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Objectives Materials and Methods Results Conclusions Intricate associations between programmed cell death (PCD) and cancer development and treatment outcomes have been increasingly appreciated. Here, we integrated 12 PCD patterns to construct a novel biomarker, cell death index (CDI), for oral squamous cell carcinoma (OSCC) prognostication and therapeutic prediction.Univariate Cox regression, Kaplan–Meier survival, and LASSO analyses were performed to construct the CDI. A nomogram combining CDI and selected clinicopathological parameters was established by multivariate Cox regression. The associations between CDI and immune landscape and therapeutic sensitivity were estimated. Single‐cell RNA‐seq data of OSCC was used to infer CDI genes in selected cell types and determine their expression along cell differentiation trajectory.Ten selected PCD genes derived a novel prognostic signature for OSCC. The predictive prognostic performance of CDI and nomogram was robust and superior across multiple independent patient cohorts. CDI was negatively associated with tumor‐infiltrating immune cell abundance and immunotherapeutic outcomes. Moreover, scRNA‐seq data reanalysis revealed that GSDMB, IL‐1A, PRKAA2, and SFRP1 from this signature were primarily expressed in cancer cells and involved in cell differentiation.Our findings established CDI as a novel powerful predictor for prognosis and therapeutic response for OSCC and suggested its potential involvement in cancer cell differentiation. [ABSTRACT FROM AUTHOR]

This article discusses a case report and literature review on the levels of serum vitamin B12 during chemotherapy for diffuse large B-cell lymphoma (DLBCL). DLBCL is a common type of non-Hodgkin lymphoma, and the DA-EPOCH-R regimen is being studied as a treatment option. The article presents the case of a 64-year-old male with DLBCL who underwent chemotherapy and experienced fluctuations in serum vitamin B12 levels. The study suggests that monitoring serum vitamin B12 levels may be a useful auxiliary index for assessing short-term chemotherapeutic response in DLBCL patients. The authors also propose the need for methodological improvements in measuring serum vitamin B12 levels. [Extracted from the article]

Background: Cellular senescence significantly associates with tumor initiation, progression, and therapeutic response across multiple cancers. Here, we sought to develop a novel senescence‐related genes (SRGs)‐derived signature for oral squamous cell carcinoma (OSCC) prognostication and therapeutic response prediction. Methods: OSCC‐specific SRG prognostic signature was established with univariate Cox regression, Kaplan–Meier survival, and LASSO‐penalized multivariate Cox regression analyses. A SRG nomogram integrating this signature and selected clinicopathological parameters were constructed by multivariate Cox regression. SiRNA‐mediated gene knockdown was exploited to validate its function in vitro. The utilities of SRG signature in predicting immune status and chemotherapeutic sensitivities were analyzed. Results: The prognostic performance of SRG signature/nomogram was satisfactory in multiple independent cohorts. CDK1 knockdown induced senescence phenotype in vitro. Moreover, SRG signature scores negatively correlated with tumor‐infiltrating immune cells and associated with multiple chemotherapeutic drug sensitivities. Conclusions: Our results established SRG‐derived signature/nomogram as powerful predictors for prognosis and chemotherapeutic response for OSCC. [ABSTRACT FROM AUTHOR]

(1) Background: Pancreatic cancer (PC) is one of the most lethal tumors. Mitochondrial dysfunction has been reported to be involved in cancer development; however, its role in PC has remained unclear. (2) Methods: The differentially expressed NMGs were selected between PC and normal pancreatic tissue. The NMG-related prognostic signature was established by LASSO regression. A nomogram was developed based on the 12-gene signature combined with other significant pathological features. An extensive analysis of the 12 critical NMGs was performed in multiple dimensions. The expression of some key genes was verified in our external cohort. (3) Results: Mitochondria-related transcriptome features was obviously altered in PC compared with normal pancreas tissue. The 12-NMG signature showed good performance in predicting prognosis in various cohorts. The high- and low-risk groups exhibited notable diversity in gene mutation characteristics, biological characteristics, chemotherapy response, and the tumor immune microenvironment. Critical gene expression was demonstrated in our cohort at the mRNA and protein levels and in organelle localization. (4) Conclusions: Our study analyzed the mitochondrial molecular characterization of PC, proving the crucial role of NMGs in PC development. The established NMG signature helps classify patient subtypes in terms of prognosis prediction, treatment response, immunological features, and biological function, providing a potential therapeutic strategy targeting mitochondrial transcriptome characterization. [ABSTRACT FROM AUTHOR]

Objective Although high‐mobility group AT‐hook 2 (HMGA2) has been shown to have crucial roles in the pathogenesis and metastasis of various malignancies, its expression and significance in osteosarcoma remain unknown. Here we evaluate the expression, clinical prognostic value, and overall function of HMGA2 in osteosarcoma. Methods Sixty‐nine osteosarcoma patient specimens within a tissue microarray (TMA) were analyzed by immunohistochemistry for HMGA2 expression. Demographics and clinicopathological information including age, gender, tumor location, metastasis, recurrence, chemotherapy response, follow‐up time, and disease status were also collected. After validation of expression, we determined whether there was a correlation between HMGA2 expression and patient clinicopathology. HMGA2 expression was also evaluated in osteosarcoma cell lines and patient tissues by Western blot, we analyzed the expression of HMGA2 in the human osteosarcoma cell lines MG63, 143B, U2OS, Saos‐2, MNNG/HOS, and KHOS. HMGA2‐specific siRNA and clonogenic assays were then used to determine the effect of HMGA2 inhibition on osteosarcoma cell proliferation, growth, and chemosensitivity. Results HMGA2 expression was elevated in the osteosarcoma patient specimens and human osteosarcoma cell lines. HMGA2 was differentially expressed in human osteosarcoma cell lines. Specifically, a relatively high expression of HMGA2 was present in KHOS, MNNG/HOS, 143B and a relatively low expression was in MG63, U2OS as well as Saos‐2. HMGA2 expression is correlated with metastasis and shorter overall survival. High HMGA2 expression is an independent predictor of poor osteosarcoma prognosis. There was no significant correlation between HMGA2 expression and the age, gender, or tumor site of the patient. HMGA2 expression is predominantly within the nucleus. The expression of HMGA2 also directly correlated to neoadjuvant chemoresistance. There was a significant reduction of HMGA2 expression in the siRNA transfection group. After the use of siRNA, the proliferation of osteosarcoma cells is decreased and the chemosensitivity of osteosarcoma cells is significantly increased. Conclusion Our study supports HMGA2 as a potential prognostic biomarker and therapeutic target in osteosarcoma.

