scholarly journals Trough levels of ipilimumab in serum as a potential biomarker of clinical outcomes for patients with advanced melanoma after treatment with ipilimumab

2021 ◽  
Vol 9 (10) ◽  
pp. e002663
Author(s):  
Yoshinobu Koguchi ◽  
Noriko Iwamoto ◽  
Takashi Shimada ◽  
Shu-Ching Chang ◽  
John Cha ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Limited Proteolysis ◽  
Serum Levels ◽  
Advanced Melanoma ◽  
Potential Utility ◽  
Term Survival ◽  
Link Type ◽  
Potential Biomarker ◽  
Pretreatment Serum ◽  
Trough Levels

BackgroundImmune checkpoint blockade (ICB) using anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of advanced cancer. However, ICB is effective for only a small fraction of patients, and biomarkers such as expression of PD-L1 in tumor or serum levels of CXCL11 have suboptimal sensitivity and specificity. Exposure–response (E-R) relationships have been observed with other therapeutic monoclonal antibodies. There are many factors influencing E-R relationships, yet several studies have shown that trough levels of anti-PD-1/PD-L1 correlated with clinical outcomes. However, the potential utility of anti-CTLA-4 levels as a biomarker remains unknown.MethodsSerum was obtained at trough levels at weeks 7 and 12 (after doses 2 and 4) from patients with advanced melanoma who received ipilimumab alone (3 mg/kg every 3 weeks for four treatments) via an expanded access program (NCT00495066). We have successfully established a proteomics assay to measure the concentration of ipilimumab in serum using an liquid chromatography with tandem mass spectrometry-based nanosurface and molecular-orientation limited proteolysis (nSMOL) approach. Serum samples from 38 patients were assessed for trough levels of ipilimumab by the nSMOL assay.ResultsWe found that trough levels of ipilimumab were higher in patients who developed immune-related adverse events but did not differ based on the presence or absence of disease progression. We found that patients with higher trough levels of ipilimumab had better overall survival when grouped based on ipilimumab trough levels. Trough levels of ipilimumab were inversely associated with pretreatment serum levels of CXCL11, a predictive biomarker we previously identified, and soluble CD25 (sCD25), a prognostic biomarker for advanced melanoma, as well as C reactive protein (CRP) and interleukin (IL)-6 levels at week 7.ConclusionsOur results suggest that trough levels of ipilimumab may be a useful biomarker for the long-term survival of patients with advanced melanoma treated with ipilimumab. The association of ipilimumab trough levels with pretreatment serum levels of CXCL11 and sCD25 is suggestive of a baseline-driven E-R relationship, and the association of ipilimumab trough levels with on-treatment levels of CRP and IL-6 is suggestive of response-driven E-R relationship. Our findings highlight the potential utility of trough levels of ipilimumab as a biomarker.Trial registration numberNCT00495066.

scholarly journals 760 Trough levels of ipilimumab in serum as a potential predictive biomarker of clinical outcomes for patients with advanced melanoma after treatment with ipilimumab

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A808-A808
Author(s):  
Yoshinobu Koguchi ◽  
Noriko Iwamoto ◽  
Takashi Shimada ◽  
Shu-Ching Chang ◽  
John Cha ◽  
...  
Keyword(s):  
Overall Survival ◽  
Limited Proteolysis ◽  
Predictive Biomarker ◽  
Advanced Melanoma ◽  
Rank Test ◽  
Lower Serum ◽  
Exposure Response ◽  
Log Rank Test ◽  
Serum Trough ◽  
Trough Levels

