C21 steroidal glycosides from the root bark of Periploca sepium and their NO production inhibitory and cytotoxic activity.

A series of C21 steroidal glycosides were isolated from the root bark of Periploca sepium, including a new compound, perisepiumoside A1 (1), and six known compounds (2-7). Their structures were elucidated by analysis of HR-ESI-MS, and 1D and 2D NMR spectroscopic data. All these compounds were tested for their NO production inhibitory activity in LPS-stimulated RAW 264.7 cells. Results showed that these C21 steroidal glycosides could remarkably inhibit NO production, particularly 1 and 2 with IC50 values of 30.81 ± 0.18 µM and 44.39 ± 0.21 µM, respectively. In addition, the cytotoxicity of these compounds was measured on A549, MCF-7, and HeLa cancer cell lines. Among them, compounds 1 and 7 displayed cytotoxicity against the A549 cell line with IC50 values of 28.41 ± 0.12 µM and 39.06 ± 0.05 µM, respectively.

Best clinical management of tenosynovial giant cell tumour (TGCT): A consensus paper from the community of experts.

Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive, mesenchymal tumor arising from the joints, bursa and tendon sheaths. TGCT comprises a nodular- and a diffuse-type, with the former exhibiting mostly indolent course and the latter a locally aggressive behavior. Although usually not life-threatening, TGCT may cause chronic pain and adversely impact function and quality of life (QoL). CSFR1 inhibitors are effective with benefit on symptoms and QoL but are not available in most countries. The degree of uncertainty in selecting the most appropriate therapy and the lack of guidelines on the clinical management of TGCT make the adoption of new treatments inconsistent across the world, with suboptimal outcomes for patients. A global consensus meeting was organized in June 2022, involving experts from several disciplines and patient representatives from SPAGN to define the best evidence-based practice for the optimal approach to TGCT and generate the recommendations presented herein.

[Reflections on supervision strategies of new Tibetan drug registration].

Tibetan medicine is an essential part of Chinese medicine and has unique theoretical experience and therapeutic advantages. According to the development principle of inheriting the essence, sticking to the truth, and keeping innovative, the supervision department should give clear and reasonable guidance considering the characteristics of Tibetan medicine, establish a standard system for quality control, clinical verification and evaluation, and accelerate the research and commercialization of new drugs. In view of the needs of drug supply-side reform and the current situation of Tibetan medicine and new pharmaceutical research, we ponder and provide suggestions on the confusion faced by the current supervision of Tibetan drug registration, hoping to contribute to the supervision strategy of Tibetan drug registration and the high-quality development of Tibetan medicine industry.

Discovery of potential Q-marker of traditional Chinese medicine based on plant metabolomics and network pharmacology: Periplocae Cortex as an example.

BACKGROUND: Quality control exerted great importance on the clinical application of drugs for ensuring effectiveness and safety. Due to chemical complexity, diversity among different producing areas and harvest seasons, as well as unintentionally mixed with non-medicinal parts, the current quality standards of traditional Chinese medicine (TCM) still faced challenges in evaluating the overall chemical consistency. PURPOSE: We aimed to develop a new strategy to discover potential quality marker (Q-marker) of TCM by integrating plant metabolomics and network pharmacology, using Periplocae Cortex (GP, the dried root bark of Periploca sepium Bge.) as an example. METHODS: First, plant metabolomics analysis was performed by UPLC/Q-TOF MS in 89 batches of samples to discover chemical markers to distinguish medicinal parts (GP) and non-medicinal parts (the dried stem bark of Periploca sepium Bge. (JP)), harvest seasons and producing region of Periplocae Cortex. Second, network pharmacology was applied to explore the initial linkages among chemical constituents, targets and diseases. Last, potential Q-marker were selected by integrating analysis of plant metabolomics and network pharmacology, and the quantification method of Q-marker was developed by using UPLC-TQ-MS. RESULTS: The chemical profiling of GP and JP was investigated. Fifteen distinguishing features were designated as core chemical markers to distinguish GP and JP. Besides, the content of 4-methoxybenzaldehyde-2-O-ß-d-xylopyranosyl-(1→6)-ß-d-glucopyranoside could be used to identify Periplocae Cortex harvested in spring-autumn or summer. Meanwhile, a total of 15 components targeted rheumatoid arthritis were screened out based on network pharmacology. Taking absorbed constituents into consideration, 23 constituents were selected as potential Q-marker. A simultaneous quantification method (together with 11 semi-quantitative analysis) was developed and applied to the analysis of 20 batches of commercial Periplocae Cortex on the market. The PLS-DA model was successfully developed to distinguish GP and JP samples. In addition, the artificially mixed GP sample, which contained no less than 10% of the adulterant (JP), could also be correctly identified. CONCLUSION: Our results indicated that 9 ingredients could be considered as Q-marker of Periplocae Cortex. This study has also demonstrated that the plant metabolomics and network pharmacology could be used as an effective approach for discovering Q-marker of TCM to fulfill the evaluation of overall chemical consistency among samples from different producing areas, harvest seasons, and even those commercial crude drugs, which might be mixed with a small amount of non-medicinal parts.

