Phase II study of apatinib plus exemestane in estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer.

PURPOSE: Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR)-2. This study was conducted to assess the efficacy and safety of apatinib combined with exemestane in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). METHODS: This single-center, single-arm phase II study enrolled patients with ER+/HER2- MBC progressed on previous letrozole or anastrozole. Stratified analysis was performed according to the number of chemotherapy regimens for metastatic disease. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS) and toxicity. Patients received apatinib at a starting dose of 500 mg/d and exemestane 25 mg/d on days 1-28 of each 4-week cycle. RESULTS: Thirty patients were enrolled with median four prior anticancer therapies. Eighty percent of patients received chemotherapy for metastatic disease. The median PFS (mPFS) and OS were 5.6 (95%CI: 4.3-6.9) months and 15.7 (95% CI: 9.7-21.7) months, respectively. The ORR, DCR, and CBR were 21.4%, 71.4%, and 46.4%, respectively. Patients with 0-1 line chemotherapy for MBC showed a slightly longer mPFS compared to those with ≥2 lines chemotherapy (mPFS: 6.4 months vs 4.8 months, P = .090). Most of the AEs were grade 1/2. One patient (3.3%) who suffered bone marrow metastases experienced grade 4 thrombocytopenia, and 14 experienced grade 3 AEs. Fifty percent of patients were given reduced dose for apatinib. CONCLUSIONS: Apatinib plus exemestane exhibited objective efficacy in patients with ER+/HER2- MBC who have failed multiple lines of treatment. The AEs of apatinib required close monitoring and most of patients were well tolerated.

Reference Range of CT Value in NC-CBBCT Based on Female Breast Structure.

BACKGROUND: As a new high-resolution three-dimensional CT imaging technology, the essential reference range of CT values in Cone-beam breast computed tomography (CBBCT) has not been established to date. PURPOSE: To determine the reference range of computed tomography (CT) values in CBBCT for clinical breast examination. MATERIALS AND METHODS: In total, 913 cases (1167 lateral) were subject to CBBCT. CT values of the glandular tissue, fat and different quadrants and different distances of CBBCT images were analyzed. The nipple and muscle were also evaluated. RESULTS: A total of 672 lateral breasts were included in the normal group for investigation. The reference range of the absolute CT value of the chest wall muscle is -136.68~43.36 HU. The reference range of the absolute CT value of the nipple is 176.39~334.02 HU. The reference range of the absolute CT value of fat is -190.4~-63.67HU, and of glandular tissue is -12.2~199.07HU. CONCLUSION: Our results firstly established the baseline CT values of Non-contrast CBBCT in female breasts, which will benefit cancer screening and lesion locating. The closer the normal breast fat and glandular tissue is to the nipple, the greater the CT value. The older the age, the lower the density. The CT values of fat are unstable in a distance of less than 5 cm, and the CT values of glandular tissues are relatively stable. The difference between the upper and lower quadrants is significant in the same lateral breast and the same section.

Efficacy and safety of continuous infusion of Rh-endostatin combined with platinum-based chemotherapy for advanced triple-negative breast cancer.

BACKGROUND: This study aimed to prospectively evaluate and investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) combined with platinum-based regimens for advanced triple-negative breast cancer (TNBC) patients. METHODS: This study was a prospective, single-arm, single-center, open-label trial. From January 2017 to August 2019, 21 women aged 18-70 years with histologically confirmed advanced TNBC were enrolled. Rh-endostatin at 30 mg/d was continuously pumped for 7 days and used synchronously with the chemotherapy cycle. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), and toxicity. RESULTS: The median PFS (mPFS) was 8.8 months (95% CI: 7.2-10.4 months), and the median OS was 13.3 months (95% CI: 11.6-15.0 months). The ORR and CBR for the whole population were 47.6% and 52.4%, respectively. Patients sensitive to anthracycline and taxane drugs showed a significantly longer mPFS compared to those who were resistant to anthracycline and taxane drugs (mPFS: 8.8 vs. 5.3 months, P=0.038). For patients who received first- and second-line therapy or beyond, the mPFS was 8.8 and 5.3 months, respectively, with a significant difference (P=0.025). No statistically significant differences in the mPFS between pemetrexed combined with platinum and gemcitabine/taxanes combined with platinum were observed. The most common grade 3-4 hematologic toxicities were neutropenia (14.3%) and anemia (14.3%). One patient (4.8%) experienced febrile neutropenia. No grade 3-4 non-hematologic toxicities were observed, and no treatment-related deaths were reported in this study. CONCLUSIONS: This study revealed that Rh-endostatin might enhance the antitumor effects of platinum-based chemotherapy for advanced TNBC patients with well-tolerated toxicities, which may provide a new basis and novel idea for the treatment of TNBC. However, further investigations and validation of its long-term efficacy and toxicity are warranted in the future.

