Language：Japanese   Publisher：Cancers  

Background/Objectives: The response rate to immune checkpoint inhibitor (ICI) therapy is limited. Further, there is a need to discover biomarkers to predict therapeutic efficacy. The vascular endothelial growth factor (VEGF) is strongly associated with intra-tumoral immunity; however, its utility as a marker remains unknown. Therefore, our objectives were to examine the isoforms of VEGF and determine whether VEGF levels predict ICI efficacy. Methods: Levels of VEGF isoforms VEGF-A121 and VEGF-A165 were measured in stored serum samples obtained from 30 patients with advanced or recurrent gastric cancer who received nivolumab monotherapy at Kagoshima University Hospital, and the association with prognosis and treatment efficacy was retrospectively analyzed. Results: The serum levels of the total VEGF, VEGF-A121, and VEGF-A165 were not significantly associated with prognosis. However, the ratio of VEGF-A121/VEGF-A165 (VEGF-A121/165) exhibited a statistically significant (p = 0.0088) difference in progression-free survival (PFS) with the low-ratio group having a 67-day prolonged median PFS time. Under univariable analysis, only VEGF-A121/165 values exhibited reduced progression-free survival with statistical significance. When comparing treatment responses in the low (n = 15) and high (n = 15) serum VEGF-A-121/165 groups, RECIST evaluation was 3 to 0 for complete response (CR), 2 to 0 for partial response (PR), 3 to 2 for stable disease (SD), and 3 to 10 for progressive disease (PD). Patients with clinically unsettled PR or SD were classified as non-CR/non-PD (4 vs. 3), with a disease control rate of 80% vs. 33%. Conclusions: The serum VEGF-A121/165 ratio may represent a new, easily measured biomarker for predicting the therapeutic response to ICIs.

DOI： 10.3390/cancers16233958

Scopus

PubMed

Language：Japanese   Publisher：PLoS ONE  

Background VEGF-A concentrations were measured in the blood of bevacizumab-treated cancer patients in previous studies, but a consensus has not formed that would develop VEGF-A into a clinical biomarker. Recently, methods to strictly distinguish between the VEGF-A isoforms have been developed but have not yet been applied to cancer patients undergoing bevacizumab treatment. Methods An ELISA that strictly distinguishes between VEGF-A121 and VEGF-A165—the major isoforms of VEGF-A—and a commercially available ELISA for VEGF-A are used to determine the concentration of VEGF-A121, VEGF-A165, and VEGF-A in the blood of 12 patients with advanced colorectal cancer receiving bevacizumab therapy. Results The serum and plasma concentrations of VEGF-A121 increased substantially post-bevacizumab administration; the median increase in serum was 860.8 pg/mL, 95% confidence interval (CI) [468.5, 1128.9], p = 0.0024, and in plasma was 808.6 pg/mL, 95% CI [748.7, 874.0], p = 0.00049. In stark contrast, VEGF-A165 after bevacizumab administration decreased in serum by a medium change of –73.8 pg/mL, 95% CI [–149.4, –10.2], p = 0.0034, with 83.3% of the post-bevacizumab concentrations falling below the high-accuracy threshold of 38 pg/mL; in plasma, all pre and post VEGF-A165 concentrations fell below this threshold. Concentrations of VEGF-A121 and VEGF-A165 in platelets did not change to a statistically significant degree. Adding recombinant VEGF-A121 (and -A165) or bevacizumab to plasma in patients post-bevacizumab administration increased or decreased, respectively, VEGF-A121 and VEGF-A165 levels. The increase in VEGF-A121 in plasma and serum after bevacizumab administration may be due to the dissociation of the complex of tumor-derived VEGF-A121 and bevacizumab when it moves from the stroma into the blood. Conclusions The VEGF-A121 isoform has been uniquely demonstrated as a clear marker of bevacizumab therapy in both plasma and serum, motivating further research on pursuing these isoforms as biomarkers in cancer care.

