Contrast-enhanced Imaging in Peripheral Pulmonary Lesions: The Role in US-guided Biopsies.

Purpose To compare the tissue adequacy and diagnostic accuracy of US-guided biopsies of peripheral pulmonary lesions (PPLs) with and without contrast agents. Materials and Methods A retrospective study was conducted at four medical centers in patients with PPLs who underwent US-guided percutaneous transthoracic needle biopsy (PTNB) between January 2017 and October 2022. The patients were divided into contrast-enhanced US (CEUS) and US groups based on whether prebiopsy CEUS evaluation was performed. Tissue adequacy and the diagnostic accuracy of PTNB, stratified by lesion size, were analyzed and compared between groups. A propensity score matching (PSM) analysis was conducted using the nearest-neighbor matching method. Results A total of 1027 lesions were analyzed, with 634 patients (mean age, 59.4 years ± 13.0 [SD]; 413 male) in the US group and 393 patients (mean age, 61.2 years ± 12.5; 270 male) in the CEUS group. The CEUS group produced more acceptable samples than the US group (98.2% vs 95.7%; P = .03) and achieved higher diagnostic accuracy (96.9% vs 94.2%; P = .04), with no evidence of a difference in sensitivity (96.7% vs 94.0%; P = .06). PSM and stratified analyses (n = 358 per group) indicated higher tissue adequacy (99.0% vs 95.7%; P = .04) and diagnostic accuracy (98.5% vs 92.9%; P = .006) in the CEUS group compared with the US group for 2-7-cm PPLs but not for lesions larger than 7 cm. Conclusion PTNB with prebiopsy CEUS evaluation demonstrated significantly better tissue adequacy and diagnostic accuracy compared with US guidance alone for PPLs ranging from 2 to 7 cm, with similar biopsy performance achieved between groups for lesions larger than 7 cm. Keywords: Contrast Material, Thoracic Diseases, Ultrasonography, Image-Guided Biopsy © RSNA, 2024.

Nomogram Based on US and Clinicopathologic Characteristics: Axillary Nodal Evaluation Following Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer.

BACKGROUND: To develop a convenient modality to predict axillary response to neoadjuvant chemotherapy (NAC) in breast cancer patients. MATERIALS AND METHODS: In this multi-center study, a total of 1019 breast cancer patients with biopsy-proven positive lymph node (LN) receiving NAC were randomly assigned to the training and validation groups at a ratio of 7:3. Clinicopathologic and ultrasound (US) characteristics of both primary tumors and LNs were used to develop corresponding prediction models, and a nomogram integrating clinicopathologic and US predictors was generated to predict the axillary response to NAC. RESULTS: Axillary pathological complete response (pCR) was achieved in 47.79% of the patients. The expression of estrogen receptor, human epidermal growth factor receptor -2, Ki-67 score, and clinical nodal stage were independent predictors for nodal response to NAC. Location and radiological response of primary tumors, cortical thickness and shape of LNs on US were also significantly associated with nodal pCR. In the validation cohort, the discrimination of US model (area under the curve [AUC], 0.76) was superior to clinicopathologic model (AUC, 0.68); the combined model (AUC, 0.85) demonstrates strong discriminatory power in predicting nodal pCR. Calibration curves of the nomogram based on the combined model demonstrated that substantial agreement can be observed between the predictions and observations. This nomogram showed a false-negative rates of 16.67% in all patients and 10.53% in patients with triple negative breast cancer. CONCLUSION: Nomogram incorporating routine clinicopathologic and US characteristics can predict nodal pCR and represents a tool to aid in treatment decisions for the axilla after NAC in breast cancer patients.

