Bispecific fibrous glue synergistically boosts vascular normalization and antitumor immunity for advanced renal carcinoma therapy.

Immune checkpoint blockade therapy represented by programmed cell death ligand 1 (PD-L1) inhibitor for advanced renal carcinoma with an objective response rate (ORR) in patients is less than 20%. It is attributed to abundant tumoral vasculature with abnormal structure limiting effector T cell infiltration and drug penetration. We propose a bispecific fibrous glue (BFG) to regulate tumor immune and vascular microenvironments simultaneously. The bispecific precursor glue peptide-1 (pre-GP1) can penetrate tumor tissue deeply and self-assemble into BFG in the presence of neuropilin-1 (NRP-1) and PD-L1. The resultant fibrous glue is capable of normalizing tumoral vasculature as well as restricting immune escape. The pre-GP1 retains a 6-fold higher penetration depth than that of antibody in the multicellular spheroids (MCSs) model. It also shows remarkable tumor growth inhibition (TGI) from 19% to 61% in a murine advanced large tumor model compared to the clinical combination therapy. In addition, in the orthotopic renal tumor preclinical model, the lung metastatic nodules are reduced by 64% compared to the clinically used combination. This pre-GP1 provides a promising strategy to control the progression and metastasis of advanced renal carcinoma.

Establishment of an Efficient Genetic Transformation System in Sanghuangporus baumii.

(1) Background: Sanghuangporus baumii, a valuable medicinal fungus, has limited studies on its gene function due to the lack of a genetic transformation system. (2) Methods: This study aimed to establish an efficient Agrobacterium tumefaciens-mediated transformation (ATMT) system for S. baumii. This study involved cloning the promoter (glyceraldehyde-3-phosphate dehydrogenase, gpd) of S. baumii, reconstructing the transformation vector, optimizing the treatment of receptor tissues, and inventing a new method for screening positive transformants. (3) Results: The established ATMT system involved replacing the CaMV35S promoter of pCAMBIA-1301 with the gpd promoter of S. baumii to construct the pCAMBIA-SH-gpd transformation vector. The vectors were then transferred to A. tumefaciens (EHA105) for infection. This study found that the transformation efficiency was higher in the infection using pCAMBIA-SH-gpd vectors than using pCAMBIA-1301 vectors. The mycelia of S. baumii were homogenized for 20 s and collected as the genetic transformation receptor. After 20 min of co-culture and 48 h of incubation in 15 mL PDL medium at 25 °C, new colonies grew. (4) Conclusions: These colonies were transferred to PDA medium (hygromycin 4 µg/mL, cefotaxime 300 µg/mL), and the transformation efficiency was determined to be 33.7% using PCR.

Structure and dynamics of endogenous cardiac troponin complex in human heart tissue captured by native nanoproteomics.

Protein complexes are highly dynamic entities that display substantial diversity in their assembly, post-translational modifications, and non-covalent interactions, allowing them to play critical roles in various biological processes. The heterogeneity, dynamic nature, and low abundance of protein complexes in their native states present challenges to study using conventional structural biology techniques. Here we develop a native nanoproteomics strategy for the enrichment and subsequent native top-down mass spectrometry (nTDMS) analysis of endogenous cardiac troponin (cTn) complex directly from human heart tissue. The cTn complex is enriched and purified using peptide-functionalized superparamagnetic nanoparticles under non-denaturing conditions to enable the isotopic resolution of cTn complex, revealing their complex structure and assembly. Moreover, nTDMS elucidates the stoichiometry and composition of the cTn complex, localizes Ca2+ binding domains, defines cTn-Ca2+ binding dynamics, and provides high-resolution mapping of the proteoform landscape. This native nanoproteomics strategy opens a paradigm for structural characterization of endogenous native protein complexes.

CT-based deep learning segmentation of ovarian cancer and the stability of the extracted radiomics features.