DOI： 10.1371/journal.pone.0316035

Scopus

PubMed

Language：Japanese   Publisher：Heart and Vessels  

Platelet functions are thought to contribute to clinical outcomes after heart surgery. This study was conducted to assess the pivotal roles of vascular endothelial growth factor-A (VEGF-A) and microRNA-126 (miR-126) during coronary artery bypass grafting (CABG). Whole blood was collected for platelet isolation from 67 patients who underwent CABG surgery between July 2013 and March 2014. VEGF-A and miR-126 levels in serum, plasma, and platelets were measured at various time points and compared with clinical characteristics. The platelet count was decreased at 3 days after CABG. This dynamic change in platelet count was larger after conventional coronary artery bypass (CCAB) than off-pump coronary artery bypass (OPCAB). VEGF-A in the same number of platelets (IP-VEGF-A) was increased at 3 days after CABG, followed by an increase of VEGF-A in serum (S-VEGF-A) at 7 days after surgery. The miR-126-3p level in serum (S-miR-126-3p) increased rapidly after CABG and then decreased below preoperative levels. The IP-VEGF-A level on day 7 after CABG in patients with peripheral artery disease (PAD), who suffered from endothelial dysfunction, was higher compared with patients without PAD. Conversely, S-miR-126-3p on day 7 after surgery was lower in patients with PAD than in patients without PAD. Low levels of S-miR-126-3p due to endothelial dysfunction may lead to high IP-VEGF-A, which is closely related to complications after CABG.

DOI： 10.1007/s00380-021-01855-6

Scopus

PubMed

Language：English   Publisher：シュプリンガー・ジャパン(株)  

冠動脈バイパス術(CABG)の治療期間を通じ、血管内皮細胞増殖因子A(VEGF-A)とマイクロRNA(miR)-126が示す役割を評価した。2013年7月～2014年3月に当大学病院を含む2施設でCABGを施行した患者67名(男性率95%、平均66±3歳)から全血を採取して解析に用いた。CABG施行の3日後には血小板数が減少していたが、こうした動的変化はオフポンプCABGを受けた症例よりも従来法でのCABG例の方がより大きく生じていた。同一数の血小板に含まれるVEGF-AのレベルはCABGの3日後に上昇し、血清中のVEGF-Aレベルは7日後に上昇した。血清中のmiR-126-3pのレベルはCABG施行後、急速に上昇し、次いで施行前の水準を下回るまでに低下した。CABGの7日後の時点では、末梢動脈疾患(PAD)であった患者群(全集団の12%)での血小板内VEGF-Aレベルは、PAD非罹患の群に比べ上昇していた。逆にCABGから7日後の血清中miR-126-3pレベルは、非PAD群よりもPAD群の方が低かった。こうした結果から、PADでみられる内皮機能障害に起因してmiR-126-3pの血清中レベルは低下し、そのため血小板内VEGF-Aレベルが上昇するという機序が存在し、これがCABG後の合併症と密接に関係していると考えられた。

Language：Japanese   Publisher：Clinical Hemorheology and Microcirculation  

BACKGROUND AND OBJECTIVE: Turbulent blood flow in patients with aortic valve stenosis (AS) results in morphological and functional changes in platelets and coagulation factors. The aim of this study is to determine how shear stress affects platelets and coagulation factors. METHODS: We retrospectively evaluated data from 78 patients who underwent AVR to treat AS between March 2008 and July 2017 at Kagoshima University Hospital. RESULTS: Platelet (PLT) count obviously decreased at three days after AVR, and increased above preoperative levels at the time of discharge. In contrast, platelet distribution width (PDW), mean platelet volume (MPV), and platelet large cell ratio (P-LCR) increased three days after AVR, then decreased to below preoperative levels. No differences were evident between groups with higher (HPPG > 100 mmHg) and lower (LPPG < 100 mmHg) peak pressure gradients (PPG) before AVR, whereas PLT count, PDW, MPV and P-LCR improved more in the HPPG group. Plateletcrit (PCT), which represents the total volume of platelets, increased after AVR due to decreased shear stress. High increasing rate of PCT was associated with lower PLT count, higher PDW and lower fibrinogen. CONCLUSION: Shear stress affects PLT count, PDW, and fibrinogen in patients with AS.

DOI： 10.3233/CH-200928

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Doctoral thesis  

DOI： 10.1055/s-0034-1371811.

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

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