A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Effects of different precursors on the structure of lignin-based biochar and its ability to adsorb benzopyrene from sesame oil.

Agricultural by-products of sesame are promising bioresources in food processing. This study extracted lignin from the by-products of sesame oil production, namely, the capsules and straw of black and white sesame. Using acid, alkali, and ethanol methods, 12 distinct lignins were obtained to prepare biochar, aiming to investigate both the structural characteristics of lignin-based biochar (LBB) and its ability to remove benzo[a]pyrene (BaP) from sesame oil. The results showed that white sesame straw was the most suitable raw material for preparing biochar. In terms of the preparation method, acid-extracted lignin biochar was more effective in removing BaP than alkaline or ethanol methods. Notably, WS-1LB (white sesame straw acid-extracted lignin biochar) exhibited the highest BaP adsorption efficiency (91.44 %) and the maximum specific surface area (1065.8187 m2/g), characterized by porous structures. The pseudo 2nd and Freundlich models were found to be the best fit for the adsorption kinetics and isotherms of BaP on LBB, respectively, suggesting that a multilayer adsorption process was dominant. The high adsorption of LBB mainly resulted from pore filling. This study provides an economical and highly efficient biochar adsorbent for the removal of BaP in oil.

Generation and characterization of antagonistic anti-human CD39 nanobodies.

CD39 is the major enzyme controlling the levels of extracellular adenosine triphosphate (ATP) via the stepwise hydrolysis of ATP to adenosine diphosphate (ADP) and adenosine monophosphate (AMP). As extracellular ATP is a strong promoter of inflammation, monoclonal antibodies (mAbs) blocking CD39 are utilized therapeutically in the field of immune-oncology. Though anti-CD39 mAbs are highly specific for their target, they lack deep penetration into the dense tissue of solid tumors, due to their large size. To overcome this limitation, we generated and characterized nanobodies that targeted and blocked human CD39. From cDNA-immunized alpacas we selected 16 clones from seven nanobody families that bind to two distinct epitopes of human CD39. Among these, clone SB24 inhibited the enzymatic activity of CD39. Of note, SB24 blocked ATP degradation by both soluble and cell surface CD39 as a 15kD monomeric nanobody. Dimerization via fusion to an immunoglobulin Fc portion further increased the blocking potency of SB24 on CD39-transfected HEK cells. Finally, we confirmed the CD39 blocking properties of SB24 on human PBMCs. In summary, SB24 provides a new small biological antagonist of human CD39 with potential application in cancer therapy.

Real-World Treatment Patterns and Clinical Outcomes in Korean Patients With AML Ineligible for First-Line Intensive Chemotherapy: A Subanalysis of the CURRENT Study, a Non-Interventional, Retrospective Chart Review.

BACKGROUND: Although most elderly patients with acute myeloid leukemia (AML) are ineligible for intensive chemotherapy (ICT), treatment options remain limited. CURRENT (UMIN000037786), a real-world, non-interventional, retrospective chart review, evaluated clinical outcomes, clinicopathologic characteristics, and treatment patterns in these patients. We present results from a subanalysis of Korean patients in this study. METHODS: Patients were aged ≥ 18 years with primary or secondary AML ineligible for ICT who initiated first-line systemic therapy or best supportive care (BSC) between 2015 and 2018 across four centers in Korea. Primary endpoint was overall survival (OS) from diagnosis. Secondary endpoints included progression-free survival (PFS), time to treatment failure, and response rates. Data analyses were primarily descriptive, with time-to-event outcomes estimated using the Kaplan-Meier method, and Cox regression used to determine prognostic factors for survival. RESULTS: Among 194 patients enrolled, 84.0% received systemic therapy and 16.0% received BSC. Median age at diagnosis was 74 and 78 years, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 was reported in 73.0% and 48.4% of patients, respectively; poor cytogenetic risk was reported in 30.1% and 16.1% of patients. Median OS was 7.83 vs. 4.50 months, and median PFS was 6.73 vs. 4.50 months in the systemic therapy vs. BSC groups. Prognostic factors affecting OS included secondary AML (hazard ratio, 1.67 [95% confidence interval, 1.13-2.45]), ECOG performance status ≥ 2 (2.41 [1.51-3.83]), poor cytogenetic risk (2.10 [1.36-3.24]), and Charlson comorbidity index ≥ 1 (2.26 [1.43-3.58]). CONCLUSION: Clinical outcomes are poor in Korean patients with AML ineligible for ICT who are prescribed current systemic therapies or BSC. There is a substantial unmet need for novel agents (monotherapy or in combination) to improve clinical outcomes in this patient population.