Heterogenous response to neoadjuvant chemotherapy in patients with multiple colorectal liver metastases (CRLM) has been associated with an acquired resistance to systemic therapy. This study evaluated the occurrence of a heterogenous inter-metastatic tumour response with regards to the proportion of viable tumour cells, and its prognostic impact. A retrospective cohort study was conducted, including all patients with CRLM surgically treated at Karolinska University Hospital, Stockholm, Sweden, from 2013 to 2018. Factors associated with the proportion of viable tumour cells and inter-metastatic heterogeneity were analysed with regression and survival analyses. Out of 640 surgically treated patients, 405 patients (1357 CRLM), received neoadjuvant chemotherapy. Multiple CRLM were present in 314 patients (78%), out of whom 72 patients (23%) presented with a heterogenous tumour response. The median overall survival (OS) for patients with a heterogenous inter-metastatic tumour response was 36 months, compared to 57 months for patients with a homogenous inter-metastatic tumour response (p <.001). Poor OS in patients receiving preoperative chemotherapy was significantly associated with a heterogenous inter-metastatic tumour response (hazard ratio (HR) 1.68 (1.02–2.78)), right-sided primary tumour (HR 2.01 (1.29–3.43)) and CRLM diameter >5 cm (HR 1.83 (1.06–3.17)). Outcome in patients with a heterogenous inter-metastatic tumour response, illustrated by the proportion of viable tumour cells, is inferior to that of patients with a homogenous response. These results suggest that heterogeneity in treatment response is an important marker of aggressive disease and could be of clinical value for decisions on post-operative therapy. [ABSTRACT FROM AUTHOR]

Objective: Many studies have drawn their attention to the immunotherapy of bladder urothelial carcinoma in terms of immunologic mechanisms of human body. These include immunogenicity of the tumor cells and involvement of long non-coding RNA (lncRNA). We constructed a necroptosis-related long noncoding RNA (nrlncRNA) risk factor model to predict BLCA outcomes and calculate correlations with chemosensitivity and immune infiltration. Methods: Transcriptomic data from BLCA specimens were accessed from The Cancer Genome Atlas, and nrlncRNAs were identified by performing co-expression analysis. Univariate analysis was performed to identify differentially expressed nrlncRNA pairs. We constructed least absolute contraction and selector operation regression models and drew receiver operating characteristic curves for 1-, 3-, and 5-year survival rates. Akaike information criterion (AIC) values for survival over 1 year were determined as cutoff values in high- and low-risk subgroups. We reassessed the differences between subgroups in terms of survival, clinicopathological characteristics, chemotherapy efficacy, tumor-infiltrating immune cells, and markers of immunosuppression. Results: We identified a total of 260 necroptosis-related lncRNA pairs, of which we incorporated 13 into the prognostic model. Areas under the curve of 1-, 3-, and 5- year survival time were 0.763, 0.836, and 0.842, respectively. We confirmed the excellent predictive performance of the risk model. Based on AIC values, we confirmed that the high-risk group was susceptible to unfavorable outcomes. The risk scores correlated with survival were age, clinical stage, grade, and tumor node metastases. The risk model was an independent predictor and demonstrated higher predictive power. The risk model can also be utilized to determine immune cell infiltration status, expression levels of immune checkpoint genes, and the sensitivity to cisplatin, doxorubicin, and methotrexate. Conclusion: We constructed a novel necroptosis-related signature that predicts BLCA outcomes and performs satisfactorily in the immune landscape and chemotherapeutic responses. [ABSTRACT FROM AUTHOR]

ObjectiveMany studies have drawn their attention to the immunotherapy of bladder urothelial carcinoma in terms of immunologic mechanisms of human body. These include immunogenicity of the tumor cells and involvement of long non-coding RNA (lncRNA). We constructed a necroptosis-related long noncoding RNA (nrlncRNA) risk factor model to predict BLCA outcomes and calculate correlations with chemosensitivity and immune infiltration.MethodsTranscriptomic data from BLCA specimens were accessed from The Cancer Genome Atlas, and nrlncRNAs were identified by performing co-expression analysis. Univariate analysis was performed to identify differentially expressed nrlncRNA pairs. We constructed least absolute contraction and selector operation regression models and drew receiver operating characteristic curves for 1-, 3-, and 5-year survival rates. Akaike information criterion (AIC) values for survival over 1 year were determined as cutoff values in high- and low-risk subgroups. We reassessed the differences between subgroups in terms of survival, clinicopathological characteristics, chemotherapy efficacy, tumor-infiltrating immune cells, and markers of immunosuppression.ResultsWe identified a total of 260 necroptosis-related lncRNA pairs, of which we incorporated 13 into the prognostic model. Areas under the curve of 1-, 3-, and 5- year survival time were 0.763, 0.836, and 0.842, respectively. We confirmed the excellent predictive performance of the risk model. Based on AIC values, we confirmed that the high-risk group was susceptible to unfavorable outcomes. The risk scores correlated with survival were age, clinical stage, grade, and tumor node metastases. The risk model was an independent predictor and demonstrated higher predictive power. The risk model can also be utilized to determine immune cell infiltration status, expression levels of immune checkpoint genes, and the sensitivity to cisplatin, doxorubicin, and methotrexate.ConclusionWe constructed a novel necroptosis-related signature that predicts BLCA outcomes and performs satisfactorily in the immune landscape and chemotherapeutic responses.

