Phase 0 Study of Vandetanib-Eluting Radiopaque Embolics as a Preoperative Embolization Treatment in Patients with Resectable Liver Malignancies

PurposeTo assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies.Materials and MethodsThe VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7–21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging.ResultsEight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441–404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%–100%). There were no significant changes in perfusion imaging parameters after TACE.ConclusionsBTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.     

TRIM59 通过结合 BCLAF1 调控人皮肤黑色素瘤 SK-MEL-2 细胞的恶 性生物学行为

目的：探究三结构域蛋白59（TRIM59）调控人皮肤黑色素瘤细胞SK-MEL-2增殖、细胞周期、凋亡及迁移侵袭的作用机制，及其与Bcl2相关转录因子1（BCLAF1)之间的关系。方法：qPCR和WB法检测人表皮黑色素细胞HEMn-LP、人皮肤黑色素瘤细胞SK-MEL-2、UACC903、A375及36例邢台市人民医院2019年2月至2021年7月收集的皮肤黑色素瘤组织中TRIM59的mRNA和蛋白表达，使用脂质体将si-con、si-TRIM59转染至SK-MEL-2细胞中，WB法检测干扰TRIM59表达对细胞中周期蛋白D1（CCND1）、细胞周期素依赖性激酶2（CDK2）、肿瘤抑制蛋白基因（TP53）和 BCLAF1 蛋白表达的影响，CCK-8法、流式细胞术、划痕愈合实验、Transwell实验检测对细胞的活性、凋亡、迁移和侵袭的影响，免疫共沉淀（Co-IP）实验检测对细胞中TRIM59蛋白与BCLAF1结合能力的影响。结果：与HEMn-LP细胞相比，SK-MEL-2、UACC903、A375细胞中TRIM59 mRNA和TRIM59、BCLAF1蛋白均呈高表达（均P<0.05），SK-MEL-2细胞中TRIM59表达水平最高。相较于si-con组和Normal组，沉默TRIM59后，SK-MEL-2细胞的活性显著降低，细胞周期阻滞于G2期，CCND1、CDK2的蛋白表达显著降低，TP53蛋白和细胞凋亡率均显著升高，划痕抑制率明显升高，迁移侵袭细胞数明显降低（均P<0.05）。免疫共沉淀实验结果显示，TRIM59与BCLAF1之间存在蛋白结合关系。TRIM59与 BCLAF1 在肿瘤组织中的表达呈显著的正相关（r=0.878，P<0.001）。结论：干扰TRIM59表达能够抑制人皮肤黑色素瘤SK-MEL-2细胞的增殖、迁移和侵袭而促进凋亡，抑制SK-MEL-2细胞的恶性生物学行为，其机制可能与TRIM59结合BCLAF1有关。     

Carcinosarcoma arising from high-grade serous carcinoma of the ovary without estrogen receptor,WT-1, and PAX8 immunoreactivity

ObjectiveWe encountered a case of high-grade serous carcinoma (HGSC) of the ovary which recurred as carcinosarcoma of the sigmoid colon. Tumor cells of both the primary carcinoma and the secondary carcinosarcoma were negative for estrogen receptor (ER), WT-1, and PAX8. It is well known that most ovarian carcinomas arising from the Müllerian duct are immunoreactive for these biologic parameters. To our knowledge, this is the first case report that provides the results of immunohistochemical analysis of WT-1 and PAX8 for a primary carcinoma and recurrent carcinosarcoma.Case reportA 61-year-old woman had an advanced right ovarian HGSC. After a primary debulking surgery (hysterectomy, bilateral salpingo-oophorectomy and omentectomy) and adjuvant chemotherapy, complete remission was achieved. However, four and a half years later, a tumor arising beside the sigmoid colon was detected. A tumorectomy was performed through combined partial resection of the ileum and sigmoid colon. Microscopically, the tumor was diagnosed as carcinosarcoma of the sigmoid colon, which had originated from HGSC of the ovary. Interestingly, the malignant cells of the primary carcinoma and epithelial components of the recurrent carcinosarcoma were negative for ER, WT-1, and PAX8. These immunohistochemical features were unusual. Three cycles of chemotherapy with the previously used regimen and three additional cycles of doxorubicin and ifosfamide combination chemotherapy were administered. Currently, 3 years after the final chemotherapy was administered, the patient remains healthy.ConclusionHGSC of the ovary can recur as carcinosarcoma. Tumor cells of the primary HGSC without ER, WT-1, and PAX8 expression may have dedifferentiated and recurred as carcinosarcoma.     

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low-grade ovarian carcinoma

Background

Advanced low-grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC.

Methods

Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium.

Results

Patients who had normal ER STP activity had a progression-free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS.

Conclusions

Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS.     

