A case-matched study of imatinib mesylate between different formulations on plasma trough concentration, adverse events, quality of life and outcomes in gastrointestinal stromal tumor patients.

Genike, the imatinib (IM)-alpha form is widely used in the treatment of gastrointestinal stromal tumor (GIST) patients in China. We wanted to investigate whether there are differences in IM plasma concentrations, adverse events, health-related quality of life (QOL) and outcomes between patients treated with Genike and Glivec. Thirty included GIST patients receiving IM treatment were matched to either Genike or Glivec according to gastrectomy, body weight, body surface area and sex. There was no statistically significant difference in IM trough plasma levels between the two groups. There were no significant differences in very common adverse events of IM between the Genike and Glivec groups. IM was well tolerated, although it was associated with a significant change in cognitive function (P < 0.001), fatigue (P = 0.015), pain (P = 0.015), nausea/vomiting (P = 0.029), insomnia (P = 0.019), diarrhea (P = 0.003) and financial difficulties (P < 0.001). Physical functioning, financial burden and insomnia were significantly different between the two groups (P = 0.026). Until Aug. 2022, there was no significant difference in time to imatinib treatment failure (TTF) between the two groups. In conclusion, there was no difference in IM plasma concentration and adverse events between Genike and Glivec. Both Genike and Glivec could partially decrease the QOL of GIST patients. Physical functioning was worse in Genike group than in Glivec group, while the economic burden and symptoms of insomnia in Glivec patients were worse. There was no significant difference in TTF between the two groups.

Design, synthesis and biological evaluation of 5H-[1,2,4]triazino[5,6-b]indole derivatives bearing a pyridinocycloalkyl moiety as iron chelators.

The avidity of cancer cells for iron highlights the potential for iron chelators to be used in cancer therapy. Herein, we designed and synthesized a novel series of 5H-[1,2,4]triazino[5,6-b]indole derivatives bearing a pyridinocycloalkyl moiety using a ring-fusion strategy based on the structure of an iron chelator, VLX600. The antiproliferative activity evaluation against cancer cells and normal cells led to the identification of compound 3k, which displayed the strongest antiproliferative activity in vitro against A549, MCF-7, Hela and HepG-2 with IC50 values of 0.59, 0.86, 1.31 and 0.92 µM, respectively, and had lower cytotoxicity against HEK293 than VLX600. Further investigations revealed that unlike VLX600, compound 3k selectively bound to ferrous ions, but not to ferric ions, and addition of Fe2+ abolished the cytotoxicity of 3k. Flow cytometry assays demonstrated that 3k arrested the cell cycle at the G1 phase and induced significant apoptosis in A549 cells in dose and time-dependent manners, corresponding to JC-1 staining assay results. Western blot analysis of Bcl-2, Bax and cleaved caspase-3 proteins further provided evidences that induction of apoptosis by 3k in A549 cells might be at least via the mitochondria pathway. These above results highlight that 3k is a valuable lead compound that deserves further investigation as an iron chelator for the treatment of cancer.

Contribution of genetic polymorphism in ABCB1 to individual variations of imatinib plasma levels in patients with gastrointestinal stromal tumor.

Background: Imatinib mesylate (IM) is a first-line treatment option for the majority of patients diagnosed with gastrointestinal stromal tumors (GISTs). Although the clinical benefit is high, interindividual response is variable. This study thus aimed to assess how genetic polymorphisms can affect the blood levels of IM and treatment outcomes in patients with GIST. Methods: A total of 31 single-nucleotide polymorphisms (SNPs) in selected cytochrome P450 (P450), ATP-binding cassette transporter (ABC), solute carrier family (SLC), interleukin-4 receptor (IL4R), and vascular endothelial growth factor (VEGF) genes were genotyped using an SNP mass array platform. A total of 192 consecutive patients with GIST who received 400 mg of IM daily were enrolled into the study, with 1,485 blood samples being analyzed. According to genotypes, IM trough concentrations were tested and compared. Progression-free survival (PFS) and overall survival (OS) were also assessed. Results: With a mean follow-up of 75.99 months, trough concentrations of imatinib were examined at average time points of 7.73 for each patient. Polymorphism in ABCB1 rs1045642 was found to be associated with steady-state IM trough plasma levels (P=0.008). Patients with the C genotype (CT + CC) of rs1045642 exhibited higher IM trough concentrations (1,271.09±306.69 ng/mL) compared to those with the TT genotype (1,106.60±206.05 ng/mL). No statistically significant differences in IM plasma concentration were observed for the other SNPs tested. None of the tested SNPs displayed a significant association with patients' survival in this study. Conclusions: This is the largest cohort study evaluating the associations of SNP and imatinib blood trough levels. The ABCB1 rs1045642 genetic polymorphism may exert an effect on the pharmacokinetics of imatinib. The presence of the C allele in ABCB1 rs1045642 is predictive of a higher plasma concentration of IM.

