Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial.

BACKGROUND: Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) shows potential for neurocognitive preservation. This study aimed to evaluate whether HA-WBRT or conformal WBRT (C-WBRT) is better for preserving neurocognitive function. METHODS: This single-blinded randomized phase II trial enrolled patients with brain metastases and randomly assigned them to receive HA-WBRT or C-WBRT. Primary endpoint is decline of the Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall at 4 months after treatment. Neurocognitive function tests were analyzed with a mixed effect model. Brain progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: From March 2015 to December 2018, seventy patients were randomized to yield a total cohort of 65 evaluable patients (33 in the HA-WBRT arm and 32 in the C-WBRT arm) with a median follow-up of 12.4 months. No differences in baseline neurocognitive function existed between the 2 arms. The mean change of HVLT-R delayed recall at 4 months was -8.8% in the HA-WBRT arm and +3.8% in the C-WBRT arm (P = 0.31). At 6 months, patients receiving HA-WBRT showed favorable perpetuation of HVLT-R total recall (mean difference = 2.60, P = 0.079) and significantly better preservation of the HVLT-R recognition-discrimination index (mean difference = 1.78, P = 0.019) and memory score (mean difference = 4.38, P = 0.020) compared with patients undergoing C-WBRT. There were no differences in Trail Making Test Part A or Part B or the Controlled Oral Word Association test between the 2 arms at any time point. There were no differences in brain PFS or OS between arms as well. CONCLUSION: Patients receiving HA-WBRT without memantine showed better preservation in memory at 6-month follow-up, but not in verbal fluency or executive function.

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.

Clinical Relevance of Liver Kinase B1(LKB1) Protein and Gene Expression in Breast Cancer.

Liver kinase B1 (LKB1) is a tumor suppressor, and its loss might lead to activation of the mammalian target of rapamycin (mTOR) and tumorigenesis. This study aimed to determine the clinical relevance of LKB1 gene and protein expression in breast cancer patients. LKB1 protein expression was evaluated using immunohistochemistry in tumors from early breast cancer patients in two Taiwanese medical centers. Data on LKB1 gene expression were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set. The correlations between LKB1 expression, clinicopathologic factors, and patient outcome were analyzed. LKB1 expression was significantly associated with estrogen receptor (ER) expression in 2 of the 4 cohorts, but not with other clinicopathologic factors. LKB1 expression was not a predictor for relapse-free survival, overall survival (OS), or breast cancer-specific survival. In a subgroup analysis of the two Taiwanese cohorts, high LKB1 protein expression was predictive of high OS in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients (P = 0.013). Our study results indicate that LKB1 expression is not prognostic in the whole population of breast cancer patients, but it is a potential predictor of OS in the subset of HER2-positive patients.

Investigations of kanuka and manuka essential oils for in vitro treatment of disease and cellular inflammation caused by infectious microorganisms.

BACKGROUND: Diseases caused by infectious and inflammatory microorganisms are among the most common and most severe nosocomial diseases worldwide. Therefore, developing effective agents for treating these illnesses is critical. In this study, essential oils from two tea tree species, kanuka (Kunzea ericoides) and manuka (Leptospermum scoparium), were evaluated for use in treating diseases and inflammation caused by microorganism infection. METHODS: Isolates of clinically common bacteria and fungi were obtained from American Type Culture Collection and from Kaohsiung Veterans General Hospital. Minimum inhibitory concentrations for Trichosporon mucoides, Malassezia furfur, Candida albicans, and Candida tropicalis were determined by the broth microdilution method with Sabouraud dextrose broth. The antibacterial susceptibility of Staphylococcus aureus, Streptococcus sobrinus, Streptococcus mutans, and Escherichia coli were determined by the broth microdilution method. A human acute monocytic leukemia cell line (THP-1) was cultured to test the effects of the essential oils on the release of the two inflammatory cytokines, tumor necrosis factor-α and interleukin-4. RESULTS: Multiple analyses of microorganism growth confirmed that both essential oils significantly inhibited four fungi and the four bacteria. The potent fungicidal properties of the oils were confirmed by minimum inhibitory concentrations ranging from 0.78% to 3.13%. The oils also showed excellent bactericidal qualities with 100% inhibition of the examined bacteria. In THP-1 cells, both oils lowered tumor necrosis factor-α released after lipopolysaccharide stimulation. Finally, the antimicrobial and anti-inflammatory effects of the oils were obtained without adversely affecting the immune system. CONCLUSION: These results indicate that the potent antimicroorganism and anti-inflammation properties of kanuka and manuka essential oils make them strong candidates for use in treating infections and immune-related disease. The data confirm the potential use of kanuka and manuka extracts as pharmaceutical antibiotics, medical cosmetology agents, and food supplements.