Characterization of chemical components of Periplocae Cortex and their metabolites in rats using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

Periplocae Cortex, named Xiang-Jia-Pi in China, has been widely used to treat autoimmune diseases, especially rheumatoid arthritis. However, the in vivo substances of Periplocae Cortex remain unknown yet. In this study, an ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used for profiling the chemical components and related metabolites of Periplocae Cortex. A total of 98 constituents were identified or tentatively characterized in Periplocae Cortex: 42 C21 steroidal glycosides, 10 cardiac glycosides, 23 organic acids, 4 aldehydes, 7 triterpenes, and 12 other types. Among them, 18 components were unambiguously identified by comparison with reference standards. In addition, 176 related xenobiotics (34 prototypes and 142 metabolites) were screened out and characterized in rats' biosamples (plasma, urine, bile, and feces) after the oral administration of Periplocae Cortex. Moreover, the metabolic fate of periplocoside S-4a, a C21 steroidal glycoside, was proposed for the first time. In summary, phase II reactions (methylation, glucuronidation, and sulfation), phase I reactions (hydrolysis reactions, oxygenation, and reduction), and their combinations were the predominant metabolic reactions of Periplocae Cortex in rat. It is the first report to reveal the in vivo substances and metabolism feature of Periplocae Cortex. This study also provided meaningful information for further pharmacodynamics study of Periplocae Cortex, as well as its quality control research.

[Managing the Adverse Effects Related to Immune Checkpoint Inhibitors].

Immune checkpoint inhibitors (ICIs) have become the new posterchild of cancer treatment in recent years largely due to their impressive clinical efficacy. Drugs targeting cytotoxic T- lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) antibodies, e.g., ipilimumab (Yervoy®), pembrolizumab (Keytruda®), and nivolumab (Opdivo®), reinvigorate cytotoxic T cells to kill cancer cells in patients. Despite the impressive clinical benefits, ICIs may induce immune-related adverse events (irAE) of the skin, gastrointestinal tract, liver, endocrine, and lung with a wide spectrum of severity. Rare but severe irAEs of critical organs such as the heart and central nervous system have also been reported. Clinical practitioners must recognize the early signs and symptoms of irAE as well as related management strategies.

[New Hope for HER2-Positive Metastatic Breast Cancer Treatment: Trastuzumab Emtansine (T-DM1) From the Perspective of Nursing Care].

Human epidermal growth factor receptor (HER2)-positive breast cancer is associated with a more aggressive disease and poor prognosis. The development of trastuzumab, a HER2-targeted agent, has changed the paradigm of HER2-positive breast cancer treatment and improved survival rates dramatically. However, metastatic HER2-positive breast cancer patients eventually develop resistance to this treatment regimen eventually. A new anti-HER2 antibody-drug conjugate, Trastuzumab emtansine (T-DM1), has been shown to improve treatment efficacy. However, side effects that differ from trastuzumab, including thrombocytopenia, liver dysfunction, fatigue, cardiotoxicity, pneumonitis, and peripheral neuropathy, may occur. Clinical nurses must understand the mechanism of this new agent and be aware of the symptoms and signs related to its side effects. Furthermore, clinical nurses should understand the varying degrees of these side effects, their probable causes, and the potential approaches to their management. Finally, clinical nurses must understand how to administer this agent in order to ensure patient safety. Understanding the side effects of T-DM1 and their management will help elevate nursing quality and caring efficacy.