Liraglutide improved the reproductive function of obese mice by upregulating the testicular AC3/cAMP/PKA pathway.

BACKGROUND: The incidence of male reproductive dysfunction is increasing annually, and many studies have shown that obesity can cause severe harm to male reproductive function. The mechanism of male reproductive dysfunction caused by obesity is unclear, and there is no ideal treatment. Identification of effective therapeutic drugs and elucidation of the molecular mechanism involved in male reproductive health are meaningful. In this study, we investigated the effects of the GLP-1 receptor agonist liraglutide on sex hormones, semen quality, and testicular AC3/cAMP/PKA levels in high-fat-diet-induced obese mice. METHODS: Obese mice and their lean littermates were treated with liraglutide or saline for 12 weeks. Body weight was measured weekly. Fasting blood glucose (FBG) was measured using a blood glucose test strip. The serum levels of insulin (INS), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), free testosterone (F-TESTO), estradiol (E2), and sex hormone binding globulin (SHBG) were detected using ELISA. The sperm morphology and sperm count were observed after Pap staining. The mRNA and protein expression levels of testicular GLP-1R and AC3 were measured by RT-qPCR and Western blot, respectively. Testicular cAMP levels and PKA activity were detected using ELISA. RESULTS: Liraglutide treatment can decrease body weight, FBG, INS, HOMA-IR, E2 and SHBG levels; increase LH, FSH, T, and F-TESTO levels; increase sperm count; decrease the sperm abnormality rate; and increase GLP-1R and AC3 expression levels and cAMP levels and PKA activity in testicular tissue. CONCLUSIONS: Liraglutide can improve the sex hormone levels and semen quality of obese male mice. In addition to its weight loss effect, liraglutide can improve the reproductive function of obese male mice, which may also be related to the upregulation of AC3/cAMP/PKA pathway in the testis. This work lays the groundwork for future clinical studies.

Efficacy and safety of ripretinib vs. sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: A phase 2, multicenter, randomized, open-label study in China.

AIM: A bridging study of INTRIGUE study to assess the efficacy and safety of ripretinib versus sunitinib as second-line treatment in Chinese GIST patients. METHODS: This was a phase 2, multicenter, randomized, open-label study in China. GIST patients previously treated with imatinib were randomized (1:1) to receive ripretinib 150 mg once daily (QD) by continuous dosing in 42-day cycles or sunitinib 50 mg QD in 42-day cycles (four weeks on/two weeks off). Primary endpoint was progression-free survival (PFS) by independent radiological review (IRR). RESULTS: Between 6 December 2020 and 15 September 2021, 108 patients were randomized to receive ripretinib (n = 54) or sunitinib (n = 54) (all-patient [AP] intention-to-treat [ITT] population). Seventy patients had primary KIT exon 11 mutations (ripretinib, n = 35; sunitinib, n = 35; Ex11 ITT population). By data cut-off (20 July 2022), in AP ITT population, PFS by IRR was comparable between ripretinib and sunitinib arms (HR 0·99, 95 % CI 0·57, 1·69; nominal p = 0·92; median PFS [mPFS] 10·3 vs 8·3 months). In Ex11 ITT population, PFS by IRR was longer for ripretinib than sunitinib (HR 0·46, 95 % CI 0·23, 0·92; nominal p = 0·03; mPFS not reached in ripretinib arm and 4·9 months in sunitinib arm). Fewer patients experienced grade 3/4 treatment-related treatment-emergent adverse events with ripretinib (17%) versus sunitinib (56%). CONCLUSIONS: Ripretinib demonstrated similar efficacy and a favorable safety profile versus sunitinib as second-line treatment in Chinese GIST patients. Furthermore, ripretinib provided greater clinically meaningful benefit versus sunitinib in patients with KIT exon 11 mutation.

