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Oesophageal squamous cell carcinoma: histogram-derived ADC parameters are not predictive of tumour response to chemoradiotherapy.

ABSTRACT: OBJECTIVES:To evaluate correlations between tumour response to definitive chemoradiotherapy (CRT) in oesophageal squamous cell carcinoma (SCC) and histogram-derived apparent diffusion coefficient (ADC) parameters on diffusion-weighted MR images. METHODS:Forty patients with clinical T3-4 oesophageal SCC underwent concurrent CRT. MR examination at 3 T was performed 1-3 days prior to CRT. Readout-segmented echo-planar diffusion imaging was used to acquire ADC maps. Pre- and post-treatment CT examinations were performed. Histogram parameters (mean, 10th, 25th, 50th, 75th, 90th percentiles, skewness and kurtosis) of the ADC values were compared with post-treatment disease status based on RECIST and the tumour regression ratio. RESULTS:None of the ADC parameters showed significant correlation with post-treatment status (range of Spearman's ? values - 0.19 to 0.14, range of p values 0.22-0.47) or tumour regression ratio (range of Spearman's ? values - 0.045 to 0.18, range of p values 0.26-0.96). Neither progression-free survival (PFS) (p = 0.17) nor overall survival (OS) (p = 0.15) was significantly different between the two groups corresponding to the lower (< median) and upper arms (? median) of the mean ADC values. CONCLUSIONS:Histogram-derived pretreatment ADC parameters were not predictive imaging biomarkers for tumour response to CRT in patients with oesophageal SCC. KEY POINTS:• Apparent diffusion coefficient (ADC) values are derived from diffusion-weighted MR imaging. • High-resolution diffusion-weighted images are generated by readout-segmented echo-planar diffusion imaging. • Readout-segmented echo-planar diffusion-weighted imaging enabled evaluation of ADC parameters. • Pretreatment ADC parameters do not predict chemoradiotherapy response in patients with oesophageal carcinoma.

SUBMITTER: Kozumi M

PROVIDER: S-EPMC6132721 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Oesophageal squamous cell carcinoma: histogram-derived ADC parameters are not predictive of tumour response to chemoradiotherapy.

Kozumi Maiko M Ota Hideki H Yamamoto Takaya T Umezawa Rei R Matsushita Haruo H Ishikawa Yojiro Y Takahashi Noriyoshi N Matsuura Tomonori T Takase Kei K Jingu Keiichi K

European radiology 20180503 10

<h4>Objectives</h4>To evaluate correlations between tumour response to definitive chemoradiotherapy (CRT) in oesophageal squamous cell carcinoma (SCC) and histogram-derived apparent diffusion coefficient (ADC) parameters on diffusion-weighted MR images.<h4>Methods</h4>Forty patients with clinical T3-4 oesophageal SCC underwent concurrent CRT. MR examination at 3 T was performed 1-3 days prior to CRT. Readout-segmented echo-planar diffusion imaging was used to acquire ADC maps. Pre- and post-trea ...[more]

PMID: 29725833

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Project description:Long-term survival in oesophageal squamous cell carcinoma (ESCC) is related with pathological response after neoadjuvant chemoradiotherapy (NCRT) followed by surgery. However, effective biomarkers to predict the pathologic response are still lacking. Therefore, a systematic analysis focusing on genes associated with the efficacy of chemoradiotherapy in ESCC will provide valuable insights into the regulation of molecular processes. By screening publications deposited in PubMed, we collected genes associated with the efficacy of chemoradiotherapy. A specific subnetwork was constructed using the Steiner minimum tree algorithm. Survival analysis in Kaplan-Meier Plotter online resources was performed to explore the relationship between gene mRNA expression and the prognosis of patients with ESCC. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemical staining (IHC) were used to evaluate the expression of key genes in cell lines and human samples. The areas under the receiver operating characteristic (ROC) curves (AUCs) were used to describe performance and accuracy. Transwell assays assessed cell migration, and cell viability was detected using the Cytotoxicity Assay. Finally, we identified 101 genes associated with efficacy of chemoradiotherapy. Additionally, specific molecular networks included some potential related genes, such as CUL3, MUC13, MMS22L, MME, UBC, VAPA, CYP1B1, and UGDH. The MMS22L mRNA expression level showed the most significant association with the ESCC patient outcome (p < 0.01). Furthermore, MMS22L was downregulated at both the mRNA (p < 0.001) and protein levels in tumour tissues compared with that in normal tissues. Lymph node metastasis was significantly associated with low MMS22L expression (p < 0.01). MMS22L levels were inversely correlated with the NCRT response in ESCC (p < 0.01). The resulting area under the ROC curve was 0.847 (95% CI: 0.7232 to 0.9703; p < 0.01). In conclusion, low expression of MMS22L is associated with poor response to NCRT, worse survival, lymph node metastasis, and enhanced migration of tumour cells in ESCC.

