellitus (T1DM ADSCs). Compared to adipose-derived stem cells from healthy humans, T1DM ADSCs degenerate differently, characterized by prominent enlarged spherical vesicles. The exosomes of T1DM ADSCs are found to be enlarged, reduced in number, and increased in the percentage of those positive for tetraspanin CD9. The findings of this study provide insight into the characteristics of stem cells in patients with type 1 diabetes mellitus.

Effects of insulin degludec and insulin glargine U300 on glycaemic stability in individuals with type 1 diabetes: A multicentre, randomized controlled crossover study.

To compare the effects of insulin degludec (IDeg) and insulin glargine U300 (IGlarU300) on glycaemic stability in subjects with type 1 diabetes. MATERIALS AND METHODS: In this multicentre, crossover trial, 46 individuals with type 1 diabetes and essentially undetectable circulating C-peptide were randomly assigned to either the IDeg-first/IGlarU300-second group or the IGlarU300-first/IDeg-second group, and were treated with the respective basal insulins for 4-week periods. Data were collected in the last week of each treatment period. The primary aim was to examine the potential non-inferiority of IDeg relative to IGlarU300 with regard to day-to-day variability, as evaluated by the standard deviation (SD) of fasting blood glucose (FBG) levels. Intra-day glycaemic variability and other variables were also determined by continuous glucose monitoring (CGM). RESULTS: The SD of FBG for IDeg was non-inferior to that for IGlarU300. The mean of FBG, coefficient of variation of FBG, and various glycaemic variability indexes determined by CGM did not differ between the two insulins. Whereas the administered doses of the insulins also did not differ, the mean glycaemic value was lower for IDeg than IGlarU300; the time above the target range (>180 mg/dL [10.0 mmol/L]) and the time below the target range (<70 mg/dL [3.9 mmol/L]) were shorter and longer, respectively, for IDeg than IGlarU300. CONCLUSIONS: Our data suggest that IDeg and IGlarU300 have comparable glucose-stabilizing effects in individuals with type 1 diabetes. However, the glucose-lowering effect of IDeg may be greater than that of IGlarU300 when titrated with a unit-based protocol.

Patients with pheochromocytoma exhibit low aldosterone renin ratio-preliminary reports.

BACKGROUND: Plasma renin activity (PRA) is generally increased in patients with pheochromocytoma (PCC) due to low circulating plasma volume and activation of ß-1 adrenergic receptor signaling. However, there has been no study on the aldosterone renin ratio (ARR) in patients with PCC. To elucidate the issue, this study aimed to determine the PRA, plasma aldosterone concentration (PAC), and ARR in patients with PCC and compare them with those in patients with subclinical Cushing's syndrome (SCS) and non-functioning adrenal adenoma (NFA). METHODS: In this retrospective single-center, cross-sectional study, 67 consecutive patients with adrenal tumors (PCC (n = 18), SCS (n = 18), and NFA (n = 31)) diagnosed at Kobe University Hospital between 2008 and 2014 were enrolled. RESULTS: PRA was significantly higher in patients with PCC than in those with SCS and NFA (2.1 (1.3 ~ 2.8) vs. 0.7 (0.5 ~ 1.8) and 0.9 (0.6 ~ 1.4) ng/mL/h; p = 0.018 and p = 0.025). Although PACs were comparable among the three groups, ARR was significantly lower in patients with PCC than in those with SCS and NFA (70.5 (45.5 ~ 79.5) vs. 156.0 (92.9 ~ 194.5) and 114.9 (90.1 ~ 153.4); p = 0.001 and p < 0.001). Receiver operating characteristic curve analysis demonstrated that, in differentiating PCC from NFA, PRA > 1.55 ng/mL/h showed a sensitivity of 70.0% and specificity of 80.6%. Interestingly, ARR < 95.4 showed a sensitivity of 83.3% and specificity of 86.7%, which were higher than those in PRA. CONCLUSIONS: ARR decreased in patients with PCC, which was a more sensitive marker than PRA. Further study is necessary to understand the usefulness of this convenient marker in the detection of PCC. TRIAL REGISTRATION: This study was not registered because of the retrospective analysis.