Background: Radiomics analysis could provide complementary tissue characterization in ovarian cancer (OC). However, OC segmentation required in radiomics analysis is time-consuming and labour-intensive. In this study, we aim to evaluate the performance of deep learning-based segmentation of OC on contrast-enhanced CT images and the stability of radiomics features extracted from the automated segmentation. Methods: Staging abdominopelvic CT images of 367 patients with OC were retrospectively recruited. The training and cross-validation sets came from center A (n=283), and testing set (n=84) came from centers B and C. The tumours were manually delineated by a board-certified radiologist. Four model architectures provided by no-new-Net (nnU-Net) method were tested in this task. The segmentation performance evaluated by Dice score, Jaccard score, sensitivity and precision were compared among 4 architectures. The Pearson correlation coefficient (ρ), concordance correlation coefficient (ρc) and Bland-Altman plots were used to evaluate the volumetric assessment of OC between manual and automated segmentations. The stability of extracted radiomics features was evaluated by intraclass correlation coefficient (ICC). Results: The 3D U-Net cascade architecture achieved highest median Dice score, Jaccard score, sensitivity and precision for OC segmentation in the testing set, 0.941, 0.890, 0.973 and 0.925, respectively. Tumour volumes of manual and automated segmentations were highly correlated (ρ=0.944 and ρc =0.933). 85.0% of radiomics features had high correlation with ICC >0.8. Conclusions: The presented deep-learning segmentation could provide highly accurate automated segmentation of OC on CT images with high stability of the extracted radiomics features, showing the potential as a batch-processing segmentation tool.

Structure and dynamics of endogenous protein complexes in human heart tissue captured by native nanoproteomics.

Protein complexes are highly dynamic entities that display substantial diversity in their assembly, post-translational modifications, and non-covalent interactions, allowing them to play critical roles in various biological processes. The heterogeneity, dynamic nature, and low abundance of protein complexes in their native states present tremendous challenges to study using conventional structural biology techniques. Here we develop a "native nanoproteomics" strategy for the native enrichment and subsequent native top-down mass spectrometry (nTDMS) of low-abundance protein complexes. Specifically, we demonstrate the first comprehensive characterization of the structure and dynamics of cardiac troponin (cTn) complexes directly from human heart tissue. The endogenous cTn complex is effectively enriched and purified using peptide-functionalized superparamagnetic nanoparticles under non-denaturing conditions to enable the isotopic resolution of cTn complexes, revealing their complex structure and assembly. Moreover, nTDMS elucidates the stoichiometry and composition of the heterotrimeric cTn complex, localizes Ca2+ binding domains (II-IV), defines cTn-Ca2+ binding dynamics, and provides high-resolution mapping of the proteoform landscape. This native nanoproteomics strategy opens a new paradigm for structural characterization of low-abundance native protein complexes.

Nano Proteolysis Targeting Chimeras (PROTACs) with Anti-Hook Effect for Tumor Therapy.

Proteolysis targeting chimera (PROTAC) is an emerging pharmacological modality with innovated post-translational protein degradation capabilities. However, off-target induced unintended tissue effects and intrinsic "hook effect" hinder PROTAC biotechnology to be maturely developed. Herein, an intracellular fabricated nano proteolysis targeting chimeras (Nano-PROTACs) modality with a center-spoke degradation network for achieving efficient dose-dependent protein degradation in tumor is reported. The PROTAC precursors are triggered by higher GSH concentrations inside tumor cells, which subsequently in situ self-assemble into Nano-PROTACs through intermolecular hydrogen bond interactions. The fibrous Nano-PROTACs can form effective polynary complexes and E3 ligases degradation network with multi-binding sites, achieving dose-dependent protein degradation with "anti-hook effect". The generality and efficacy of Nano-PROTACs are validated by degrading variable protein of interest (POI) such as epidermal growth factor receptor (EGFR) and androgen receptor (AR) in a wide-range dose-dependent manner with a 95 % degradation rate and long-lasting potency up to 72 h in vitro. Significantly, Nano-PROTACs achieve in vivo dose-dependent protein degradation up to 79 % and tumor growth inhibition in A549 and LNCap xenograft mice models, respectively. Taking advantages of in situ self-assembly strategy, the Nano-PROTACs provide a generalizable platform to promote precise clinical translational application of PROTAC.

Structure and dynamics of endogenous protein complexes in human heart tissue captured by native nanoproteomics.