A pilot study to determine the timing and effect of bevacizumab on vascular normalization of metastatic brain tumors in breast cancer.

BACKGROUND: To determine the appropriate time of concomitant chemotherapy administration after antiangiogenic treatment, we investigated the timing and effect of bevacizumab administration on vascular normalization of metastatic brain tumors in breast cancer patients. METHODS: Eight patients who participated in a phase II trial for breast cancer-induced refractory brain metastases were enrolled and subjected to 4 dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) examinations that evaluated Peak, Slope, iAUC 60 , and Ktrans before and after treatment. The treatment comprised bevacizumab on Day 1, etoposide on Days 2-4, and cisplatin on Day 2 in a 21-day cycle for a maximum of 6 cycles. DCE-MRI was performed before treatment and at 1 h, 24 h, and 21 days after bevacizumab administration. RESULTS: Values of the 4 DCE-MRI parameters reduced after bevacizumab administration. Compared with baseline values, the mean reductions at 1 and 24 h were -12.8 and -24.7 % for Peak, -46.6 and -65.8 % for Slope, -27.9 and -55.5 % for iAUC 60 , and -46.6 and -63.9 % for Ktrans, respectively (all P < .05). The differences in the 1 and 24 h mean reductions were significant (all P < .05) for all the parameters. The generalized estimating equation linear regression analyses of the 4 DCE-MRI parameters revealed that vascular normalization peaked 24 h after bevacizumab administration. CONCLUSION: Bevacizumab induced vascular normalization of brain metastases in humans at 1 and 24 h after administration, and the effect was significantly higher at 24 h than at 1 h. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT01281696 , registered prospectively on December 24, 2010.

18F-NaF PET/CT Images of Cardiac Metastasis From Osteosarcoma.

Osteosarcomas are aggressive with a high incidence of recurrence and metastasis. Cardiac osteosarcoma metastasis is rare. We described a 17-year-old boy who had right distal femoral osteosarcoma with lung metastases. During follow-up, right ventricular (RV) metastasis was noted and confirmed by histopathological examination of the surgical specimen. F-NaF PET/CT was then arranged 1 month after debulking surgery for residual tumor survey. The images showed intense F-NaF uptake at RV region, suggestive of residual cardiac metastases.

TP53 Mutational Analysis Enhances the Prognostic Accuracy of IHC4 and PAM50 Assays.

IHC4 and PAM50 assays have been shown to provide additional prognostic information for patients with early breast cancer. We evaluated whether incorporating TP53 mutation analysis can further enhance their prognostic accuracy. We examined TP53 mutation and the IHC4 score in tumors of 605 patients diagnosed with stage I-III breast cancer at National Taiwan University Hospital (the NTUH cohort). We obtained information regarding TP53 mutation and PAM50 subtypes in 699 tumors from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. We found that TP53 mutation was significantly associated with high-risk IHC4 group and with luminal B, HER2-enriched, and basal-like subtypes. Despite the strong associations, TP53 mutation independently predicted shorter relapse-free survival (hazard ratio [HR] = 1.63, P = 0.007) in the NTUH cohort and shorter breast cancer-specific survival (HR = 2.35, P = <0.001) in the METABRIC cohort. TP53 mutational analysis added significant prognostic information in addition to the IHC4 score (∆ LR-χ(2) = 8.61, P = 0.002) in the NTUH cohort and the PAM50 subtypes (∆ LR-χ(2) = 18.9, P = <0.001) in the METABRIC cohort. We conclude that incorporating TP53 mutation analysis can enhance the prognostic accuracy of the IHC4 and PAM50 assays.