Relation between HOMA-IR and insulin sensitivity index determined by hyperinsulinemic-euglycemic clamp analysis during treatment with a sodium-glucose cotransporter 2 inhibitor.

We had aimed to determine whether homeostasis model assessment-insulin resistance (HOMA-IR) reflects insulin resistance-sensitivity during treatment with a sodium-glucose cotransporter 2 inhibitor (SGLT2i). Hyperinsulinemic-euglycemic clamp analysis was performed in 22 patients with type 2 diabetic patients taking dapagliflozin (5 mg/day before or after breakfast). Propensity score matching of these individuals (SGLT2i group) for age, sex, body mass index, and clamp-derived tissue glucose uptake rate with 44 type 2 diabetic patients who had undergone clamp analysis without SGLT2i treatment (control group) identified 17 paired subjects in each group for further analysis of the relation between HOMA-IR and a clamp-derived insulin sensitivity index (ISI). Natural log-transformed HOMA-IR was negatively correlated with ISI in both SGLT2i (r = -0.527, p = 0.030) and control (r = -0.534, p = 0.027) groups. The simple regression lines for log-transformed HOMA-IR and ISI in the two groups showed similar slopes but differed in their intercepts. Multivariate analysis revealed that HOMA-IR for patients with the same ISI in the two groups was related by the formula: HOMA-IRcontrol = HOMA-IRSGLT2i × 2.45. In conclusion, HOMA-IR was well correlated with ISI during SGLT2i treatment, but values corresponding to the same ISI were lower in the SGLT2i group than in the control group.

Peptide TNIIIA2 Derived from Tenascin-C Contributes to Malignant Progression in Colitis-Associated Colorectal Cancer via ß1-Integrin Activation in Fibroblasts.

Inflammatory bowel diseases increase the risk of colorectal cancer and colitis-associated colorectal cancer (CAC). Tenascin-C, a matricellular protein, is highly expressed in inflammatory bowel diseases, especially colorectal cancer. However, the role of tenascin-C in the development of CAC is not yet fully understood. We previously showed that a peptide derived from tenascin-C, peptide TNIIIA2, induces potent and sustained activation of ß1-integrin. Moreover, we recently reported that peptide TNIIIA2 promotes invasion and metastasis in colon cancer cells. Here, we show the pathological relevance of TNIIIA2-related functional site for the development of CAC. First, expression of the TNIIIA2-containing TNC peptides/fragments was detected in dysplastic lesions of an azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. In vitro experiments demonstrated that conditioned medium from peptide TNIIIA2-stimulated human WI-38 fibroblasts induced malignant transformation in preneoplastic epithelial HaCaT cells. Indeed, these pro-proliferative effects stimulated by peptide TNIIIA2 were abrogated by peptide FNIII14, which has the ability to inactivate ß1-integrin. Importantly, peptide FNIII14 was capable of suppressing polyp formation in the AOM/DSS model. Therefore, tenascin-C-derived peptide TNIIIA2 may contribute to the formation of CAC via activation of stromal fibroblasts based on ß1-integrin activation. Peptide FNIII14 could represent a potential prophylactic treatment for CAC.

Gut Microbiome and Plasma Microbiome-Related Metabolites in Patients With Decompensated and Compensated Heart Failure.

