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The aim of our study was to compare strain elastography (SE), acoustic radiation force impulse-inducing Virtual Touch Imaging ([VTI] Siemens Medical Solutions, Mountain View, CA, USA), Virtual Touch Imaging Quantification ([VTIQ] Siemens Medical Solutions) and combined methods in the evaluation of ultrasound (US) Breast Imaging-Reporting and Data System (BI-RADS) category 4 lesions to explore an applicable way to reduce unnecessary biopsy by reducing false positives of conventional US without yielding false-negative cases. A total of 267 patients with 278 BI-RADS category 4 lesions (151 benign and 127 malignant) were evaluated with conventional B-mode US, SE, VTI and VTIQ implemented on a Siemens Acuson S2000 US system. Diagnostic performance, including area under the receiver operating characteristic curve, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were evaluated. Overall, VTI alone exhibited the highest NPV (91.74%), although combined elastic methods exhibited higher NPV than single methods, with the highest NPV at 100% when the VTI, SE and VTIQ methods were combined. Compared with conventional US, PPV increased from 45.7% (127 of 278) to 63.18% (127 of 201) when adding combined elastography (VTI + SE +VTIQ). In addition, 52.5% (63/120) and 50.8% (61/120) of BI-RADS 4 A lesions were downgraded when using combined methods (VTI + SE and VTI + SE + VTIQ, respectively) without missing any cancer. However, 2 intraductal papillomas and 1 phyllodes tumor were not identified. In conclusion, the combination of different elastic methods have the potential to downgrade BI-RADS 4A lesions to reduce false-positive biopsies without increasing the risk of missing cancers.

BackgroundAnti-programmed death (PD)-1 therapy has recently been used in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). The long-term survival and its biomarkers responding to anti-PD-1 treatment in patients with R/M NPC remain unclear.MethodsPatients with R/M NPC were enrolled between March 2016 and January 2018 from two phase I clinical trials. The median follow-up period was 24.7 months. Eligible patients progressed on standard chemotherapy had measurable disease by Response Evaluation Criteria in Solid Tumor V.1.1. Non-obligatory contemporaneous tumor samples were collected for whole-exome sequencing. The primary outcome was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were secondary outcomes assessed in all patients.ResultsAmong 124 evaluable patients, anti-PD-1 therapy achieved an ORR of 29.8% and a durable clinical benefit rate of 60.5%. The median OS (mOS) was 17.1 months (95% CI 14.2 to 24.7), median PFS (mPFS) was 3.8 months (95% CI 3.4 to 6.0), and median DOR was 9.5 months. Significant OS benefit from treatment was observed in patients without liver metastasis (23.8 vs 13.3 months, p=0.006). Copy number deletion in genes encoding granzyme B or granzyme H (GZMB/H) was associated with poor treatment outcome (mPFS altered vs wildtype: 1.7 vs 3.6 months, p=0.03; mOS altered vs wildtype: 10.1 vs 18 months, p=0.012).ConclusionsAnti-PD-1 treatment provided promising clinical benefit in pretreated patients with R/M NPC. Copy number loss in either GZMB or GZMH genes was associated with reduced survival.

Background The central lymph node is the most common involvement for papillary thyroid carcinoma (PTC), which is correlated to recurrence and survival. But it is difficult to accurately evaluate lymph node prior to an operation. This retrospective study was designed to develop a risk model and risk stratification to preoperatively predict central lymph node metastasis (CLNM) in PTC and validate this model. Methods A series of 1,714 initial treatment PTC patients were enrolled. Among these patients, 1,001 patients were used to develop a predictive model and establish a stratification scoring system. This was validated through the remaining 713 patients. Results The multivariate analysis revealed that CLNM and lateral lymph node metastasis (LLNM) in ultrasound (US), tumor size, gender, capsule invasion in US, microcalcification and age were significant independent predictors for CLNM. The area under the curve (AUC) of the model was 0.778. Furthermore, the cutoff value to predict CLNM was 8 points, and the sensitivity and specificity were 77% and 65%, respectively. In the scoring system for CLNM, a score of ≤8, 8-18 and >18 were defined as low, intermediate and high risk, respectively. The risk of CLNM was approximately 30%, 60% and 80%, corresponding to the stratification. When validated, the model predicted the risk of CLNM with an AUC of 0.811, a sensitivity and specificity of 83% and 63%, respectively. Conclusions This study presented a predictive model to preoperatively assess the risk of CLNM in PTC. The predictive model performed well, but needed to be prospectively validated in external center.

