Apremilast Long-Term Safety Up to 5 Years from 15 Pooled Randomized, Placebo-Controlled Studies of Psoriasis, Psoriatic Arthritis, and Behçet's Syndrome.

BACKGROUND: Since US FDA approval in 2014, apremilast has consistently demonstrated a favorable benefit-risk profile in 706,585 patients (557,379 patient-years of exposure) worldwide across approved indications of plaque psoriasis, psoriatic arthritis, and Behçet's syndrome; however, long-term exposure across these indications has not been reported. OBJECTIVE: The aim of this study was to conduct a pooled analysis of apremilast data from 15 clinical studies with open-label extension phases, focusing on long-term safety. METHODS: We analyzed longer-term safety and tolerability of apremilast 30 mg twice daily across three indications for up to 5 years, focusing on adverse events of special interest, including thrombotic events, malignancies, major adverse cardiac events (MACE), serious infections, and depression. Data were pooled across 15 randomized, placebo-controlled studies and divided into placebo-controlled or all-apremilast-exposure groups. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Overall, 4183 patients were exposed to apremilast (6788 patient-years). Most TEAEs were mild to moderate in the placebo-controlled period (96.6%) and throughout all apremilast exposure (91.6%). TEAE rates of special interest were similar between treatment groups in the placebo-controlled period and remained low throughout all apremilast exposure. Exposure-adjusted incidence rates per 100 patient-years during all apremilast exposure were MACE, 0.30; thrombotic events, 0.10; malignancies, 1.0; serious infections, 1.10; serious opportunistic infections, 0.21; and depression, 1.78. Safety findings were consistent across indications and regions. No new safety signals were identified. CONCLUSIONS: The incidence of serious TEAEs and TEAEs of special interest was low despite long-term exposure, further establishing apremilast as a safe oral option for long-term use across indications with a favorable benefit-risk profile. CLINICAL TRIAL REGISTRATION: NCT00773734, NCT01194219, NCT01232283, NCT01690299, NCT01988103, NCT02425826, NCT03123471, NCT03721172, NCT01172938, NCT01212757, NCT01212770, NCT01307423, NCT01925768, NCT00866359, NCT02307513.

Quality of Life and Severity of Symptom Differences Between Post Open Colectomy and Laparoscopic Colectomy in Colorectal Cancer Patients.

BACKGROUND: Worldwide, colorectal cancer is the third most common cancer in men and the second in women. The main surgical methods for colorectal cancer patients include a conventional open colectomy and laparoscopic-assisted colectomy. Laparoscopic-assisted colectomy is associated with less blood loss, faster recovery of bowel function, and shorter hospital stays. OBJECTIVE: The aim of this study was to compare the quality of life and symptom severity in patients with colorectal cancer 1 month after conventional open colectomy or laparoscopic-assisted colectomy. METHODS: A comparative cross-sectional study design was conducted from September 2015 to May 2016. Participants were recruited through convenience sampling from the surgical outpatient department of a medical center in Northern Taiwan; 33 patients underwent each type of surgery. RESULTS: The laparoscopic-assisted colectomy group scored 9.39 points higher in quality of life and lower in symptom severity by 14.88 points than the conventional open colectomy group (P = .03 and P = .05, respectively). Both groups reported low symptom severity; "changes in bowel habits" was the symptom with the highest severity. The conventional open colectomy group had higher insomnia and worried about their future more than did the laparoscopic-assisted colectomy group. CONCLUSIONS: Patients who received the laparoscopic-assisted colectomy procedure reported a better quality of life and lower symptom severity than those who received the conventional open colectomy surgical method. IMPLICATIONS FOR PRACTICE: Patients who will have a conventional open colectomy will likely need enhanced management of symptoms and attention to their quality of life.

Mediating effects of shoulder-arm exercise on the postoperative severity of symptoms and quality of life of women with breast cancer.