A pilot study of bevacizumab combined with etoposide and cisplatin in breast cancer patients with leptomeningeal carcinomatosis.

BACKGROUND: Elevated vascular endothelial growth factor (VEGF) was associated with poor prognosis in leptomeningeal carcinomatosis and anti-angiogenic therapy was found to prolong the survival of mice in preclinical studies. This prospective pilot study investigated the efficacy of anti-VEGF therapy plus chemotherapy in patients with leptomeningeal carcinomatosis originating from breast cancer. METHODS: Eligible patients were scheduled to receive bevacizumab combined with etoposide and cisplatin (BEEP) every 3 weeks for a maximum of 6 cycles or until unacceptable toxicity. The primary objective was the central nervous system (CNS)-specific response rate, which was defined as disappearance of cancer cells in the cerebrospinal fluid (CSF) and an improved or stabilized neurologic status. The impact of VEGF inhibition on etoposide penetration into the CSF was analyzed. RESULTS: Eight patients were enrolled. The CNS-specific response rate was 60% in 5 evaluable patients. According to intent-to-treat analysis, the median overall survival of the eight patients was 4.7 months (95% confidence interval, CI, 0.3-9.0) and the neurologic progression-free survival was 4.7 months (95% CI 0-10.5). The most common grade 3/4 adverse events were neutropenia (23.1%), leukopenia (23.1%), and hyponatremia (23.1%). The etoposide concentrations in the CSF were much lower than those in plasma, and bevacizumab did not increase etoposide delivery to the CSF. CONCLUSIONS: BEEP exhibited promising efficacy in breast cancer patients with leptomeningeal carcinomatosis. Additional studies are warranted to verify its efficacy and clarify the role of anti-angiogenic therapy in this disease. TRIAL REGISTRATION: ClinicalTrials.gov identifying number NCT01281696 .

High Prevalence of the BIM Deletion Polymorphism in Young Female Breast Cancer in an East Asian Country.

BACKGROUND: A rapid surge of female breast cancer has been observed in young women in several East Asian countries. The BIM deletion polymorphism, which confers cell resistance to apoptosis, was recently found exclusively in East Asian people with prevalence rate of 12%. We aimed to evaluate the possible role of this genetic alteration in carcinogenesis of breast cancer in East Asians. METHOD: Female healthy volunteers (n = 307), patients in one consecutive stage I-III breast cancer cohort (n = 692) and one metastatic breast cancer cohort (n = 189) were evaluated. BIM wild-type and deletion alleles were separately genotyped in genomic DNAs. RESULTS: Both cancer cohorts consistently showed inverse associations between the BIM deletion polymorphism and patient age (≤35 y vs. 36-50 y vs. >50 y: 29% vs. 22% vs. 15%, P = 0.006 in the consecutive cohort, and 40% vs. 23% vs. 13%, P = 0.023 in the metastatic cohort). In healthy volunteers, the frequencies of the BIM deletion polymorphism were similar (13%-14%) in all age groups. Further analyses indicated that the BIM deletion polymorphism was not associated with specific clinicopathologic features, but it was associated with poor overall survival (adjusted hazard ratio 1.71) in the consecutive cohort. CONCLUSIONS: BIM deletion polymorphism may be involved in the tumorigenesis of the early-onset breast cancer among East Asians.

Prognostic factors of metastatic or recurrent esophageal squamous cell carcinoma in patients receiving three-drug combination chemotherapy.