Project description:BackgroundRadiotherapy resistance is a major obstacle in the treatment of oesophageal squamous cell carcinoma (OSCC). Hypoxia is a critical cause of radioresistance. However, the communication between hypoxic cells and aerobic cells via exosomes during the transfer of radiation resistance remains unclear.MethodsExo-miR-340-5p levels were analysed by RNA-seq and qRT-PCR. We co-cultured OSCC cells with isolated normoxic and hypoxic exosomes to study their impact on radiosensitivity. We used a specific exo-miR-340-5p mimic and knock-down retrovirus to explore the role of this miRNA in the transfer of radioresistance from hypoxic to normoxic cells. Dual-luciferase reporter and RIP assays were used to verify KLF10 as a putative target of miR-340-5p. Several in vitro assays were conducted and xenograft models were established to investigate the effect of exo-miR-340-5p on OSCC radiosensitivity. The plasma exo-miR-340-5p levels in OSCC patients were analysed to study the clinical value of this parameter.ResultsHypoxic exosomes alleviated radiation-induced apoptosis and accelerated DNA damage repair. miR-340-5p was highly expressed in hypoxic exosomes and was transferred into normoxic cells, where it induced radioresistance. Overexpression of miR-340-5p in normoxic OSCC cells mimicked the radioresistance of cells co-cultured with hypoxic exosomes. Knockdown of miR-340-5p in hypoxic exosomes reversed the radioresistance effect, indicating that exo-miR-340-5p is critical for hypoxic EV-transferred radioresistance. KLF10 was identified as the direct target of miR-340-5p. Moreover, metformin was found to increase the expression of KLF10 and enhance the radiosensitivity of OSCC. Higher levels of miR-340-5p in the plasma exosomes from OSCC patients are related to a poorer radiotherapy response and prognosis.ConclusionsHypoxic tumour cell-derived exosomal miR-340-5p confers radioresistance in OSCC by targeting KLF10/UVRAG, suggesting that miR-340-5p could be a potential biomarker and therapeutic target for the enhancement of radiosensitivity in OSCC. Metformin can increase KLF10 expression, which ameliorates the radioresistance induced by exo-miR-340-5p transfer. Therefore, metformin could be further investigated as a therapeutic option for the treatment of OSCC.