Neuromyelitis optica spectrum disorders associated with AQP4-positive-cancer-A case series.

Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune, astrocytopathic diseases affecting the central nervous system(CNS), especially the central optic nerve and spinal cord. Aquaporin 4-immunoglobulin G (AQP4-IgG) is the dominant pathogenic antibody and can be detected in about 80% of patients with NMOSD. Although only a few cases were reported on NMOSD associated with cancer, they demonstrated the potential paraneoplastic link between cancer and NMOSD. In the present study, we report three NMOSD cases associated with cancer, which are teratoma and lung adenocarcinoma, teratoma, and transverse colon adenocarcinoma, respectively. Pathological staining of tumor sections revealed a high AQP4 expression. After tumor removal, all cases were stable and suffered no further relapses, which revealed the potential paraneoplastic mechanism between cancer and NMOSD. One of our patient's serum AQP4-IgG was transiently slightly elevated even though AQP4 was highly expressed in tumor cells, which indicates that AQP4 is not the main pathogenic antibody but might be induced by other underlying pathogenic antibody-antigen reactions.

Evaluation of nanobody-based biologics targeting purinergic checkpoints in tumor models in vivo.

Adenosine triphosphate (ATP) represents a danger signal that accumulates in injured tissues, in inflammatory sites, and in the tumor microenvironment. ATP promotes tumor growth but also anti-tumor immune responses notably via the P2X7 receptor. ATP can also be catabolized by CD39 and CD73 ecto-enzymes into immunosuppressive adenosine. P2X7, CD39 and CD73 have attracted much interest in cancer as targets offering the potential to unleash anti-tumor immune responses. These membrane proteins represent novel purinergic checkpoints that can be targeted by small drugs or biologics. Here, we investigated nanobody-based biologics targeting mainly P2X7, but also CD73, alone or in combination therapies. Blocking P2X7 inhibited tumor growth and improved survival of mice in cancer models that express P2X7. P2X7-potentiation by a nanobody-based biologic was not effective alone to control tumor growth but enhanced tumor control and immune responses when used in combination with oxaliplatin chemotherapy. We also evaluated a bi-specific nanobody-based biologic that targets PD-L1 and CD73. This novel nanobody-based biologic exerted a potent anti-tumor effect, promoting tumor rejection and improving survival of mice in two tumor models. Hence, this study highlights the importance of purinergic checkpoints in tumor control and open new avenues for nanobody-based biologics that may be further exploited in the treatment of cancer.

Real-world treatment patterns and clinical outcomes in patients with AML in Japan who were ineligible for first-line intensive chemotherapy.

Acute myeloid leukemia (AML) predominantly affects elderly adults, and its prognosis worsens with age. Treatment options for patients in Japan ineligible for intensive chemotherapy include cytarabine/aclarubicin ± granulocyte colony-stimulating factor (CA ± G), azacitidine (AZA), low-dose cytarabine (LDAC), targeted therapy, and best supportive care (BSC). The country's aging population and the evolving treatment landscape are contributing to a need to understand treatment pathways and associated outcomes. This retrospective chart review evaluated outcomes in patients across Japan with primary/secondary AML who were ineligible for intensive chemotherapy and began first-line treatment or BSC between 01/01/2015 and 12/31/2018. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and healthcare resource utilization (HRU). Of 199 patients (58% > 75 years), 121 received systemic therapy (38 CA ± G, 37 AZA, 7 LDAC, 39 other) and 78 received BSC. Median OS was 5.4, 9.2, 2.2, 3.8, and 2.2 months for CA ± G, AZA, LDAC, other systemic therapy, and BSC, respectively; median PFS was 3.4, 7.7, 1.6, 2.3, and 2.1 months, respectively. HRU rates were uniformly high, with > 80% patients hospitalized in each cohort. The poor clinical outcomes and high HRU among Japanese AML patients who are ineligible for intensive chemotherapy highlight an unmet need for novel therapies.

Healthcare resource utilization trends in patients with acute myeloid leukemia ineligible for intensive chemotherapy receiving first-line systemic treatment or best supportive care: A multicenter international study.