Reduced-Volume Irradiation of Uninvolved Neck in Patients With Nasopharyngeal Cancer: Updated Results From an Open-Label, Noninferiority, Multicenter, Randomized Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported comparable 3-year regional relapse-free survival (RRFS) using elective upper-neck irradiation (UNI) in N0-1 nasopharyngeal carcinoma (NPC) compared with standard whole-neck irradiation (WNI). Here, we present the prespecified 5-year overall survival (OS), RRFS, late toxicity, and additional analyses. In this randomized trial, patients received UNI (n = 224) or WNI (n = 222) for an uninvolved neck. After a median follow-up of 74 months, the UNI and WNI groups had similar 5-year OS (95.9% v 93.1%, hazard ratio [HR], 0.63 [95% CI, 0.30 to 1.35]; P = .24) and RRFS (95.0% v 94.9%, HR, 0.96 [95% CI, 0.43 to 2.13]; P = .91) rates. The 5-year disease-free survivors in the UNI group had a lower frequency of hypothyroidism (34% v 48%; P = .004), neck tissue damage (29% v 46%; P < .001), dysphagia (14% v 27%; P = .002), and lower-neck common carotid artery stenosis (15% v 26%; P = .043). The UNI group had higher postradiotherapy circulating lymphocyte counts than the WNI group (median: 400 cells/µL v 335 cells/µL, P = .007). In conclusion, these updated data confirmed that UNI of the uninvolved neck is a standard of care in N0-1 NPC, providing outstanding efficacy and reduced long-term toxicity, and might retain more immune function.

Delta Radiomics Based on Longitudinal Dual-modal Ultrasound Can Early Predict Response to Neoadjuvant Chemotherapy in Breast Cancer Patients.

RATIONALE AND OBJECTIVES: To develop a monitoring model using radiomics analysis based on longitudinal B-mode ultrasound (BUS) and shear wave elastography (SWE) to early predict pathological response to neoadjuvant chemotherapy (NAC) in breast cancer patients. MATERIALS AND METHODS: In this prospective study, 112 breast cancer patients who received NAC between September 2016 and March 2022 were included. The BUS and SWE data of breast cancer were obtained prior to treatment as well as after two and four cycles of NAC. Radiomics features were extracted followed by measuring the changes in radiomics features compared to baseline after the second and fourth cycles of NAC (△R [C2], △R [C4]), respectively. The delta radiomics signatures were established using a support vector machine classifier. RESULTS: The area under receiver operating characteristic curve (AUC) values of △RBUS (C2) and △RBUS (C4) for predicting the response to NAC were 0.83 and 0.84, while those of △RSWE (C2) and △RSWE (C4) were 0.88 and 0.90, respectively. △RSWE exhibited significantly superior performance to △RBUS for predicting NAC response (Delong test, p < 0.01). No significant differences were observed in the performances between △R (C2) and △R (C4) based on BUS or SWE data. The longitudinal dual-modal ultrasound radiomics (LDUR) model had an excellent discrimination, good calibration and clinical usefulness, with the AUC, sensitivity and specificity of 0.97, 95.52% and 91.11%, respectively. CONCLUSION: The LDUR model achieved excellent performance in predicting the pathological response to chemotherapy during the early stages of NAC for breast cancer.

Abdominal Ultrasonography After Transrectal Filling With Contrast Agents in Colorectal Cancer With Severely Stenotic Lesions.

OBJECTIVE: Abdominal ultrasonography after transrectal filling with contrast agent (AU-TFCA) was retrospectively evaluated with respect to determination of T stage and lesion length in patients with colorectal cancer (CRC) who had previously failed colonoscopy because of severe intestinal stenosis. METHODS: The population comprised 83 patients with CRC with intestinal stenosis and previously failed colonoscopy who underwent AU-TFCA, and in addition contrast-enhanced computed tomography (CECT) and/or magnetic resonance imaging (MRI), 2 wk before surgery. The diagnostic performance of AU-TFCA and CECT/MRI was evaluated relative to the post-operative pathological results (PPRs) by paired sample t-test, receiver operator characteristic (ROC) curve, Pearson's χ2-test and κ and intraclass correlation coefficients. RESULTS: The T staging identified via AU-TFCA, but not CECT/MRI, was relatively consistent with that of the PPRs (linearly weighted κ coefficient: 0.558, p < 0.001, and linearly weighted κ coefficient: 0.237, p < 0.001, respectively). The overall diagnostic accuracy of T staging based on AU-TFCA (83.1%) was significantly higher than that based on CECT/MRI (50.6%). Regarding lesion length, the results of AU-TFCA and PPRs were comparable (t = 1.852, p = 0.068), but those of CECT/MRI and PPRs were significantly different (t = 8.450, p < 0.001). CONCLUSION: AU-TFCA is effective in evaluation of lesion length and T stage in patients with severely stenotic CRC lesions who previously failed colonoscopy. The diagnostic accuracy of AU-TFCA is significantly better compared with that of CECT/MRI.