BACKGROUND: Gut microbiome composition or circulating microbiome-related metabolites in patients with heart failure (HF) have not been investigated at different time points (i.e., in the decompensated (Decomp) and compensated (Comp) phases). Methods and Results: We prospectively enrolled 22 patients admitted for HF and 11 age-, sex-, and comorbidity-matched hospitalized control subjects without a history of HF. Gut flora and plasma microbiome-related metabolites were evaluated by amplicon sequencing of the bacterial 16S ribosomal RNA gene and capillary electrophoresis time-of-flight mass spectrometry, respectively. HF patients were evaluated in both the Decomp and Comp phases during hospitalization. The phylum Actinobacteria was enriched in HF patients compared with control subjects. At the genus level, Bifiodobacterium was abundant while Megamonas was depleted in HF patients. Meanwhile, plasma concentration of trimethylamine N-oxide (TMAO), a gut microbiome-derived metabolite, was increased in HF patients (Decomp HF vs. control, P=0.003; Comp HF vs. control, P=0.004). A correlation analysis revealed positive correlations between the abundance of the genus Escherichia/Shigella and levels of TMAO and indoxyl sulfate (IS, a microbe-dependent uremic toxin) in Comp HF (TMAO: r=0.62, P=0.002; IS: r=0.63, P=0.002). Escherichia/Shigella was more abundant in Decomp than in Comp HF (P=0.030). CONCLUSIONS: Our results suggest that gut microbiome composition and microbiome-related metabolites are altered in HF patients.

Sex Differences in the Blood Concentration of Tacrolimus in Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients with CYP3A5*3/*3.

The purpose of this study was to describe the impact of sex and cytochrome P450 3A5 (CYP3A5) variant on the blood concentration of tacrolimus in patients with systemic lupus erythematosus or rheumatoid arthritis. The blood concentration of tacrolimus (ng/mL) divided by the daily dose of tacrolimus (mg/day) and the patient's weight (kg) (C/D) was obtained from 55 patients. The C/D value was analysed according to genetic variation in CYP3A5 or ATP binding cassette subfamily B member 1 (ABCB1), sex, and age. The C/D value in the CYP3A5*3/*3 group was significantly higher than in the CYP3A5*1/*1 and *1/*3 groups (p < 0.05, effect size: d = 1.40). In the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in men than in women (p < 0.05, effect size: d = 1.78). Furthermore, in the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in women aged over 50 years than in women aged under 50 years (p < 0.05, effect size: d = 1.18). In contrast, ABCB1 genetic variations did not show any significant effect on the C/D value. Since the blood concentration of tacrolimus in patients with CYP3A5*3/*3 varies depending on sex and age, these factors should be considered when studying the difference of sex in CYP3A.

The Promoting Effect of the Extracellular Matrix Peptide TNIIIA2 Derived from Tenascin-C in Colon Cancer Cell Infiltration.

The extracellular matrix (ECM) molecule tenascin C (TNC) is known to be highly expressed under various pathological conditions such as inflammation and cancer. It has been reported that the expression of TNC is correlated with the malignant potential of cancer. In our laboratory, it was found that the peptide derived from the alternative splicing domain A2 in TNC, termed TNIIIA2, has been shown to influence a variety of cellular processes, such as survival, proliferation, migration, and differentiation. In this study, we investigated the effect of TNC/TNIIIA2 on the invasion and metastasis of colon cancer cells, Colon26-M3.1, or PMF-Ko14, using an in vitro and in vivo experimental system. The degree of cell invasion was increased by the addition of TNC and TNIIIA2 in a dose-dependent manner. The invasion by TNC and TNIIIA2 were suppressed by an MMP inhibitor or TNIIIA2-blocking antibody. In an in vivo experiment, pulmonary metastasis was promoted conspicuously by the addition of TNIIIA2. In this study, we found that colon cancer cell invasion and metastasis was accelerated by TNC/TNIIIA2 via MMP induction. This result suggests the possibility of a new strategy targeting TNC/TNIIIA2 for colon cancer.

[Two cases of pancreatic cancer treated with FOLFIRINOX regimen and G-CSF prophylaxis at the standard therapeutic dose].

