Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study.

This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.

Role of cedazuridine/decitabine in the management of myelodysplastic syndrome and chronic myelomonocytic leukemia.

Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal hematopoietic stem cell disorders. Complex disease biology has posed significant challenge to the development of novel therapeutics. Despite myriad clinical trials, none have been superior to azacitidine and decitabine (DEC) therapy. These therapies present a substantial burden for patients with 5 and 7 days of parenteral treatment in an infusion clinic. To overcome this limitation, a fixed drug combination of oral DEC-cedazuridine (C-DEC), a cytidine deaminase inhibitor with documented safety profile was developed. This drug was recently approved by the US FDA, Australian TGA and Health Canada for newly diagnosed or previously treated intermediate or high risk by international prognostic scoring system, MDS and CMML. In this review, we detail the pharmacokinetic and clinical activity of C-DEC in the management of MDS and CMML.

Lay abstract Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia are rare types of blood cancers. When treatment for these conditions is required, azacitidine or decitabine are the most commonly used chemotherapies. These medications are administered into blood through a medical port. Since these cancers are common in elderly, management of the port and frequent visits to infusion centers for treatment leads to noncompliance with treatment plan. With addition of a new compound by name cedazuridine to decitabine, now a new US FDA-approved medication, INQOVI^® (decitabine and cedazuridine) can be taken by mouth at home. This new treatment has shown to be equally effective with a similar safety profile to decitabine. In this review article, we describe the investigational details and drug development of the oral medication, INQOVI^®.

Design, Synthesis, and Molecular Docking Study of Novel Heterocycles Incorporating 1,3,4-Thiadiazole Moiety as Potential Antimicrobial and Anticancer Agents.

A new series of 5-(3,5-dinitrophenyl)-1,3,4-thiadiazole derivatives were prepared and evaluated for their in vitro antimicrobial, antitumor, and DHFR inhibition activity. Compounds 9, 10, 13, and 16 showed strong and broad-spectrum antimicrobial activity comparable to Amoxicillin and Fluconazole as positive antibiotic and antifungal controls, respectively. Compounds 6, 14, and 15 exhibited antitumor activity against four human cancer cell lines, CCRF-CEM leukemia, HCT-15 colon, PC-3 prostate, and UACC-257 melanoma cell lines using Doxorubicin as a reference drug. Compounds 10, 13, 14, and 15 proved to be the most active DHFR inhibitors with an IC50 range of 0.04 ± 0.82⁻1.00 ± 0.85 µM, in comparison with Methotrexate (IC50 = 0.14 ± 1.38 µM). The highly potent DHFR inhibitors shared a similar molecular docking mode and made a critical hydrogen bond and arene‒arene interactions via Ser59 and Phe31 amino acid residues, respectively.

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia.

BACKGROUND: Outcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next-generation hypomethylating agent, could be useful in treating such patients. METHODS: In this multicenter, open-label, phase 2 dose-expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m2 on 5 consecutive days in each 28-day cycle (5-day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m2 (10-day regimen). RESULTS: Between June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m2 /d, respectively [5-day regimen] and 53 patients who were assigned to 60 mg/m2 /d [10-day regimen]). The 90 mg/m2 dose showed no benefit in clinical outcomes in comparison with 60 mg/m2 in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10-day regimen versus the 5-day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10-day regimen. Early all-cause mortality was low and similar between regimens. Twenty patients (8 on the 5-day regimen and 12 on the 10-day regimen) were bridged to hematopoietic cell transplantation. CONCLUSIONS: Guadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2018;124:325-34. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Plasma and saliva levels of three metals in waterpipe smokers: a case control study.

In this case-control study, the influence of waterpipe tobacco smoking on the plasma and saliva levels of cadmium, lead and zinc was examined in participants who were waterpipe tobacco smokers (WS) or never-smokers (NS). The concentration of metals was higher in WS relative to NS. The mean (SEM) cadmium concentration in plasma was 3.3 (0.18) µg/dL in WS versus 0.82 (0.09) µg/L in NS (p < .001) and in saliva was 5.1 (0.36) µg/L in WS versus 0.64 (0.2) µg/L in NS (p < .001). The mean (SEM) lead concentration in plasma was 5.2 (0.25) µg/dL in WS versus 3.4 (0.41) µg/dL in NS (p < .01) and in saliva was 4.8 (0.58) µg/L in WS versus 2.8 (0.27) µg/L in NS (p < .05). Similarly, a significant difference in zinc concentration was observed, with a mean of 2.0 (0.17) µg/mL in WS plasma versus 1.49 (0.16) µg/mL in NS (p < .05) and a mean 0.94 (0.07) µg/mL in WS saliva versus 0.45 (0.06) µg/mL in NS (p < .01). In conclusion, waterpipe tobacco smoking is associated with elevated levels of metals in body fluids. These results provide another demonstration of how waterpipe tobacco smoking exposes smokers to harmful toxicants.

Chromosomal damage at bone-marrow cells is induced by exposure of rats to waterpipe water filtrate.