Design, synthesis and biological evaluation of VEGFR-2/HDAC dual inhibitors as multitargeted antitumor agents based on fruquintinib and vorinostat.

Herein, a series of 4-(benzofuran-6-yloxy)quinazoline derivatives as VEGFR-2/HDAC dual inhibitors were designed and synthesized based on fruquintinib and vorinostat. Among them, compound 13 exhibited potent inhibitory activity against VEGFR-2 and HDAC1 with IC50 values of 57.83 nM and 9.82 nM, and displayed moderate to significant antiproliferative activity against MCF-7, A549, HeLa and HUVEC. The cellular mechanism studies revealed that compound 13 arrested the cell cycle at the S and G2 phases, and induced significant apoptosis in HeLa cells. Tube formation assay in HUVECs demonstrated that 13 had a significant anti-angiogenic effect. Additionally, a molecular docking study supported the initial design strategy. These results highlighted that 13 was a valuable VEGFR-2/HDAC dual inhibitor and deserved further study for cancer therapy.

Changes in imatinib plasma trough level during long-term treatment in patients with intermediate- or high-risk gastrointestinal stromal tumors: Relationship between covariates and imatinib plasma trough level.

Background: Imatinib is the first-line adjuvant treatment for gastrointestinal stromal tumors (GISTs). Considering that some studies have suggested that imatinib (IM) plasma trough levels (Cmin) change with time, the aim of this study is to assess the changes in IM Cmin in patients with GIST in a long-term study and to elucidate the relationships between clinicopathological features and IM Cmin. Methods: In 204 patients with intermediate- or high-risk GIST who were taking IM, IM Cmin was analyzed. Patient data were grouped according to the duration of medication (A: 1-3 months, B: 4-6 months, C: 7-9 months, D: 10-12 months, E: ≤12 months, F: 12<-≤36 months, G: >36 months). The correlation between IM Cmin at different time stages and clinicopathological characteristics was assessed. Results: Statistically significant differences were observed between Groups A, C, and D (P = 0.049 and 0.01, respectively). In Group E, IM Cmin correlated with sex (P = 0.049) and age (P = 0.029) and negatively correlated with body weight, height, and body surface area (P = 0.007, 0.002, and 0.001, respectively). In Groups F and G, IM Cmin was significantly higher in non-gastric operation patients than in patients with gastrectomy (P = 0.002, 0.036) and was significantly higher in patients with the primary sites of others than in the stomach (P < 0.001, = 0.012). In addition, IM Cmin was much higher in patients with mutation sites other than KIT exon 11 in Group F (P = 0.011). Conclusion: This is the first study of IM Cmin during the long-term treatment of patients with intermediate- or high-risk GIST. IM Cmin was the highest for the first 3 months and then declined, and long-term administration of IM showed a relatively stable plasma trough level. The IM Cmin correlated with different clinical characteristics at different durations of medication. This meant that future "trough level-clinicopathological characteristics" analyses should be time-point-specific. We also need to formulate time-specific medication monitoring plans in clinical practice to study disease progression caused by the occurrence of drug resistance.

Factors associated with prevalent Mycobacterium tuberculosis infection and disease among adolescents and adults exposed to rifampin-resistant tuberculosis in the household.

BACKGROUND: Understanding factors associated with prevalent Mycobacterium tuberculosis infection and prevalent TB disease in household contacts of patients with drug-resistant tuberculosis (TB) may be useful for TB program staff conducting contact investigations. METHODS: Using data from a cross-sectional study that enrolled index participants with rifampin-resistant pulmonary TB and their household contacts (HHCs), we evaluated HHCs age ≥15 years for factors associated with two outcomes: Mycobacterium tuberculosis infection and TB disease. Among HHCs who were not already diagnosed with current active TB disease by the TB program, Mycobacterium tuberculosis infection was determined by interferon-gamma release assay (IGRA). TB disease was adjudicated centrally. We fitted logistic regression models using generalized estimating equations. RESULTS: Seven hundred twelve HHCs age ≥15 years enrolled from 279 households in eight high-TB burden countries were a median age of 34 years, 63% female, 22% current smokers and 8% previous smokers, 8% HIV-positive, and 11% previously treated for TB. Of 686 with determinate IGRA results, 471 tested IGRA positive (prevalence 68.8% (95% Confidence Interval: 64.6%, 72.8%)). Multivariable modeling showed IGRA positivity was more common in HHCs aged 25-49 years; reporting prior TB treatment; reporting incarceration, substance use, and/or a period of daily alcohol use in the past 12 months; sharing a sleeping room or more evenings spent with the index participant; living with smokers; or living in a home of materials typical of low socioeconomic status. Forty-six (6.5% (95% Confidence Interval: 4.6%, 9.0%)) HHCs age ≥15 years had prevalent TB disease. Multivariable modeling showed higher prevalence of TB disease among HHCs aged ≥50 years; reporting current or previous smoking; reporting a period of daily alcohol use in the past 12 months; and reporting prior TB treatment. CONCLUSION: We identified overlapping and distinct characteristics associated with Mycobacterium tuberculosis infection and TB disease that may be useful for those conducting household TB investigations.