Project description:Abstract Rationale A high risk of post‐operative recurrence contributes to the poor prognosis and low survival rate of oesophageal squamous cell carcinoma (ESCC) patients. Increasing experimental evidence suggests that integrin adhesion receptors, in particular integrin αv (ITGAV), are important for cancer cell survival, proliferation and migration. Therefore, targeting ITGAV may be a rational approach for preventing ESCC recurrence. Materials and methods Protein levels of ITGAV were determined in human ESCC tumour tissues using immunohistochemistry. MTT, propidium iodide staining, and annexin V staining were utilized to investigate cell viability, cell cycle progression, and induction of apoptosis, respectively. Computational docking was performed with the Schrödinger Suite software to visualize the interaction between indomethacin and ITGAV. Cell‐derived xenograft mouse models, patient‐derived xenograft (PDX) mouse models, and a humanized mouse model were employed for in vivo studies. Results ITGAV was upregulated in human ESCC tumour tissues and increased ITGAV protein levels were associated with poor prognosis. ITGAV silencing or knockout suppressed ESCC cell growth and metastatic potential. Interestingly, we identified that indomethacin can bind to ITGAV and enhance synovial apoptosis inhibitor 1 (SYVN1)‐mediated degradation of ITGAV. Integrin β3, one of the β subunits of ITGAV, was also decreased at the protein level in the indomethacin treatment group. Importantly, indomethacin treatment suppressed ESCC tumour growth and prevented recurrence in a PDX mouse model. Moreover, indomethacin inhibited the activation of cytokine TGFβ, reduced SMAD2/3 phosphorylation, and increased anti‐tumour immune responses in a humanized mouse model. Conclusion ITGAV is a promising therapeutic target for ESCC. Indomethacin can attenuate ESCC growth through binding to ITGAV, promoting SYVN1‐mediated ubiquitination of ITGAV, and potentiating cytotoxic CD8+ T cell responses. Integrin αvβ3 was upregulated in ESCC tumour tissue compared to adjacent tissue. Indomethacin binds to ITGAV and promotes SYVN1‐mediated ubiquitination of ITGAV, thereby attenuating the αvβ3/PI3K/AKT/GS3Kβ signalling pathway. Inhibition of αvβ3 by indomethacin treatment blocks TGFβ/SMAD2/SMAD3 signalling and increases anti‐tumour immune responses in a humanized mouse model. Indomethacin suppresses ESCC tumour growth and recurrence in a PDX mouse model.

Project description:PURPOSE:To assess the predictive value of volumetric apparent diffusion coefficient (vADC) histogram quantification obtained before and 6?weeks (6w) post-treatment for assessment of hepatocellular carcinoma (HCC) response to 90Yttrium radioembolization (RE). METHODS:In this retrospective study, 22 patients (M/F 15/7, mean age 65y) who underwent lobar RE were included between October 2013 and November 2014. All patients underwent routine liver MRI pre-treatment and 6w after RE. Two readers assessed index tumor response at 6?months after RE in consensus, using mRECIST criteria. vADC histogram parameters of index tumors at baseline and 6w, and changes in vADC (?vADC) histogram parameters were calculated. The predictive value of ADC metrics was assessed by logistic regression with stepwise parameter selection and ROC analyses. RESULTS:Twenty two HCC lesions (mean size 3.9?±?2.9?cm, range 1.2-12.3?cm) were assessed. Response at 6?months was as follows: complete response (CR, n?=?6), partial response (PR, n?=?3), stable disease (SD, n?=?12) and progression (PD, n?=?1). vADC median/mode at 6w (1.81-1.82 vs. 1.29-1.35?×?10-?3?mm2/s) and ?vADC median/max (27-44% vs. 0-10%) were significantly higher in CR/PR vs. SD/PD (p?=?0.011-0.036), while there was no significant difference at baseline. Logistic regression identified vADC median at 6w as an independent predictor of response (CR/PR) with odds ratio (OR) of 3.304 (95% CI: 1.099-9.928, p?=?0.033) and AUC of 0.77. ?vADC mean was identified as an independent predictor of CR with OR of 4.153 (95%CI: 1.229-14.031, p?=?0.022) and AUC of 0.91. CONCLUSION:Diffusion histogram parameters obtained at 6w and early changes in ADC from baseline are predictive of subsequent response of HCCs treated with RE, while pre-treatment vADC histogram parameters are not. These results need confirmation in a larger study. TRIAL REGISTRATION:This retrospective study was IRB-approved and the requirement for informed consent was waived.

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Oesophageal squamous cell carcinoma: histogram-derived ADC parameters are not predictive of tumour response to chemoradiotherapy.

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Oesophageal squamous cell carcinoma: histogram-derived ADC parameters are not predictive of tumour response to chemoradiotherapy.

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