Development and validation of an interpretable model integrating multimodal information for improving ovarian cancer diagnosis.

Ovarian cancer, a group of heterogeneous diseases, presents with extensive characteristics with the highest mortality among gynecological malignancies. Accurate and early diagnosis of ovarian cancer is of great significance. Here, we present OvcaFinder, an interpretable model constructed from ultrasound images-based deep learning (DL) predictions, Ovarian-Adnexal Reporting and Data System scores from radiologists, and routine clinical variables. OvcaFinder outperforms the clinical model and the DL model with area under the curves (AUCs) of 0.978, and 0.947 in the internal and external test datasets, respectively. OvcaFinder assistance led to improved AUCs of radiologists and inter-reader agreement. The average AUCs were improved from 0.927 to 0.977 and from 0.904 to 0.941, and the false positive rates were decreased by 13.4% and 8.3% in the internal and external test datasets, respectively. This highlights the potential of OvcaFinder to improve the diagnostic accuracy, and consistency of radiologists in identifying ovarian cancer.

Development and validation of ultrasound-based radiomics model to predict germline BRCA mutations in patients with breast cancer.

BACKGROUND: Identifying breast cancer (BC) patients with germline breast cancer susceptibility gene (gBRCA) mutation is important. The current criteria for germline testing for BC remain controversial. This study aimed to develop a nomogram incorporating ultrasound radiomic features and clinicopathological factors to predict gBRCA mutations in patients with BC. MATERIALS AND METHODS: In this retrospective study, 497 women with BC who underwent gBRCA genetic testing from March 2013 to May 2022 were included, including 348 for training (84 with and 264 without a gBRCA mutation) and 149 for validation(36 patients with and 113 without a gBRCA mutation). Factors associated with gBRCA mutations were identified to establish a clinicopathological model. Radiomics features were extracted from the intratumoral and peritumoral regions (3 mm and 5 mm) of each image. The least absolute shrinkage and selection operator regression algorithm was used to select the features and logistic regression analysis was used to construct three imaging models. Finally, a nomogram that combined clinicopathological and radiomics features was developed. The models were evaluated based on the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness. RESULTS: Age at diagnosis, family history of BC, personal history of other BRCA-related cancers, and human epidermal growth factor receptor 2 status were independent predictors of the clinicopathological model. The AUC of the imaging radiomics model combining intratumoral and peritumoral 3 mm areas in the validation set was 0.783 (95% confidence interval [CI]: 0.702-0.862), which showed the best performance among three imaging models. The nomogram yielded better performance than the clinicopathological model in validation sets (AUC: 0.824 [0.755-0.894] versus 0.659 [0.563-0.755], p = 0.007). CONCLUSION: The nomogram based on ultrasound images and clinicopathological factors performs well in predicting gBRCA mutations in BC patients and may help to improve clinical decisions about genetic testing.

Clinical sonochemotherapy of inoperable pancreatic cancer using diagnostic ultrasound and microbubbles: a multicentre, open-label, randomised, controlled trial.

OBJECTIVES: Sonochemotherapy, which uses microbubble (MB)-assisted ultrasound (US) to deliver chemotherapeutic agents, has the potential to enhance tumour chemotherapy. The combination of US and MB has been demonstrated to prolong the survival of patients with pancreatic cancer. This phase 2 clinical trial aimed to determine the clinical efficacy and safety of sonochemotherapy for inoperable pancreatic ductal adenocarcinoma by using US and MB. METHODS: Eighty-two patients with stage III or IV pancreatic cancer were recruited from July 2018 to March 2021 and followed up until September 2022. US treatment was performed with a modified diagnostic US scanner for 30 min after chemotherapeutic infusion. The primary endpoint was overall survival (OS), and the secondary endpoints were Eastern Cooperative Oncology Group (ECOG) status < 2, progression-free survival (PFS), disease control rate (DCR), and adverse events. RESULTS: Seventy-eight patients were randomly allocated (40 to chemotherapy and 38 to sonochemotherapy). The median OS was longer with sonochemotherapy than with chemotherapy (9.10 vs. 6.10 months; p = 0.037). The median PFS with sonochemotherapy was 5.50 months, compared with 3.50 months (p = 0.080) for chemotherapy. The time of ECOG status < 2 was longer with sonochemotherapy (7.20 months) than with chemotherapy (5.00 months; p = 0.029). The DCR was 73.68% for sonochemotherapy compared with 42.50% for the control (p = 0.005). The incidence of overall adverse events was balanced between the two groups. CONCLUSIONS: The use of sonochemotherapy can extend the survival and well-being time of stage III or IV pancreatic cancer patients without any increase in serious adverse events. TRIAL REGISTRATION: ChineseClinicalTrials.gov ChiCTR2100044721 CLINICAL RELEVANCE STATEMENT: This multicentre, randomised, controlled trial has proven that sonochemotherapy, namely, the combination of diagnostic ultrasound, microbubbles, and chemotherapy, could extend the overall survival of patients with end-stage pancreatic ductal adenocarcinoma from 6.10 to 9.10 months without increasing any serious adverse events. KEY POINTS: • This is the first multicentre, randomised, controlled trial of sonochemotherapy for clinical pancreatic cancer treatment using ultrasound and a commercial ultrasound contrast agent. • Sonochemotherapy extended the median overall survival from 6.10 (chemotherapy alone) to 9.10 months. • The disease control rate increased from 42.50% with chemotherapy to 73.68% with sonochemotherapy.