BackgroundImmune checkpoint blockade (ICB) using anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of advanced cancer. However, ICB cures only a fraction of patients, and biomarkers such as PD-L1 expression or CXCL11 have suboptimal sensitivity and specificity. Exposure-response (E-R) relationships have been observed in other therapeutic mAbs. There are many factors that can influence E-R,1 yet several studies have shown that trough levels of anti-PD-1/PD-L1 correlated with clinical outcomes. Little is known about the potential utility of anti-CTLA-4 levels as a predictive biomarker.MethodsSerum was obtained after doses 2 and 4 from patients with advanced melanoma who received ipilimumab alone (3 mg/kg every 3 weeks for 4 treatments) via an expanded access program. We have successfully established a proteomics assay to measure ipilimumab concentration in serum using a versatile LC-MS/MS-based nano-surface and molecular-orientation limited proteolysis (nSMOL) approach.2ResultsSerum samples from 38 patients were assessed for the ipilimumab trough levels by the nSMOL assay. The ipilimumab concentrations after dose 2 were ranged between 4.44 and 33.63 ug/ml (median:16.30, IQR: 11.41 – 20.87). We found that patients with lower serum trough levels of ipilimumab had poorer overall survival when we grouped patients based on the ipilimumab trough level (figure1 Median survival: < median = 199.5 days, > median = 519.0 days. Log-rank test: p = 0.0057). A similar result was observed for ipilimumab trough levels after dose 4. We also found that trough levels of ipilimumab inversely associated with CXCL11 (p = 0.0095. R2 = 0.1818), a predictive biomarker we previously identified,3 and soluble CD25 (sCD25) (p = 0.0038. R2 =0.2210), a prognostic biomarker for advanced melanoma but not with other biomarkers such as absolute lymphocyte counts, LDH, VEGF, sMICA, and sMICB.Abstract 760 Figure 1Poorer OS in patients with lower trough levels of ipilimumabPatients with lower serum trough levels of ipilimumab had poorer overall survival when we grouped patients based on the ipilimumab trough level (Median survival: < median = 199.5 days, > median = 519.0 days. Log-rank test: p = 0.0057).ConclusionsOur results suggest that the trough levels of ipilimumab might be a useful predictive biomarker for the long-term survival of the patients with advanced melanoma treated by ipilimumab. The weak association of ipilimumab trough levels with CXCL11 and sCD25 as well as no association with known biomarkers highlights the potential usefulness of trough levels of ipilimumab as the biomarker. Further studies are required to understand the mechanisms for lower levels of ipilimumab in refractory patients to improve the efficacy of ICB.AcknowledgementsThis study was funded by Providence Portland Medical Foundation and Shimadzu Corporation.Trial RegistrationNCT00495066Ethics ApprovalAll patients provided written informed consent and all studies were carried out in accordance with the Declaration of Helsinki under good clinical practice and Institutional Review Board approval.ReferencesDai HI, Vugmeyster Y, Mangal N. Characterizing exposure-response relationship for therapeutic monoclonal antibodies in immuno-oncology and beyond: challenges, perspectives, and prospects. Clin Pharmacol Ther 2020. 10.1002/cpt.1953.Iwamoto N, et al. Selective detection of complementarity-determining regions of monoclonal antibody by limiting protease access to the substrate: nano-surface and molecular-orientation limited proteolysis. Analyst 2014;139:576–580.Koguchi Y, et al. Serum immunoregulatory proteins as predictors of overall survival of metastatic melanoma patients treated with ipilimumab. Cancer Res 2015;75:5084–5092.

scholarly journals Evaluation of the Relationship Between Serum levels of Zinc, Vitamin B12, Vitamin D and Clinical outcomes in Patients with COVID‐19

2021 ◽  
Author(s):  
Habibesadat Shakeri ◽  
Amir Azimian ◽  
Hamed Ghasemzadeh‐Moghaddam ◽  
Mohammadreza Safdari ◽  
Mehdi Haresabadi ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin B12 ◽  
Clinical Outcomes ◽  
Serum Levels ◽  
The Relationship

scholarly journals Identification of the Response-Related Biomarker of Bimonthly Hepatic Arterial Infusion Chemotherapy

2021 ◽  
Vol 10 (4) ◽  
pp. 629
Author(s):  
Kei Moriya ◽  
Tadashi Namisaki ◽  
Hiroaki Takaya ◽  
Kosuke Kaji ◽  
Hideto Kawaratani ◽  
...  
Keyword(s):  
Hepatic Arterial Infusion ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Hepatic Arterial Infusion Chemotherapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Arterial Infusion ◽  
Term Survival ◽  
Arterial Infusion Chemotherapy ◽  
Infusion Chemotherapy ◽  
Molecularly Targeted Agents