Primary Localized Gastrointestinal Stromal Tumors: Medication Adherence and Prognosis According to Gender.

Objective: Gender is associated with medication adherence for imatinib, but whether it is related to the prognosis of primary localized gastrointestinal stromal tumors (GISTs) is unclear. The goal of this study was to clarify the relationship between gender and prognosis in GIST patients, with differences in medication adherence considered. Methods: The data of 320 GIST patients were retrospectively collected from the First Affiliated Hospital of Chongqing Medical University. Survival analysis was performed using the Kaplan-Meier method (Log rank test) and the risk factors of recurrence were determined using Cox multivariate analysis. Medication adherence-stratified analyses were performed to control for confounding factors. Results: Kaplan-Meier analysis revealed that among patients who received postoperative adjuvant imatinib therapy, men had a higher recurrence rate than women (P<0.01). Pearson's chi-square test revealed better medication adherence in women than in men (P<0.01). Cox regression analysis revealed that gender was not an independent risk factor for recurrence-free survival (RFS; P=0.25), but medication adherence was (P<0.01). Among GIST patients with a medication possession ratio (MPR) of less than 90%, 62.86% of male patients took imatinib irregularly or not at all due to limited understanding of the disease, whereas 55.74% of female patients' took imatinib irregularly because they could not tolerate adverse drug reactions. Conclusion: Adherence was poorer in male than in female patients, which might explain the worse prognoses of the former among patients who received adjuvant treatment with imatinib. The gender difference in the degree of adherence should be considered in postoperative pharmacotherapy for patients with primary localized GISTs.

Expression of HIF-1α, ANXA3, CD133 and their associations with clinicopathological parameters in human colon carcinoma.

Background: Our previous study found an association between the expression of hypoxia-inducible factor-1alpha (HIF-1α) and annexin A3 (ANXA3) in colon cancer. ANXA3 correlated with expansion of CD133+ tumor cells in hepatocellular carcinoma cancer stem-like cells (CSCs), for which CD133 has been recognized as a typical marker in many cancer cells, including: gastric cancer, lung cancer and colorectal cancer. But the expression and association of HIF-1α, ANXA3 and CD133 in colon cancer has not been reported. The purpose of the present study was to evaluate the correlation among the expression of HIF-1α, ANXA3 and CD133 in human colon cancer and to investigate its clinicopathological parameters. Methods: The data for 35 patients diagnosed with colon adenocarcinoma in The First Affiliated Hospital of Chongqing Medical University and who had undergone colectomy, tumor and adjacent normal colon tissues were collected. The expressions of HIF-1α, ANXA3, and CD133 were measured by immunohistochemistry in colon cancer and surrounding non-tumor tissues and measured by using a semiquantitative score system. Finally, relationships between HIF-1α, ANXA3, and CD133 immunohistochemical staining and clinicopathologic variables were analyzed using the Fisher's exact probability test. Associations between the expression levels of HIF-1α, ANXA3, and CD133 were analyzed by the Spearman's rank correlation. Results: The positive rate of expression of HIF-1α in colon cancer and normal colon tissue was 80% (28/35) and 14% (5/35), 77% (27/35) and 20% (7/35) for ANXA3, and 71% (25/35) and 23% (8/35) for CD133, respectively. The coefficient of correlation for the association among HIF-1α, ANXA3 and CD133 showed that the expression of HIF-1α was positively related with ANXA3 and CD133 in colon cancer tissues (r1=0.408, P1=0.015, r2=0.474, P2=0.004) and a positive correlation was observed between the expression of ANXA3 and CD133 (r3=0.409, P3=0.015). Expression of HIF-1α, ANXA3 and CD133 were associated with tumor size, lymphatic metastasis and clinic stage of colon cancer (all P<0.05). Conclusions: HIF-1α, ANXA3 and CD133 were overexpressed in human colon cancer and showed positive correlations among themselves. The expression of HIF-1α, ANXA3 and CD133 were closely related to the size of the tumor, lymphatic metastasis and clinical stage of colon cancer, which indicated that they could be promising biomarkers for the study of colon CSCs and treatment of colon carcinoma.