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.

7-Hydroxydehydronuciferine induces human melanoma death via triggering autophagy and apoptosis.

Melanoma is the deadliest cancer. We identified 7-hydroxydehydronuciferine (7-HDNF) isolated from the leaves of Nelumbo nucifera Gaertn cv. Rosa-plena to be a bio-active agent that antagonizes melanoma tumor growth in mice xenograft model in vivo. Cell proliferation assay demonstrated strong anticancer effects of 7-HDNF to exhibit a dose-dependent behaviour and displayed minor cytotoxicities on normal human skin cells, including epidermal keratinocytes and melanocytes, and dermal fibroblasts. With acridine orange (AO) staining and flow analysis, we found 7-HDNF induced the formation of intracellular vacuoles and the augmentation of acidic vesicular organelles (AVO). The apoptotic cell death ratio was measured via two-dimensional flow cytometry by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double stained to confirm the cellular membrane asymmetry lost. One-dimensional flow cytometric analysis showed 7-HDNF increased the cellular arrest in cell cycle at the G2/M phase. Through Western blot examinations, protein expressions were discovered to verify autophagy and apoptosis response mechanisms sharing the associated pathways. Finally, 7-HDNF presented a high-quality antimigratory activity in wound-healing assay. Overall, 7-HDNF presented high-quality anticancer bio-functions and inhibited melanoma tumor growth in vivo and in vitro.

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.

Bevacizumab preconditioning followed by Etoposide and Cisplatin is highly effective in treating brain metastases of breast cancer progressing from whole-brain radiotherapy.

PURPOSE: We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain metastases of breast cancer (BMBC). EXPERIMENTAL DESIGN: A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m(2)/day; days 2-4) and cisplatin (70 mg/m(2); day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS)-objective response rate according to volumetric response criteria. RESULTS: A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33-75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients [77.1%; 95% confidence interval (CI), 59.9-89.6] achieved a CNS-objective response, including 13 patients (37.1%) with a ≥80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5-8.1) and 10.5 months (95% CI, 7.8-13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%). CONCLUSIONS: By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted.

Piper betle leaf extracts induced human hepatocellular carcinoma Hep3B cell death via MAPKs regulating the p73 pathway in vitro and in vivo.

Extracts of Piper betle leaf (PBLs) are rich in bioactive compounds with potential chemopreventive ability. In this study, Hep3B cells which are p53 null were used to investigate the anti-tumor effect of PBLs in the cell and in the xenograft model. The results revealed that PBLs (0.1 to 1 mg mL(-1)) induced a dose- and time-dependent increase of cell toxicity. The underlying mechanisms as evidenced by flow cytometry and western blot analysis showed that PBLs triggered ATM, cAbl, and p73 expressions and activated JNK and p38 pathways that subsequently led to cell cycle arrest and mitochondria-dependent apoptosis. PBLs also inhibited tumor growth in Hep3B-bearing mice via inducing the MAPK-p73 pathway. Our results demonstrated the in vitro and in vivo anti-tumor potential of PBLs, supporting their application as a novel chemopreventive agent for the treatment of human hepatocellular carcinoma (HCC) in the future via targeting the p73 pathway.

Isophilippinolide A arrests cell cycle progression and induces apoptosis for anticancer inhibitory agents in human melanoma cells.