Objective: Although high‐mobility group AT‐hook 2 (HMGA2) has been shown to have crucial roles in the pathogenesis and metastasis of various malignancies, its expression and significance in osteosarcoma remain unknown. Here we evaluate the expression, clinical prognostic value, and overall function of HMGA2 in osteosarcoma. Methods: Sixty‐nine osteosarcoma patient specimens within a tissue microarray (TMA) were analyzed by immunohistochemistry for HMGA2 expression. Demographics and clinicopathological information including age, gender, tumor location, metastasis, recurrence, chemotherapy response, follow‐up time, and disease status were also collected. After validation of expression, we determined whether there was a correlation between HMGA2 expression and patient clinicopathology. HMGA2 expression was also evaluated in osteosarcoma cell lines and patient tissues by Western blot, we analyzed the expression of HMGA2 in the human osteosarcoma cell lines MG63, 143B, U2OS, Saos‐2, MNNG/HOS, and KHOS. HMGA2‐specific siRNA and clonogenic assays were then used to determine the effect of HMGA2 inhibition on osteosarcoma cell proliferation, growth, and chemosensitivity. Results: HMGA2 expression was elevated in the osteosarcoma patient specimens and human osteosarcoma cell lines. HMGA2 was differentially expressed in human osteosarcoma cell lines. Specifically, a relatively high expression of HMGA2 was present in KHOS, MNNG/HOS, 143B and a relatively low expression was in MG63, U2OS as well as Saos‐2. HMGA2 expression is correlated with metastasis and shorter overall survival. High HMGA2 expression is an independent predictor of poor osteosarcoma prognosis. There was no significant correlation between HMGA2 expression and the age, gender, or tumor site of the patient. HMGA2 expression is predominantly within the nucleus. The expression of HMGA2 also directly correlated to neoadjuvant chemoresistance. There was a significant reduction of HMGA2 expression in the siRNA transfection group. After the use of siRNA, the proliferation of osteosarcoma cells is decreased and the chemosensitivity of osteosarcoma cells is significantly increased. Conclusion: Our study supports HMGA2 as a potential prognostic biomarker and therapeutic target in osteosarcoma. [ABSTRACT FROM AUTHOR]

Methyltransferase-like 3 (METTL3) and N6-methyladenosine (m6A) are involved in many types of biological and pathological processes, including DNA repair. However, the function and mechanism of METTL3 in DNA repair and chemotherapeutic response remain largely unknown. In present study, we identified that METTL3 participates in the regulation of homologous recombination repair (HR), which further influences chemotherapeutic response in both MCF-7 and MDA-MB-231 breast cancer (BC) cells. Knockdown of METTL3 sensitized these BC cells to Adriamycin (ADR; also named as doxorubicin) treatment and increased accumulation of DNA damage. Mechanically, we demonstrated that inhibition of METTL3 impaired HR efficiency and increased ADR-induced DNA damage by regulating m6A modification of EGF/RAD51 axis. METTL3 promoted EGF expression through m6A modification, which further upregulated RAD51 expression, resulting in enhanced HR activity. We further demonstrated that the m6A ‘reader,’ YTHDC1, bound to the m6A modified EGF transcript and promoted EGF synthesis, which enhanced HR and cell survival during ADR treatment in BC. Our findings reveal a pivotal mechanism of METTL3-mediated HR and chemotherapeutic drug response, which may contribute to cancer therapy.

Abstract Background Several studies have previously indicated that nuclear factor erythroid 2‐related factor 2 (Nrf2) expression may promote tumor progression when the Keap1/Nrf2 pathway is activated, but few reports have demonstrated the role of cytoplasmic Nrf2 on tumorigenesis. Methods Immunohistochemistry was conducted to evaluate Nrf2 expression in 167 tumors from surgically‐resected patients with non‐small cell lung cancer (NSCLC). Univariate and multivariate analyses were performed to examine the association of Nrf2 expression with patients' prognosis. This study was conducted to examine the association of Nrf2 expression with tumor response to cisplatin‐based chemotherapy. Results Among these tumors, 56 and 32 of 167 tumors expressed Nrf2 in the cytoplasm (34% for C+/N‐) and in the cytoplasm/nucleus (19% for C+/N+), but not in the nucleus of tumor cells. Nrf2 was negatively expressed in the remainder of the tumor samples (C‐/N‐, 79 of 167, 47%). Univariate analysis indicated that patients with Nrf2 positive tumors (C+/N‐ plus C+/N+) had worse overall survival (OS), but not relapse‐free survival (RFS) than with Nrf2 negative tumors (C‐/N‐). However, patients with C+/N‐ tumors possessed worse OS and RFS than those with Nrf2 negative tumors (C‐/N‐). Multivariate analysis further confirmed the prognostic significance of patients with Nrf2 positive and C+/N‐ tumors on OS and RFS, but not on RFS for patients with Nrf2 positive tumors. Patients with Nrf2 positive and C+/N‐ tumors were determined to more frequently have an unfavorable response to cisplatin‐based chemotherapy than those with Nrf2 negative tumors. Conclusions Cytoplasmic Nrf2 expression might potentially be used to predict poor prognosis and unfavorable response to cisplatin‐based chemotherapy in patients with NSCLC. Key points The expression of cytoplasmic Nrf2 showed a significant relationship with patients' response to cisplatin‐based chemotherapy and influenced NSCLC prognosis. A proteasomal inhibitor such as carfilzomib might be used to improve the outcomes and therapeutic response to cisplatin‐based chemotherapy in patients with tumors showing cytoplasmic Nrf2 expression.

Abstract Background High-grade serous carcinoma (HGSC) of the ovary is the most common subtype of epithelial ovarian cancer (EOC) and has an overall poor prognosis. There is increasing awareness of the importance of immune cell populations and tumor-infiltrating lymphocytes (TILs) in various immune pathways in the tumor microenvironment. The present study evaluated immune-related gene expressions and TIL levels, as well as associated chemotherapeutic responses, to elucidate the correlation between gene expression and TIL levels in HGSC. Materials and methods Fresh tissue samples from 12 HGSC patients were included in this study. Depending on their response to adjuvant chemotherapy, the patients were divided into two groups: chemosensitive (CS) or chemoresistant (CR). The expression levels of 770 genes were analyzed using the nCounter® PanCancer Immune Profiling Panel of the NanoString nCounter® Analysis System. Quantitative real-time polymerase chain reaction (qPCR) was performed to validate the NanoString data obtained. The TIL levels in representative sections were examined via hematoxylin and eosin staining. Gene and TIL levels were subsequently correlated with the chemotherapeutic response. Results Several genes were differentially expressed in the two study groups. Eleven representative genes were selected for further evaluation. Of those, 9 genes (IRF1, CXCL9, LTB, CCL5, IL-8, GZMA, PSMB9, CD38, and VCAM1) were significantly overexpressed in the CS group; whereas expressions of 2 genes (CD24 and CD164) were increased in the CR group. Results of qPCR were consistent with those of the NanoString nCounter® analysis. Stromal TIL levels were significantly associated with adjuvant chemotherapeutic response (p = 0.001). Conclusions Significant differences between the CS and CR groups were observed in the expression levels of immune-related genes. Immune-related gene expressions were significantly higher in the CS group, which also had higher levels of TILs. We, therefore, suggest that, in patients with HGSC, immune-related gene expressions and TIL levels may be associated with chemotherapeutic sensitivity.