Protein complexes are highly dynamic entities that display substantial diversity in their assembly, post-translational modifications, and non-covalent interactions, allowing them to play critical roles in various biological processes. The heterogeneity, dynamic nature, and low abundance of protein complexes in their native states present tremendous challenges to study using conventional structural biology techniques. Here we develop a "native nanoproteomics" strategy for the native enrichment and subsequent native top-down mass spectrometry (nTDMS) of low-abundance protein complexes. Specifically, we demonstrate the first comprehensive characterization of the structure and dynamics of cardiac troponin (cTn) complexes directly from human heart tissue. The endogenous cTn complex is effectively enriched and purified using peptide-functionalized superparamagnetic nanoparticles under non-denaturing conditions to enable the isotopic resolution of cTn complexes, revealing their complex structure and assembly. Moreover, nTDMS elucidates the stoichiometry and composition of the heterotrimeric cTn complex, localizes Ca2+ binding domains (II-IV), defines cTn-Ca2+ binding dynamics, and provides high-resolution mapping of the proteoform landscape. This native nanoproteomics strategy opens a new paradigm for structural characterization of low-abundance native protein complexes.

An In Vivo Self-Assembled Bispecific Nanoblocker for Enhancing Tumor Immunotherapy.

Anti-PD-L1 monoclonal antibody has achieved substantial success in tumor immunotherapy by T-cells activation. However, the excessive accumulation of extracellular matrix components induced by unsatisfactory T-cells infiltration and poor tumor penetration of antibodies make it challenging to realize efficient tumor immunotherapy. Herein, a peptide-based bispecific nanoblocker (BNB) strategy is reported for in situ construction of CXCR4/PD-L1 targeted nanoclusters on the surface of tumor cells that are capable of boosting T-cells infiltration through CXCR4 blockage and enhancing T-cells activation by PD-L1 occupancy, ultimately realizing high-performance tumor immunotherapy. Briefly, the BNB strategy selectively recognizes and bonds CXCR4/PD-L1 with deep tumor penetration, which rapidly self-assembles into nanoclusters on the surface of tumor cells. Compared to the traditional bispecific antibody, BNB exhibits an intriguing metabolic behavior, that is, the elimination half-life (t1/2 ) of BNB in the tumor is 69.3 h which is ≈50 times longer than that in the plasma (1.4 h). The higher tumor accumulation and rapid systemic clearance overcome potential systemic side effects. Moreover, the solid tumor stress generated by excessive extracellular matrix components is substantially reduced to 44%, which promotes T-cells infiltration and activation for immunotherapy efficacy. Finally, these findings substantially strengthen and extend clinical applications of PD-1/PD-L1 immunotherapy.

A bispecific glycopeptide spatiotemporally regulates tumor microenvironment for inhibiting bladder cancer recurrence.

Up to 75% of bladder cancer patients suffer from recurrence due to postoperative tumor implantation. However, clinically used Bacillus Calmette-Guerin (BCG) treatment failed to inhibit the recurrence. Here, we report a bispecific glycopeptide (bsGP) that simultaneously targets CD206 on tumor-associated macrophages (TAMs) and CXCR4 on tumor cells. bsGP repolarizes protumoral M2-like TAMs to antitumor M1-like that mediated cytotoxicity and T cell recruitment. Meanwhile, bsGP is cleaved by the MMP-2 enzyme to form nanostructure for the long-term inhibition of CXCR4 downstream signaling, resulting in reduced tumor metastasis and promoted T cell infiltration. In orthotopic bladder tumor models, bsGP reduced the postoperative recurrence rate to 22%. In parallel, the recurrence rates of 89 and 78% were treated by doxycycline and BCG used in clinic, respectively. Mechanistic studies reveal that bsGP reduces the matrix microenvironment barrier, increasing the spatially redirected CD8+ T cells to tumor cells. We envision that bis-targeting CD206 and CXCR4 may pave the way to inhibit tumor metastasis and recurrence.

Computed Tomographic Radiomics in Differentiating Histologic Subtypes of Epithelial Ovarian Carcinoma.