Three new butanolides, isophilippinolide A, philippinolide A, and philippinolide B, and an amide, cinnaretamine, were isolated from the roots of Cinnamomum philippinense to be identified by spectroscopic analysis. Four isolated compounds were screened to examine their radical-scavenging ability, metal-chelating power, and ferric-reducing antioxidant power assay (FRAP). Cinnaretamine showed powerful antioxidative properties in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and a reducing activity; all compounds presented minor inhibition of metal-chelating capacities. The effects of anti-tyrosinase of C. philippinense constituents were determined by the level of the suppression of hydroxylation that turned from L-tyrosine to L-dopa through an in vitro mushroom tyrosinase assay, and all testing samples illustrated slight mushroom tyrosinase inhibitory properties. Isophilippinolide A exhibited inhibitory effectivenesses against the A375.S2 melanoma cell line in a cell viability assay at concentrations ranging from 0 to 200 µM for 24 h. Propidium iodide staining and flow cytometry analyses were applied to assess cell cycle accumulative distribution. It was discovered that isophilippinolide A caused sub-G1 phase accumulation in positive correlation for apoptosis to inhibit cell growth. Further investigation revealed that isophilippinolide A induced A375.S2 cells with an increase of caspase-dependent apoptotic proteins to trigger correlated pathway mechanisms according to Western blotting results. Finally, isophilippinolide A displayed only low cytotoxicities to human normal epidermal cells (melanocytes) and dermal cells (fibroblasts). Altogether, the results implied C. philippinense compounds could be considered functional ingredients in cosmetics, foods, and pharmaceutical products, particularly for their anticancer ability on human skin melanoma cells.

Inhibitory effect of Piper betel leaf extracts on copper-mediated LDL oxidation and oxLDL-induced lipid accumulation via inducing reverse cholesterol transport in macrophages.

Piper betel leaf (PBL) has the biological capabilities of detoxification and can work as an anti-inflammatory agent and an anti-oxidant. In this study, we evaluated the anti-oxidative activity of the extract of Piper betel leaves (PBLs) on the basis of Cu(2+)-mediated oxidation, and its ability to prevent foam cell formation in a model for oxidised low density lipoprotein (oxLDL)-induced lipid accumulation in macrophages. Our data demonstrated that PBLs were able to inhibit LDL oxidation in vitro and are able to reduce the lipid accumulation in macrophages. We showed the underlying mechanisms to be the following: PBLs up-regulated the protein levels of the class A and class B scavenger receptors, the membrane lipid transporter ABCA1, and its upstream regulator Liver X receptor (LXR) in the macrophages exposed to oxLDL. The results suggested that PBLs activated the reverse cholesterol transport mechanism to enhance the metabolism of the oxLDL that could prevent both lipid accumulation and foam cell formation and further minimise the possible damage of vessels caused by the oxLDL.

Phosphorylated insulin-like growth factor-1 receptor (pIGF1R) is a poor prognostic factor in brain metastases from lung adenocarcinomas.

A greater understanding of brain metastases is imperative for developing novel therapeutic strategies. Our previous study showed that insulin-like growth factor (IGF) signaling pathway was activated in brain-tropic cancer cells. In this study, we investigated the clinical relevance of activated (phosphorylated) IGF-1 receptor (pIGF1R) expression in brain metastases originating from lung adenocarcinomas. All pathologically confirmed brain metastases from lung adenocarcinomas, with available archived specimens from January 1998 to December 2009 at National Taiwan University Hospital, were assessed immunohistochemically for pIGF1R expression using H-score criteria. A median H-score was used as a cutoff point to define high or low pIGF1R expression. The mutation status in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) was examined using direct sequencing. The prognostic significance of pIGF1R expression, its correlations with clinicopathological characteristics, and EGFR status were evaluated. In the 86 cases, high membranous/cytoplasmic pIGF1R expression in brain metastases correlated with a shorter median survival (10.8 vs 27.8 mo, P = 0.003). This correlation was more significant in patients with EGFR mutations [hazard ratio (HR) 2.38, 95 % confidence interval (CI) 1.19-4.77 for EGFR mutations; HR 1.99, 95 % CI 0.95-4.15 for EGFR wild type] and remained statistically significant in multivariate analysis after adjusting for the effects of other potential prognostic factors, including the graded prognostic assessment score, solitary brain metastasis, extracranial metastatic status, EGFR mutations, and treatment using EGFR tyrosine kinase inhibitors. Although we also identified nuclear pIGF1R expression, this result was prognostically non-significant. Our study results showed that high membranous/cytoplasmic pIGF1R expression in brain metastases was a poor prognostic factor, more significantly in patients with EGFR mutations than in those with wild-type EGFRs.