Background Area under time-concentration curve (AUC) of docetaxel is related with its toxicity and efficacy. The aim of this study is to investigate the target range of docetaxel AUC in Chinese head and neck cancer (HNC) patients. Methods Eligible HNC patients were enrolled and received at least 2 cycles of docetaxel-based chemotherapy. A simplified pharmacokinetic (PK) strategy (2 monitored samples) was developed to simulate docetaxel AUC using the nonlinear mixed-effect modelling program. Preliminary target range of AUC was pre-set as 2.5-3.7 µg·hr/mL according to pooled analysis from 8 previous studies. Fisher exact test was used to analyze the relationship between AUC with neutropenia and efficacy, and to verify the target range. Results Thirty-nine eligible patients were enrolled. Grade 3-4 and grade 4 neutropenia rate in 1st cycle was 64% and 36%, respectively. AUC simulation by simplified PK strategy was acceptable compared to full sampling method from the analysis of archived 300 patients' data, with -5.67% of mean prediction error (MPE). Median AUC of all patients was 2.58 µg·hr/mL (range from 1.28 to 9.39). A significant correlation (P=0.007) was detected between AUC and body surface area (BSA)-dosage, but BSA contributed only 18.3% of AUC inter-individual variability. Docetaxel AUC was significantly related with the severity (grade 3-4) of neutropenia (correlation of coefficient was 0.452, P=0.004). Fourteen patients (36%) were within the target AUC range. Patients with AUC above the target experienced more severe neutropenia (grade 3-4 rate 100% vs. 56%, P=0.036; grade 4 rate 86% vs. 25%, P=0.005). No significant difference of response rate was found between patients within the target or not. Conclusions A simplified samples PK strategy was developed for docetaxel AUC simulation. The target range of docetaxel AUC in Chinese HNC patients was suggested at 2.5-3.7 µg·hr/mL for reduced toxicity without compromising efficacy of docetaxel treatment.

Background: The current study is aimed to examine the impact of pharmacokinetics and gene polymorphisms of enzymes involving in absorption, distribution, metabolism and excretion (ADME) on the efficacy of gefitinib in non-small cell lung cancer (NSCLC) patients. Methods: Eligible patients with indication of gefitinib treatment were prospectively enrolled in this study. Two peripheral blood samples at baseline and before cycle 2 day 1 were collected for the detection of single nucleotide polymorphisms (SNPs) of drug ADME enzymes and trough drug concentration (C trough ) at steady state. Thirteen SNPs were genotyped using the Sequenom Massarray system. C trough was determined by validated high-performance liquid chromatographic method with tandem mass spectrometric (LC-MS/MS). Results: Fifty-eight NSCLC patients were enrolled in this study. The median of C trough was 175ng/ mL (range from 47.8 to 470 ng/mL). The trough concentration was not associated with either objective response or progression free survival (PFS). C trough was significantly lower in CYP3A4 rs2242480 CC + CT genotype than in TT genotype (P=0.019) and in ABCG2 rs2231142 AA genotype than in AC + CC genotype (P=0.031). ABCB1 rs2032582 dominant model was significantly correlated with overall response rate (ORR) and patients with GG phenotype respond better than patients with GT + TT phenotypes (84.6% vs . 51.2%, P=0.032). ABCB1 rs10256836 recessive model was significantly correlated with PFS and patients with GG phenotype achieved longer PFS than patients with GC + CC phenotypes (17.40 vs . 10.33 months, P=0.040). Conclusions: The C trough of gefitinib was significantly different between CYP3A4 and ABCG2 genotypes, but not with the efficacy of gefitinib treatment. ABCB1 rs2032582 and rs10256836 polymorphisms were correlated treatment outcome. Polymorphisms analysis of ABCB1 could be a predictive biomarker for gefitinib treatment.