Importance: Epithelial ovarian carcinoma is heterogeneous and classified according to the World Health Organization Tumour Classification, which is based on histologic features and molecular alterations. Preoperative prediction of the histologic subtypes could aid in clinical management and disease prognostication. Objective: To assess the value of radiomics based on contrast-enhanced computed tomography (CT) in differentiating histologic subtypes of epithelial ovarian carcinoma in multicenter data sets. Design, Setting, and Participants: In this diagnostic study, 665 patients with histologically confirmed epithelial ovarian carcinoma were retrospectively recruited from 4 centers (Hong Kong, Guangdong Province of China, and Seoul, South Korea) between January 1, 2012, and February 28, 2022. The patients were randomly divided into a training cohort (n = 532) and a testing cohort (n = 133) with a ratio of 8:2. This process was repeated 100 times. Tumor segmentation was manually delineated on each section of contrast-enhanced CT images to encompass the entire tumor. The Mann-Whitney U test and voted least absolute shrinkage and selection operator were performed for feature reduction and selection. Selected features were used to build the logistic regression model for differentiating high-grade serous carcinoma and non-high-grade serous carcinoma. Exposures: Contrast-enhanced CT-based radiomics. Main Outcomes and Measures: Intraobserver and interobserver reproducibility of tumor segmentation were measured by Dice similarity coefficients. The diagnostic efficiency of the model was assessed by receiver operating characteristic curve and area under the curve. Results: In this study, 665 female patients (mean [SD] age, 53.6 [10.9] years) with epithelial ovarian carcinoma were enrolled and analyzed. The Dice similarity coefficients of intraobserver and interobserver were all greater than 0.80. Twenty radiomic features were selected for modeling. The areas under the curve of the logistic regression model in differentiating high-grade serous carcinoma and non-high-grade serous carcinoma were 0.837 (95% CI, 0.835-0.838) for the training cohort and 0.836 (95% CI, 0.833-0.840) for the testing cohort. Conclusions and Relevance: In this diagnostic study, radiomic features extracted from contrast-enhanced CT were useful in the classification of histologic subtypes in epithelial ovarian carcinoma. Intraobserver and interobserver reproducibility of tumor segmentation was excellent. The proposed logistic regression model offered excellent discriminative ability among histologic subtypes.

A Lysosome-Targeting Self-Condensation Prodrug-Nanoplatform System for Addressing Drug Resistance of Cancer.

Lysosome-targeting self-assembling prodrugs had emerged as an attractive approach to overcome the acquisition of resistance to chemotherapeutics by inhibiting lysosomal sequestration. Taking advantage of lysosomal acidification induced intracellular hydrolytic condensation, we developed a lysosomal-targeting self-condensation prodrug-nanoplatform (LTSPN) system for overcoming lysosome-mediated drug resistance. Briefly, the designed hydroxycamptothecine (HCPT)-silane conjugates self-assembled into silane-based nanoparticles, which were taken up into lysosomes by tumor cells. Subsequently, the integrity of the lysosomal membrane was destructed because of the acid-triggered release of alcohol, wherein the nanoparticles self-condensed into silicon particles outside the lysosome through intracellular hydrolytic condensation. Significantly, the LTSPN system reduced the half-maximal inhibitory concentration (IC50) of HCPT by approximately 4 times. Furthermore, the LTSPN system realized improved control of large established tumors and reduced regrowth of residual tumors in several drug-resistant tumor models. Our findings suggested that target destructing the integrity of the lysosomal membrane may improve the therapeutic effects of chemotherapeutics, providing a potent treatment strategy for malignancies.

OGA activated glycopeptide-based nano-activator to activate PKM2 tetramerization for switching catabolic pathways and sensitizing chemotherapy resistance.