Divergent reactivity of nitric oxide with metal-metal quintuple bonds.

Reactions of NO with the quintuple bonded chromium and molybdenum amidinate dimers, respectively, gave dichromium nitrosyl nitrito amidinato complexes, and the quadruple bonded dimolybdenum nitrito amidinato species with a paddlewheel configuration.

Biofunctional constituents from Liriodendron tulipifera with antioxidants and anti-melanogenic properties.

From the stems of Liriodendron tulipifera, seventeen known compounds have been extracted, isolated and purified. By using spectroscopic analysis, the structures of these pure constituents were determined as three lignans, four steroids and ten benzenoids. Identified compounds were screened for antioxidant abilities using: 1,1-diphenyl-2-picrylhydrazul (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) scavenging free radical activity assays; metal chelating power test; and ferric reducing/antioxidant power (FRAP) examination. The result revealed that seventeen compounds had potential anti-oxidative capabilities. In addition, the anti-tyrosinase effect was determined by calculating the hydroxylation of L-tyrosine to L-dopa and the oxidization of L-dopa to dopaquinone, according to in vitro mushroom tyrosinase evaluation platform. Furthermore, based on assays on B16F10 cell line, our data suggest that five compounds isolated from L. tulipifera would be able to inhibit tyrosinase activity and reduce the melanin content in animal cells. Therefore, some of the examined compounds could be potentially used in the cosmetic skin whitening business, therapeutic applications or the food industry.

Adherence to the National Institute of Clinical Excellence guidance on parenteral nutrition screening is not enough to improve outcomes.

BACKGROUND & AIM: Majority of the National Institute of Clinical Excellence (NICE) nutrition guidance recommendations were based on Grade D evidence due to absence of randomised controlled trials. The aim was to assess outcomes of parenteral nutrition (PN) administration when the guidance was adhered to. METHODS: The prospective study included patients referred for PN. Patients were divided into two groups: guidance compliant and guidance non-compliant. Primary outcome measures were duration of PN treatment, number of PN bags used per patient, length of hospital stay and mortality. RESULTS: There were 262 patients, aged 54(42-67) [median (IQR)] years. The guidance compliant and the non-compliant groups consisted of 143 and 119 patients respectively. In the guidance compliant group all patients were screened on admission compared to 40% in the non-compliant group (p < 0.001). Among those malnourished/at risk of malnutrition all were referred for early dietetic assessment in the compliant group but only 14% in the non-compliant group (p < 0.001). There was no difference in any of the outcome measures between the groups. CONCLUSION: Compliance with the nutritional guidance in the UK was not enough to improve outcomes in patients requiring PN in our cohort. Evidence based changes to PN practice are required to optimise care.

A small sample test of the factor structure of postural movement and bilateral motor integration using structural equation modeling.

The goal of this study was to examine the relationship between the validity of postural movement and bilateral motor integration in terms of sensory integration theory. Participants in this study were 61 Chinese children ages 48 to 70 months. Structural equation modeling was applied to assess the relation between measures tapping postural movement and bilateral motor integration: for postural movement, the measures involve the Monkey Task, Side-Sit Co-contraction, Prone on Elbows, Wheelbarrow Walk, Airplane, and Scooter Board Co-contraction from the DeGangi-Berk Test of Sensory Integration, and Standing Balance with Eyes Closed/Opened in Southern California Sensory Integration Tests. For bilateral motor integration, the measures chosen were the Rolling Pin Activity, Jump and Turn, Diadokokinesis, Drumming, and Upper Extremity Control from the DeGangi-Berk Test of Sensory Integration, and Cross the Midline in Southern California Sensory Integration Tests (SCSIT). Postural movement was highly correlated with the bilateral motor integration. The factor structure fit the theoretical conceptualization, classifying postural movement and bilateral motor integration together in the same category. Therapists could combine two separate objectives (postural movement and bilateral motor integration) of intervention in an activity to improve the adaptive skills based on the vestibular-proprioceptive integration.