Deep Learning-assisted Diagnosis of Breast Lesions on US Images: A Multivendor, Multicenter Study.

Purpose: To evaluate the diagnostic performance of a deep learning (DL) model for breast US across four hospitals and assess its value to readers with different levels of experience. Materials and Methods: In this retrospective study, a dual attention-based convolutional neural network was built and validated to discriminate malignant tumors from benign tumors by using B-mode and color Doppler US images (n = 45 909, March 2011-August 2018), acquired with 42 types of US machines, of 9895 pathologic analysis-confirmed breast lesions in 8797 patients (27 men and 8770 women; mean age, 47 years ± 12 [SD]). With and without assistance from the DL model, three novice readers with less than 5 years of US experience and two experienced readers with 8 and 18 years of US experience, respectively, interpreted 1024 randomly selected lesions. Differences in the areas under the receiver operating characteristic curves (AUCs) were tested using the DeLong test. Results: The DL model using both B-mode and color Doppler US images demonstrated expert-level performance at the lesion level, with an AUC of 0.94 (95% CI: 0.92, 0.95) for the internal set. In external datasets, the AUCs were 0.92 (95% CI: 0.90, 0.94) for hospital 1, 0.91 (95% CI: 0.89, 0.94) for hospital 2, and 0.96 (95% CI: 0.94, 0.98) for hospital 3. DL assistance led to improved AUCs (P < .001) for one experienced and three novice radiologists and improved interobserver agreement. The average false-positive rate was reduced by 7.6% (P = .08). Conclusion: The DL model may help radiologists, especially novice readers, improve accuracy and interobserver agreement of breast tumor diagnosis using US.Keywords: Ultrasound, Breast, Diagnosis, Breast Cancer, Deep Learning, Ultrasonography Supplemental material is available for this article. © RSNA, 2023.

Ultrasound-guided core needle biopsy for accessing laryngeal masses with unsatisfactory laryngoscopy and biopsy results.

BACKGROUND: Laryngoscopy and biopsy is the standard techniques to sample and diagnose laryngeal neoplasms, but not all patients with laryngeal neoplasm are eligible for biopsy via laryngoscopy (e.g., submucosal neoplasms). PURPOSE: This study was conducted to evaluate the feasibility and diagnostic yield of ultrasound-guided core needle biopsy (US-CNB) for submucosal laryngeal neoplasms with unsatisfactory laryngoscopy and biopsy results. METHODS: We retrospectively reviewed the medical records of 24 patients with unsatisfactory laryngoscopy and biopsy results who were referred to our center for US-CNB from January 2017 to November 2021. For all enrolled patients, we assessed consistency between the laryngoscopic biopsy, US-CNB, and final results. The final results were determined from the surgical biopsy results or clinical follow-up information (at least 3 month). Differences between biopsy techniques were compared using the Fisher's exact test. A P value less than 0.05 indicated statistical significance. RESULTS: Twenty-four patients (median [range] age: 60.6 [41-76] years, 20 men) were included in our study. Among the 24 patients, 12 were eligible for laryngoscopic biopsy. In total, 24 patients underwent 26 US-CNB. Two patients underwent a repeat US-CNB for conformation of a benign histological result or due to inadequate specimen collection. The results of laryngoscopic biopsy and US-CNB were compared with the final result. The overall accuracy of US-CNB for differentiating benign from malignant lesions was 95.8 % (23/24), and this procedure had a sensitivity, specificity, positive predictive value, and negative predictive value of 95.2 %, 100 %, 100 %, and 75 %, respectively. The results of US-CNB are significantly better than those of laryngoscopic biopsy. CONCLUSIONS: US-CNB is a safe, effective, and feasible technique for investigating suspicious submucosal laryngeal neoplasms and can serve as a complementary method for early and timely diagnosis of those neoplasms.

Benefit of [18F] FDG PET/CT in the diagnosis and salvage treatment of recurrent nasopharyngeal carcinoma.