Deep Learning Model Based on Dual-Modal Ultrasound and Molecular Data for Predicting Response to Neoadjuvant Chemotherapy in Breast Cancer.

RATIONALE AND OBJECTIVES: To carry out radiomics analysis/deep convolutional neural network (CNN) based on B-mode ultrasound (BUS) and shear wave elastography (SWE) to predict response to neoadjuvant chemotherapy (NAC) in breast cancer patients. MATERIALS AND METHODS: In this prospective study, 255 breast cancer patients who received NAC between September 2016 and December 2021 were included. Radiomics models were designed using a support vector machine classifier based on US images obtained before treatment, including BUS and SWE. And CNN models also were developed using ResNet architecture. The final predictive model was developed by combining the dual-modal US and independently associated clinicopathologic characteristics. The predictive performances of the models were assessed with five-fold cross-validation. RESULTS: Pretreatment SWE performed better than BUS in predicting the response to NAC for breast cancer for both the CNN and radiomics models (P < 0.001). The predictive results of the CNN models were significantly better than the radiomics models, with AUCs of 0.72 versus 0.69 for BUS and 0.80 versus 0.77 for SWE, respectively (P = 0.003). The CNN model based on the dual-modal US and molecular data exhibited outstanding performance in predicting NAC response, with an accuracy of 83.60% ± 2.63%, a sensitivity of 87.76% ± 6.44%, and a specificity of 77.45% ± 4.38%. CONCLUSION: The pretreatment CNN model based on the dual-modal US and molecular data achieved excellent performance for predicting the response to chemotherapy in breast cancer. Therefore, this model has the potential to serve as a non-invasive objective biomarker to predict NAC response and aid clinicians with individual treatments.

The benefit of contrast-enhanced ultrasound in biopsies for focal liver lesions: a retrospective study of 820 cases.

OBJECTIVE: This study compared the performance between ultrasound (US)- and contrast-enhanced US (CEUS)-guided liver biopsies and evaluated the benefit of CEUS in percutaneous biopsy for focal liver lesions (FLLs). METHODS: We performed a retrospective study of 820 patients with FLLs, who underwent percutaneous liver biopsy in our center between 2017 and 2019. The patients were divided into two groups based on whether US (n = 362) or CEUS (n = 458) used before a biopsy. The two groups were compared based on specimen adequacy for pathological diagnosis and diagnostic accuracy of liver biopsy. Stratification analysis was performed based on lesion and protocol characteristics to provide detailed information for selecting the imaging guidance for biopsy. RESULTS: Compared with the US group, the CEUS group yielded more acceptable samples (97.6% vs. 99.4%, p < 0.05) and improved diagnostic accuracy (92.6% vs. 96.4%, p < 0.05), and achieved better sensitivity (92.5% vs. 96.2%, p < 0.05) for liver biopsies, especially in FLLs ≥ 5 cm, heterogeneous hypoechoic FLLs, or FLLs with an obscure boundary. The CEUS group showed significantly higher accuracy compared with the US group pertaining to single-puncture biopsies (100% vs. 92.7%, p < 0.05) or biopsies with punctures ≤ 2 (97.6% vs. 94.3%, p < 0.05). CONCLUSION: CEUS achieved an enhanced success rate for sampling and diagnostic accuracy of liver biopsies, especially in FLLs ≥ 5 cm, heterogeneous hypoechoic FLLs, or FLLs with an obscure boundary. CEUS can be used to decrease the number of punctures needed, which might increase the safety of liver biopsy. KEY POINTS: • CEUS can help confirm an adequate biopsy site, increasing the sampling success rate and diagnostic accuracy of the liver biopsy. • CEUS can be used to decrease the number of punctures needed to improve the safety of liver biopsy. • It is recommended to use CEUS guidance for liver biopsies, especially with FLLs ≥ 5 cm, heterogeneous hypoechoic FLLs, or FLLs with an obscure boundary.

Combining conventional ultrasound and sonoelastography to predict axillary status after neoadjuvant chemotherapy for breast cancer.