BACKGROUND: The postoperative severity of symptoms among women with breast cancer affects their quality of life (QoL). Although it is recommended that performing shoulder-arm exercise 30 min/day can alleviate symptoms and improve the QoL, there is little research on the mediating effects of performing shoulder-arm exercise 30 min/day on the postoperative severity of symptoms and QoL among patients with breast cancer. METHODS: A cross-sectional study was conducted 2 ~ 4 months after surgery on women diagnosed with breast cancer but with no distant metastasis and who had undergone breast cancer surgery for the first time. A structured questionnaire was employed which included a severity of symptoms scale, performing shoulder-arm exercise for 30 min/day, a QoL scale, demographic characteristics, and medical status. RESULTS: In total, 117 women with breast cancer completed the survey. The severity of symptoms and performing shoulder-arm exercise 30 min/day separately affected the QoL (B = -0.447, standard error (SE) = 0.050, p < 0.001; B = 15.666, SE = 4.542, p = 0.001, respectively). In model 3, performing shoulder-arm exercise for 30 min/day played a partial mediating role in the relationship of the severity of symptoms and QoL (R2 = 0.51, F = 5.41, p < 0.001). CONCLUSIONS: During 2 ~ 4 months after surgery, regular shoulder-arm exercise for 30 min/day could decrease the effect of the severity of symptoms on the QoL among women with breast cancer. Clinical healthcare providers may inform and educate patients as to the benefits of regular shoulder-arm exercise for 30 min/day.

FOXC1 Regulation of miR-31-5p Confers Oxaliplatin Resistance by Targeting LATS2 in Colorectal Cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-related illness worldwide and one of the most common malignancies. Therefore, colorectal cancer research and cases have gained increasing attention. Oxaliplatin (OXA) is currently used in first-line chemotherapy to treat stage III and stage IV metastatic CRC. However, patients undergoing chemotherapy often develop resistance to chemo drugs being used. Evidence has confirmed that microRNAs regulate downstream genes in cancer biology and thereby have roles related to tumor growth, proliferation, invasion, angiogenesis, and multi-drug resistance. The aim of our study is to establish whether miR-31-5p is an oncogene in human colorectal cancers that are resistant to OXA and further confirm its malignant phenotype-associated target molecule. From the results of miRNA microarray assay, we establish that miR-31-5p expression was upregulated in oxaliplatin-resistant (OR)-LoVo cells compared with parental LoVo cells. Moreover, through in vitro and in vivo experiments, we demonstrate that miR-31-5p and large tumor suppressor kinase 2 (LATS2) were inversely related and that miR-31-5p and Forkhead box C1 (FOXC1) were positively correlated in the same LoVo or OR-LoVo cells. Importantly, we reveal a novel drug-resistance mechanism in which the transcription factor FOXC1 binds to the miR-31 promoter to increase the expression of miR31-5p and regulate LATS2 expression, resulting in cancer cell resistance to OXA. These results suggest that miR-31-5p may be a novel biomarker involved in drug resistance progression in CRC patients. Moreover, the FOXC1/miR31-5p/LATS2 drug-resistance mechanism provides new treatment strategies for CRC in clinical trials.

Lupeol alters ER stress-signaling pathway by downregulating ABCG2 expression to induce Oxaliplatin-resistant LoVo colorectal cancer cell apoptosis.

Colorectal cancer (CRC) is one of the most common cancers and causes of cancer-related death. There are several first-line chemotherapeutic drugs used to treat CRC. Oxaliplatin (OXA) is an alkylating cytotoxic agent that is usually combined with other chemotherapeutic drugs to treat stage II and stage III CRC. However, cancer cells commonly acquire multidrug resistance (MDR), which is a major obstruction to cancer treatment. Recent studies have shown that natural components from traditional Chinese medicine or foods that have many biological functions may be new adjuvant therapies in clinical trials. We challenged LoVo CRC cell lines with OXA in a dose-dependent manner to create an OXA-resistant model. The expression of ABCG2 was significantly higher, and levels of endoplasmic reticulum (ER) stress markers were lower than those Parental cells. However, Lupeol, which is found in fruits and vegetables, has been shown to have bioactive properties, including anti-tumor properties that are relevant to many diseases. In our study, Lupeol downregulated cell viability and activated cell apoptosis. Moreover, Lupeol decreased the expression of ABCG2 and activated ER stress to induce OXA-resistant cell death. Importantly, the anti-tumor effect of Lupeol in OXA-resistant cells was higher than that of LoVo Parental cells. In addition, we also confirmed our results with a xenograft animal model, and the tumor size significantly decreased after Lupeol injections. Our findings show that Lupeol served as a strong chemoresistant sensitizer and could be a new adjuvant therapy method for chemoresistant patients.

Clopidogrel pharmacodynamics and pharmacokinetics in the fed and fasted state: a randomized crossover study of healthy men.