Comparison of the Suitability Between NRS2002 and MUST as the First-Step Screening Tool for GLIM Criteria in Hospitalized Patients With GIST.

Objective: The Global Leader Initiative on Malnutrition (GLIM) criteria have been recommended for malnutrition diagnosis recently, for which the first step is malnutrition risk screening with any validated tool. This study aims to investigate the incidence of malnutrition risk in gastrointestinal stromal tumor (GIST) inpatients and compare the suitability of Nutritional Risk Screening 2002 (NRS2002) and Malnutrition Universal Screening Tool (MUST) as the first-step screening tool for GLIM criteria. Methods: We retrospectively analyzed the clinical data of GIST inpatients in our hospital from January 2015 to December 2019. NRS2002 and MUST were used to screen malnutrition risk at the time of admission. The diagnostic consistency of these two tools with GLIM criteria for malnutrition was analyzed, and the predictive performance of both tools for the length of hospital stay and the occurrence of complications was also evaluated in surgical and non-surgical inpatients. Results: A total of 269 GIST inpatients were included in this study, of which 45.7 and 40.9% were at malnutrition risk determined by NRS2002 and MUST, respectively. In non-surgical inpatients, NRS2002 and MUST had similar diagnostic consistency with GLIM criteria in sensitivity (93.0 vs. 97.7%), specificity (81.1 vs. 81.1%), and Kappa value (K = 0.75 vs. 0.80), and high nutritional risk classified by NRS2002 and malnutrition identified by GLIM criteria were found to be associated with the length of hospital stay. In surgical inpatients, MUST had better diagnostic consistency with GLIM criteria in sensitivity (86.1 vs. 53.5%) and Kappa value (K = 0.61 vs. 0.30) than NRS2002, but no factors were found associated with the length of postoperative hospital stay or the occurrence of complications. Conclusion: The malnutrition risk is common in GIST inpatients. NRS2002 is more suitable than MUST for the first-step risk screening of the GLIM scheme in non-surgical inpatients, considering its better performance in screening malnutrition risk and predicting clinical outcomes. MUST was found to have good diagnostic consistency with GLIM criteria for malnutrition in both non-surgical and surgical GIST inpatients, and further studies need to be conducted to investigate its predictive performance on clinical outcomes.

High Prevalence of Tuberculosis Infection and Disease in Child Household Contacts of Adults With Rifampin-resistant Tuberculosis.

BACKGROUND: Household contact (HHC) investigation is an important strategy to identify individuals with tuberculosis (TB) exposure, infection and disease, including those who may benefit from tuberculosis preventive therapy (TPT). Data in children exposed to rifampin-resistant TB are limited. METHODS: In preparation for and to inform the feasibility of an interventional trial, HHC of adults with pulmonary rifampin-resistant TB from high TB-burden countries were evaluated in a cross-sectional study. Using interferon-gamma release assay and study-specific and 2015 international consensus definitions of intrathoracic TB in children, we evaluated the prevalence and predictors of TB infection and disease in child (<15 years) HHCs. RESULTS: Of 303 child HHCs, median age (range) 7 years (0-14), 57% [95% confidence interval (CI): 50%-64%] had a positive interferon-gamma release assay result (TB infected). TB infection was associated with the index case smoking (P = 0.034), being the parent or sleeping in the same room (P = 0.002) and the child HHC being age ≥5 years and having attended school (P = 0.013). Four had study-defined confirmed TB and 9 had probable TB, a prevalence of 4.3% (95% CI: 2.6%-7.1%). Using the international consensus definitions, 4 had confirmed TB and 49 had unconfirmed TB, a prevalence of 17.2% (95% CI: 12.9%-22.4%). Twenty (7%) children had received TPT. CONCLUSIONS: The prevalence of TB infection and disease was high in child HHC exposed to rifampin-resistant TB. Few children had routinely received TPT. High-quality evidence is needed to inform strong recommendations for and access to TPT in children exposed to TB resistant to rifampin.