OBJECTIVE: To determine the ability of conventional ultrasound (US) combined with shear wave elastography (SWE) to reveal axillary status after neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: From September 2016 to December 2021, 201 patients with node-positive breast cancer who underwent NAC were enrolled in this prospective study. Conventional US features of axillary lymph nodes and SWE characteristics of breast lesions after NAC were analyzed. The diagnostic performances of US, SWE, and their combination were assessed using multivariate logistic regression and receiver operator characteristic curve (ROC) analyses. RESULTS: The area under the ROC curve (AUC) for the ability of conventional US features to determine axillary status after NAC was 0.82, with a sensitivity of 85.23%, a specificity of 67.39%, and an accuracy of 76.11%. Shear wave velocity (SWV) displayed moderate performance for predicting axilla status after NAC with SWVmean demonstrating an AUC of 0.85. Cortical thickness and shape of axillary nodes and SWVmean of breast tumors were independently associated with axillary nodal metastasis after NAC. Compared to conventional US, the combination of conventional US of axillary lymph nodes with SWE of breast lesions achieved a significantly higher AUC (0.90 vs 0.82, p < 0.01, Delong's test) with a sensitivity of 87.50%, improved specificity of 82.61% and accuracy of 85.00%. CONCLUSIONS: Breast SWE was independently associated with residual metastasis of axillary node after NAC in patients with initially diagnosed positive axilla. Combining SWE with conventional US showed good diagnostic performance for axillary node disease after NAC. KEY POINTS: • Breast SWE can serve as a supplement to axilla US for the evaluation of the axilla after NAC. • The combination of axilla US with breast SWE may be a promising method to facilitate less-invasive treatment in patients receiving NAC.

Evaluation of liver parenchyma stiffness in patients with liver tumours: optimal strategy for shear wave elastography.

OBJECTIVES: To determine the methodology of non-invasive test for evaluation of liver stiffness (LS) with tumours using two-dimensional (2D) shear wave elastography (SWE). METHODS: One hundred and twenty-seven patients with liver tumours underwent 2D-SWE before surgery to measure liver and spleen stiffness (SS). Two-dimensional SWE values were obtained in the liver at 0-1 cm, 1-2 cm and >2 cm from the tumour edge (PLS-1, PLS-2 and RLS, respectively). The influence of tumour-associated factors was evaluated. The area under the receiver operating characteristic curve (AUC) for each value was analysed to diagnose cirrhosis. RESULTS: PLS-1 was higher than PLS-2, which was even higher than RLS (p < 0.001). The AUCs of PLS-1, PLS-2, RLS and SS for diagnosing cirrhosis were 0.760, 0.833, 0.940 and 0.676, with the specificity of 75.7%, 67.6%, 90.3% and 77.4%, respectively. Tumour sizes, locations or types showed no apparent influence on 2D-SWE values except for RLS, which was higher in patients with primary hepatic carcinomas (p < 0.05). CONCLUSIONS: LS with tumours is best measured at >2 cm away from the tumour edge. SS measurement could be used as an alternative to LS measurement in the event of no available liver for detection. KEY POINTS: • Tumour-associated factors impact background liver stiffness assessment. • Background liver stiffness is best measured at >2 cm from tumour edge. • Spleen stiffness can be an alternative to assess background liver stiffness.

Diagnostic value, safety, and histopathologic discrepancy risk factors for endoscopic forceps biopsy and transrectal ultrasound-guided core needle biopsy in rectum lesions.