Clopidogrel requires CYP450-mediated hepatic metabolism to form its active metabolite (clopi-H4). This randomized, placebo-controlled, crossover study was designed to characterize the effect of a high-fat or standard breakfast on adenosine diphosphate (ADP)-induced platelet aggregation and exposure to unchanged clopidogrel and clopi-H4 following clopidogrel (300-mg loading dose, 75 mg/d for 4 days) in 72 healthy men. At day 5 and as assessed by liquid chromatography-tandem mass spectrometry, unchanged clopidogrel area under the concentration- time curve from 0 to 24 hours (AUC(0-24)) increased 3.32-fold (90% confidence interval [CI], 2.88-3.84), and clopi-H4 AUC(0-24) decreased nonsignificantly by 12% (90% CI, 0.82-0.94) upon administration of clopidogrel with a standard breakfast. The estimated treatment difference in maximum platelet aggregation (MPA) induced by ADP 5 µM and assessed by light transmission aggregometry was 4.7%, with the 90% CI (0.9%-8.5%) contained within the prespecified equipotency range of ±15%. The mean ± standard deviation of day 5 inhibition of platelet aggregation was 49.7% ± 17.2% and 54.0% ± 13.3% in the fed and fasted states, respectively. Despite increased unchanged clopidogrel and slightly decreased clopi-H4 exposure following clopidogrel administration, the numerical increase in MPA in the fed versus fasted state was small and within the prespecified limit of equipotency. These findings confirm that clopidogrel can be taken with or without food.

Changes in quality of life among newly diagnosed breast cancer patients in Taiwan.

AIM: To examine changes in quality of life among patients with breast cancer and factors related to it, during the first three months after diagnosis. BACKGROUND: Numerous studies have examined quality of life among cancer survivors or among patients with cancer after aggressive treatment; such research has demonstrated that quality of life in the third month after surgery can significantly predict quality of life in the long run. In contrast, changes in quality of life causes among patients during the acute treatment phase have not been well studied. DESIGN: Prospective longitudinal study. METHODS: Newly diagnosed patients with breast cancer were recruited during 2008-2009. Sixty-one cases completed the four data collections on the day before operation and one, two and three months after surgery. Data were collected using the Functional Living Index-Cancer, Symptom Distress Scale, the Self-Efficacy Scale and a 0-10 Anxiety Numeric Rating Scale. Generalized Estimating Equations were applied for data analysis. RESULTS: There were significant changes in quality of life over the three months following surgery, and the worst quality of life was observed in the first month after surgery. Less advanced stages of cancer, lower anxiety, less symptom distress and higher perceived self-efficacy in the preoperative interview could significantly predict which patients experienced more positive quality of life trends. Fatigue, limited shoulder function and perceived poor appearance were the most significant factors predicting changes of quality of life. CONCLUSION: Preoperative physical and psychological factors, as well as sense of self-efficacy for managing the cancer, are important factors for predicting changes in patients' quality of life. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should be alert to factors contributing to changes of quality of life among patients receiving chemotherapy. Interventions based on these results should be developed and their effectiveness tested for their impact on breast cancer patients' quality of life. Clinical interventions based on these results should be developed to improve breast cancer patients' quality of life.

Psychometric testing of the Chinese-version cancer needs questionnaire short form head and neck cancer-specific version in oral cavity cancer patients.

PURPOSE: The purposes of this two-phase study were to (1) develop and examine the content validity and feasibility of the Chinese-version cancer needs questionnaire, short form, head and neck cancer-specific version (CNQ-SF-hn) (phase I), and (2) examine its psychometric characteristics as supported by reliability and construct validity (phase II) in oral cavity cancer patients in Taiwan. METHODS: Newly diagnosed oral cavity cancer patients (N = 206) were recruited from a medical center in northern Taiwan. Data were analyzed using descriptive statistics and psychometric analyses. RESULTS: The results showed that the CNQ-SF-hn (1) had good internal consistency reliability for the overall scale and subscales; (2) had good 1-week test-retest reliability (correlation = 0.80) for the overall scale; (3) had construct validity, supported by six clearly identified factors explaining 74.87% of the variance; and (4) had convergent validity, supported by correlations among its subscales and related scales, as well as by discriminating care needs according to undergoing versus not undergoing reconstructive surgery and cancer stage. CONCLUSIONS: The Chinese-version CNQ-SF-hn is a psychometrically satisfactory instrument. Further validation is suggested for its factor structure and different head and neck cancers.

Arm Exercise Promotion Scale: instrument validation.