Recently, novel therapeutic regimens, such as FOLFIRINOX, have been demonstrated to show promising anti-cancer activity and to be superior to single-agent gemcitabine for unresectable pancreatic cancer patients with good performance status. In this study, we report 2 cases of pancreatic cancer treated with FOLFIRINOX and G-CSF prophylaxis at the standard therapeutic dose, after treatment with gemcitabine and S-1 chemotherapy failed. It has been reported that grade 3-4 neutropenia frequently occurs in patients treated with the FOLFIRINOX regimen. Furthermore, granulocyte colony-stimulating factor(G-CSF) has not been recommended for helping with neutropenia in pancreatic cancer patients treated with FOLFIRINOX: however, prophylactic use of G-CSF is recommended for cancer patients who are at high risk of neutropenic events. On the other hand, modified FOLFIRINOX(no bolus 5-FU)has demonstrated an improved safety profile with maintained efficacy, and further randomized studies to compare the overall survivals of the modified FOLFIRINOX versus FOLFIRINOX regimen and G-CSF prophylaxis are hence needed in the future.

Organ-specific changes in norepinephrine turnover against various stress conditions in thermoneutral mice.

The effects of three stressors of different categories, namely cold exposure, immobilization, and lipopolysaccharide (LPS) treatment, on sympathetic nerve activity were examined by assessing its biochemical index norepinephrine (NE) turnover in peripheral organs of C57BL/6 mice. NE turnover was assessed by measuring the decrease in the organ NE concentration 3 h after inhibition of catecholamine biosynthesis with alpha-methyl-p-tyrosine. NE turnover in brown adipose tissue (BAT) in the room temperature (23 degrees C) control group was as high as that in the cold exposure (4 degrees C) group. Similarly, the mRNA level of the thermogenic marker uncoupling protein 1 (UCP1) in the room temperature control group was as high as that in the cold exposure group. As sympathetic stimulation upregulates the UCP1 mRNA level, we thought that sympathetic nerve tonus in BAT was already accelerated at room temperature. To exclude factors affecting basal sympathetic nerve activity, mice housed at thermoneutral temperature (30 degrees C) were used as controls for the subsequent experiments. In this condition, cold exposure accelerated NE turnover in the BAT, as well as heart and pancreas. The corticosterone level showed a higher trend in the cold exposure group in comparison to the control group. Immobilization accelerated NE turnover in the spleen, pancreas, and white adipose tissue and elevated the corticosterone level. LPS (3 mg/kg, i.p.) did not affect NE turnover in all peripheral organs but elevated the corticosterone level. In summary, the sympathetic nervous and adrenocortical responses to three stressors differed greatly. In particular, sympathetic responses showed clear organ-specific acceleration patterns. This important feature may improve our understanding of the multiplicity of biological responses.

Mathematical Models of the Effect of Glucagon on Glycemia in Individuals With Type 2 Diabetes Treated With Dapagliflozin.

Context: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by promoting urinary glucose excretion, but their overall effects on hormonal and metabolic status remain unclear. Objective: We here investigated the roles of insulin and glucagon in the regulation of glycemia in individuals treated with an SGLT2 inhibitor using mathematical model analysis. Methods: Hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests were performed in 68 individuals with type 2 diabetes treated with the SGLT2 inhibitor dapagliflozin. Data previously obtained from such tests in 120 subjects with various levels of glucose tolerance and not treated with an SGLT2 inhibitor were examined as a control. Mathematical models of the feedback loops connecting glucose and insulin (GI model) or glucose, insulin, and glucagon (GIG model) were generated. Results: Analysis with the GI model revealed that the disposition index/clearance, which is defined as the product of insulin sensitivity and insulin secretion divided by the square of insulin clearance and represents the glucose-handling ability of insulin, was significantly correlated with glycemia in subjects not taking an SGLT2 inhibitor but not in those taking dapagliflozin. Analysis with the GIG model revealed that a metric defined as the product of glucagon sensitivity and glucagon secretion divided by glucagon clearance (designated production index/clearance) was significantly correlated with blood glucose level in subjects treated with dapagliflozin. Conclusion: Treatment with an SGLT2 inhibitor alters the relation between insulin effect and blood glucose concentration, and glucagon effect may account for variation in glycemia among individuals treated with such drugs.

miR-125b develops chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor.