BACKGROUND: Accurate preoperative pathologic diagnosis is very important for making appropriate therapeutic decisions for patients with rectal lesions. This study aimed (I) to determine diagnostic value and safety of endoscopic forceps biopsy (EFB) and transrectal ultrasound (TRUS)-guided core needle biopsy (CNB), and (II) to analyze the risk factors for their histopathologic discrepancies, with a particular focus in identifying the indicators for re-biopsy using TRUS-guided CNB after EFB. METHODS: We retrospectively reviewed the records of 102 patients who received EFB and TRUS-guided CNB before surgery. The histopathologic concordance and risk factors for underdiagnosis by EFB and TRUS-guided CNB were analyzed. RESULTS: Compared with postoperative pathology, the histopathologic discrepancy rate of EFB and TRUS-guided CNB was 51.0% (52/102 lesions) and 8.8% (9/102 lesions), respectively. The kappa value for consistency with postoperative pathology findings was 0.420 for EFB and 0.876 for TRUS-guided CNB. The multivariate analyses and receiver operating characteristic (ROC) curve indicated that lesions thickness ≥13.5 mm [OR 1.080 (95% CI: 1.021-1.142), P=0.007] and flat/depressed shape [OR 0.206 (95% CI: 0.076-0.564), P=0.002] were significantly associated with histopathologic discrepancies in EFB. CONCLUSIONS: EFB was of limited clinical value in identifying the preoperative diagnosis of rectal lesions. Lesions thickness and flat/depressed shape at EFB were independent risk factors for pathologic discrepancies. TRUS-guided CNB may serve as a safe and effective supplement to routine EFB.

Contrast-enhanced ultrasonography vs MRI for evaluation of local invasion by cervical cancer.

OBJECTIVE:: The purpose of this study is to compare contrast-enhanced ultrasound (CEUS) to MRI for evaluating local invasion of cervical cancer. METHODS:: A total of 108 patients with cervical cancer were included in this study. All the enrolled patients were Stage IIA2-IVB according to the International Federation of Obstetrics and Gynecology and treated with volumetric modulated arc therapy. Tumour size in different dimensions was compared between MRI and CEUS. The correlation coefficients (r) between MRI and CEUS for diagnosing local invasion, parametrial extension, and invasion to vagina, uterine corpus and adjacent organs were assessed. RESULTS:: Measurements by MRI and CEUS were strongly correlated in the three dimensions: left-right r = 0.84, craniocaudal r = 0.86 and anteroposterior r = 0.88. Vaginal and parametrial invasion were detected by both MRI and CEUS with moderate concordance, and invasion of uterine corpus, bladder and rectum with good concordance. CONCLUSION:: CEUS is comparable to MRI for measuring tumour size, with good concordance for evaluating invasion of cervical cancer. ADVANCES IN KNOWLEDGE:: CEUS is a less expensive non-invasive modality for assessment of tumour size and invasion of cervical cancer.

Ultrasound elastography as an imaging biomarker for detection of early tumor response to chemotherapy in a murine breast cancer model: a feasibility study.

OBJECTIVE: This study investigated the feasibility of using strain elastography (SE) and real time shear wave elastography (RT-SWE) to evaluate early tumor response to cytotoxic chemotherapy in a murine xenograft breast cancer tumor model. METHODS: MCF-7 breast cancer-bearing nude mice were treated with either cisplatin 2 mg kg-1 plus paclitaxel 10 mg kg-1 (treatment group) or sterile saline (control group) once daily for 5 days. The tumor elasticity was measured by SE or RT-SWE before and after therapy. Tumor cell density was assessed by hematoxylin and eosin staining, and the ratio of collagen fibers in the tumor was evaluated by Van Gieson staining. The correlation between tumor elasticity, as determined by SE and SWE, as well as the pathological tumor responses were analyzed. RESULTS: Chemotherapy significantly attenuated tumor growth compared to the control treatment (p < 0.05). Chemotherapy also significantly increased tumor stiffness (p < 0.05) and significantly decreased (p < 0.05) tumor cell density compared with the control. Moreover, chemotherapy significantly increased the ratio of collagen fibers (p < 0.05). Tumor stiffness was positively correlated with the ratio of collagen fibers but negatively correlated with tumor cell density. CONCLUSION: The study suggests that ultrasound elastography by SE and SWE is a feasible tool for assessing early responses of breast cancer to chemotherapy in our murine xenograft model. Advances in knowledge: This study showed that the tumor elasticity determined by ultrasound elastography could be a feasible imaging biomarker for assessing very early therapeutic responses to chemotherapy.

Transvaginal Ultrasound-Guided Core Needle Biopsy of Pelvic Masses.