Despite the availability of molecularly targeted agents for advanced hepatocellular carcinoma (aHCC), these are limited to compensated cirrhotic patients, and concerns about decreased hepatic functional reserve (HFR) and unknown adverse events, which may affect long-term survival, remain unaddressed. In this study, we enrolled 96 aHCC patients treated with bimonthly hepatic arterial infusion chemotherapy (B-HAIC) with cisplatin or sorafenib monotherapy (oral sorafenib 400 mg twice daily) not only to demonstrate its efficacy and significance but also to indicate preferable candidates by setting a response-related biomarker. Differences in treatment had no significant effect on overall survival (OS). The response rate in patients treated with B-HAIC was relatively higher than those treated with sorafenib. HFR was well maintained over the treatment course with B-HAIC, while it was significantly impaired with sorafenib. By employing multivariate analysis, we found negative trends between progression-free survival (PFS) periods and serum levels of alpha fetoprotein as well as des-gamma-carboxy prothrombin (DCP). In addition, a logistic regression analysis of the relationship between serum DCP levels and PFS periods over 420 days (14 months) showed that the PFS periods of patients with higher DCP was significantly shorter than those of patients with lower DCP (p = 0.02). Subsequently, the present study demonstrated the efficacy and safety of B-HAIC and identified a predictor of unpreferable patients. Based on these results, B-HAIC might be an alternative treatment after the implementation of new molecularly targeted therapies.

scholarly journals Serum levels and gene polymorphisms of angiopoietin 2 in systemic lupus erythematosus patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jia-Min Wang ◽  
Wang-Dong Xu ◽  
Zhi-Chao Yuan ◽  
Qian Wu ◽  
Jie Zhou ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Gene Polymorphisms ◽  
Serum Levels ◽  
Healthy Individuals ◽  
Systemic Lupus ◽  
Potential Biomarker ◽  
Angiopoietin 2 ◽  
Inflammatory Autoimmune Diseases

AbstractThis study aimed to discuss association between serum Angiopoietin2 (Ang2) levels, Ang2 gene polymorphisms and systemic lupus erythematosus (SLE) susceptibility. It was carried out by 235 SLE, 342 other inflammatory autoimmune diseases patients and 380 healthy individuals. Serum Ang2 levels was examinated by ELISA, and Ang2 rs12674822, rs1823375, rs1868554, rs2442598, rs3739390 and rs734701 polymorphisms were genotyped using KASP. Increased Ang2 concentrations in SLE patients were observed compared with healthy controls and patients with other inflammatory autoimmune diseases. For allelic contrast, except for rs1823375 (P = 0.058) and rs2442598 (P = 0.523), frequencies of alleles for other polymorphisms were significantly different between SLE patients and controls. Genotypes for rs12674822 (TT), rs1868554 (TT, TA and TT+TA), rs734701 (TT) were negatively correlated with SLE susceptibility (OR = 0.564 for rs12674822; OR = 0.572, OR = 0.625, OR = 0.607 for rs1868554; OR = 0.580 for rs734701). Patients carrying rs1868554 T allele and rs3739390 G allele were more likely to develop hematuria (P = 0.039; P = 0.003). The G allele frequencies of rs12674822 and rs2442598 were higher in SLE patients with proteinuria (P = 0.043; P = 0.043). GC genotype frequency of rs3739390 was higher in patients with ds-DNA (+) (P = 0.024). In summary, SLE had increased serum Ang2, which may be a potential biomarker, and the polymorphisms correlated with SLE.