PURPOSE: To compare PET/CT, MRI and ultrasonography in detecting recurrence of nasopharyngeal carcinoma and identify their benefit in staging, contouring and overall survival (OS). METHODS: Cohort A included 1453 patients with or without histopathology-confirmed local recurrence, while cohort B consisted of 316 patients with 606 histopathology-confirmed lymph nodes to compare the sensitivities and specificities of PET/CT, MRI and ultrasonography using McNemar test. Cohorts C and D consisted of 273 patients from cohort A and 267 patients from cohort B, respectively, to compare the distribution of PET/CT-based and MRI-based rT-stage and rN-stage and the accuracy of rN-stage using McNemar test. Cohort E included 30 random patients from cohort A to evaluate the changes in contouring with or without PET/CT by related-samples T test or Wilcoxon rank test. The OS of 61 rT3-4N0M0 patients staged by PET/CT plus MRI (cohort F) and 67 MRI-staged rT3-4N0M0 patients (cohort G) who underwent similar salvage treatment were compared by log-rank test and Cox regression. RESULTS: PET/CT had similar specificity to MRI but higher sensitivity (93.9% vs. 79.3%, P < 0.001) in detecting local recurrence. PET/CT, MRI and ultrasonography had comparable specificities, but PET/CT had greater sensitivity than MRI (90.9% vs. 67.6%, P < 0.001) and similar sensitivity to ultrasonography in diagnosing lymph nodes. According to PET/CT, more patients were staged rT3-4 (82.8% vs. 68.1%, P < 0.001) or rN + (89.9% vs. 69.3%, P < 0.001), and the rN-stage was more accurate (90.6% vs. 73.8%, P < 0.001). Accordingly, the contours of local recurrence were more precise (median Dice similarity coefficient 0.41 vs. 0.62, P < 0.001) when aided by PET/CT plus MRI. Patients staged by PET/CT plus MRI had a higher 3-year OS than patients staged by MRI alone (85.5% vs. 60.4%, P = 0.006; adjusted HR = 0.34, P = 0.005). CONCLUSION: PET/CT more accurately detected and staged recurrence of nasopharyngeal carcinoma and accordingly complemented MRI, providing benefit in contouring and OS.

A Robust Oxygen Microbubble Radiosensitizer for Iodine-125 Brachytherapy.

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.

Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma.

BACKGROUND: Anti-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. METHODS: Patients 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. RESULTS: Among 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). CONCLUSIONS: Anti-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.

Laminin γ2-mediating T cell exclusion attenuates response to anti-PD-1 therapy.

PD-1/PD-L1 blockade therapies provide notable clinical benefits for patients with advanced cancers, but the factors influencing the effectiveness of the treatment remain incompletely cataloged. Here, the up-regulation of laminin γ2 (Ln-γ2) predicted the attenuated efficacy of anti-PD-1 drugs and was associated with unfavorable outcomes in patients with lung cancer or esophageal cancer. Furthermore, Ln-γ2 was transcriptionally activated by transforming growth factor-ß1 (TGF-ß1) secreted from cancer-associated fibroblasts via JNK/AP1 signaling, which blocked T cell infiltration into the tumor nests by altering the expression of T cell receptors. Coadministration of the TGF-ß receptor inhibitor galunisertib and chemotherapy drugs provoked vigorous antitumor activity of anti-PD-1 therapy in mouse tumor models. Therefore, Ln-γ2 may represent a useful biomarker to optimize clinical decisions and predict the response of cancer patients to treatment with anti-PD-1 drugs.

Transoral Robotic Retropharyngeal Lymph Node Dissection in Nasopharyngeal Carcinoma With Retropharyngeal Lymph Node Recurrence.

OBJECTIVES: Nasopharyngeal carcinoma (NPC) patients with retropharyngeal lymph node (RPLN) recurrence typically undergo reirradiation and experience severe radiotoxicity. Salvage open surgery is challenging because gaining access to the retropharyngeal space is complex and risky. Thus, only several centers can perform this procedure, and complications are common. We applied transoral robotic surgery RPLN dissection (TORS-RPLND) to NPC patients with RPLN recurrence to address the problem with open surgery. MATERIALS AND METHODS: From March 2017 to October 2020, 10 NPC patients with RPLN recurrence underwent TORS-RPLND using the da Vinci Si/Xi Surgical System. We applied the balloon occlusion test to protect the internal carotid artery, induction chemotherapy to shrink large tumors preoperatively, and ultrasound positioning to effectively locate unrecognizable RPLNs during surgery. Clinical characteristics, complications, and survival outcome data were retrospectively collected. RESULTS: Of 10 patients, 8 underwent en bloc resection via TORS-RPLND, and the remaining 2 patients were converted to open surgery because we failed to identify the RPLN during TORS. After introducing intraoperative ultrasound positioning, no such failure occurred. The mean operative time and intraoperative blood loss were 297 ± 120 min and 40 ± 43 ml, respectively. All surgical margins were negative. TORS-related complications were mild, and the most severe one was grade 3 dysphagia in one patient who underwent conversion to open surgery (10%). With a median follow-up of 19 months, only 1 (10%) patient developed cervical recurrence. CONCLUSIONS: TORS-RPLND is feasible, safe, and effective in the treatment of NPC patients with RPLN recurrence, especially with the help of intraoperative ultrasound positioning. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1895-E1902, 2021.