OBJECTIVES: This study assessed the efficacy and safety of transvaginal ultrasound (US)-guided core needle biopsy (CNB) for obtaining adequate pelvic mass samples for histologic analysis and evaluated factors that may affect biopsy success. METHODS: Two hundred cases underwent transvaginal US-guided CNBs for primary inoperable tumors, suspicion of metastases to the ovaries or peritoneum, recurrence, or other solid lesions in the pelvis. Biopsy samples were obtained from the pelvic cavity (67.0%), vaginal cuff or vaginal wall (17.5%), or peritoneal cake (15.5%). The potential influences of the biopsy site (pelvic cavity, vaginal cuff or vaginal wall, or peritoneal cake), vascularization, ascites, tumor size, and tumor type (inoperable, metastases, recurrence, or solid pelvic tumor) on the success of transvaginal US-guided CNB were evaluated by a univariate analysis. RESULTS: Adequate samples were obtained in 192 of 200 biopsies (96.0%), of which 190 yielded successful diagnoses (95.0%). The biopsy site had a significant effect on biopsy adequacy, as there was a significantly lower probability of obtaining satisfactory specimens for histologic verification from the peritoneal cake compared to pelvic tumors and the vaginal cuff or vaginal wall (P < .01). Adequacy was also affected by tumor size (P < .05) but not by vascularization, ascites, or tumor type. No complications occurred during the biopsy procedures. CONCLUSIONS: Transvaginal US-guided CNB is a safe and effective alternative to more invasive methods for evaluating pelvic lesions, such as laparoscopy and laparotomy.

Survival in signet ring cell carcinoma varies based on primary tumor location: a Surveillance, Epidemiology, and End Results database analysis.

BACKGROUND: The aim of this study was to investigate the survival of patients with signet ring cell carcinoma (SRCC) based on primary tumor location. METHODS: Patient data were obtained from the Surveillance, Epidemiology, and End Results database (1988-2012) with ≥200 cases per tumor location. Cox regression analysis was used to investigate prognostic factors of cause-specific survival (CSS). RESULTS: We identified 24,171 patients. Of the patients, 63.4% had gastric SRCC, followed by colon (18.2%), esophageal (5.0%), rectal (3.5%), lung (3.1%), pancreatic (1.8%), breast (1.5%), bladder (1.3%), small intestine (1.1%), and gallbladder SRCC (1.0%). The 5-year CSS was 22.1%, 69.0%, 33.2%, 28.1%, 24.8%, 16.1%, 13.6%, 12.6%, 11.0%, 6.4% in patients with gastric, breast, colon, rectum, bladder, small intestine, esophageal, gallbladder, lung, and pancreatic SRCC, respectively (P < 0.001). Multivariate analyses showed that the primary tumor location was an independent prognostic factor of survival. Patients with lung, small intestine, and bladder SRCC had a comparable CSS to gastric SRCC, while breast and colorectal SRCC had better survival than gastric SRCC. Esophageal, gallbladder, and pancreatic SRCC were significantly associated with poor CSS compared with gastric SRCC. CONCLUSION: Our study suggests a major difference in survival of SRCC based on the primary tumor locations.

Remote ischaemic preconditioning suppresses endogenous plasma nitrite during ischaemia-reperfusion: a randomized controlled crossover pilot study.

AIM: The aim of this article is to test the hypothesis that remote ischaemic preconditioning (RIPC) increases circulating endogenous local and systemic plasma (nitrite) during RIPC and ischaemia-reperfusion (IR) as a potential protective mechanism against ischaemia-reperfusion injury (IRI). METHODS: Six healthy male volunteers (mean age 29.5 ± 7.6 years) were randomized in a crossover study to initially receive either RIPC (4 × 5 min cycles) to the left arm, or no RIPC (control), both followed by an ischaemia-reperfusion (IR) sequence (20 min cuff inflation to 200 mmHg, 20 min reperfusion) to the right arm. The volunteers returned at least 7 days later for the alternate intervention. The primary outcome was the effect of RIPC vs. control on local and systemic plasma (nitrite). RESULTS: RIPC did not significantly change plasma (nitrite) in either the left or the right arm during the RIPC sequence. However, compared to control, RIPC decreased plasma (nitrite) during the subsequent IR sequence by ~26% (from 118 ± 9 to 87 ± 5 nmol l-1 ) locally in the left arm (P = 0.008) overall, with an independent effect of -58.70 nmol l-1 (95% confidence intervals -116.1 to -1.33) at 15 min reperfusion, and by ~24% (from 109 ± 9 to 83 ± 7 nmol l-1 ) systemically in the right arm (P = 0.03). CONCLUSIONS: RIPC had no effect on plasma (nitrite) during the RIPC sequence, but instead decreased plasma (nitrite) by ~25% during IR. This would likely counteract the protective mechanisms of RIPC, and contribute to RIPC's lack of efficacy, as observed in recent clinical trials. A combined approach of RIPC with nitrite administration may be required.