OBJECTIVES: This retrospective chart review examined real-world healthcare resource utilization (HRU) in patients with AML ineligible for intensive therapy who received first-line systemic therapy or best supportive care (BSC). METHODS: Data were collected anonymously on patients with AML who initiated first-line hypomethylating agents (HMA), low-dose cytarabine (LDAC), other systemic therapy, or BSC. HRU endpoints included hospitalizations, outpatient consultations, transfusions, and supportive care. RESULTS: Of 1762 patients included, 46% received HMA, 11% received LDAC, 17% received other systemic therapy, 26% received BSC; median treatment durations were 118, 35, 33, and 57 days, respectively. Most patients were hospitalized, most commonly for treatment administration, transfusion, or infection (HMA 82%, LDAC 93%, other systemic therapy 83%, BSC 83%). A median number of hospitalizations were 2-6 across systemic groups and two for BSC, with median durations of 8-18 days. Transfusion rates and outpatient consultations were highest for HMA (80% and 79%) versus LDAC (57% and 53%), other systemic therapy (57% and 63%), and BSC (71% and 66%). Antivirals/antibiotics and antifungals were used more frequently than growth factors (72-92%, 34-63%, and 7-27%, respectively). CONCLUSION: Patients with AML ineligible for intensive therapy have high HRU; novel therapies are needed to alleviate this burden.

Real-world treatment patterns and clinical outcomes in patients with AML unfit for first-line intensive chemotherapy.

Acute myeloid leukemia (AML) predominantly affects the elderly, and prognosis declines with age. Induction chemotherapy plus consolidation therapy is standard of care for fit patients; options for unfit patients include hypomethylating agents (HMA), low-dose cytarabine (LDAC), targeted therapies, and best supportive care (BSC). This retrospective chart review evaluated clinical outcomes in unfit patients with AML who initiated first-line treatment or BSC 01/01/2015-12/31/2018. Overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF), and response rates were assessed. Of 1762 patients, 1310 received systemic therapies: 809 HMA, 199 LDAC, and 302 other therapies; 452 received BSC. Median OS was 9.9, 7.9, 5.4, and 2.5 months for HMA, LDAC, other, and BSC, respectively. Median PFS was 7.5, 5.3, 4.1, and 2.1 months for HMA, LDAC, other, and BSC, respectively; median TTF was 4.9, 2.1, 2.2, and 2.1 months, respectively. Our findings highlight the unmet need for novel therapies for unfit patients.

Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and IDH1/2 Mutations.

PURPOSE: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML). PATIENTS AND METHODS: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle). RESULTS: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group. CONCLUSIONS: Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut. See related commentary by Perl and Vyas, p. 2719.

Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia.

PURPOSE: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with FLT3-mutant acute myeloid leukemia. PATIENTS AND METHODS: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle). FLT3 mutation was analyzed centrally on pretreatment bone marrow aspirates. RESULTS: In the biomarker evaluable population, FLT3 mutation was detected in 42 (15%) and 22 (19%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc; complete remission (CR) + CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) for FLT3-mutant patients were 67%/36%, median duration of remission (DoR) was 17.3/5.0 months, and median OS was 12.5/8.6 months. The CRc rates among FLT3 wild-type patients were 67%/25%, median DoR 18.4/13.4 months, and median OS 14.7/10.1 months. In patients treated with venetoclax + azacitidine, CRc in patients with FLT3-ITD and FLT3-TKD was 63% and 77% and median OS was 9.9 and 19.2 months, and in comutated FLT3-ITD + NPM1 patients, CRc was 70%, median DoR was not reached, and median OS was 9.1 months. There were no unexpected toxicities in the venetoclax + azacitidine group. CONCLUSIONS: When treated with venetoclax + azacitidine, patients with FLT3 mutations and FLT3 wild-type had similar outcomes. Future analyses in larger patient populations may further define the impact of venetoclax + azacitidine in patients harboring FLT3-ITD. See related commentary by Perl and Vyas, p. 2719.

Combined Blockade of TIGIT and CD39 or A2AR Enhances NK-92 Cell-Mediated Cytotoxicity in AML.