BACKGROUND: Diverse functions of microRNAs (miRNAs), including effects on tumorigenesis, proliferation, and differentiation, have been reported, and several miRNAs have also been demonstrated to play an important role in apoptosis. In this study, we investigated the possible role that miRNAs may play in the development of chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor (EWS). METHODS: We screened doxorubicin (Dox)-resistant EWS cells to identify any distinct miRNA sequences that may regulate the chemoresistance of EWS cells. The effects of miRNAs were evaluated using a chemosensitivity assay. The possible target genes of the miRNAs were predicted using a web-based prediction program. RESULTS: We found miR-125b to be upregulated in two different Dox-resistant EWS cell lines. The upregulation of miR-125b was also confirmed in the EWS tumors having survived chemotherapy regimen which includes doxorubicin. When miR-125b was knocked down in EWS cells, both the Dox-resistant and parental cells showed an enhanced sensitivity to doxorubicin, which was associated with the upregulation of the pro-apoptotic molecules, p53 and Bak. Inversely, the overexpression of miR-125b in parental EWS cells resulted in enhanced drug resistance, not only to doxorubicin, but also to etoposide and vincristine. CONCLUSIONS: Our findings suggest that miR-125b may play a role in the development of chemoresistance in EWS by suppressing the expression of the apoptotic mediators, such as p53 and Bak.

[Axillo-axillary bypass for coronary-subclavian steal syndrome].

We describe a case of coronary-subclavian steal syndrome in a 77-year-old man who presented with progressive coronary ischemia 8 years after coronary artery bypass grafting with an in-situ left internal thoracic artery graft. Coronary and left subclavian artery angiogram revealed completely patent internal thoracic artery graft and 90% stenosis in the proximal left subclavian artery. We performed axilloaxillary artery bypass using expanded polytetrafluoroethylene (ePTFE)[8 mm] graft. No coronary ischemia was noted postoperatively. Axillo-axillary artery bypass grafting was effective for coronary subclavian steal syndrome.

Combined Hypophysitis and Type 1 Diabetes Mellitus Related to Immune Checkpoint Inhibitors.

Context: The occurrence of multiple endocrinopathies due to immune checkpoint inhibitors (ICIs) is a relatively common adverse event. However, the occurrence of a combination of hypophysitis and type 1 diabetes mellitus (T1DM) is extremely rare, and its clinical features are unclear. Objective: We comparatively analyzed the clinical features of this combination and each individual ICI-induced endocrinopathy. Methods: We reported 3 cases that we encountered and reviewed previously reported cases of patients with combined hypophysitis and T1DM due to ICIs. Results: Anti-programmed cell death-1 (anti-PD-1) antibodies were prescribed to all 3 cases. The duration from ICI initiation to the onset of endocrine disease was 12 to 48 weeks. Several human leukocyte antigen (HLA) haplotypes that have disease susceptibility to hypophysitis were detected in all 3 patients. With the 17 previously reported cases, combined endocrinopathies were more common in men (85%). The onset age was in the 60s for both combined and single endocrinopathies. Anti-PD-1 antibodies were used in most of the cases (90%). The time from ICI initiation to the onset of endocrinopathies was 24 (8-76) weeks for hypophysitis and 32 (8-76) weeks for T1DM in patients with combined endocrinopathies, which was not significantly different from that for each single endocrinopathy. Conclusion: We presented 3 cases of patients with combined endocrinopathies of hypophysitis and T1DM that may have been caused by anti-PD-1 antibodies. There was no difference in the time from ICI initiation to the onset of endocrinopathies between combined and single endocrinopathies. Further case accumulation and pathogenic investigations are required.