Can quantitative contrast-enhanced ultrasonography predict cervical tumor response to neoadjuvant chemotherapy?

OBJECTIVE: To evaluate the feasibility of quantitative contrast-enhanced ultrasonography (CEUS) for predicting and assessing cervical tumor response to neoadjuvant chemotherapy (NACT). METHODS: Thirty-eight cases with stage IB2 or IIA cervical cancer were studied using CEUS before and after one cycle of NACT. The quantitative CEUS parameters maximum intensity (IMAX), rise time (RT), time to peak (TTP), and mean transit time (MTT) were compared between cervical tumors and myometrium (reference zone) using Sonoliver software. Absolute and relative changes in quantitative CEUS parameters were also compared among complete response, partial response, and non-responsive groups. Correlations between pre-treatment IMAX and changes in quantitative parameters were assessed after one cycle of NACT. RESULTS: There were significant changes in cervical tumor IMAX (P<0.001), RT (P<0.05), and TTP (P<0.05) after one cycle of NACT. According to the Response Evaluation Criteria In Solid Tumors guidelines, the enrollments were divided into complete response, partial response, stable disease and progressive disease groups. There were no significant differences in quantitative CEUS parameters among complete response, partial response, and non-responsive groups (P>0.05). In the stable disease group (n=17), cervical tumor IMAX, RT, and TTP decreased significantly after NACT (P<0.001). The absolute and percentage changes in IMAX were positively correlated with pre-treatment IMAX in all 38 patients (r=0.576, P<0.001 and r=0.429, P<0.001). CONCLUSION: Quantitative CEUS analysis can reveal changes in tumor perfusion following NACT. Tumor perfusion values changes likely precede size changes during the NACT course, and pre-treatment IMAX may be a valuable predictor of cervical tumor perfusion response to NACT with a great decrease in IMAX correlated with better perfusion response.

Contrast-enhanced ultrasonography of cervical carcinoma: perfusion pattern and relationship with tumour angiogenesis.

OBJECTIVE: This study aimed to investigate the use of contrast-enhanced ultrasonography (CEUS) and time-intensity curves to assess angiogenesis in cervical cancer. METHODS: 60 patients who were scheduled to undergo radical surgery for biopsy-proven cervical cancers underwent CEUS. Surgical tissue sections from 32 patients who did not receive neoadjuvant chemotherapy were analyzed with CD34 staining to estimate intratumoral microvessel density (MVD). CEUS images were analyzed for maximum intensity (IMAX), rise time (RT), time to peak (TTP) and mean transit time. RESULTS: Cervical lesions had a higher IMAX and shorter RT and TTP (p < 0.001) than reference regions. There was a linear association between the IMAX of the cervical lesion and the mean intratumoral MVD (r = 0.624, p < 0.001). There were no significant differences in CEUS variables according to histological type, grade and stage. CONCLUSION: Quantitative CEUS variables have potential use for monitoring perfusion changes in tumours after non-surgical therapy for advanced cervical cancer. ADVANCES IN KNOWLEDGE: The article demonstrates the capability and value of quantitative CEUS as a non-invasive strategy for detecting the perfusion and angiogenic status of cervical cancer. Quantitative CEUS variables have potential use for monitoring tumour response to non-surgical therapy.

CLDN14 is epigenetically silenced by EZH2-mediated H3K27ME3 and is a novel prognostic biomarker in hepatocellular carcinoma.