Risk model and risk stratification to preoperatively predict central lymph node metastasis in papillary thyroid carcinoma.

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.

Clinical pharmacokinetics and drug exposure-toxicity correlation study of docetaxel based chemotherapy in Chinese head and neck cancer patients.

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.

Development of prognostic index based on autophagy-related genes analysis in breast cancer.

BACKGROUND: Autophagy is a self-digesting process that can satisfy the metabolic needs of cells, and is closely related to development of cancer. However, the effect of autophagy-related genes (ARGs) on the prognosis of breast cancer remains unclear. RESULTS: We first found that 27 ARGs were significantly associated with overall survival in breast cancer. The prognosis-related ARGs signature established using the Cox regression model consists of 12 ARGs that can be divided patients into high-risk and low-risk groups. The overall survival of patients with high-risk scores (HR 3.652, 2.410-5.533; P < 0.001) was shorter than patients with low-risk scores. The area under the receiver operating characteristic (ROC) curve for 1-year, 3-year, and 5-year survival rates were 0.739, 0.727, and 0.742, respectively. CONCLUSION: The12-ARGs marker can predict the prognosis of breast cancer and thus help individualized treatment of patients at different risks. METHODS: Based on the TCGA dataset, we integrated the expression profiles of ARGs in 1,039 breast cancer patients. Differentially expressed ARGs and survival-related ARGs were evaluated by computational difference algorithm and COX regression analysis. In addition, we also explored the mutations in these ARGs. A new prognostic indicator based on ARGs was developed using multivariate COX analysis.

Reducing Unnecessary Biopsy of Breast Lesions: Preliminary Results with Combination of Strain and Shear-Wave Elastography.

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.

pH-Responsive Oxygen Nanobubbles for Spontaneous Oxygen Delivery in Hypoxic Tumors.

Tumor hypoxia is a significant factor leading to the resistance of tumors to treatment, especially for photodynamic therapy and radiotherapy where oxygen is needed to kill cancer cells. Oxygen delivery agents such as oxygen-saturated perfluorocarbon nanoemulsions and lipid oxygen microbubbles have been employed to supply oxygen to hypoxic tumors with ultrasound activation. Such oxygen delivery systems are still associated with several drawbacks, including premature oxygen release and the dependence of external stimuli. To address these limitations, we developed oxygen nanobubbles that were enclosed by the acetalated dextran polymer shells for spontaneous oxygeneration in response to a minor pH drop in the tumor microenvironment. The acetalated dextran polymer shell serves as a robust barrier against gas dissolution in the circulating blood to retain the majority of the oxygen payload, and its pH-responsive property enables an abrupt burst release of oxygen in the mild acidic tumor microenvironment. The acetalated dextran oxygen nanobubbles exhibited excellent stability and biocompatibility. In vitro and in vivo experiments were conducted to investigate the pH-responsive oxygen release. The external stimuli-free supply of oxygen by the acetalated dextran oxygen nanobubbles was evaluated on CNE2 tumor-bearing mice, and the intratumoral oxygen level increased by 6-fold after the administration of the oxygen nanobubbles, manifesting that our pH-responsive oxygen nanobubbles hold great potential as a potent oxygen delivery agent to overcome the hypoxia-induced resistance.

The analysis of pharmacokinetic and pharmacogenomic impact on gefitinib efficacy in advanced non-small cell lung cancer patients: results from a prospective cohort study.

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 (Ctrough) at steady state. Thirteen SNPs were genotyped using the Sequenom Massarray system. Ctrough 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 Ctrough 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). Ctrough 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 Ctrough 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.

Endobronchial ultrasound-guided transbronchial needle aspiration and cervical mediastinoscopy for mediastinal staging of non-small cell lung cancer: a retrospective comparison study.

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<0.001). In lymph nodes with a short axis ≥15 mm, the malignant rate was 48.8%. More complications and injuries were found in patients receiving CMS. CONCLUSIONS: For clinically suspected lung cancers with enlarged mediastinal lymph nodes, both EBUS-TBNA and CMS are favorable invasive mediastinal staging options. EBUS-TBNA may be preferred for its higher malignant diagnostic sensitivity and fewer complications.

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.

Ultrasonic RF time series for early assessment of the tumor response to chemotherapy.

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.