This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and peripheral blood cells from acute myeloid leukemia (AML) patients and healthy donors (HDs). Our data show that CD56dimCD16- and CD56brightCD16- NK cells represent the predominant NK cell subpopulations in AML, while the CD56dimCD16+ NK cells are significantly reduced compared to HDs. Moreover, TIGIT+ and PVRIG+ cells cluster on the CD56dimCD16+ subset whereas CD39+ and CD38+ cells do so on CD56brightCD16- NK cells in AML. Furthermore, functional effects of (co-)blockade of TIGIT and CD39 or A2AR on NK cell functionality were analyzed. These experiments revealed that the single blockade of the TIGIT receptor results in an increased NK-92 cell-mediated killing of AML cells in vitro. Combined targeting of CD39 or A2AR significantly augments the anti-TIGIT-mediated lysis of AML cells. Our data indicate that distinct NK cell subsets in AML exhibit different immunosuppressive patterns (via the TIGIT/PVRIG receptors and the purinergic pathway). In summary, we conclude that TIGIT, CD39, and A2AR constitute relevant inhibitory checkpoints of NK cells in AML patients. A combinatorial blockade synergistically strengthens NK-92 cell-mediated cytotoxicity. As inhibitors of TIGIT, CD39, and A2AR are clinically available, studies on their combined use could be conducted in the near future.

Identification of the Mouse T Cell ADP-Ribosylome Uncovers ARTC2.2 Mediated Regulation of CD73 by ADP-Ribosylation.

Mouse T cells express the ecto-ADP-ribosyltransferase ARTC2.2, which can transfer the ADP-ribose group of extracellular nicotinamide adenine dinucleotide (NAD+) to arginine residues of various cell surface proteins thereby influencing their function. Several targets of ARTC2.2, such as P2X7, CD8a and CD25 have been identified, however a comprehensive mouse T cell surface ADP-ribosylome analysis is currently missing. Using the Af1521 macrodomain-based enrichment of ADP-ribosylated peptides and mass spectrometry, we identified 93 ADP-ribsoylated peptides corresponding to 67 distinct T cell proteins, including known targets such as CD8a and CD25 but also previously unknown targets such as CD73. We evaluated the impact of ADP-ribosylation on the capability of CD73 to generate adenosine from adenosine monophosphate. Our results show that extracellular NAD+ reduces the enzymatic activity of CD73 HEK cells co-transfected with CD73/ARTC2.2. Importantly, NAD+ significantly reduced CD73 activity on WT CD8 T cells compared to ARTC2ko CD8 T cells or WT CD8 T cells treated with an ARTC2.2-blocking nanobody. Our study provides a comprehensive list of T cell membrane proteins that serve as targets for ADP-ribosylation by ARTC2.2 and whose function may be therefore affected by ADP-ribosylation.

Cost analysis of alpha blocker treatments for benign prostatic hyperplasia in Medicare beneficiaries.

OBJECTIVES: Tamsulosin is the most widely used alpha-1 blocker medication for managing benign prostatic hyperplasia (BPH) as indicated in the current practice guideline. The aim of this study was to compare all-cause medical costs and BPH-specific medical costs in older male adults with BPH treated with tamsulosin vs other alpha-1 blockers (i.e., doxazosin, terazosin, and alfuzosin). METHODS: This was a retrospective propensity-score matched cohort study based on 2006-2012 Medicare claims data. All-cause medical costs and BPH-specific medical costs were compared between tamsulosin and other alpha-1 blockers treatment groups using baseline-adjusted quantile regression analyses. The comparisons were performed at different percentiles of the cost distributions. RESULTS: 176,793 older male adults with BPH who used alpha-1 blockers were included in the analysis. All-cause medical costs in 75th and 95th percentiles of the cost distribution are substantially higher in tamsulosin treatment group when compared to other alpha-1 blocker medications (p < 0.05 for all). Tamsulosin treatment group had substantially higher BPH-specific medical costs in 99th percentile of the cost distribution when compared to doxazosin and terazosin (p < 0.001 for all). Overall, the top 5% of the patients with the highest all-cause medical costs accounted for approximately 45% of the overall all-cause medical costs, and the top 1% of the patients with the highest BPH-specific medical costs accounted for 39-51% of those costs. CONCLUSION: Older adults with BPH who encountered higher medical expenses had substantially higher medical costs when treated with tamsulosin than other common alpha blockers. Cost-related quality of measures should be assessed to improve health outcomes in older adults with BPH.

Baseline Characteristics from UNITE: An Observational, International, Multicentre Registry to Evaluate Hidradenitis Suppurativa (Acne Inversa) in Clinical Practice.