Tumor cells intensively engage in metabolic reprogramming for enhancing the availability of glycolytic metabolites and support cell proliferation. As the most important rate-limiting enzyme in aerobic glycolysis, activating the pyruvate kinase muscle isoform 2 (PKM2) from dimers to tetramers has become a key tumor chemotherapy method to control glucose metabolism. Herein, we developed a glycopeptide-based PKM2 nano-activator, which could induce the tetramerization of PKM2 based on serine bonding to Domain C of PKM2. The bound and trapped PKM2 tetramers significantly hindered glycolytic intermediates, prevented the nucleus translocation of dimeric PKM2, and ultimately inhibited the proliferation, chemoresistance and metastasis of tumor. The glycopeptide assembled into nanoparticles under aqueous conditions and in the circulation, which in situ transformed into PKM2 nano-activator with nanofibrillar structure after specifically activated by O-GlcNAcase recognition upregulated in a wide range of human tumors. Moreover, the glycopeptide-based PKM2 nano-activator successfully accumulated at the tumor sites and boosted the chemo-drug sensitivity against prostate and breast cancers. Attributed to these intriguing results, the newly developed glycopeptide-based PKM2 nano-activator can be envisioned a promising candidate for the treatment of tumors by switching catabolic pathways.

An activated excretion-retarded tumor imaging strategy towards metabolic organs.

Intraoperative fluorescence-based tumor imaging plays a crucial role in performing the oncological safe tumor resection with the advantage of differentiating tumor from normal tissues. However, the application of these fluorescence contrast agents in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) was dramatically hammered as a result of lacking active targeting and poor retention time in tumor, which limited the Signal to Noise Ratio (SNR) and narrowed the imaging window for complicated surgery. Herein, we reported an activated excretion-retarded tumor imaging (AERTI) strategy, which could be in situ activated with MMP-2 and self-assembled on the surface of tumor cells, thereby resulting in a promoted excretion-retarded effect with an extended tumor retention time and enhanced SNR. Briefly, the AERTI strategy could selectively recognize the Integrin αvß3. Afterwards, the AERTI strategy would be activated and in situ assembled into nanofibrillar structure after specifically cleaved by MMP-2 upregulated in a variety of human tumors. We demonstrated that the AERTI strategy was successfully accumulated at the tumor sites in the 786-O and HepG2 xenograft models. More importantly, the modified modular design strategy obviously enhanced the SNR of AERTI strategy in the imaging of orthotopic RCC and HCC. Taken together, the results presented here undoubtedly confirmed the design and advantage of this AERTI strategy for the imaging of tumors in metabolic organs.

Selenopeptide Nanomedicine Activates Natural Killer Cells for Enhanced Tumor Chemoimmunotherapy.

Chemoimmunotherapy using nanotechnology has shown great potential for cancer therapy in the clinic. However, uncontrolled transportation and synergistic responses remain challenges. Here, a self-assembled selenopeptide nanoparticle that strengthens tumor chemoimmunotherapy through the activation of natural killer (NK) cells by the oxidative metabolite of the selenopeptide is developed. With the advantages of the enzyme-induced size-reduction and the reactive-oxygen-species-driven deselenization, this selenopeptide is able to deliver therapeutics, e.g., doxorubicin (DOX), to solid tumors and further activate the NK cells in a programmed manner. Importantly, in vitro and in vivo results prove the mutual promotion between the DOX-induced chemotherapy and the selenopeptide-induced immunotherapy, which synergistically contribute to the improved antitumor efficacy. It is anticipated that the selenopeptide may provide a type of promising stimuli-responsive immune modulator for versatile biomedical applications.

In Situ Constructed Nano-Drug Depots through Intracellular Hydrolytic Condensation for Chemotherapy of Bladder Cancer.

Intravesical administration of first-line drugs has shown failure in the treatment of bladder cancer owing to the poor tumor retention time of chemotherapeutics. Herein, we report an intracellular hydrolytic condensation (IHC) system to construct long-term retentive nano-drug depots in situ, wherein sustained drug release results in highly efficient suppression of bladder cancer. Briefly, the designed doxorubicin (Dox)-silane conjugates self-assemble into silane-based prodrug nanoparticles, which condense into silicon particle-based nano-drug depots inside tumor cells. Significantly, we demonstrate that the IHC system possesses highly potent antitumor efficacy, which leads to the regression and eradication of large established tumors and simultaneously extends the overall survival of air pouch bladder cancer mice compared with that of mice treated with Dox. The concept of intracellular hydrolytic condensation can be extended via conjugating other chemotherapeutic drugs, which may facilitate rational design of novel nanomedicines for augmentation of chemotherapy.

