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.

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 Evaluation of 8-(o-Tolyl)quinazoline Derivatives as Small-Molecule PD-1/PD-L1 Antagonists.

Small-molecule inhibitors targeting programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions can compensate for the shortcomings of antibody-based inhibitors and have attracted considerable attention, some of which have already entered clinical trials. Herein, based on our previous study on small-molecule PD-L1 inhibitors, we reported a series of 8-(o-tolyl)quinazoline derivatives by the skeleton merging strategy. Homogenous time-resolved fluorescence (HTRF) assay against PD-1/PD-L1 interaction identified compound A5, which showed the most potent inhibition with an IC50 value of 23.78 nM. Meanwhile, based on the results of HTRF assay, the structure-activity relationships (SARs) of the tail were focused on. Cell-based PD-1/PD-L1 blockade assay further revealed that A5 significantly blocked the PD-1/PD-L1 interaction at 1.1 µM in the co-culture system of Jurkat-NFAT-PD-1 cells and Hep3B-OS8-hPD-L1 cells with no significant cytotoxicity on Jurkat cells. Moreover, the proposed binding mode of A5 was investigated by a docking analysis. These results indicate that compound A5 is a promising lead compound that deserves further investigation.

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.

Weight Gain After Antiretroviral Therapy Initiation and Subsequent Risk of Metabolic and Cardiovascular Disease.

BACKGROUND: Weight gain following initiation of antiretroviral therapy (ART) is common. We assessed the impact of changes in weight in the year following ART initiation with subsequent cardiometabolic disease among AIDS Clinical Trials Group (ACTG) participants. METHODS: Linear regression models were fit to examine the association between change in weight/waist circumference (WC) in weeks 0-48 and change in metabolic parameters in weeks 0-48 and 48-96. Cox proportional hazard models were fit to examine the association between changes in weight/WC in weeks 0-48 and diabetes mellitus (DM), metabolic syndrome, or cardiometabolic and cardiovascular events after week 48. RESULTS: Participants (N = 2624) were primarily male (81%) and non-White (60%). Mean weight gain from 0-48 weeks was 3.6 kg (SD 7.3); 130 participants developed DM; 360 metabolic syndrome; 424 any cardiometabolic event; 28 any cardiovascular event, over 480 weeks of follow-up. In adjusted models, total cholesterol increased by 0.63 mg/dL (95% confidence interval [CI] [.38, .089]) and LDL by 0.39 mg/dL (0.19, 0.59) per 1 kg increase in weight from weeks 0 to48. Participants who experienced >10% weight gain (vs -5% to 5%) had an increased risk of DM (hazard ratio [HR] 2.01, 95% CI [1.30, 3.08]), metabolic syndrome (HR 2.24, 95% CI [1.55, 2.62]), and cardiometabolic outcomes (HR 1.54, 95% CI [1.22, 1.95]). Participants who lost more than 5% of their baseline weight had a lower risk of incident metabolic syndrome (HR 0.67, 95% CI [0.42, 1.07]). Trends for WC were similar. CONCLUSIONS: Weight and body composition changes in the first year following ART initiation are associated with contemporaneous changes in metabolic parameters and subsequent cardiometabolic disease.

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.

1-Year Incidence of Tuberculosis Infection and Disease Among Household Contacts of Rifampin- and Multidrug-Resistant Tuberculosis.

BACKGROUND: Tuberculosis infection (TBI) and TB disease (TBD) incidence remains poorly described following household contact (HHC) rifampin-/multidrug-resistant TB exposure. We sought to characterize TBI and TBD incidence at 1 year in HHCs and to evaluate TB preventive treatment (TPT) use in high-risk groups. METHODS: We previously conducted a cross-sectional study of HHCs with rifampin-/multidrug-resistant TB in 8 high-burden countries and reassessed TBI (interferon-gamma release assay, HHCs aged ≥5 years) and TBD (HHCs all ages) at 1 year. Incidence was estimated across age and risk groups (<5 years; ≥5 years, diagnosed with human immunodeficiency virus [HIV]; ≥5 years, not diagnosed with HIV/unknown, baseline TBI-positive) by logistic or log-binomial regression fitted using generalized estimating equations. RESULTS: Of 1016 HHCs, 850 (83.7%) from 247 households were assessed (median, 51.4 weeks). Among 242 HHCs, 52 tested interferon-gamma release assay-positive, yielding a 1-year 21.6% (95% confidence interval [CI], 16.7-27.4) TBI cumulative incidence. Sixteen of 742 HHCs developed confirmed (n = 5), probable (n = 3), or possible (n = 8) TBD, yielding a 2.3% (95% CI, 1.4-3.8) 1-year cumulative incidence (1.1%; 95% CI, .5-2.2 for confirmed/probable TBD). TBD relative risk was 11.5-fold (95% CI, 1.7-78.7), 10.4-fold (95% CI, 2.4-45.6), and 2.9-fold (95% CI, .5-17.8) higher in age <5 years, diagnosed with HIV, and baseline TBI high-risk groups, respectively, vs the not high-risk group (P = .0015). By 1 year, 4% (21 of 553) of high-risk HHCs had received TPT. CONCLUSIONS: TBI and TBD incidence continued through 1 year in rifampin-/multidrug-resistant TB HHCs. Low TPT coverage emphasizes the need for evidence-based prevention and scale-up, particularly among high-risk groups.