Waterpipe smoking is continuing to spread globally. The aim of this study is to investigate the effect of waterpipe water filtrate on chromosomal integrity in the bone-marrow cells of rats. Chromosomal damage was examined using in vivo chromosomal aberrations (CAs) and SCEs assays. Young Wistar male rats were exposed to WWF via drinking water. Chromosomal damage was measured in bone marrow cells after 6 weeks of treatment using fluorescent-plus-Giemsa staining. Treatment of rats with waterpipe water filtrate for 6 weeks did not affect food/liquid consumption and gain in body weight. The results showed that waterpipe water filtrate increased the frequencies of chromosomal breaks and exchanges by more than 30% (p < 0.01). In addition, waterpipe water filtrate significantly increased SCEs in the bone-marrow cells of rats. In conclusion, waterpipe water filtrate contains genotoxic compounds providing additional evidence for genotoxicity of waterpipe smoke.

Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.

BACKGROUND: The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. METHODS: We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m2 on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS: Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m2 and 28 to 90 mg/m2) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m2 on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m2 on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). INTERPRETATION: More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m2 in a 5-day schedule versus standard of care. FUNDING: Astex Pharmaceuticals and Stand Up To Cancer.

Assessment of genotoxicity of pyrethrin in cultured human lymphocytes.

Pyrethrin is an insecticide that is obtained from the Chrysanthemum flower (Pyrethrum). In this study, we examined the genotoxic effects of pyrethrin on cultured human lymphocytes using sister chromatid exchanges (SCEs) and 8-hydroxy deoxyguanosine (8-OHdG) assays. Cultures were treated with different concentrations of pyrethrin (25, 50, and 100 µg/mL), which was dissolved in in dimethyl sulfoxide (DMSO). The results showed that treatment of cultured lymphocytes with pyrethrin at 50 µg/mL and 100 µg/mL induced significant elevation in SCEs (p < 0.05). In addition, the 100 µg/mL concentration significantly affected both mitotic and proliferative indices (p < 0.05). Finally, pyrethrin induced significant elevation in the oxidative stress marker 8-OHdG in a dose-dependent manner (p < 0.001). In conclusion, the results suggest that pyrethrin is genotoxic as measured by two independent assays on genetic toxicity.

Synthesis, Antimicrobial and Anti-inflammatory Activity of Some New Benzoxazinone and Quinazolinone Candidates.

Benzoxazinones and quinazolinones have a wide spectrum of biological activity. In this paper we focused on studying the antimicrobial and anti-inflammatory activities of some newly synthesized benzoxazinone and quinazolinone derivatives. Thus we prepared 2-[α-benzoylaminostyryl]-6,8-dibromo-3,1-benzoxazin-4(H)-one 2 which underwent a reaction with primary and secondary amines, and hydrazine hydrate to give compounds 3, 4 and 5, respectively. Treatment of 2 with hydroxylamine hydrochloride, formamide and/or NaN3/AcOH afforded compounds 7, 8, 11 and 12, respectively. Also, compound 2 reacted with maleic anhydride, aromatic hydrocarbons and/or active methylene compounds to produce compounds 13, 15a-c and 16, respectively. Most of the newly synthesized compounds showed significant antimicrobial and anti-inflammatory activities comparable to ampicillin, mycostatine and indomethacin positive controls.

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

BACKGROUND: Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. METHODS: In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS: Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). INTERPRETATION: Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. FUNDING: Astex Pharmaceuticals, Stand Up To Cancer.

Synthesis and in silico studies of certain benzo[f]quinoline-based heterocycles as antitumor agents.

A series of benzoquinoline-employing heterocycles was synthesized by treating 3-chlorobenzo[f]quinoline-2-carbaldehyde with N-phenyl-3-methylpyrazolone, 4-aminoacetophenone, 1,2-diaminoethane, and 2-cyanoethanohydrazide. Also, pyridine, chromene, α,ß-unsaturated nitrile, thiosemicarbazone, and 1,2-bis-aryl hydrazine derivatives were prepared from the cyanoethanohydrazone obtained. The DFT calculations and experiment outcomes were consistent. In vitro screening of their antiproliferative efficacy was examined against HCT116 and MCF7 cancer cell lines. The pyrazolone 2 and cyanoethanohydrazone 5 derivatives exhibited the most potency, which was demonstrated by their molecular docking towards the CDK-5 enzyme. The binding energies of compounds 2 and 5 were - 6.6320 kcal/mol (with RMSD of 0.9477 Å) and - 6.5696 kcal/mol (with RMSD of 1.4889 Å), respectively, which were near to that of co-crystallized ligand (EFP). This implies a notably strong binding affinity towards the CDK-5 enzyme. Thus, pyrazolone derivative 2 would be considered a promising candidate for further optimization to develop new chemotherapeutic agents. In addition, the ADME (absorption, distribution, metabolism, and excretion) analyses displayed its desirable drug-likeness and oral bioavailability properties.

Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial.