Abstract Background Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-associated deaths and a majority of its histological type is manifested as serous ovarian cancer (SOC). In this study, we investigated whether the timing of onset of chemotherapy-induced neutropenia (CIN) is related to chemotherapeutic response and disease outcome of SOC. Methods One hundred sixty-nine primary SOC patients receiving six doses of carboplatin plus paclitaxel adjuvant chemotherapy following cytoreductive surgery were retrospectively included in this research. CIN was grouped as early onset and late onset neutropenia depending on the timing of development. Development of CIN prior to or with administration of 3rd cycle of chemotherapy was listed as early onset neutropenia, while those CIN due to later stage chemotherapy were grouped into non-early type. The relevance of time of CIN onset with the clinical characteristics, chemotherapeutic response, progression free survival (PFS) and overall survival (OS) were determined and analyzed by using Kaplan–Meier curves, Logistic regression method, Cox proportional hazards models, and Chi-square tests. Results The age distribution of the patients was between 27 to 77 years. Fifty years was the median. No statistical significances of difference in age, FIGO stage, histological grade, tumor residual and lymph node invasion, as well as CA125 level in each CIN group were found (all P>0.05). The patients from non-early onset group showed higher chemoresistance rates (78.33%) compared to those from early onset group (9.17%). Additionally, patients in early onset group showed improved median PFS (23 vs. 9 months; P

Purpose: Metabolomics is an emerging field in cancer research. Plasma free amino acid profiles (PFAAs) have shown different features in various cancers, but the characteristic in advanced sarcoma remains unclear. We aimed to uncover the specific PFAAs in advanced sarcoma and to find the relationship between the altering of PFAAs and response to chemotherapy. Patients and methods: We analyzed the differences in PFAAs between 23 sarcoma patients and 30 healthy subjects basing on liquid chromatography–tandem mass spectrometry (LC–MS/MS). Then, we compared the dynamics of PFAAs after chemotherapy between improvement group and deterioration group. Results: We identified seven biological differential amino acids and four pathways which were perturbed in the sarcoma patients compared with healthy subjects. After one cycle chemotherapy, the levels of γ-aminobutyric acid (GABA) and carnosine (Car) decreased significantly in the improvement group but not in deterioration group. The levels of α-aminobutyric acid (Abu) increased significantly in the deterioration group but not in the improvement group. Conclusion: Our study suggests the potential specific PFAAs in sarcoma patients. The unusual amino acids and metabolic pathways may provide ideas for clinical drugs targeting therapy. Three amino acids including Car, GABA and Abu may be metabolic biomarkers playing a role in dynamic monitoring of the therapeutic effect. [ABSTRACT FROM AUTHOR]

In spite of the significant advancements in the treatment modalities, 30% of advanced stage ovarian cancer (OC) patients do not respond to the standard chemotherapeutic regimen and most of the responders finally relapse over time due to the escalation of multidrug resistance (MDR) Phenomenon. Our present study evaluated chemotherapeutic sensitivity response among 47 ovarian tumor patients of which we found 37 (78.8%) sensitive and remaining 10 (21.2%) resistant. Among the resistant, seven tumor samples were found to be platinum resistant or refractory to platinum (CB/TX), one to carboplatin, and two to 5FU. Notably, all these resistant cases were observed in the disease recurrence group of patients identified at stage III or IV. The stage III resistant cases revealed heterozygous mutation (C/T) in exon 12 (C1236T) and 26 (C3435T) and increased level of mRNA, whereas homozygous mutation (T/T) was found at stage IV tumor patients. The genotypic difference was found to be significant (p = 0.03) for exon 12, and p = 0.003 for exon 26 mutant genotypes. No significant association between genotypes of different exons with tumor stages and tumor grade was observed (p > 0.05). However, a significant association was observed between the genotype of exon-12 and histopathology of tumor tissue (p = 0.028). Statistically, the chemotherapy response was found to be significantly associated with the tumor stage (p = 0.019). We also observed a significant difference in PFS (P = 0.019) and OS (P = 0.047) between tumor grades 1 and 3. Notably, the highest mRNA expression was observed in resistant tumor sample T-32, where interestingly we found homozygosity TT in all of the exons 12, 21, and 26. Thus, we suggest that exons 12 (C1236T) and exon 26 (C3435T) polymorphism may play a role in inducing drug resistance by altering the expression level of the MDR1 gene. To summarize, we suggest that the expression of MDR1 in OC is influenced by tumor stage and genotype variants as well as by chemotherapeutic drugs. Thus our findings suggest that inter individual variability in platinum based therapy may be anticipated by MDR1 genotypes. Further studies on a large number of samples shall eventually lead to provide beneficial information for the individualized chemotherapy.

Leucine‐rich repeat containing 15 (LRRC15) is a member of the leucine‐rich repeat superfamily that is overexpressed in various cancers and associated with higher tumor grade and aggression. Despite its known tumorigenicity, its roles within osteosarcoma are unknown, prompting us to evaluate its expression and clinical significance within this rare yet aggressive cancer. Western blots showed differential expression of LRRC15 in the osteosarcoma cell lines MNNG/HOS, KHOS, 143B, MG63, Saos‐2, and U2OS. We additionally validated this positive expression, as well as sublocalization to the cell membrane, with immunofluorescence. A tissue microarray constructed from 69 osteosarcoma patient tissues was immunohistochemically stained for LRRC15 expression, stratified, and used for clinicopathological analysis. Publicly available databases on LRRC15 expression, including RNA sequencing data from the Therapeutically Applicable Research to Generate Effective Treatments on Osteosarcoma (TARGET‐OS) and the Gene Expression database of Normal and Tumor tissues 2 (GENT2) were also analyzed. We found 63 of the 69 (91.3%) patient tissues exhibited some degree of LRRC15 immunostaining, including no staining (6 of 69, 8.7%), 1+ staining (12 of 69, 17.4%), 2+ staining (25 of 69, 36.2%), and 3+ staining (26 of 69, 37.7%). The patients with osteosarcomas having elevated LRRC15 expression demonstrated comparatively increased metastasis, chemoresistance, and shorter 5‐year survival rates. Our analysis of the TARGET‐OS and GENT2 databases also showed increased LRRC15 gene expression in osteosarcoma. Taken together, our study supports LRRC15 as a prognostic biomarker and emerging therapeutic target in osteosarcoma. [ABSTRACT FROM AUTHOR]