The cone-beam breast computed tomography characteristics of breast non-mass enhancement lesions.

BACKGROUND: Cone-beam computed tomography (CBBCT) of the breast is emerging as a way of improving breast cancer diagnostic yield. PURPOSE: To find characteristics of non-mass enhancement (NME) lesions on breast CBBCT and to identify the characteristics that distinguish malignant and benign lesions. MATERIAL AND METHODS: Breast CBBCT images of 84 NME lesions were analyzed. Internal enhancement distribution and patterns, calcification distribution and suspicious morphology, and ΔHU enhancement values were compared between post-contrast and pre-contrast malignant and benign lesions. Univariate analyses were applied to find the strongest indicators of malignancy, and logistic regression analysis was used to develop a fitting equation for the combined diagnostic model. RESULTS: In the 84 NME lesions, the indicators of malignancy were as follows: segmental enhancement distribution (P = 0.011, 53.62% sensitivity, 86.67% specificity, 94.87% positive predictive value [PPV], and 28.89% negative predictive value [NPV]), clumped internal enhancement patterns (P = 0.017, 50.72% sensitivity, 86.67% specificity, 94.59% PPV, and 27.66% NPV), ΔHU ≥ 93.57 Hounsfield units (HU) (P = 0.004, 66.67% sensitivity, 73.33% specificity, 92.00% PPV, and 32.35% NPV), and NME lesions with calcification (P = 0.002, 36.23% sensitivity, 20.00% specificity, 82.14% PPV, and 67.57% NPV). The fitting equation for the combined diagnostic model was as follows: Logit (P) = -0.579 +1.318 × enhancement distribution + 1.000 × internal enhancement patterns + 1.539 × ΔHU value + 1.641 ×NME type. CONCLUSION: Individual diagnostic criteria based on breast CBBCT characteristics (segmental enhancement distribution, clumped internal enhancement patterns, ΔHU values > 93.57 HU, and NME lesions with calcification) had high specificity and PPV; when combined, they had high sensitivity in predicting malignant NME lesions.

A three-gene signature based on tumour microenvironment predicts overall survival of osteosarcoma in adolescents and young adults.

Evidences shows that immune and stroma related genes in the tumour microenvironment (TME) play a key regulator in the prognosis of Osteosarcomas (OSs). The purpose of this study was to develop a TME-related risk model for assessing the prognosis of OSs. 82 OSs cases aged ≤25 years from TARGET were divided into two groups according to the immune/stromal scores that were analyzed by the Estimate algorithm. The differentially expressed genes (DEGs) between the two groups were analyzed and 122 DEGs were revealed. Finally, three genes (COCH, MYOM2 and PDE1B) with the minimum AIC value were derived from 122 DEGs by multivariate cox analysis. The three-gene risk model (3-GRM) could distinguish patients with high risk from the training (TARGET) and validation (GSE21257) cohort. Furthermore, a nomogram model included 3-GRM score and clinical features were developed, with the AUC values in predicting 1, 3 and 5-year survival were 0.971, 0.853 and 0.818, respectively. In addition, in the high 3-GRM score group, the enrichment degrees of infiltrating immune cells were significantly lower and immune-related pathways were markedly suppressed. In summary, this model may be used as a marker to predict survival for OSs patients in adolescent and young adults.

Mannan-modified adenovirus targeting TERT and VEGFR-2: A universal tumour vaccine.