BACKGROUND: Hidradenitis suppurativa (HS), also known as acne inversa, is a recurring, painful, chronic, and sometimes disfiguring inflammatory skin disease. OBJECTIVES: Our objective was to report the baseline clinical characteristics, natural history, and associated outcomes of patients with HS from the ongoing, prospective, non-interventional UNITE registry that is collecting data regarding the natural history and associated outcomes of HS. METHODS: Patients with inflammatory HS lesions were enrolled, including adolescents (aged 12 to < 18 years) and adults (aged ≥ 18 years). None had participated in previous or current originator-adalimumab studies/registries. Patients received treatment consistent with site-specific, routine clinical practice. HS disease status was assessed by HS lesions and disease flare; treatment and outcomes data were collected at enrolment and every 6 months for ≤ 4 years. RESULTS: Enrolment (N = 594; 89.1% adults; 10.9% adolescents) occurred from 29 October 2013 to 29 December 2015 at 73 sites in 12 countries. At baseline, the majority were female (69.7%) and White (81.2%), had moderate-to-severe disease (Hurley stage II or III; 93.3%), and had undergone prior procedures/surgery for HS (68.7%). In total, 61.6% of adults and 49.2% of adolescents were obese; 40.2% of patients reported current tobacco use. Scarring due to lesions occurred in 91.2% of patients. The prevalence of comorbidities of interest was as follows: depression (13.3%), other psychiatric disorders (9.6%), inflammatory bowel disease (2.7%), diabetes (9.1%), and polycystic ovary syndrome (5.2%). CONCLUSIONS: In this population from the UNITE HS registry, obesity and smoking were common, and disease burden was high, manifesting as multiple lesions, scarring, surgical history, and considerable comorbidities.

Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia.

PURPOSE: Clinicians use tamsulosin, an α1-adrenoceptor antagonist, to manage symptomatic benign prostatic hyperplasia (BPH). Because α1-adrenoceptors are also present in the brain, the potential exists for adverse effects on cognitive functions. We explored the association between tamsulosin use and dementia risk. METHODS: We used Medicare data (2006-2012) to conduct a cohort study among patients aged ≥65 years and diagnosed with BPH. Men taking tamsulosin (n = 253 136) were matched at a 1:1 ratio using propensity-scores to each of 6 comparison cohorts: patients who used no BPH-medication (n = 180 926), and patients who used the following alternative-BPH-medications: doxazosin (n = 28 581), terazosin (n = 23 858), alfuzosin (n = 17 934), dutasteride (n = 34 027), and finasteride (n = 38 767). Assessment began following the first fill of BPH-medication to identify incident dementia by ICD-9 diagnosis codes. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for dementia using Cox proportional hazard regression for each of the 6 propensity-score-matched cohort-pairs. RESULTS: The median follow-up period for all cohorts was 19.8 months. After propensity-score matching, the tamsulosin cohort had an incidence of dementia of 31.3/1000 person-years compared with only 25.9/1000 person-years in the no-BPH-medication cohort. The risk of dementia was significantly higher in the tamsulosin cohort, when compared with the no-BPH-medication cohort (HR [95% CI]: 1.17 [1.14, 1.21]) and each of the alternative-BPH-medication cohorts: doxazosin (1.20 [1.12, 1.28]), terazosin (1.11 [1.04, 1.19]), alfuzosin (1.12 [1.03, 1.22]), dutasteride (1.26 [1.19, 1.34]), and finasteride (1.13 [1.07, 1.19]). The significance of these findings persisted in sensitivity analyses. CONCLUSION: Tamsulosin may increase the risk of dementia in older men with BPH.

Triterpenoid saponins from the stem barks of Schefflera heptaphylla.

Nine new triterpenoid saponins, including four ursane-type triterpenoid saponins named heptursosides A-D (1-4), four oleanane-type triterpenoid saponins named heptoleosides A-D (5-8), and one dammarane-type triterpenoid saponin, heptdamoside A (9), along with two known saponins, asiaticoside D (10) and scheffoleoside B (11), were isolated from the stem barks of Schefflera heptaphylla. Their structures were determined on the basis of spectroscopic analysis and chemical methods. It is noteworthy in this study that the aglycone of 1-6 is reported for the first time, and to the best of our knowledge, this is the first report for the presence of the tetracyclic triterpenoid saponin from Schefflera. All the saponins were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells, and 2, 6, 7, and 10 showed anti-inflammatory activities under their noncytotoxic concentrations.