AIM: This paper is a report of psychometric testing of the Arm Exercise Promotion Scale. BACKGROUND: Patients with breast cancer having mastectomy are taught postoperative arm exercises during hospitalization; however, clinical observations suggest that patients infrequently practise them. It is important to develop an instrument that can be easily applied to evaluate women's motivation for arm exercises. METHOD: An instrument validation design with a cross-sectional survey was conducted during 2008-09. The previously developed 15-item Likert-type Arm Exercise Promotion Scale was further tested for test-retest reliability, internal consistency reliability, theoretically supported construct validity, and concurrent validity. A total of 94 patients with breast cancer were recruited to the study. RESULTS: The Arm Exercise Promotion Scale has satisfactory internal consistency reliability (Cronbach's alpha 0.88) and a test-retest reliability of 0.90. Three theoretically supported factors were abstracted by principal component analysis: perceived benefits, learning support and situational support. These factors were inter-correlated and statistically significantly correlated with arm exercise behaviour, indicating concurrent and construct validity. CONCLUSION: There is strong evidence to further support the Arm Exercise Promotion Scale as a valid instrument in assessing factors which promote arm exercises with patients with breast cancer. Future longitudinal clinical studies using this scale could add knowledge about the experiences of carrying out arm exercises in patients with breast cancer across time.

Gamma-linolenic acid inhibits inflammatory responses by regulating NF-kappaB and AP-1 activation in lipopolysaccharide-induced RAW 264.7 macrophages.

Gamma linolenic acid (GLA) is a member of the n-6 family of polyunsaturated fatty acids and can be synthesized from linoleic acid (LA) by the enzyme delta-6-desaturase. The therapeutic values of GLA supplementation have been documented, but the molecular mechanism behind the action of GLA in health benefits is not clear. In this study, we assessed the effect of GLA with that of LA on lipopolysaccharide (LPS)-induced inflammatory responses and further explored the molecular mechanism underlying the pharmacological properties of GLA in mouse RAW 264.7 macrophages. GLA significantly inhibited LPS-induced protein expression of inducible nitric oxide synthase, pro-interleukin-1beta, and cyclooxygenase-2 as well as nitric oxide production and the intracellular glutathione level. LA was less potent than GLA in inhibiting LPS-induced inflammatory mediators. Both GLA and LA treatments dramatically inhibited LPS-induced IkappaB-alpha degradation, IkappaB-alpha phosphorylation, and nuclear p65 protein expression. Moreover, LPS-induced nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) nuclear protein-DNA binding affinity and reporter gene activity were significantly decreased by LA and GLA. Exogenous addition of GLA but not LA significantly reduced LPS-induced expression of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK)-1. Our data suggest that GLA inhibits inflammatory responses through inactivation of NF-kappaB and AP-1 by suppressed oxidative stress and signal transduction pathway of ERK and JNK in LPS-induced RAW 264.7 macrophages.

Effects of a walking intervention on fatigue-related experiences of hospitalized acute myelogenous leukemia patients undergoing chemotherapy: a randomized controlled trial.

The purpose of this randomized, controlled clinical trial was to preliminarily examine the effects of a three-week walking exercise program (WEP) on fatigue-related experiences of acute myelogenous leukemia (AML) patients receiving chemotherapy. Eligible AML patients were randomly assigned to either an experimental group (n=11), which received 12 minutes of WEP per day, five days per week for three consecutive weeks, or to a control group (n=11), which received standard ward care. Effects of the WEP were assessed by seven indicators: worst and average fatigue intensities, fatigue interference with patients' daily life, 12-minute walking distance, overall symptom distress, anxiety, and depressive status. All patients were evaluated four times: before chemotherapy (baseline or Day 1), Day 7, Day 14, and Day 21 of chemotherapy. Data were analyzed by Generalized Estimating Equation and revealed that AML patients in the three-week WEP group had a significantly greater increase in 12-minute walking distance than the control group. Patients in the WEP also had lower levels of fatigue intensity and interference, symptom distress, anxiety, and depressive status than the control group. Although preliminary, our results strongly suggest that three weeks of systematic walking exercise is clinically feasible for AML patients undergoing chemotherapy and can effectively improve their fatigue-related experiences.

Apoptotic effects of over-expressed estrogen receptor-beta on LoVo colon cancer cell is mediated by p53 signalings in a ligand-dependent manner.