// Qingguang Lin 1, * , Jianwei Wang 1, * , Qing Li 1, * , Chunyi Lin 2 , Zhixing Guo 1 , Wei Zheng 1 , Cuiju Yan 1 , Anhua Li 1 and Jianhua Zhou 1 1 Department of Ultrasound, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, P.R. China 2 School of Electronic and Information Engineering, South China University of Technology, Guangzhou, 510640, P.R. China * These authors have contributed equally to this work Correspondence to: Jianhua Zhou, email: zhoujh@sysucc.org.cn Keywords: chemotherapy; cancer; ultrasonic radio-frequency time series; microstructure Received: March 21, 2017 Accepted: December 15, 2017 Published: December 23, 2017 ABSTRACT Ultrasound radio-frequency (RF) time series have been shown to carry tissue typing information. To evaluate the potential of RF time series for early prediction of tumor response to chemotherapy, 50MCF-7 breast cancer-bearing nude mice were randomized to receive cisplatin and paclitaxel (treatment group; n = 26) or sterile saline (control group; n = 24). Sequential ultrasound imaging was performed on days 0, 3, 6, and 8 of treatment to simultaneously collect B-mode images and RF data. Six RF time series features, slope, intercept, S1, S2, S3 , and S4 , were extracted during RF data analysis and contrasted with microstructural tumor changes on histopathology. Chemotherapy administration reduced tumor growth relative to control on days 6 and 8. Compared with day 0, intercept, S1 , and S2 were increased while slope was decreased on days 3, 6, and 8 in the treatment group. Compared with the control group, intercept, S1, S2, S3 , and S4 were increased, and slope was decreased, on days 3, 6, and 8 in the treatment group. Tumor cell density decreased significantly in the latter on day 3. We conclude that ultrasonic RF time series analysis provides a simple way to noninvasively assess the early tumor response to chemotherapy.

Iodine‐125 (125I) brachytherapy, a promising form of radiotherapy, is increasingly applied in the clinical treatment of a wide range of solid tumors. However, the extremely hypoxic microenvironment in solid tumors can cause hypoxia‐induced radioresistance to 125I brachytherapy, resulting in therapeutic inefficacy. In this study, the aim is to sensitize hypoxic areas in solid tumors using ultrasound‐activated oxygen microbubbles for 125I brachytherapy. A modified emulsion freeze‐drying method is developed to prepare microbubbles that can be lyophilized for storage and easily reconstituted in situ before administration. The filling gas of the microbubbles is modified by the addition of sulfur hexafluoride to oxygen such that the obtained O2/SF6 microbubbles (OS MBs) achieve a much longer half‐life (>3×) than that of oxygen microbubbles. The OS MBs are tested in nasopharyngeal carcinoma (CNE2) tumor‐bearing mice and oxygen delivery by the OS MBs induced by ultrasound irradiation relieve hypoxia instantly. The post‐treatment results of brachytherapy combined with the ultrasound‐triggered OS MBs show a greatly improved therapeutic efficacy compared with brachytherapy alone, illustrating ultrasound‐mediated oxygen delivery with the developed OS MBs as a promising strategy to improve the therapeutic outcome of 125I brachytherapy in hypoxic tumors., Tumor‐specific ultrasound‐activated oxygen microbubbles are developed to sensitize hypoxic tumor cells for 125I brachytherapy. The microbubbles, lyophilized for storage and easily reconstituted in situ before administration, have much better stability by the addition of sulfur hexafluoride into oxygen. Ultrasound‐mediated oxygen delivery with the microbubbles demonstrate a greatly improved therapeutic outcome of 125I brachytherapy in hypoxic tumors.