While amplified expressed cyclin E1 is a well‐known tumorigenic factor and prognostic biomarker in several malignancies, its prognostic predictive potential and function in osteosarcoma is poorly understood. Here we reveal discrete expression pattern, correlation to clinicopathological characteristics and prognosis and overall function of cyclin E1 in osteosarcoma. Sixty‐nine osteosarcoma patient tumor specimens were enrolled to construct a tissue microarray to evaluate cyclin E1 expression through immunohistochemical staining. Cyclin E1 expression in osteosarcoma cell lines and fresh tissues was assessed by Western blot. Cyclin E1 gene expression was evaluated using RNA sequencing data acquired from the public database. We correlated staining intensity to clinical characteristics. Cyclin E1 small interfering RNA was used to determine the effect of cyclin E1 silencing on osteosarcoma cell proliferation and chemotherapeutic sensitivity. Sixty‐one percent of the osteosarcoma patient specimens in the tissue microarray had high cyclin E1 expression. Cyclin E1 gene was significantly highly expressed in osteosarcoma tissues and cell lines compared to normal tissues. The expression of cyclin E1 positively correlated with disease status, and inversely correlated to prognosis and response to neoadjuvant chemotherapy. The expression of cyclin E1 was an independent prognostic factor for osteosarcoma patients. In addition, silencing cyclin E1 expression in osteosarcoma cells significantly inhibited cell proliferation and increased sensitivity to chemotherapeutics. We conclude that cyclin E1 is overexpressed in osteosarcoma and is a promising biomarker for prognosis and chemotherapeutic response. We confirm aberrant cyclin E1 expression is a potent therapeutic target in osteosarcoma, and its selective inhibition is a rational treatment strategy for osteosarcoma. [ABSTRACT FROM AUTHOR]

The purpose of this study was to describe patients' characteristics, correlation between staging non-seminoma cancer and chemotherapy response. Data on age, location of tumor, staging, serum levels of the tumor marker post operative, adjuvant therapy, chemotherapy side effects, and response of patient to chemotherapy were gained from medical records in Soetomo Hospital Surabaya from January 2012 to December 2015, and analyzed with SPSS. Correlation between staging and chemotherapy response, correlation primary tumor staging (pT) and Metastasis (M), correlation regional lymph nodes staging (N) and metastasis (M), correlation serum tumor marker and chemotherapy response was proccessed by Spearman correlation test. There were no significant correlation between pT staging and M and no significant correlation between N and M staging. Based on tumor markers (S), mostly patients were S2. There were no significant correlation between the response to chemotherapy and serum tumor marker levels. In category of staging group, the most are 14 patients stage III. BEP was the most adjuvant Chemotherapy. Nausea and vomiting were The most complained during chemotherapy. Anemia were the most hematologic side effects of chemotherapy. There are no significant correlation between the staging of non-seminoma and the response to chemotherapy. Conclusion: Non seminoma mostly happened in young males. Non-seminoma responses to chemotherapy. Patients in early stage would give a good response to chemotherapy compared to those with advanced stage. After chemotherapy, evaluation should be done to the patients' complaints and complete blood count to detect side effects. [ABSTRACT FROM AUTHOR]

Background: Several studies have previously indicated that nuclear factor erythroid 2‐related factor 2 (Nrf2) expression may promote tumor progression when the Keap1/Nrf2 pathway is activated, but few reports have demonstrated the role of cytoplasmic Nrf2 on tumorigenesis. Methods: Immunohistochemistry was conducted to evaluate Nrf2 expression in 167 tumors from surgically‐resected patients with non‐small cell lung cancer (NSCLC). Univariate and multivariate analyses were performed to examine the association of Nrf2 expression with patients' prognosis. This study was conducted to examine the association of Nrf2 expression with tumor response to cisplatin‐based chemotherapy. Results: Among these tumors, 56 and 32 of 167 tumors expressed Nrf2 in the cytoplasm (34% for C+/N‐) and in the cytoplasm/nucleus (19% for C+/N+), but not in the nucleus of tumor cells. Nrf2 was negatively expressed in the remainder of the tumor samples (C‐/N‐, 79 of 167, 47%). Univariate analysis indicated that patients with Nrf2 positive tumors (C+/N‐ plus C+/N+) had worse overall survival (OS), but not relapse‐free survival (RFS) than with Nrf2 negative tumors (C‐/N‐). However, patients with C+/N‐ tumors possessed worse OS and RFS than those with Nrf2 negative tumors (C‐/N‐). Multivariate analysis further confirmed the prognostic significance of patients with Nrf2 positive and C+/N‐ tumors on OS and RFS, but not on RFS for patients with Nrf2 positive tumors. Patients with Nrf2 positive and C+/N‐ tumors were determined to more frequently have an unfavorable response to cisplatin‐based chemotherapy than those with Nrf2 negative tumors. Conclusions: Cytoplasmic Nrf2 expression might potentially be used to predict poor prognosis and unfavorable response to cisplatin‐based chemotherapy in patients with NSCLC. Key points: The expression of cytoplasmic Nrf2 showed a significant relationship with patients' response to cisplatin‐based chemotherapy and influenced NSCLC prognosis.A proteasomal inhibitor such as carfilzomib might be used to improve the outcomes and therapeutic response to cisplatin‐based chemotherapy in patients with tumors showing cytoplasmic Nrf2 expression. [ABSTRACT FROM AUTHOR]