Epidemiologic studies reported that the prevalence of hereditary non-polyposis colon cancer (HNPCC) in male is about 1.5-fold higher than that in female. Decreases in circulatory estradiol (E2) have been reported to downregulate the expression of E2 receptor (ER) and significantly increase the risk of colorectal cancer. Patients that received E2 replacement therapy were found to have a reduction in the incidence of colon adenoma and carcinoma. Furthermore, significant decreases in the expression of ER have been found in colorectal cancer specimens. These data strongly suggest the protective roles of E2 and ER against colorectal cancer. However, the mechanisms remain unexplored. LoVo cells were transient transfected to overexpress ER-beta, DNA fragmentation and caspase activity assay were performed to evaluate apoptotic effects. Western blotting was used to evaluate protein levels, and luciferase activity assay to measure the TNF-alpha promoter activity. Our data clearly demonstrated that E2 and ER-beta alone could upregulate p21 and p27 proteins, which further activate caspase-8 and caspase-9 to induce apoptosis in LoVo cell, and the ER-beta. effects were enhanced by E2. However, overexpressed ER-beta did not influence the expression and promoter activity of TNF-alpha. In addition, E2 and overexpressed ER-beta downregulated the beta-catenin proteins which cause the downregulation of its target genes, cyclin D1 and Rb, to inhibit the cell cycle and cell proliferation. The results indicate that overexpressed ER-beta may induce LoVo cell apoptosis and anti-proliferation by increasing p53 signaling in a ligand-dependent manner, and without hTNF-alpha involvement. Efforts aiming at enhancing ER-beta expression and/or activity may prove to be an attractive alternative therapy against colorectal cancer.

Over-expressed estrogen receptor-alpha up-regulates hTNF-alpha gene expression and down-regulates beta-catenin signaling activity to induce the apoptosis and inhibit proliferation of LoVo colon cancer cells.

Epidemiologic studies reported that the prevalence of hereditary non-polyposis colon cancer (HNPCC) in male is about 1.5-fold higher than that in female. Decreases in circulatory estrogen (E(2)) have been reported to downregulate the expression of E(2) receptor (ER) and significantly increase the risk of colorectal cancer. Patients that received E(2) replacement therapy were found to have a reduction in the incidence of colon adenoma and carcinoma. Furthermore, significant decreases in the expression of ER have been found in colorectal cancer specimens. Evidences strongly suggest the protective roles of E(2) and ER against colorectal cancer. However, the mechanisms of ERalpha effects on colorectal cancer cells remained un-clear. LoVo cells were transient transfected to overexpress ERalpha, DNA fragmentation and the activated caspases measurements were performed to evaluate apoptotic effects. Western blotting was used to evaluate protein levels, and luciferase activity assay to measure the Htnf-a promoter activity. The results clearly demonstrated that overexpressed ERalpha with or without E(2) (10(-8) M) treatment could activate caspase -8, -9, and 3 and induce DNA fragmentation in LoVo cell. At the same time, overexpressed ERalpha plus E(2) significantly increases the expression and promoter activity of hTNF-alpha, and the DNA fragmentation effect induced by E(2) plus ERalpha were reduced by the addition of hTNF antibody (0.1 ng(ml). In addition, E(2) plus ERalpha significantly upregulated p21 and p27 levels and downregulated the beta-catenin and its target genes, cyclin D1 and Rb, which regulate the cell cycle and cell proliferation. The results indicate that E(2) plus overexpressed ERalpha induce LoVo cell apoptosis might mediate through the increase of hTNF-alpha gene expression, which in turn activate caspase-8, -9 and caspase-3 and lead to the DNA fragmentation and apoptosis. E(2) plus ERalpha also showed the downregulation of beta-catenin signalings implicating the suppression of proliferation and metastasis of colorectal cells. Efforts aiming at enhancing ERalpha expression and(or activity may be proved to be an alternative therapy against colorectal cancer.

Fatigue patterns and correlates in male liver cancer patients receiving transcatheter hepatic arterial chemoembolization.

Liver cancer is a leading cancer in Taiwan, especially in males. Transcatheter arterial chemoembolization (TACE) is a major treatment for these patients, but research examining their fatigue experiences is limited. The purposes of this longitudinal, correlational study were to identify (1) changes in fatigue, symptom distress, anxiety and depression in cancer patients across four time points during the first week of TACE treatment, and (2) factors predicting changes in fatigue across the four time points. Eligible male inpatients with liver cancer were recruited from a medical center in Taipei. Subjects (n=40) were assessed 1 day before (T1), and during days 2 (T2), 4 (T3) and 6 (T4) of TACE. Data were analyzed by descriptive statistics, Pearson's correlations, repeated measures analysis of variance (ANOVA) and the generalized estimating equation (GEE). Subjects had mild to moderate levels of fatigue that peaked at T2, and showed a decrease at T3 and T4 but were still slightly higher than at T1. The GEE analysis showed that greater symptom distress, anxiety and depression, higher Adriamycin dosage, longer duration of previous fatigue, and less education significantly predicted fatigue changes. The results indicate that the pattern of fatigue in TACE during the first week is similar to fatigue in patients receiving chemotherapy. The results also further indicate that fatigue is associated to several factors. The causal relationships between fatigue and these related factors should be examined. Interventions targeting these factors should also be tested in future studies.