Safety and Pharmacokinetics of Double-Dose Lopinavir/Ritonavir + Rifampin Versus Lopinavir/Ritonavir + Daily Rifabutin for Treatment of Human Immunodeficiency Virus-Tuberculosis Coinfection.

BACKGROUND: Protease inhibitor-based antiretroviral therapy may be used in resource-limited settings in persons with human immunodeficiency virus and tuberculosis (HIV-TB). Data on safety, pharmacokinetics/pharmacodynamics (PK/PD), and HIV-TB outcomes for lopinavir/ritonavir (LPV/r) used with rifampin (RIF) or rifabutin (RBT) are limited. METHODS: We randomized adults with HIV-TB from July 2013 to February 2016 to arm A, LPV/r 400 mg/100 mg twice daily + RBT 150 mg/day; arm B, LPV/r 800 mg/200 mg twice daily + RIF 600 mg/day; or arm C, LPV/r 400 mg/100 mg twice daily + raltegravir (RAL) 400 mg twice daily + RBT 150 mg/day. All received two nucleoside reverse transcriptase inhibitors and other TB drugs. PK visits occurred on day 12 ± 2. Within-arm HIV-TB outcomes were summarized using proportions and 95% CIs; PK were compared using Wilcoxon tests. RESULTS: Among 71 participants, 52% were women; 72% Black; 46% Hispanic; median age, 37 years; median CD4+ count, 130 cells/mm3; median HIV-1 RNA, 4.6 log10 copies/mL; 46% had confirmed TB. LPV concentrations were similar across arms. Pooled LPV AUC12 (157 203 hours × ng/mL) and Ctrough (9876 ng/mL) were similar to historical controls; RBT AUC24 (7374 hours × ng/mL) and Ctrough (208 ng/mL) were higher, although 3 participants in arm C had RBT Cmax <250 ng/mL. Proportions with week 48 HIV-1 RNA <400 copies/mL were 58%, 67%, and 61%, respectively, in arms A, B, and C. CONCLUSIONS: Double-dose LPV/r+RIF and LPV/r+RBT 150mg/day had acceptable safety, PK and TB outcomes; HIV suppression was suboptimal but unrelated to PK. Faster RBT clearance and low Cmax in 3 participants on RBT+RAL requires further study.

Ripretinib in treatment of repeatedly relapsing rectal gastrointestinal stromal tumor: a case report.

Gastrointestinal stromal tumor (GIST) is the most common type of gastrointestinal mesenchymal tumor. Fewer than 2% of patients with metastatic GIST treated with imatinib experience a pathologic complete response. Furthermore, response to imatinib and subsequent-line tyrosine kinase inhibitor is limited by most patients developing drug resistance; median time to progression is 2 years for imatinib, and about half a year for sunitinib and regorafenib. In recent years, ripretinib, a fourth-line medicine, is been of the most important advances in the treatment of GIST. The ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial study showed that ripretinib can significantly reduce the risk of disease progression and mortality in patients with advanced GIST ≥4 lines, and has obvious clinical activity for a variety of KIT/platelet-derived growth factor receptor α (PDGFR α) gene mutations. This paper presents a case of advanced rectal GIST treated with ripretinib in China. In the years preceding, the patient did not respond well to first-third line agent therapies. However, a partial remission (PR) of the tumor was found after 3-courses of ripretinib treatment. For GIST patients with drug-resistant mutations (both primary and secondary), treatment may be a more accurate and reasonable when mutation-inhibitor agents are prescribed at an early stage.

Therapeutic drug monitoring-based dose optimization for imatinib-associated serious cutaneous reactions in a patient with gastrointestinal stromal tumours: A case report.

WHAT IS KNOWN AND OBJECTIVE: Imatinib mesylate (IM) is the first-line therapy for unresectable or metastatic gastrointestinal stromal tumours (GISTs). Here, we report a case of successful progressive dose optimization by therapeutic drug monitoring (TDM) for a patient with GISTs who developed IM-associated serious cutaneous reactions. CASE DESCRIPTION: A 72-year-old female patient received IM at a dose of 400 mg/day for GISTs. The patient developed serious eczematoid drug eruptions and desquamation, following which IM was discontinued. One year later, the GISTs recurred with metastasis, and IM was re-administered at a dose of 100 mg/day, and the dose was gradually increased on the basis of TDM. The final dose of IM was 200 mg/day, and the trough concentration (Ctrough ) of IM was 1457.76 ng/mL. The images obtained from follow-up computed tomography (CT) showed a marked anti-tumour response. IM was well tolerated and the patient developed tolerable IM-associated cutaneous reactions. WHAT IS NEW AND CONCLUSION: The strategy of TDM-guided dose optimization makes it possible to achieve optimal clinical efficacy for patients with GISTs who develop IM-associated serious cutaneous reactions.