Background: High-grade serous carcinoma (HGSC) of the ovary is the most common subtype of epithelial ovarian cancer (EOC) and has an overall poor prognosis. There is increasing awareness of the importance of immune cell populations and tumor-infiltrating lymphocytes (TILs) in various immune pathways in the tumor microenvironment. The present study evaluated immune-related gene expressions and TIL levels, as well as associated chemotherapeutic responses, to elucidate the correlation between gene expression and TIL levels in HGSC. Materials and methods: Fresh tissue samples from 12 HGSC patients were included in this study. Depending on their response to adjuvant chemotherapy, the patients were divided into two groups: chemosensitive (CS) or chemoresistant (CR). The expression levels of 770 genes were analyzed using the nCounter® PanCancer Immune Profiling Panel of the NanoString nCounter® Analysis System. Quantitative real-time polymerase chain reaction (qPCR) was performed to validate the NanoString data obtained. The TIL levels in representative sections were examined via hematoxylin and eosin staining. Gene and TIL levels were subsequently correlated with the chemotherapeutic response. Results: Several genes were differentially expressed in the two study groups. Eleven representative genes were selected for further evaluation. Of those, 9 genes (IRF1, CXCL9, LTB, CCL5, IL-8, GZMA, PSMB9, CD38, and VCAM1) were significantly overexpressed in the CS group; whereas expressions of 2 genes (CD24 and CD164) were increased in the CR group. Results of qPCR were consistent with those of the NanoString nCounter® analysis. Stromal TIL levels were significantly associated with adjuvant chemotherapeutic response (p = 0.001). Conclusions: Significant differences between the CS and CR groups were observed in the expression levels of immune-related genes. Immune-related gene expressions were significantly higher in the CS group, which also had higher levels of TILs. We, therefore, suggest that, in patients with HGSC, immune-related gene expressions and TIL levels may be associated with chemotherapeutic sensitivity. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that miRNA (miR) can be stably detected in serum, and aberrant expression of various miRNAs has shown diagnostic value in non-small cell lung cancer (NSCLC) patients. However, the role of miRNA in the context of prognosis has not been extensively investigated. Our previous study reported that miR- 22, miR-125b, and miR-15b in serum had potential for use as tumor markers for auxiliary diagnosing of NSCLC. Therefore, the objective of this study was to detect the levels of miR-22, miR-125b, and miR-15b in serum from NSCLC patients and explore the potential prognostic significance of the three selected miRNAs. Methods: The relative expression of miR-22, miR-125b, and miR-15b in 74 patients with advanced NSCLC in preand post-chemotherapy were detected by real-time quantitative polymerase chain reaction. Results: Serum level of miR-125b significantly decreased after chemotherapy (p < 0.05) and the levels of miR-15b significantly increased (p < 0.01), while there was no change in the level of serum miR-22 (Z = 0.716, p > 0.05). Compared with pre-chemotherapy, serum miR-125b expression in advanced NSCLC patients of responders (CR + PR) were significantly decreased post-chemotherapy (p < 0.05); serum miR-15b expression in advanced NSCLC patients of responders (CR + PR) were increased (p < 0.01). The chemotherapy sensitivity of advanced NSCLC patients with high expression of miR-125b was lower than that of NSCLC patients with low expression (p < 0.05). The chemotherapy sensitivity of advanced NSCLC patients with high expression of miR-15b was higher than that of NSCLC patients with low expression (p < 0.05). High levels of serum miR-125b and low levels of serum miR- 15b were related to poor overall survival (p < 0.05). Conclusions: The serum levels of miR-125b and miR-15b in advanced NSCLC patients were changed pre- and post-chemotherapy and these changes were associated with chemotherapeutic response. Serum miR-125b and miR-15b have certain potential clinical value for chemotherapeutic response in advanced NSCLC. The serum levels of miR-125b and miR-15b in patients with advanced NSCLC before treatment may be used to estimate the overall survival. [ABSTRACT FROM AUTHOR]

In spite of the significant advancements in the treatment modalities, 30% of advanced stage ovarian cancer (OC) patients do not respond to the standard chemotherapeutic regimen and most of the responders finally relapse over time due to the escalation of multidrug resistance (MDR) Phenomenon. Our present study evaluated chemotherapeutic sensitivity response among 47 ovarian tumor patients of which we found 37 (78.8%) sensitive and remaining 10 (21.2%) resistant. Among the resistant, seven tumor samples were found to be platinum resistant or refractory to platinum (CB/TX), one to carboplatin, and two to 5FU. Notably, all these resistant cases were observed in the disease recurrence group of patients identified at stage III or IV. The stage III resistant cases revealed heterozygous mutation (C/T) in exon 12 (C1236T) and 26 (C3435T) and increased level of mRNA, whereas homozygous mutation (T/T) was found at stage IV tumor patients. The genotypic difference was found to be significant (p = 0.03) for exon 12, and p = 0.003 for exon 26 mutant genotypes. No significant association between genotypes of different exons with tumor stages and tumor grade was observed (p > 0.05). However, a significant association was observed between the genotype of exon-12 and histopathology of tumor tissue (p = 0.028). Statistically, the chemotherapy response was found to be significantly associated with the tumor stage (p = 0.019). We also observed a significant difference in PFS (P = 0.019) and OS (P = 0.047) between tumor grades 1 and 3. Notably, the highest mRNA expression was observed in resistant tumor sample T-32, where interestingly we found homozygosity TT in all of the exons 12, 21, and 26. Thus, we suggest that exons 12 (C1236T) and exon 26 (C3435T) polymorphism may play a role in inducing drug resistance by altering the expression level of the MDR1 gene. To summarize, we suggest that the expression of MDR1 in OC is influenced by tumor stage and genotype variants as well as by chemotherapeutic drugs. Thus our findings suggest that inter individual variability in platinum based therapy may be anticipated by MDR1 genotypes. Further studies on a large number of samples shall eventually lead to provide beneficial information for the individualized chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-associated deaths and a majority of its histological type is manifested as serous ovarian cancer (SOC). In this study, we investigated whether the timing of onset of chemotherapy-induced neutropenia (CIN) is related to chemotherapeutic response and disease outcome of SOC.Methods: One hundred sixty-nine primary SOC patients receiving six doses of carboplatin plus paclitaxel adjuvant chemotherapy following cytoreductive surgery were retrospectively included in this research. CIN was grouped as early onset and late onset neutropenia depending on the timing of development. Development of CIN prior to or with administration of 3rd cycle of chemotherapy was listed as early onset neutropenia, while those CIN due to later stage chemotherapy were grouped into non-early type. The relevance of time of CIN onset with the clinical characteristics, chemotherapeutic response, progression free survival (PFS) and overall survival (OS) were determined and analyzed by using Kaplan-Meier curves, Logistic regression method, Cox proportional hazards models, and Chi-square tests.Results: The age distribution of the patients was between 27 to 77 years. Fifty years was the median. No statistical significances of difference in age, FIGO stage, histological grade, tumor residual and lymph node invasion, as well as CA125 level in each CIN group were found (all P>0.05). The patients from non-early onset group showed higher chemoresistance rates (78.33%) compared to those from early onset group (9.17%). Additionally, patients in early onset group showed improved median PFS (23 vs. 9 months; P<0.001) and median OS (55 vs.24 months; P<0.001).Conclusions: Early onset neutropenia may be potentially used as a potential indicator for chemosensitivity and favorable prognosis of SOC in patients who underwent six cycles of carboplatin plus paclitaxel adjuvant chemotherapy following primary cytoreductive surgery. [ABSTRACT FROM AUTHOR]