Antigen-presenting cells including dendritic cells (DCs) express mannan receptors (MR) on their surface, which can be exploited in cancer therapy by designing immune-stimulatory viruses coated with mannan-modified capsids that then bind to DCs and initiate a potent immune response. Although the combination of anti-angiogenesis and cancer immunotherapy agents has a synergistic antitumor effect, more effective strategies for delivering such combinations are still required. Here we report the design and application of mannan-modified adenovirus that expresses both telomerase reverse transcriptase (TERT) and vascular endothelial growth factor receptor-2 (VEGFR-2). Cytotoxic T lymphocytes that are reactive to TERT and VEGFR-2 are capable of mounting an anti-tumour response in murine breast and colon tumour models and in a lung metastatic model. Compared with mannan-modified TERT adenovirus vaccine or mannan-modified VEGFR-2 adenovirus vaccine alone, the combined vaccine showed remarkably synergistic anti-tumour immunity in these models. Both TERT- and VEGFR-2-specific cytotoxic T lymphocytes (CTL) were identified in an in vitro cytotoxicity assay, and the CTL activity against tumour cells was significantly elevated in the combined vaccine group. Furthermore, CTL-mediated toxicity was blocked by anti-CD8 monoclonal antibodies. Thus, the combined mannan-modified TERT and VEGFR-2 adenovirus confers potent anti-tumour immunity by targeting both tumour cells and intratumoural angiogenesis.

The willingness and actual situation of Chinese cancer patients and their family members participating in medical decision-making.

OBJECTIVE: In China, not only patients and physicians are involved in medical decision-making (MDM) but also the patients' family members. The objective is to investigate the willingness and actual situation of cancer patients and their family members participating in the MDM process. METHODS: In this cross-sectional study, questionnaires were administered to 247 pairs of cancer inpatients and their relatives. Information regarding participants' willingness and actual experience during the decision-making process was documented. Eligible participants were cancer inpatients or their relatives, 18 years of age or older, and informed of the cancer diagnosis. All the patients should have received chemotherapy. RESULTS: The effective response rate was 72.9% (180/247). Over half of the patients (53.3%) and family members (57.8%) were willing to be part of the MDM process. In contrast, only 35.0% of patients and 46.1% of family members actually experienced this process (p = 0.001 and p = 0.011, respectively). Fewer family members (42.2%) than patients (53.3%) believed that patients should be involved in the MDM process (p < 0.001). Patients who were the head of their family (odds ratio 2.577, 95% CI 1.198-5.556, p = 0.015) experienced more involvement in MDM. CONCLUSIONS: Although more than half of Chinese cancer patients and family members wanted to be part of MDM, the actual participation was below their expectation. Majority of family members do not want the patients to be involved in the process of MDM.

Combined histological and hematological assessment of iron-induced organ damage in a gerbil model of iron overload.

BACKGROUND: Previous studies with gerbil models have suggested that excessive iron exposure causes cardiomyopathy and hepatic injury, but pathological analysis was not comprehensive, preventing a detailed understanding of how the metal induces this damage. METHODS AND RESULTS: Gerbils received single intraperitoneal injections of iron dextran (200 mg/kg) or saline and were then analyzed comprehensively for hematological and histological signs of organ damage. These tests included hematology parameters and determination of liver iron concentration, malondialdehyde levels and glutathione peroxidase activity; examination of heart and liver tissue stained with hematoxylin and eosin, Prussian-blue and Masson stain; and electron microscopy analysis of heart and liver ultrastructure. Iron-overloaded animals showed significantly different hematology parameters and significantly higher liver iron concentrations than saline-injected animals, as well as significantly higher malondialdehyde levels and significantly lower glutathione peroxidase activity. Histology analyses showed cellular damage, iron deposits, and both myocardial and liver fibrosis, while electron microscopy of heart and liver sections showed abundant iron deposition lysosomes, and disordered and swollen mitochondria. All these pathological changes increased with exposure time. CONCLUSIONS: This comprehensive assessment of iron overload in a gerbil model suggests that excessive iron deposition induces extensive cellular damage, particularly fibrosis in heart and liver. This damage may be the direct result of iron-mediated lipid peroxide damage and of iron deposition that cause compression of myocardial and liver cells, as well as vascular occlusion.

Mannan-modified adenovirus encoding VEGFR-2 as a vaccine to induce anti-tumor immunity.