Overexpression of KLF15 transcription factor in adipocytes of mice results in down-regulation of SCD1 protein expression in adipocytes and consequent enhancement of glucose-induced insulin secretion.

Krüppel-like factor 15 (KLF15), a member of the Krüppel-like factor family of transcription factors, has been found to play diverse roles in adipocytes in vitro. However, little is known of the function of KLF15 in adipocytes in vivo. We have now found that the expression of KLF15 in adipose tissue is down-regulated in obese mice, and we therefore generated adipose tissue-specific KLF15 transgenic (aP2-KLF15 Tg) mice to investigate the possible contribution of KLF15 to various pathological conditions associated with obesity in vivo. The aP2-KLF15 Tg mice manifest insulin resistance and are resistant to the development of obesity induced by maintenance on a high fat diet. However, they also exhibit improved glucose tolerance as a result of enhanced insulin secretion. Furthermore, this enhancement of insulin secretion was shown to result from down-regulation of the expression of stearoyl-CoA desaturase 1 (SCD1) in white adipose tissue and a consequent reduced level of oxidative stress. This is supported by the findings that restoration of SCD1 expression in white adipose tissue of aP2-KLF15 Tg mice exhibited increased oxidative stress in white adipose tissue and reduced insulin secretion with hyperglycemia. Our data thus provide an example of cross-talk between white adipose tissue and pancreatic ß cells mediated through modulation of oxidative stress.

Macrophage infiltration predicts a poor prognosis for human ewing sarcoma.

Ewing sarcoma-primitive neuroectodermal tumor (EWS) is associated with the most unfavorable prognosis of all primary musculoskeletal tumors. The objective of the present study was to investigate whether tumor-associated macrophages (TAMs) affect the development of EWS. TAMs were isolated from mouse xenografts using CD11b magnetic beads and examined for their cytokine expression and osteoclastic differentiation. To evaluate the role of TAMs in xenograft formation, liposome-encapsulated clodronate was used to deplete TAMs in mice. Macrophage infiltration and tumor microvascular density were histologically evaluated in 41 patients with EWS, and association with prognosis was examined using Kaplan-Meier survival analysis. In mouse EWS xenografts, TAMs expressed higher concentrations of cytokines including interleukin-6, keratinocyte-derived chemokine, and monocyte chemotactic protein-1. TAMs were more capable than normal monocytes of differentiating into tartrate-resistant acid phosphatase-positive giant cells. Depleting macrophages using liposome-encapsulated clodronate significantly inhibited development of EWS xenografts. In human EWS samples, higher levels of CD68-positive macrophages were associated with poorer overall survival. In addition, enhanced vascularity, increase in the amount of C-reactive protein, and higher white blood cell counts were also associated with poor prognosis and macrophage infiltration. TAMs seem to enhance the progression of EWS by stimulating both angiogenesis and osteoclastogenesis. Further investigation of the behavior of TAMs may lead to development of biologically targeted therapies for EWS.

[A case of neurotoxicity reduced with pregabalin in R-CHOP chemotherapy for diffuse large B-cell lymphoma].

When performing R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)for diffuse large B-cell lymphoma(DLBCL), neurotoxicity of vincristine(VCR)is the serious dose-limiting factor.Pregabalin is one of the first-line treatments for painful diabetic peripheral neuropathy in many countries, and we have administered it to relieve the neurotoxicity associated with adverse effects of VCR in a DLBCL patient treated with the R-CHOP regimen.A 49-year-old man with kidney DLBCL had surgery performed.Afterward, the R-CHOP regimen was introduced.In order to relieve the neurotoxicity of VCR, pregabalin was used from day 8 in the second course.The severity of sensory neurotoxicity after the administration of pregabalin was improved from CTCAE(v4.0)grade 3 to grade 1.Therefore, there is a possibility that VCR-induced neurotoxicity is relieved by pregabalin.Further trials are needed to confirm the value of pregabalin.