Corrigendum to "The development of a sensitive fluorescent protein-based transcript reporter for high throughput screening of negative modulators of lncRNAs" [Genes & Diseases 5 (2018) 62-74].

[This corrects the article DOI: 10.1016/j.gendis.2018.02.001.].

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.

Regional Differences in Risk of Recurrent Falls Among Older U.S. Women and Men with HIV in the HIV Infection, Aging, and Immune Function Long-Term Observational Study.

Geographic location was a strong predictor of falls among women with and without HIV in the Women's Interagency HIV Study. We examined regional variation in falls in a more geographically diverse cohort of older people with HIV (PWH) and explored whether physical activity, sex, or body-mass index modified these associations. PWH enrolled in the A5322 HAILO (HIV Infection, Aging, and Immune Function Long-Term Observational Study). Participants who reported falls in the 6 months before each semiannual visit and had ≥1 consecutive pair of fall assessments were included. We examined associations of geographic region [Northeast, Midwest, South, and West] with recurrent falls (≥2) over each 12-month period using repeated measures multinomial logistic regression models and assessed effect modification by adding an interaction term between geographic region and each potential effect modifier. A total of 788 men and 192 women with median age of 51 years at study entry contributed up to 240 weeks of data. U.S. regions included Northeast (22%), Midwest (29%), South (20%), and West (28%). In multivariable analyses, compared with the Western region, greater risk was seen among Midwestern (odds ratio [OR] = 2.35 [95% confidence interval (CI) = 1.29-4.28]) and Southern regions (OR = 2.09 [95% CI = 1.09-4.01]). Among those with higher physical activity, the Midwestern region had higher odds of recurrent falls than the Western region. Among obese individuals, the Southern region had higher odds of recurrent falls than the Western region. Sex did not modify the association between region and recurrent falls. Among older PWH, fall risk varied by geographic region. Associations between geographic region and recurrent falls appeared to be modified by physical activity and obesity. This may help identify subgroups of older PWH for targeted fall screening/interventions.

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.

A Semimechanistic Pharmacokinetic Model for Depot Medroxyprogesterone Acetate and Drug-Drug Interactions With Antiretroviral and Antituberculosis Treatment.

Depot medroxyprogesterone acetate is an injectable hormonal contraceptive, widely used by women of childbearing potential living with HIV and/or tuberculosis. As medroxyprogesterone acetate is a cytochrome P450 (CYP3A4) substrate, drug-drug interactions (DDIs) with antiretroviral or antituberculosis treatment may lead to subtherapeutic medroxyprogesterone acetate concentrations (< 0.1 ng/mL), resulting in contraception failure, when depot medroxyprogesterone is dosed at 12-week intervals. A pooled population pharmacokinetic analysis with 744 plasma medroxyprogesterone acetate concentrations from 138 women treated with depot medroxyprogesterone and antiretroviral/antituberculosis treatment across three clinical trials was performed. Monte Carlo simulations were performed to predict the percentage of participants with subtherapeutic medroxyprogesterone acetate concentrations and to derive alternative dosing strategies. Medroxyprogesterone acetate clearance increased by 24.7% with efavirenz coadministration. Efavirenz plus antituberculosis treatment (rifampicin + isoniazid) increased clearance by 52.4%. Conversely, lopinavir/ritonavir and nelfinavir decreased clearance (28.7% and 15.8%, respectively), but lopinavir/ritonavir also accelerated medroxyprogesterone acetate's appearance into the systemic circulation, thus shortening the terminal half-life. A higher risk of subtherapeutic medroxyprogesterone acetate concentrations at Week 12 was predicted on a typical 60-kg woman on efavirenz (4.99%) and efavirenz with antituberculosis treatment (6.08%) when compared with medroxyprogesterone acetate alone (2.91%). This risk increased in women with higher body weight. Simulations show that re-dosing every 8 to 10 weeks circumvents the risk of subtherapeutic medroxyprogesterone acetate exposure associated with these DDIs. Dosing depot medroxyprogesterone every 8 to 10 weeks should eliminate the risk of subtherapeutic medroxyprogesterone acetate exposure caused by coadministered efavirenz and/or antituberculosis treatment, thus reducing the risk of contraceptive failure.

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.