PURPOSE: Dendritic cell (DC) vaccines are a promising immunotherapeutic approach for treatment and prevention of cancer. While this methodology is widely accepted, it also has some limitations. Antigen-presenting cells including DCs express the mannan receptor (MR). The delivery of a mannan-modified tumor antigen to the MR has been demonstrated to be efficient. Vascular endothelial growth factor receptor-2 (VEGFR-2) is mainly responsible for angiogenesis and tumor growth. The goal of our study was to deliver VEGFR-2 to DCs by means of mannan-modified adenovirus. METHODS: VEGFR-2 recombinant adenovirus modified with oxidized mannan was constructed as a tumor vaccine to immunize mice in vivo. IFN-γ in mouse sera and spleen was detected by ELISA and ELISPOT. The killing activity of cytotoxic T lymphocyte (CTL) against VEGFR-2 was measured with a lactate dehydrogenase assay. Vessel densities in tumor tissues were detected by immunohistochemistry. Flow cytometry was used to test CD4(+) and CD8(+) T-cell counts in tumor tissues. RESULTS: The vaccine exhibited both protective and therapeutic efficacy in the inhibition of tumor growth and markedly prolonged survival in mice. Protection against metastasis was also observed. Furthermore, vaccination led to greater IFN-γ and VEGFR-2-specific CTLs. The specific immunity resulted in the suppression of angiogenesis and an increase in CD8(+) cells in tumor tissues. CONCLUSION: Oxidized mannan-modified adenovirus expressing VEGFR-2 could extraordinarily stimulate both protective and therapeutic immune response in a mice model. Our data suggest that the combination of cancer immunity and anti-angiogenesis via modified mannan is a promising strategy in tumor prophylaxis and therapy.

The diagnostic role of a short screening tool--the distress thermometer: a meta-analysis.

PURPOSE: The Distress Thermometer (the DT) is a commonly used screening tool to detect distress in cancer patients. This meta-analysis aims to examine the diagnostic role and the optimal cut-off score of the DT compared with various different reference standards. METHODS: We searched PubMed and Embase from 1997 to September 2013 for relevant studies. After extracting data, we estimated the pooled sensitivity, specificity, likelihood ratios, diagnostic odds ratios, and constructed summary receiver operating characteristics curves to determine the optimal cut-off score. RESULTS: Forty-two relevant studies and 14,808 patients were included in total. When we pooled all the results together, the DT showed a good balance between pooled sensitivity (0.81, 95% confidence intervals (CI) 0.79-0.82) and pooled specificity (0.72, 95% CI 0.71-0.72) at the cut-off score of 4. The value of area under the curve (AUC) is 0.8321. When the DT is compared with the HADS-Total, the cut-off score of 4 maximized the balance between the pooled sensitivity (0.82, 95% CI 0.80-0.84) and pooled specificity (0.73, 95% CI 0.72-0.74). The AUC is 0.8432. CONCLUSIONS: This meta-analysis suggests that the DT is a valid tool to detect potential distress in cancer patients. According to our results, 4 as the optimal cut-off, is recommended. Further studies are needed to be done to examine the accuracy and optimal cut-off score in different regions globally and different cancer subtypes to guide the use of the DT for different patients.

Measurement of distress and its alteration during treatment in patients with nasopharyngeal carcinoma.

BACKGROUND: We examined the criterion-related validity of the Distress Thermometer (DT) for screening distress in patients with nasopharyngeal carcinoma (NPC) and investigated prospectively how distress changes. METHODS: In the cross-sectional study, the DT was tested against the Hospital Anxiety and Depression Scale (HADS) in 295 patients with NPC. In the prospective study, 61 newly diagnosed patients with NPC completed the DT and HADS 6 times. RESULTS: Adopting HADS as the standard tool for screening distress, 31.5% of the patients with NPC had distress. A DT cutoff score ≥ 4 had best sensitivity (0.73) and specificity (0.85). In the prospective study, the proportion of patients with distress rose significantly during treatment. CONCLUSION: Receiver operating characteristic (ROC) findings provide initial support for the validity of the DT among patients with NPC. Nearly one third of patients with NPC exceeded cutoff values for distress in the cross-sectional study. In the prospective study, the level of distress increased significantly during concurrent chemoradiotherapy for patients with NPC.