Histologic response to neoadjuvant chemotherapy is an essential prognostic criterion in osteosarcoma. Non-invasive assessment of the effect of neoadjuvant chemotherapy influences the timing and method of definitive surgery. Aim: This study evaluated the use of Dynamic Contrast Enhanced-MRI (DCE-MRI) in preoperative estimation of residual viable tumor present in Osteosarcoma following chemotherapy. Patients and methods: We conducted a prospective study from July 2011 till April 2013 on 50 pediatric patients with a mean age of 12.8 years diagnosed as Highgrade osteosarcoma in long bones at the Children Cancer Hospital Egypt. Conventional and dynamic MRI performed before definitive surgery was compared with histopathology assessment of necrosis. For DCE-MRI, 3 regions of interest (ROIs) were chosen and the signal intensity was plotted against time. Signal intensity values and curve pattern were compared to percent of necrosis of the corresponding areas on the resected specimens. Results: DCE-MRI showed sensitivity of 92.5% and specificity of 96% with positive predictive value of 92% and negative predictive value of 96%. Negative correlation was found between signal intensity values and percent of necrosis. Conclusions: DCE-MRI can be used preoperatively as a sensitive, specific, and non-invasive method for detection of viability and necrosis within osteosarcoma.

Background: Bladder cancer (BCa) is a common malignancy in the urinary system. Necroptosis, a recently discovered form of programmed cell death, is closely associated with the development and progression of various types of tumors. Targeting necroptosis through anti-cancer strategies has shown potential as a therapy for cancer. We aimed to develop a necroptosis-related lncRNAs (NRlncRNAs) risk model that can predict the survival and tumor immunity of BCa patients., Methods: We analyzed sequencing data obtained from the TCGA database, and applied least absolute shrinkage and selection operator (LASSO) and Cox regression analysis to identify crucial NRlncRNAs for building a risk model. Using the risk score, we categorized patients into high- and low-risk groups, and assessed the accuracy with the area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves. We performed the RT-qPCR to detect the expression differences of the genes based on the risk model., Results: We identified a total of 296 NRlncRNAs, and 6 of them were included in the prognostic model. The AUC values for 1-, 3-, and 5-year predictions were 0.675, 0.726 and 0.734, respectively. Our risk model demonstrated excellent predictive performance and served as an independent predictor with high predictive power. Additionally, we performed PCA, TMB, GSEA analyses, and evaluated immune cell infiltration, to reveal significant differences between the high- and low-risk groups in functional signaling pathways, immunological status, and mutation profiles. Finally, we assessed the chemotherapeutic response of several drugs. According to the RT-qPCR results, we found that four NRlncRNAs of the risk model were more highly expressed in BCa cell lines than human immortalized uroepithelial cell line and regulated the occurrence and progression of bladder cancer., Conclusion: We constructed a novel NRlncRNAs-associated risk model, which could predict the prognosis and immune response of BCa patients.

Objectives: To study the role of the neutrophil‐to‐lymphocyte ratio in predicting survival outcomes for patients with advanced bladder cancer. Methods: We retrospectively reviewed 150 patients diagnosed with advanced or metastatic bladder cancer between January 2004 and June 2014. The neutrophil‐to‐lymphocyte ratio was computed on diagnosis and after the first cycle of chemotherapy. A neutrophil‐to‐lymphocyte ratio cut‐off of 3.0 was determined, with a concordance index of 0.89. Kaplan–Meier curves, log–rank tests, Cox proportional hazards and logistic regression models were used to predict the association of the neutrophil‐to‐lymphocyte ratio with survival outcomes. Results: Just five patients were alive at the end of the study; the rest died from metastatic bladder cancer. On multivariate analysis, higher Eastern Cooperative Oncology Group status, lymphadenopathy, visceral metastases and neutrophil‐to‐lymphocyte ratio ≥3.0 were associated with poorer overall survival (hazard ratio 1.67, P = 0.03; hazard ratio 1.97, P = <0.01; hazard ratio 2.02, P = <0.01; hazard ratio 5.06, P = <0.01), whereas chemotherapy conferred better overall survival (hazard ratio 0.546, P = 0.01). Furthermore, the role of chemotherapy prolonged survival longer in patients with a neutrophil‐to‐lymphocyte ratio <3.0 (median overall survival 13.0 vs 22.0 months, hazard ratio 0.273, P = 0.008) compared with a neutrophil‐to‐lymphocyte ratio ≥3.0 (median overall survival 4.0 vs 7.0 months, hazard ratio 0.452, P = 0.020). More importantly, when dichotomized to the four different pre‐ and post‐chemotherapy groups, patients with a pre‐ and post‐chemotherapy neutrophil‐to‐lymphocyte ratio <3.0 had the best additional median overall survival of 19.0 months compared with patients with a pre‐ and post‐chemotherapy neutrophil‐to‐lymphocyte ratio ≥3.0 (3.0 months). Conclusions: Elevated neutrophil‐to‐lymphocyte ratio is independently associated with poorer chemotherapeutic response and overall survival in patients with advanced or metastatic bladder cancer. The neutrophil‐to‐lymphocyte ratio can be an inexpensive novel factor in prognosticating disease progression and providing better patient counseling. [ABSTRACT FROM AUTHOR]