Early fixation of the humeral component in stemless total shoulder arthroplasty

2022 ◽  
Vol 104-B (1) ◽  
pp. 76-82
Author(s):  
Bart ten Brinke ◽  
Brechtje Hesseling ◽  
Denise Eygendaal ◽  
Max A. Hoelen ◽  
Nina M. C. Mathijssen
Keyword(s):  
Clinical Outcomes ◽  
Shoulder Arthroplasty ◽  
Total Shoulder Arthroplasty ◽  
Future Research ◽  
Dash Score ◽  
Term Survival ◽  
Early Migration ◽  
Humeral Component ◽  
Initial Fixation ◽  
Early Fixation

Aims Stemless humeral implants have been developed to overcome stem-related complications in total shoulder arthroplasty (TSA). However, stemless implant designs may hypothetically result in less stable initial fixation, potentially affecting long-term survival. The aim of this study is to investigate early fixation and migration patterns of the stemless humeral component of the Simpliciti Shoulder System and to evaluate clinical outcomes. Methods In this prospective cohort study, radiostereometric analysis (RSA) radiographs were obtained in 24 patients at one day, six weeks, six months, one year, and two years postoperatively. Migration was calculated using model-based RSA. Clinical outcomes were evaluated using the visual analogue scale (VAS), the Oxford Shoulder Score (OSS), the Constant-Murley Score (CMS), and the Disabilities of the Arm, Shoulder and Hand (DASH) score. Results At two years, median translation along the x-, y-, and z-axis was -0.12 mm (interquartile range (IQR) -0.18 to 0.02), -0.17 mm (IQR -0.27 to -0.09), and 0.09 mm (IQR 0.02 to 0.31). Median rotation around the x-, y-, and z-axis was 0.12° (IQR -0.50 to 0.57), -0.98° (IQR -1.83 to 1.23), and 0.09° (IQR -0.76 to 0.30). Overall, 20 prostheses stabilized within 12 months postoperatively. Four prostheses showed continuous migration between 12 and 24 months. At two-year follow-up, with the exception of one revised prosthesis, all clinical scores improved significantly (median VAS difference at rest: -3.0 (IQR -1.5 to -6.0); OSS 22.0 (IQR 15.0 to 25.0); CMS 29.5 (IQR 15.0 to 35.75); and DASH -30.0 (IQR -20.6 to -41.67) (all p < 0.001)) with the exception of one revised prosthesis. Conclusion In conclusion, we found that 20 out of 24 implants stabilized within 12 months postoperatively. The significance of continuous migration in four implants is unclear and future research on the predictive value of early migration for future loosening in TSA is required. Clinical results revealed a clinically relevant improvement. Cite this article: Bone Joint J 2022;104-B(1):76–82.

High serum miR-421 is associated with metabolic dysregulation and inflammation in patients with metabolic syndrome

Epigenomics ◽  
2021 ◽  
Author(s):  
Aécio A Braga ◽  
Raul H Bortolin ◽  
Magda E Graciano-Saldarriaga ◽  
Thiago DC Hirata ◽  
Alvaro Cerda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
High Sensitivity ◽  
Serum Levels ◽  
High Serum ◽  
Reactive Protein ◽  
Metabolic Dysregulation ◽  
Inflammatory Status ◽  
Potential Biomarker ◽  
Screening Study

Aim: To explore the association of circulating miRNAs with adiposity, metabolic status and inflammatory biomarkers in patients with metabolic syndrome (MetS). Patients & methods: Serum levels of 372 miRNAs were measured in patients with (n = 6) and without MetS (n = 6) by quantitative PCR array, and dysregulated miRNAs were validated in a larger cohort (MetS, n = 89; non-MetS, n = 144). Results: In the screening study, seven miRNAs were dysregulated in patients with MetS, and miR-421 remained increased in the validation study. miR-421 was associated with a high risk of MetS and insulin resistance and hypertension and correlated with glycated hemoglobin, triacylglycerols, high-sensitivity C-reactive protein, IL-6, resistin and adiponectin (p < 0.05). Conclusion: Circulating miR-421 is a potential biomarker for insulin resistance, metabolic dysregulation and inflammatory status in patients with MetS.

scholarly journals Serum levels of sclerostin as a potential biomarker in central arterial stiffness among hypertensive patients

2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Yu-Chi Chang ◽  
Bang-Gee Hsu ◽  
Hung-Hsiang Liou ◽  
Chung-Jen Lee ◽  
Ji-Hung Wang
Keyword(s):  
Arterial Stiffness ◽  
Serum Levels ◽  
Hypertensive Patients ◽  
Potential Biomarker
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