In Situ Self-Assembly of Bispecific Peptide for Cancer Immunotherapy.

Precise and effective manipulation of protein functions still faces tremendous challenges. Herein we report a programmable peptide molecule, consisted of targeting and self-assembly modules, that enables specific and highly efficient assembly governed by targeting receptor proteins. Upon binding to the cell membrane receptor, peptide conformation is somewhat stabilized along with decreased self-assembly activation energy, promoting peptide-protein complex oligomerization. We first design a GNNQQNY-RGD peptide (G7-RGD) to recognize integrin αV ß3 receptor for proof-of-concept study. In the presence of αV ß3 protein, the critical assembly concentration of free G7-RGD decreases from 525 to 33 µM and the resultant G7-RGD cluster drives integrin receptor oligomerization. Finally, a bispecific assembling peptide antiCD3-G7-RGD is rationally designed for cancer immunotherapy, which validates CD3 oligomerization and concomitant T cell activation, leading to T cell-mediated cancer cell cytolysis.

Radiomic Features of T2-weighted Imaging and Diffusion Kurtosis Imaging in Differentiating Clinicopathological Characteristics of Cervical Carcinoma.

RATIONALE AND OBJECTIVES: Clinicopathological characteristics including histological subtypes, tumour grades and International Federation of Gynecology and Obstetrics (FIGO) stages are crucial factors in the clinical decision for cervical carcinoma (CC). The purpose of this study was to evaluate the ability of T2-weighted imaging (T2WI) and diffusion kurtosis imaging (DKI) radiomics in differentiating clinicopathological characteristics of CC. MATERIALS AND METHODS: One hundred and seventeen histologically confirmed CC patients (mean age 56.5 ± 14.0 years) with pre-treatment magnetic resonance imaging were retrospectively reviewed. DKI was acquired with 4 b-values (0-1500 s/mm2). Volumes of interest were contoured around the tumours on T2WI and DKI. Radiomic features including shape, first-order and grey-level co-occurrence matrix with wavelet transforms were extracted. Intraclass correlation coeffient between 2 radiologists was used for features reduction. Feature selection was achieved by elastic net and minimum redundancy maximum relevance. Selected features were used to build random forest (RF) models. The performances for differentiating histological subtypes, tumour grades and FIGO stages were assessed by receiver operating characteristic analysis. RESULTS: Area under the curves (AUCs) for T2WI-only RF models for discriminating histological subtypes, tumour grades and FIGO stages were 0.762, 0.686, and 0.719. AUCs for DWI-only models were 0.663, 0.645, and 0.868, respectively. AUCs of the combined T2WI and DKI models were 0.823, 0.790, and 0.850, respectively. CONCLUSION: T2WI and DKI radiomic features could differentiate the clinicopathological characteristics of CC. A combined model showed excellent diagnostic discrimination for histological subtypes, while a DKI-only model presented the best performance in differentiating FIGO stages.

Targeted in situ self-assembly augments peptide drug conjugate cell-entry efficiency.

Peptide drug conjugate (PDC) has emerged as one of the new generations of targeted therapeutics for cancer, which owns the advantages of improved drug targetability and reduced adverse effects compared with traditional chemotherapy. However, the poor permeability of PDC drugs regarding tumor cells is an urgent problem to be solved. Herein, we design a PDC drug molecule, which is composed of three modules: targeting motif (RGD target), assembly motif (GNNNQNY) and cytotoxic payload (CPT molecule). This PDC in situ forms nanoclusters upon binding cellular receptor, resulting in improved PDC cell-entry efficiency and treatment efficacy. In addition, the PDC shows increased therapeutic efficacy and raises the maximum tolerance dose of the drug in breast and bladder xenografted mice models. This strategy leverages the assembly principle to promote penetration of peptide molecules into cells and increase intracellular drug bioavailability, which is of great significance for the development of PDC drugs in the future.

Repeatability of MR fingerprinting in normal cervix and utility in cervical carcinoma.