The purpose of this study was to evaluate the diagnostic accuracy and efficiency of categories 4 and 5 of the second edition of the Breast Imaging Reporting and Data System (BI-RADS) ultrasound (US) lexicon in diagnosing breast lesions. In our retrospective study, 579 lesions in 544 patients were assessed by US as the preliminary diagnosis and classified in subcategories 4a-4c and category 5 based on the second edition of the BI-RADS US lexicon with some obvious changes, such as the redefined margin, new calcification type, associated features and some special cases. Inter-observer agreement was determined. Ultrasound results were compared with the pathologic results for confirmation. Positive predictive values (PPVs) of subcategories 4a-4c were compared with theoretical values using the χ(2) test; the binomial test was used for category 5 lesions. Of the 579 lesions, 212 were confirmed as benign (36.61%), and the remaining 367 lesions were confirmed as borderline/malignant (63.39%). Inter-observer agreement was moderate for subcategories 4a-4c (κ = 0.52), moderate for subcategories 4a-4c and category 5 (κ = 0.56) and substantial for categories 4 and 5 (κ = 0.67). The PPVs for subcategories 4a-4c were 23.74%, 70.67% and 81.25%, respectively. In addition, the total PPV for category 4 was 46.92% (183/390), and the total PPV for category 5 was 97.35% (184/189). Statistical results revealed that the PPVs of subcategories 4a and 4b differed significantly from the theoretical values (p 0.05); the PPVs of subcategory 4c and category 5 were significantly correlated with the theoretical PPVs (p 0.05). In conclusion, subcategories 4a and 4b have lower diagnostic efficiency than subcategory 4c and category 5. Inter-observer agreement for subcategories 4a-4c remains to be improved. The most common features of subcategories 4a-4c differ, but overlap. It is recommended that inexperienced doctors in primary hospitals not classify lesions into subcategories in clinical practice.

Background: Invasive mediastinal lymph node staging is essential to resectable non-small cell lung cancer (NSCLC) patients. This retrospective study aimed to compare the diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) against cervical mediastinoscopy (CMS) in radiologically enlarged mediastinal lymph nodes.> Methods: Retrospective data were collected from January 2009 to March 2016. Suspected lung cancer patients with enlarged mediastinal lymph nodes (short axis ≥10 mm), underwent EBUS-TBNA or CMS for invasive mediastinal staging were enrolled. Substantial radical resection with systematic mediastinal lymphadenectomy (SML) was used as the gold standard. Mediastinal lymph nodes diagnostic comparison and N staging analysis were conducted in this study. Results: Fifty-five patients received EBUS-TBNA and one hundred and ninety patients received CMS were included into the analysis set. In per case analysis, no significant differences were seen between EBUS-TBNA and CMS in N staging accuracy (83.6% vs. 78.9%, P=0.444). EBUS-TBNA had significantly higher sensitivity than CMS (82.4% vs. 47.6%, P=0.039) in malignant lymph nodes diagnosis. In lymph nodes diagnosis comparison (station #2, #4 and #7), both EBUS-TBNA and CMS showed high diagnostic sensitivity, specificity and accuracy (82.4% vs. 94.7%, P=0.130; 97.4% vs. 100%, P=0.173; 98.8% vs. 92.9%, P=0.025; respectively), CMS had slightly better diagnostic accuracy rate than EBUS-TBNA. Malignant lymph nodes had longer short axis than benign nodes (mean 14.2 vs. 6.5 mm, P

e20066 Background: Invasive mediastinal lymph node staging is essential for resectable lung cancers. This retrospective study compares the diagnosis yield of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and cervical mediastinoscopy (CMS). Methods: Consecutive patients were analyzed from Jan 2009 to March 2016. Only pathologically confirmed results were accepted, and systematic mediastinal lymphadenectomy (SML) were used as the standard. The disease diagnosis and N stagingaccuracywere compared in this study. Results: 103 EBUS-TBNA patients and 232 CMS patients were included, 1014 mediastinal lymph nodes were biopsied in lung cancer patients. In per case analysis, there was no significant differences between EBUS-TBNA and CMS in disease diagnosis accuracy (89.4% vs. 81.2%, P = 0.097), and no significant difference in N staging accuracy (75.0% vs. 78.3%, P = 0.629). However, EBUS-TBNA had significantly higher disease diagnosis sensitivity than CMS (82.4% vs. 47.6%, P < 0.001). In lymph nodes diagnosis comparison (station #2, #4 and #7), both EBUS-TBNA and CMS showed very high accuracy, sensitivity, and specificity (94.7% vs. 99.6%, 88.6% vs. 94.8%, 97.2% vs. 100%), however CMS were slightly better. Positive lymph nodes had longer major and minor axes than negative nodes, and the positive rateswere as high as 59.2% in lymph nodes with a minor axis measuring ≥21mm. More complications and injuries were found in patients receiving CMS. Conclusions: For clinically suspected lung cancers, both EBUS-TBNA and CMS are favorable options for invasive mediastinal staging. EBUS-TBNA may be preferred for its higher disease diagnosis sensitivity and fewer complications.