ANXA3 is upregulated by hypoxia-inducible factor 1-alpha and promotes colon cancer growth.

BACKGROUND: Annexin A3 (ANXA3) is overexpressed in various cancers and is a potential target for cancer treatment. However, clinical implication and biological function of ANXA3 in colon cancer remain unknown. This study aimed to investigate the relationship between hypoxia-inducible factor 1-alpha (HIF-1α) and ANXA3, and explore the function of ANXA3 in colon carcinoma. METHODS: Expression levels of HIF-1α and ANXA3 in human colon carcinoma specimens and colon cancer cell lines were detected by immunohistochemistry, real-time PCR and Western blot analysis. The proliferation of colon cancer cells was examined. Nude mice were used for xenograft tumor model, and HIF-1α siRNA or control adenovirus was injected into the tumor. RESULTS: HIF-1α and ANXA3 expression levels were higher in colon cancer tissues than their expression levels in normal colon tissues. In addition, HIF-1α and ANXA3 expression increased in colon cancer cells under hypoxic condition. Knockdown of HIF-1α decreased HIF-1α and ANXA3 expression, and inhibited the proliferation and growth of colon cancer cells. In nude mouse model, silencing HIF-1α decreased volume of xenograft tumor and ANXA3 expression. CONCLUSIONS: ANXA3 expression is upregulated by HIF-1α in colon cancer in response to hypoxic stress and contributes to colon tumor growth. ANXA3 may represent a new therapeutic target for colon carcinoma.

Pharmacokinetics and Pharmacodynamics of Depot Medroxyprogesterone Acetate in African Women Receiving Treatment for Human Immunodeficiency Virus and Tuberculosis: Potential Concern for Standard Dosing Frequency.

BACKGROUND: Effective contraception is critical to young women with HIV-associated tuberculosis (TB), as unintended pregnancy is associated with increased perinatal morbidity and mortality. The effects of co-administration of efavirenz and rifampicin on the pharmacokinetics of depot medroxyprogesterone acetate (DMPA) are unknown. We hypothesized that clearance of medroxyprogesterone acetate (MPA) would increase when given with rifampicin and efavirenz, thus increasing risk of ovulation. METHODS: This pharmacokinetics (PK) study assessed DMPA among HIV/TB coinfected women on an efavirenz-based antiretroviral treatment and rifampicin-based TB treatment. Plasma MPA concentrations and progesterone were measured predose (MPA only) and 2, 4, 6, 8, 10, and 12 weeks after a single DMPA 150 mg intramuscular injection. The primary outcome measure, MPA concentration (<0.1 ng/mL) at week 12, was assessed using exact 95% Clopper-Pearson confidence intervals. MPA PK parameters were calculated using noncompartmental analysis. RESULTS: Among 42 PK-evaluable women from 5 African countries, median age was 32 years and median CD4 was 414 cells/mm3. Five women (11.9%; 95% CI, 4.0-25.6%) had MPA <0.1 ng/mL at week 12; of these, one had MPA <0.1 ng/mL at week 10. The median clearance of MPA was 19 681 L/week compared with 12 118 L/week for historical controls. There were no adverse events related to DMPA, and progesterone concentrations were <1 ng/mL for all women for the study duration. CONCLUSIONS: DMPA, when given with rifampicin and efavirenz, was safe. MPA clearance was higher than in women with HIV not on ART, leading to subtherapeutic concentrations of MPA in 12% of women, suggesting that more frequent dosing might be needed. CLINICAL TRIALS REGISTRATION: NCT02412436.

High Expression of PhospholipaseD2 Induced by Hypoxia Promotes Proliferation of Colon Cancer Cells through Activating NF- κ Bp65 Signaling Pathway.