术前SCC与CYFRA21-1在肺鳞癌患者表达上调及临床意义

目的 分析术前SCC、CYFRA21-1与肺鳞癌临床病理特征、预后之间的关系。方法 收集2017年3月~2018年4月在云南省肿瘤医院确诊的肺鳞癌患者100例为观察组，确诊为肺良性肿瘤患者90名为肺良性肿瘤组、以及正常人群90名为健康人群组。通过电化学发光法对SCC、CYFRA21-1两种指标进行检测。检测SCC、CYFRA21-1含量，分析在肺鳞癌中表达的临床意义。结果 SCC、CYFRA21-1在肺鳞癌中比在肺良性肿瘤、健康人群中含量要高，差异有统计学意义（P＜0.001），并且敏感性均高于其他两组；男性患者的SCC、CYFRA21-1含量高于女性患者，差异具有统计学意义（P＜0.05）；SCC、CYFRA21-1含量在年龄≥60岁的含量高于＜60岁患者，差异无统计学意义（P＞0.05）；有吸烟史患者的SCC含量高于无吸烟史患者，差异无统计学意义（P＞0.05）。CYFRA21-1在吸烟史患者中高表达，差异有统计学意义（P＜0.05）；SCC、CYFRA21-1在有淋巴结转移、远处转移、肿瘤直径≥5 cm、病理分期为晚期时高表达，差异具有统计学意义（P＜0.05）；SCC、CYFRA21-1阳性患者OS、PFS比阴性患者短；SCC、CYFRA21-1两者之间呈正相关,相关系数（r）为0.630。结论 SCC、CYFRA21-1在肺鳞癌中表达上调；SCC、CYFRA21-1与性别之间存在某种内在联系；SCC、CYFRA21-1与肺鳞癌的TNM分期呈正相关；SCC、CYFRA21-1阳性患者OS、PFS比阴性患者短；SCC、CYFRA21-1两者之间呈正相关,相关系数（r）为0.630。     

Adopting global tools for the advancement of pharmacy practice and workforce in Saudi Arabia

BackgroundThe continuing expansion of the pharmacist’s role necessitates continuous evaluation of current practice to identify strategies for improvements. The International Pharmaceutical Federation (FIP) has developed tools to support stakeholders in identifying development needs and planning advancement strategies. The aim of this research was to utilise the FIP Global Competency Framework, version 2 (GbCF v2), and FIP Development Goals (DGs) to evaluate competencies related to pharmacy practice in Saudi Arabia, and to understand the strategies needed to develop and improve the current practice.MethodsThe study involved four phases. Phase 1 involved translation of the FIP GbCF v2 into the Arabic language. Phase 2 was a consensus panel validation to establish the initial relevance of the competencies to current practice. Phase 3 included a national survey distributed to all registered pharmacists in Saudi Arabia. The final phase was conducted through mapping ‘not relevant’ competencies to FIP DGs to identify priorities.ResultsThe translation phase yielded a bilingual framework that could be utilized by pharmacists in Saudi Arabia. The initial validation phase identified 61 behavioral statements (from 124 in the GbCF v2) as ‘highly relevant’ or ‘relevant’ to pharmacy practice. Findings from the national survey identified a list of ‘not relevant’ competencies that could highlight gaps in current practice. The final mapping phase generated a list of three FIP DG priorities: DG5 (competency development), DG8 (working with others) and DG11 (impact and outcomes).ConclusionThe study indicated that competencies in the GbCF v2 were relevant to pharmacists practicing in the country. However, some competencies were perceived as ‘not relevant’ to current practice and these highlighted gaps in the current practice that need attention. Mapping ‘not relevant’ competencies to FIP DGs should be used as a starting point towards developing strategies, systems, and protocols to advance pharmacy practice in Saudi Arabia.     

Communicating regulatory high-throughput sequencing data using BioCompute Objects

This project demonstrates the use of the IEEE 2791–2020 Standard (BioCompute Objects [BCO]) to enable the complete and concise communication of results from next generation sequencing (NGS) analysis. One arm of a clinical trial was replicated using synthetically generated data made to resemble real biological data and then two independent analyses were performed. The first simulated a pharmaceutical regulatory submission to the US Food and Drug Administration (FDA) including analysis of results and a BCO. The second simulated an FDA review that included an independent analysis of the submitted data. Of the 118 simulated patient samples generated, 117 (99.15%) were in agreement in the two analyses. This process exemplifies how a template BCO (tBCO), including a verification kit, facilitates transparency and reproducibility, thereby reinforcing confidence in the regulatory submission process.     

High Order Finite Difference Hermite WENO Fixed-Point Fast Sweeping Method for Static Hamilton-Jacobi Equations

In this paper, we combine the nonlinear HWENO reconstruction in [43] and the fixed-point iteration with Gauss-Seidel fast sweeping strategy, to solve the static Hamilton-Jacobi equations in a novel HWENO framework recently developed in [22]. The proposed HWENO frameworks enjoys several advantages. First, compared with the traditional HWENO framework, the proposed methods do not need to introduce additional auxiliary equations to update the derivatives of the unknown function $\phi$. They are now computed from the current value of $\phi$ and the previous spatial derivatives of $\phi$. This approach saves the computational storage and CPU time, which greatly improves the computational efficiency of the traditional HWENO scheme. In addition, compared with the traditional WENO method, reconstruction stencil of the HWENO methods becomes more compact, their boundary treatment is simpler, and the numerical errors are smaller on the same mesh. Second, the fixed-point fast sweeping method is used to update the numerical approximation. It is an explicit method and does not involve the inverse operation of nonlinear Hamiltonian, therefore any Hamilton-Jacobi equations with complex Hamiltonian can be solved easily. It also resolves some known issues, including that the iterative number is very sensitive to the parameter $ε$ used in the nonlinear weights, as observed in previous studies. Finally, to further reduce the computational cost, a hybrid strategy is also presented. Extensive numerical experiments are performed on two-dimensional problems, which demonstrate the good performance of the proposed fixed-point fast sweeping HWENO methods.