Trimethylation of lysine 27 on histone H3 (H3K27ME3) is a transcription-suppressive histone mark mediated by enhancer of zeste homolog 2 (EZH2). We have previously suggested that EZH2-mediated H3K27ME3 plays a critical oncogenic role in human hepatocellular carcinoma (HCC) aggressiveness. However, the direct downstream targets of EZH2-H3K27ME3 and the molecular mechanisms by which regulates HCC pathogenesis remain unclear. In this study, we used chromatin immunoprecipitation together with high-throughput sequencing (ChIP-seq) and gene expression profiling by microarray analysis to assess genome-wide chromatin occupancy of H3K27ME3 in HCC cells. We identified that claudin14 (CLDN14) is a potentially direct target for EZH2-mediated H3K27ME3 in HCC. In a large cohort of clinical HCC tissues, we found that low expression of CLDN14 was significantly associated with advanced tumor stage and determined to be an independent predictor of shortened survival of HCC patients. Next, functional experiment demonstrated that depletion of CLDN14 substantially restored EZH2-silenced HCC cells motility and invasive capacities and supported cell epithelial-mesenchymal transition (EMT). Furthermore, downregulation of CLDN14 dramatically re-enhanced the wnt/ß-catenin signaling activity in EZH2-silenced HCC cells by increasing the levels of active ß-catenin and promoting the nuclear localization of ß-catenin. These results, collectively, uncover that CLDN14 is a novel direct target of EZH2-mediated H3K27ME3, and provide an explanation for the aggressive nature of HCC with downregulation of CLDN14 and the underling mechanism that links the tumor suppressor CLDN14 to the wnt/ß-catenin signaling pathway.

Development of a ten-signature classifier using a support vector machine integrated approach to subdivide the M1 stage into M1a and M1b stages of nasopharyngeal carcinoma with synchronous metastases to better predict patients' survival.

The aim of this study was to develop a prognostic classifier and subdivided the M1 stage for nasopharyngeal carcinoma patients with synchronous metastases (mNPC). A retrospective cohort of 347 mNPC patients was recruited between January 2000 and December 2010. Thirty hematological markers and 11 clinical characteristics were collected, and the association of these factors with overall survival (OS) was evaluated. Advanced machine learning schemes of a support vector machine (SVM) were used to select a subset of highly informative factors and to construct a prognostic model (mNPC-SVM). The mNPC-SVM classifier identified ten informative variables, including three clinical indexes and seven hematological markers. The median survival time for low-risk patients (M1a) as identified by the mNPC-SVM classifier was 38.0 months, and survival time was dramatically reduced to 13.8 months for high-risk patients (M1b) (P < 0.001). Multivariate adjustment using prognostic factors revealed that the mNPC-SVM classifier remained a powerful predictor of OS (M1a vs. M1b, hazard ratio, 3.45; 95% CI, 2.59 to 4.60, P < 0.001). Moreover, combination treatment of systemic chemotherapy and loco-regional radiotherapy was associated with significantly better survival outcomes than chemotherapy alone (the 5-year OS, 47.0% vs. 10.0%, P < 0.001) in the M1a subgroup but not in the M1b subgroup (12.0% vs. 3.0%, P = 0.101). These findings were validated by a separate cohort. In conclusion, the newly developed mNPC-SVM classifier led to more precise risk definitions that offer a promising subdivision of the M1 stage and individualized selection for future therapeutic regimens in mNPC patients.

miR-200c inhibits breast cancer proliferation by targeting KRAS.

The microRNA, miR-200c, is involved in the tumorigenesis and progression of a variety of cancers. The purpose of this study was to investigate the expression, mechanism and prognostic roles of miR-200c in breast cancer. We found that miR-200c was downregulated in both breast cancer tissue and cell lines using quantitative real-time PCR (qRT-PCR). In situ hybridization (ISH) and microarrays showed that low miR-200c expression was associated with poor patient overall survival (OS) and disease free survival (DFS). We used luciferase reporter plasmids to find that miR-200c inhibited the AKT and ERK pathways by directly targeting KRAS. Repression of KRAS by miR-200c suppressed the proliferation and survival of breast cancer cells in vitro and in vivo. miR-200c also had an anti-tumor effect by negatively regulating KRAS in a xenograft mouse model. Our findings provide clues regarding the role of miR-200c as a tumor suppressor in breast cancer through the inhibition of KRAS translation both in vitro and in vivo. miR-200c could be a potential therapeutic target in breast cancer.