Hypoxia is a typical feature of colon cancer occurrence and progression. We have reported that high expression and activity of PhospholipaseD2 (PLD2) induced by hypoxia in colon cancer cells. In order to further investigate the role of PLD2 in colon cancer under hypoxic conditions. MTT assay was used to detect the proliferation of human colon cancer cells (SW480 and SW620) under hypoxic conditions by decrease the PLD2 gene expression or inhibit the activity of PLD2. Expression level of p-P65/T-P65 and Cyclin D1 were detected in those cells treated as above through using western blot and RT-PCR analysis. Effect of NF-Bp65 inhibitor (BAY-117082) on the proliferation and expression level of Cyclin D1 and PLD2 of colon cancer cells under hypoxic conditions were further analysised. As a result, decreased the expression of PLD2 or inhibited the activity of PLD2 leaded to the proliferation of hypoxia colon cancer cells reduced, and along with the expression level of p-P65/T-P65 and Cyclin D1 reduced. However, inhibition the expression level of p-P65/T-P65 lead to the proliferation and expression of Cyclin D1 in those hypoxia colon cancer cells also reduced. In vivo growth decreased in response to PLD2 and NF-Bp65 inhibition. Our study indicates that high expression of PLD2 induced by hypoxia promotes the proliferation of colon cancer cells, and it may elevate the expression level of Cyclin D1 through activating NF-Bp65 signaling pathway. Inhibition of the PLD2 expression may provide a new clue for treatment for colon cancer.

Monensin inhibits cell proliferation and tumor growth of chemo-resistant pancreatic cancer cells by targeting the EGFR signaling pathway.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly malignancies with <5% five-year survival rate due to late diagnosis, limited treatment options and chemoresistance. There is thus an urgent unmet clinical need to develop effective anticancer drugs to treat pancreatic cancer. Here, we study the potential of repurposing monensin as an anticancer drug for chemo-resistant pancreatic cancer. Using the two commonly-used chemo-resistant pancreatic cancer cell lines PANC-1 and MiaPaCa-2, we show that monensin suppresses cell proliferation and migration, and cell cycle progression, while solicits apoptosis in pancreatic cancer lines at a low micromole range. Moreover, monensin functions synergistically with gemcitabine or EGFR inhibitor erlotinib in suppressing cell growth and inducing cell death of pancreatic cancer cells. Mechanistically, monensin suppresses numerous cancer-associated pathways, such as E2F/DP1, STAT1/2, NFkB, AP-1, Elk-1/SRF, and represses EGFR expression in pancreatic cancer lines. Furthermore, the in vivo study shows that monensin blunts PDAC xenograft tumor growth by suppressing cell proliferation via targeting EGFR pathway. Therefore, our findings demonstrate that monensin can be repurposed as an effective anti-pancreatic cancer drug even though more investigations are needed to validate its safety and anticancer efficacy in pre-clinical and clinical models.

ShRNA-mediated BMI-1 gene silencing inhibits gastrointestinal stromal tumor cell telomerase activity and enhances apoptosis.

Gastrointestinal stromal tumors (GISTs) are the most frequently occurring mesenchymal tumors of the gastrointestinal tract. Telomerase activity is well acknowledged as a critical factor in oncogenesis. The objective of the present study is to evaluate the effect of BMI gene silencing on proliferation, apoptosis and telomerase activity in human GIST882 cells. GIST882 cells were transfected with a eukaryotic expression vector of an shRNA fragment. The silencing efficiency in the GIST882 cells was determined by RT-qPCR and a western blot analysis. After the shRNA-BMI-1 plasmid was transfected into the GIST882 cells and nude mice, a cell counting kit-8 (CCK-8) assay and flow cytometry were utilized to detect the GIST882 cell proliferation, the apoptosis rate and the cell cycle. Tumor growth was observed by tumor xenograft in nude mice. Telomerase activity and telomere length were detected by a Southern blot and a target region amplified polymorphism. The shRNA-BMI-1 recombinant plasmid was successfully constructed. The mRNA and protein expression of the BMI-1 gene in GIST882 cells was suppressed by the shRNA-BMI-1 recombinant plasmid. Meanwhile, BMI-1 gene silencing inhibited the cell proliferation, tumor growth, and cell cycle in the GIST882 cells. However, cell apoptosis was increased and telomerase activity was decreased with the silencing of the BMI-1 gene. Collectively, the results of this study suggest that silencing the BMI-1 gene may provide a new target for the treatment of GISTs.