BACKGROUND: Three-drug combination therapy based on cisplatin/fluorouracil might improve treatment efficacy for metastatic esophageal squamous cell carcinoma (ESCC), but at the risk of increasing toxicity. The study sought to identify factors associated with outcomes of metastatic ESCC in patients who were treated with three-drug combinations. PATIENTS AND METHODS: One-hundred and thirteen patients with metastatic or recurrent ESCC who were treated with cisplatin/fluorouracil-based three-drug combination during 2000-2009 were studied. The prognostic impact of clinicopathological characteristics were evaluated by Cox proportional hazard regression analyses. RESULTS: The third chemotherapeutic agents comprised of paclitaxel, docetaxel, and methotrexate in 76 (67%), 13 (12%), and 24 (21%) of patients, respectively. The overall response rate was 41%. The median overall survival (OS) was 8.5 months. Results of the Cox proportional hazard regression models showed that age ≥65 years, Eastern Cooperative Oncology Group performance status of 0 and 1, lymph node-only metastasis and baseline white blood cell (WBC) count ≤10,000/mm(3) were significant prognostic factors for better OS. The OS curves were significantly separated by risk groups comprising of age, metastasis status and WBC count as risk factors. CONCLUSION: The identification of prognostic factors could facilitate for future design of randomized studies on the efficacy of three-drug combinations for metastatic ESCC.

The first two lines of chemotherapy for anthracycline-naive metastatic breast cancer: a comparative study of the efficacy of anthracyclines and non-anthracyclines.

For anthracycline-naive metastatic breast cancer (AN-MBC), early anthracycline treatment is a common practice. However, with the availability of newer chemotherapies, comparative studies on the efficacy of anthracyclines and non-anthracyclines as early treatments for AN-MBC are lacking. We collected retrospective clinicopathological data from 253 AN-MBC patients treated at National Taiwan University Hospital between 2001 and 2006. Patients were categorised into anthracycline or non-anthracycline groups according to their regimens in the first two lines of chemotherapy. The overall survival (OS, 33.3 vs. 34.2 months, p = 0.179), time to treatment failure of the first two lines of chemotherapy drugs (13.3 vs. 12.7 months, p = 0.104) and best composite response rate (59.5% vs. 61.1%, p = 0.81) were not significantly different between the two groups. Multivariate analysis showed that early anthracycline treatment was not a significant prognostic factor of OS (p = 0.052). Thus, the results of this study show that anthracyclines may not be necessary as an early treatment option for AN-MBC.

The impact of diabetes mellitus on prognosis of early breast cancer in Asia.

BACKGROUND: Diabetes mellitus (DM) has been implicated in influencing the survival duration of patients with breast cancer. However, less is known about the impact of DM and other comorbidities on the breast cancer-specific survival (BCS) and overall survival (OS) outcomes of Asian patients with early-stage breast cancer. PATIENTS AND METHODS: The characteristics of female patients with newly diagnosed, early-stage breast cancer were collected from the Taiwan Cancer Registry database for 2003-2004. DM status and other comorbidities were retrieved from Taiwan's National Health Insurance database. The BCS and OS times of patients according to DM status were estimated via the Kaplan-Meier method. Cox's proportional hazard model was used to estimate adjusted hazard ratios (HRs) for the effects of DM, comorbidities, and other risk factors on mortality. RESULTS: In total, 4,390 patients were identified and 341 (7.7%) presented with DM. The 5-year BCS and OS rates were significantly greater in DM patients than in non-DM patients (BCS, 85% versus 91%; OS, 79% versus 90%). Furthermore, after adjusting for clinicopathologic variables and comorbidities, DM remained an independent predictor of shorter BCS (adjusted HR, 1.53) and OS (adjusted HR, 1.71) times. Subgroup analyses also demonstrated a consistent prognostic influence of DM across different groups. CONCLUSION: In Asian patients with early-stage breast cancer, DM is an independent predictor of lower BCS and OS rates, even after adjusting for other comorbidities. The integration of DM care as part of the continuum of care for early-stage breast cancer should be emphasized.

Small-displacement sensing system based on multiple total internal reflections in heterodyne interferometry.

A small-displacement sensing system based on multiple total internal reflections in heterodyne interferometry is proposed. In this paper, a small displacement can be obtained only by measuring the variation in phase difference between s- and p-polarization states for the total internal reflection effect. In order to improve the sensitivity, we increase the number of total internal reflections by using a parallelogram prism. The theoretical resolution of the method is better than 0.417 nm. The method has some merits, e.g., high resolution, high sensitivity, and real-time measurement. Also, its feasibility is demonstrated.