BACKGROUND: Magnetic resonance fingerprinting (MRF) is a fast-imaging acquisition technique that generates quantitative and co-registered parametric maps. The aim of this feasibility study was to evaluate the agreement between MRF and phantom reference values, scan-rescan repeatability of MRF in normal cervix, and its ability to distinguish cervical carcinoma (CC) from normal cervical tissues. METHODS: An International Society of Magnetic Resonance in Medicine/National Institute of Standards and Technology (ISMRM/NIST) phantom was scanned using MRF 15 times over 65 days. Agreement between MRF and phantom reference T1 and T2 values was assessed by linear regression. Healthy volunteers and patients with suspected CC were prospectively recruited. MRF was repeated twice for healthy volunteers (MRF1 and MRF2). Volumes of interest of normal cervical tissues and CC were delineated on T1 and T2 maps. MRF scan-rescan repeatability was evaluated by Bland-Altman plots, within-subject coefficients of variation (wCV), and intraclass correlation coefficients (ICC). T1 and T2 values were compared between CC and normal cervical tissues using Mann-Whitney U test. Receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic efficiency. RESULTS: Strong correlations were observed between MRF and phantom (R2=0.999 for T1, 0.981 for T2). Twelve healthy volunteers (28.7±5.1 years) and 28 patients with CC (54.6±15.2 years) were recruited for the in-vivo experiments. Repeatability of MRF parameters were wCV <3% for T1, <5% for T2 and ICC ≥0.92 for T1, ≥0.94 for T2. T1 value of CC (1,529±112 ms) was higher than normal mucosa [MRF1: 1,430±129 ms, MRF2: 1,440±130 ms; P=0.031, area under the curve (AUC) ≥0.717] and normal stroma (MRF1: 1,258±101 ms, MRF2: 1,276±105 ms; P<0.001, AUC ≥0.946). T2 value of CC (69±9 ms) was lower than normal mucosa (MRF1: 88±16 ms, MRF2: 87±13 ms; P<0.001, AUC ≥0.854), but was not different from normal stroma (P=0.919). CONCLUSIONS: Excellent agreement was observed between MRF and phantom reference values. MRF exhibited excellent scan-rescan repeatability in normal cervix with potential value in differentiating CC from normal cervical tissues.

Association between IVIM parameters and treatment response in locally advanced squamous cell cervical cancer treated by chemoradiotherapy.

OBJECTIVE: To examine the associations of intravoxel incoherent motion (IVIM) parameters with treatment response in cervical cancer following concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: Forty-five patients, median age of 58 years (range: 28-82), with pre-CCRT and post-CCRT MRI, were retrospectively analysed. The IVIM parameters pure diffusion coefficient (D) and perfusion fraction (f) were estimated using the full b-value distribution (BVD) as well as an optimised subsample BVD. Dice similarity coefficient (DSC) and intraclass correlation coefficient (ICC) were used to measure observer repeatability in tumour delineation at both time points. Treatment response was determined by the response evaluation criteria in solid tumour (RECIST) 1.1 between MRI examinations. Mann-Whitney U tests were used to test for significant differences in IVIM parameters between treatment response groups. RESULTS: Pre-CCRT tumour delineation repeatability was good (DSC = 0.81) while post-CCRT delineation repeatability was moderate (DSC = 0.67). Values of D and f had good repeatability at both time points (ICC > 0.80). Pre-CCRT f estimated using the full BVD and optimised subsample BVD were found to be significantly higher in patients with partial response compared to those with stable disease or disease progression (p = 0.01 and 95% CI = -0.02-0.00 for both cases). CONCLUSION: Pre-CCRT f was associated with treatment response in cervical cancer with good observer repeatability. Similar discriminative ability was also observed in estimated pre-CCRT f from an optimised subsample BVD. KEY POINTS: • Pre-treatment tumour delineation and IVIM parameters had good observer repeatability. • Post-treatment tumour delineation was worse than at pre-treatment, but IVIM parameters retained good ICC. • Pre-treatment perfusion fraction estimated from all b-values and an optimised subsample of b-values were associated with treatment response.