Chemotherapy is widely administered to patients with advanced lung cancer; however, data regarding chemotherapeutic sensitivity are limited. The present study aimed to investigate the predictive value of inflammatory indexes for chemotherapeutic efficacy in advanced lung cancer. Patients with stage III and IV unresectable lung cancer that were treated with first‑line chemotherapy between January 2007 and December 2011 were retrospectively identified, and chemotherapeutic response was evaluated following 2 or 3 chemotherapy cycles. Prior to chemotherapy, hematologic data and clinicopathological parameters were collected using electronic medical records. The associations between the main inflammatory indexes [which included the pretreatment neutrophil count (PNC), neutrophil‑lymphocyte ratio (NLR), platelet‑lymphocyte ratio (PLR)] and the chemotherapeutic efficacy, as well as the prognostic value of the indexes, were analyzed. According to the receiver operating characteristic curve, PLR failed to reach diagnostic accuracy for overall chemotherapeutic response. PNC and NLR were each classified into two groups according to the cut‑off values (4.635x109/l for PNC and 2.443 x109/l for NLR). The overall response rate was significantly higher in the low PNC [odds ratio, 3.261; 95% confidence interval (CI), 2.102‑5.060; P<0.001, vs. high PNC] and low NLR groups (odds ratio, 1.596; 95% CI, 1.037‑2.454; P=0.033, vs. high NLR). Univariate analyses showed that the high PNC (HR, 1.487) and high NLR groups (HR, 1.288) were associated with poor progression‑free survival (PFS); however, NLR was considered statistically insignificant in multivariate analysis. In summary, high PNC and NLR values are associated with chemoresistance and an unfavorable prognosis, with the present study demonstrating that PNC has increased sensitivity when compared with other inflammatory indexes in predicting chemotherapeutic efficacy. Therefore, PNC has the potential to be used as a reliable and suitable predictor to stratify a high risk of chemoresistance in patients with stage III and IV unresectable lung cancer. [ABSTRACT FROM AUTHOR]

Histologic response to neoadjuvant chemotherapy is an essential prognostic criterion in osteosarcoma. Non-invasive assessment of the effect of neoadjuvant chemotherapy influences the timing and method of definitive surgery. Aim This study evaluated the use of Dynamic Contrast Enhanced-MRI (DCE-MRI) in preoperative estimation of residual viable tumor present in Osteosarcoma following chemotherapy. Patients and methods We conducted a prospective study from July 2011 till April 2013 on 50 pediatric patients with a mean age of 12.8 years diagnosed as Highgrade osteosarcoma in long bones at the Children Cancer Hospital Egypt. Conventional and dynamic MRI performed before definitive surgery was compared with histopathology assessment of necrosis. For DCE-MRI, 3 regions of interest (ROIs) were chosen and the signal intensity was plotted against time. Signal intensity values and curve pattern were compared to percent of necrosis of the corresponding areas on the resected specimens. Results DCE-MRI showed sensitivity of 92.5% and specificity of 96% with positive predictive value of 92% and negative predictive value of 96%. Negative correlation was found between signal intensity values and percent of necrosis. Conclusions DCE-MRI can be used preoperatively as a sensitive, specific, and non-invasive method for detection of viability and necrosis within osteosarcoma. [ABSTRACT FROM AUTHOR]

Background Diffusion-weighted MRI (DWI) signal attenuation is often not mono-exponential (i.e. non-Gaussian diffusion) with stronger diffusion weighting. Several non-Gaussian diffusion models have been developed and may provide new information or higher sensitivity compared with the conventional apparent diffusion coefficient (ADC) method. However the relative merits of these models to detect tumor therapeutic response is not fully clear. Methods Conventional ADC, and three widely-used non-Gaussian models, (bi-exponential, stretched exponential, and statistical model), were implemented and compared for assessing SW620 human colon cancer xenografts responding to barasertib, an agent known to induce apoptosis via polyploidy. Bayesian Information Criterion (BIC) was used for model selection among all three non-Gaussian models. Results All of tumor volume, histology, conventional ADC, and three non-Gaussian DWI models could show significant differences between control and treatment groups after four days of treatment. However, only the non-Gaussian models detected significant changes after two days of treatment. For any treatment or control group, over 65.7% of tumor voxels indicate the bi-exponential model is strongly or very strongly preferred. Conclusion Non-Gaussian DWI model-derived biomarkers are capable of detecting tumor earlier chemotherapeutic response of tumors compared with conventional ADC and tumor volume. The bi-exponential model provides better fitting compared with statistical and stretched exponential models for the tumor and treatment models used in the current work. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hepatocellular carcinoma (HCC) often suffers from poor response to chemotherapy. • The early assessment of its chemotherapy is helpful for rational treatment. • The prognostic model based on SERS spectra has high accuracy. • SERS technique is a potential prognostic tool for its early assessment. In clinical practice, the transcatheter arterial chemoembolization (TACE) has been widely accepted as the first option for non-surgical hepatocellular carcinoma (HCC) treatment. However, patients with HCC often suffer from poor response to TACE therapy. This can be prevented if the chemotherapeutic response can be early and accurately assessed, which is essential to guide timely and rational management. In this study, the serum SERS technique was for the first time investigated as a potential prognostic tool for early assessment of HCC chemotherapeutic response. According to the SERS spectral analysis results, it is newly found that not only the absolute circulating nucleic acids and collagen levels in pre-therapeutic serum but also the changes in circulating nucleic acids and amino acids between pre-therapeutic and post-therapeutic serum are expected to be potential serum markers for HCC prognosis. By further applying chemometrics methods to establish prognostic models, excellent prognostic accuracies were achieved within only 3 days after TACE therapy. Thus, the proposed method is expected to provide guidance on timely and rational management of HCC to improve its survival rate. [ABSTRACT FROM AUTHOR]

Purpose To apply k-means clustering of two pharmacokinetic parameters derived from 3T dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict the chemotherapeutic response in bladder cancer at the mid-cycle timepoint. Materials and Methods With the predetermined number of three clusters, k-means clustering was performed on nondimensionalized Amp and kep estimates of each bladder tumor. Three cluster volume fractions (VFs) were calculated for each tumor at baseline and mid-cycle. The changes of three cluster VFs from baseline to mid-cycle were correlated with the tumor's chemotherapeutic response. Receiver-operating-characteristics curve analysis was used to evaluate the performance of each cluster VF change as a biomarker of chemotherapeutic response in bladder cancer. Results The k-means clustering partitioned each bladder tumor into cluster 1 (low kep and low Amp), cluster 2 (low kep and high Amp), cluster 3 (high kep and low Amp). The changes of all three cluster VFs were found to be associated with bladder tumor response to chemotherapy. The VF change of cluster 2 presented with the highest area-under-the-curve value (0.96) and the highest sensitivity/specificity/accuracy (96%/100%/97%) with a selected cutoff value. Conclusion The k-means clustering of the two DCE-MRI pharmacokinetic parameters can characterize the complex microcirculatory changes within a bladder tumor to enable early prediction of the tumor's chemotherapeutic response. J. Magn. Reson. Imaging 2015;41:1374-1382. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]