Serum IgG4 Concentration is a Potential Predictive Biomarker in Glucocorticoid Treatment for Idiopathic Retroperitoneal Fibrosis

Objectives: To evaluate the management and outcome of idiopathic retroperitoneal fibrosis (iRPF) in Japan, and identify its clinical biomarker. Methods: We retrospectively analyzed 129 patients with iRPF treated between January 2008 and May 2018 at 12 university and related hospitals. Patients treated with glucocorticoid were analyzed to identify a predictive biomarker. These patients were classified into three groups according to overall effectiveness (no change: NC, complete response: CR and partial response groups: PR), and each parameter was compared statistically.Results: Male-female ratio was 5: 1, and median age at diagnosis was 69 (33-86) years. Smoking history was reported in 59.6% of the patients. As treatment, 95 patients received glucocorticoid therapy with an overall response rate of 84%. As a result, serum concentration of IgG4 was significantly decreased in NC group compared with the other two groups (56.6mg/dL vs 255mg/dL, 206mg/dL, P=0.0059 and 0.0078). ROC analysis was performed between the non-responder (NC) and responder groups (CR+PR) to identify the cut-off value of serum IgG4 as a predictive marker. As a result, AUC was 0.793 and the values of sensitivity and specificity were 0.85 and 0.64, respectively, under the cut-off values of 67.6mg/dL. Conclusions: In the majority of iRPF patients, glucocorticoid therapy resulted in a favorable response. Pre-treatment serum IgG4 concentration may have potential as a predictive biomarker of steroid treatment.

Unplanned Hemodialysis Initiation and Low Geriatric Nutritional Risk Index Scores are Associated with End-Stage Renal Disease Outcomes

Background Patients with end-stage renal disease (ESRD) have low nutritional status, presenting a high mortality risk. The geriatric nutritional risk index (GNRI) is a predictive marker of malnutrition. However, it is unclear whether the association between unplanned hemodialysis (HD) and GNRI scores is related to mortality. Methods The 180 patients who underwent HD at our hospital were divided into two groups: unplanned initiation with a central venous catheter (CVC; n=73) or planned initiation with prepared vascular access (n=107). Results There were no significant differences in sex, age, malignant tumor, hypertension, and vascular disease, while there were significant differences in time from the first visit to HD initiation (0 vs. 7 times, p=0.012) and days between the first visit and HD (12 vs. 186 days, p<0.001). The CVC insertion group had significantly lower GNRI scores at initiation (85.5 vs. 98.8, p<0.001). The adjusted hazard ratios were 4.115 and 3.077 for the GNRI scores and frequency, respectively. Three-year survival was significantly lower in the CVC + low GNRI group (p<0.0001). GNRI after 1 month was significantly inferior in the CVC insertion group. Conclusions Inadequate general management due to late referral to the nephrology department is a risk factor for patients with ESRD.

Preclinical evidence for mitochondrial DNA as a potential blood biomarker for chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting side effect of several first-line chemotherapeutic agents including paclitaxel, oxaliplatin and bortezomib, for which no predictive marker is currently available. We have previously shown that mitochondrial dysfunction is associated with the development and maintenance of CIPN. The aim of this study was to evaluate the potential use of mitochondrial DNA (mtDNA) levels and complex I enzyme activity as blood biomarkers for CIPN. Real-time qPCR was used to measure mtDNA levels in whole blood collected from chemotherapy- and vehicle-treated rats at three key time-points of pain-like behaviour: prior to pain development, at the peak of mechanical hypersensitivity and at resolution of pain-like behaviour. Systemic oxaliplatin significantly increased mtDNA levels in whole blood prior to pain development. Furthermore, paclitaxel- and bortezomib-treated animals displayed significantly higher levels of mtDNA at the peak of mechanical hypersensitivity. Mitochondrial complex I activity in whole blood was assessed with an ELISA-based Complex I Enzyme Activity Dipstick Assay. Complex I activity was not altered by any of the three chemotherapeutic agents, either prior to or during pain-like behaviour. These data demonstrate that blood levels of mtDNA are altered after systemic administration of chemotherapy. Oxaliplatin, in particular, is associated with higher mtDNA levels before animals show any pain-like behaviour, thus suggesting a potential role for circulating mtDNA levels as non-invasive predictive biomarker for CIPN.

A Linear Discriminant Analysis Model Based on the Changes of 7 Proteins in Plasma Predicts Response to Anlotinib Therapy in Advanced Non-Small Cell Lung Cancer Patients

BackgroundAnlotinib is a multi-targeted tyrosine kinase inhibitor mainly targeting angiogenesis signaling. The predictive marker of anlotinib’s efficacy remains elusive. This study was designed to explore the predictive marker of anlotinib in non-small cell lung cancer (NSCLC).MethodsWe prospectively enrolled 52 advanced NSCLC patients who underwent at least one line of targeted therapy or chemotherapy between August 2018 and March 2020. Patients were divided into durable responders (DR) and non-durable responders (NDR) based on the median progression-free survival (PFS, 176 days). The Olink Immuno-Oncology panel (92 proteins) was used to explore the predictive protein biomarkers in plasma samples before treatment (baseline) and on the first treatment evaluation (paired).ResultsAt baseline, the response to anlotinib was not significantly associated with age, gender, smoke history, histology, oligo-metastases, EGFR mutations, and other clinical characteristics. The results of PFS-related protein biomarkers at baseline were all not satisfying. Then we assessed the changes of 92 proteins levels in plasma on the first treatment evaluation. We obtained a Linear discriminant analysis (LDA) model based on 7 proteins, with an accuracy of 100% in the original data and an accuracy of 89.2% in cross validation. The 7 proteins were CD70, MIC-A/B, LAG3, CAIX, PDCD1, MMP12, and PD-L2. Multivariate Cox analysis further showed that the changes of CD70 (HR 25.48; 95% CI, 4.90–132.41, P=0.000) and MIC-A/B (HR 15.04; 95% CI, 3.81–59.36, P=0.000) in plasma were the most significant prognostic factors for PFS.ConclusionWe reported herein a LDA model based on the changes of 7 proteins levels in plasma before and after treatment, which could predict anlotinib responders among advanced NSCLC patients with an accuracy of 100%. Further studies are warranted to verify the prediction performance of the LDA model.

Relevance of Circulating Tumor Cells as Predictive Markers for Cancer Incidence and Relapse

Shedding of cancer cells from the primary site or undetectable bone marrow region into the circulatory system, resulting in clinically overt metastasis or dissemination, is the hallmark of unfavorable invasive cancers. The shed cells remain in circulation until they extravasate to form a secondary metastatic lesion or undergo anoikis. The circulating tumor cells (CTCs) found as single cells or clusters carry a plethora of information, are acknowledged as potential biomarkers for predicting cancer prognosis and cancer progression, and are supposed to play key roles in determining tailored therapies for advanced diseases. With the advent of novel technologies that allow the precise isolation of CTCs, more and more clinical trials are focusing on the prognostic and predictive potential of CTCs. In this review, we summarize the role of CTCs as a predictive marker for cancer incidence, relapse, and response to therapy.

FCGBP Is a Prognostic Biomarker and Associated With Immune Infiltration in Glioma

The Fc Fragment of IgG Binding Protein (FCGBP) has been proven to participate in intestinal tumor immunity. However, the biological role of FCGBP has remained unclear in glioma. The differential expression of FCGBP was explored by Oncomine and GEPIA databases. The effect of FCGBP on prognosis was analyzed via Kaplan–Meier plotter and GEPIA. The Tumor Immune Estimation Resource (TIMER) tool was used to determine the correlations of FCGBP expression with tumor immune infiltration. Firstly, FCGBP was highly expressed in glioma and correlated with a worse prognosis. Gene Ontology (GO) and KEGG pathway enrichment analyses revealed that the differentially expressed genes (DEGs) and co-expression genes of FCGBP were mainly involved in the immune response. Furthermore, FCGBP expression was positively associated with multiple immune cells infiltrates as well as the expression levels of multiple immune markers in glioma. FCGBP co-expression networks mostly participated in the regulation of immune response. Finally, immunohistochemistry (IHC) assays were conducted to explore the expression of FCGBP, PD-L1, CCL2 and CD8 in glioma and correlations between them. We found that PDL1 and FCGBP were synchronously upregulated in glioma tissues. These findings revealed a new mechanism by which FCGBP participates in the immune tolerance of glioma, and implied the potential of FCGBP as a therapeutic target or predictive marker for patients.

Radiotherapy for HPV-related cancers: prediction of therapeutic effects based on the mechanism of tumor immunity and the application of immunoradiotherapy

Human papillomavirus (HPV)-related cancer is one of the diseases entities for which the applications of radiotherapy have been increasing. Recently, the process of carcinogenesis from HPV infection and the mechanism of tumor immunity that develops during disease progression have been elucidated. In this review, we will describe the mechanism of tumor immunity and how chemoradiotherapy may overcome and improve the efficacy of tumor immunity. We will also discuss the usefulness of proteins involved with tumor immunity as a predictive marker of radiotherapy response, and present an overview of ongoing clinical trials of combinations of immune checkpoint inhibitors and radiotherapy to demonstrate the promising combination therapy that has been currently emerging.

Diagnostic Benefit of the Detection of Mitotic Figures in Endometriotic Lesions

Objectives Endometriosis is a chronic disease which is diagnosed by surgical intervention combined with a histological work-up. Current international and national recommendations do not require the histological determination of the proliferation rate. The diagnostic and clinical importance of the mitotic rate in endometriotic lesions still remains to be elucidated. Methods In this retrospective study, the mitotic rates and clinical data of 542 patients with histologically diagnosed endometriosis were analyzed. The mean patient age was 33.5 ± 8.0 (17 – 72) years, and the mean reproductive lifespan was 21.2 ± 7.8 (4 – 41) years. Patients were divided into two groups and patientsʼ reproductive history and clinical endometriosis characteristics were compared between groups. The study group consisted of women with confirmed mitotic figures (n = 140, 25.83%) and the control group comprised women without proliferative activity according to their mitotic rates (n = 402, 74.27%). Results Women with endometriotic lesions and histologically confirmed mitotic figures were significantly more likely to have a higher endometriosis stage (p = 0.001), deep infiltrating endometriosis (p < 0.001), ovarian endometrioma (p = 0.012), and infertility (p = 0.049). A mitotic rate > 0 was seen significantly less often in cases with incidental findings of endometriosis (p = 0.031). The presence of symptoms and basic characteristics such as age, age at onset of menarche, reproductive lifespan and parity did not differ between the group with and the group without mitotic figures. Conclusion This study shows that a simple histological assessment of the mitotic rate offers additional diagnostic value for the detection of advanced stages of endometriosis. The possible role as a predictive marker for the recurrence of endometriosis or the development of endometriosis-associated cancer will require future study.