ABSTRACT: Guadecitabine is a novel hypomethylating agent (HMA) resistant to deamination by cytidine deaminase. Patients with relapsed/refractory acute myeloid leukemia (AML) were randomly assigned to guadecitabine or a preselected treatment choice (TC) of high-intensity chemotherapy, low-intensity treatment with HMAs or low-dose cytarabine, or best supportive care (BSC). The primary end point was overall survival (OS). A total of 302 patients were randomly assigned to guadecitabine (n = 148) or TC (n = 154). Preselected TCs were low-intensity treatment (n = 233 [77%; mainly HMAs]), high-intensity chemotherapy (n = 63 [21%]), and BSC (n = 6 [2%]). The median OS were 6.4 and 5.4 months for guadecitabine and TC, respectively (hazard ratio 0.88 [95% confidence interval, 0.67-1.14]; log-rank P = .33). Survival benefit for guadecitabine was suggested in several prospective subgroups, including age <65 years, Eastern Cooperative Oncology Group performance status 0 to 1, refractory AML, and lower peripheral blood blasts ≤30%. Complete response (CR) + CR with partial hematologic recovery rates were 17% for guadecitabine vs 8% for TC (P < .01); CR+CR with incomplete count recovery rates were 27% for guadecitabine vs 14% for TC (P < .01). Safety was comparable for the 2 arms, but guadecitabine had a higher rate of grade ≥3 neutropenia (32% vs 17%; P < .01). This study did not demonstrate an OS benefit for guadecitabine. Clinical response rates were higher for guadecitabine, with comparable safety to TC. There was an OS benefit for guadecitabine in several prespecified subgroups. This study was registered at www.clinicaltrials.gov as #NCT02920008.

Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study.

BACKGROUND: The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine. METHODS: We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine-cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC0-24 for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264. FINDINGS: Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade 3 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1]). INTERPRETATION: Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia. FUNDING: Astex Pharmaceuticals.

Synthesis and antibacterial evaluation of novel heterocyclic compounds containing a sulfonamido moiety.

Aiming for the synthesis of new heterocyclic compounds containing a sulfonamido moiety suitable for use as antibacterial agents, the precursor ethyl {[4-N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenylazo}cyanoacetate was reacted with a variety of active methylene compounds producing pyran, pyridine and pyridazine derivatives. Also, the reactivity of the precursor hydrazone towards hydrazine derivatives to give pyrazole and oxazole derivatives was studied. On the other hand, treatment of the same precursor with urea, thiourea and/or guanidine hydrochloride furnished pyrimidine and thiazine derivatives, respectively. The newly synthesized compounds were tested for antibacterial activity, whereby eight compounds were found to have high activities.

Overview of Optical Biosensors for Early Cancer Detection: Fundamentals, Applications and Future Perspectives.

Conventional cancer detection and treatment methodologies are based on surgical, chemical and radiational processes, which are expensive, time consuming and painful. Therefore, great interest has been directed toward developing sensitive, inexpensive and rapid techniques for early cancer detection. Optical biosensors have advantages in terms of high sensitivity and being label free with a compact size. In this review paper, the state of the art of optical biosensors for early cancer detection is presented in detail. The basic idea, sensitivity analysis, advantages and limitations of the optical biosensors are discussed. This includes optical biosensors based on plasmonic waveguides, photonic crystal fibers, slot waveguides and metamaterials. Further, the traditional optical methods, such as the colorimetric technique, optical coherence tomography, surface-enhanced Raman spectroscopy and reflectometric interference spectroscopy, are addressed.

Modified Lateral Orbitotomy Approach to Lesions of the Orbital Apex, Superior Orbital Fissure, Cavernous Sinus, and Middle Cranial Fossa.

BACKGROUND: The lateral orbitotomy approach (LOA) provides minimally invasive access to the orbit, cavernous sinus region, and middle cranial fossa. Orbital retraction with this approach can nonetheless injure orbital structures, causing unnecessary morbidity. OBJECTIVE: To describe our clinical experience with the modified LOA (mLOA), wherein the medial aspect of the lateral orbital wall posterior to the orbital rim is preserved. METHODS: This is a retrospective, single-institution case series of patients undergoing a mLOA for lesions of the orbital apex, superior orbital fissure, cavernous sinus, and middle cranial fossa. The dimensions and variance of selected anatomic parameters relevant to this approach (orbital rim-superior orbital fossa depth, lateral orbital wall angle) were also analyzed using computed tomography scans from 30 adult patients. RESULTS: Eight patients underwent a mLOA (mean age 54.0 ± 19.6 years; 3 males). Surgical targets included the superior orbital fissure (2; cavernoma and meningioma), sphenoid wing with or without the orbital apex (2; meningioma), cavernous sinus (2; rule out carcinoma and smooth muscle tumor), and anterior/mesial temporal lobe (2; cavernoma). Visual acuity/fields and diplopia was stable or improved in all patients postoperatively. One patient experienced a cerebrospinal fluid leak. On computed tomography analysis, the relevant bony anatomy displayed limited variability, with a mean orbital fossa depth of 42.7 ± 2.8 mm and a lateral orbital wall angle of 44.4° ± 2.7°. CONCLUSION: The mLOA can provide safe, minimally invasive access to select lesions of the orbital apex, superior orbital fissure, cavernous sinus, and middle cranial fossa. The operative corridor has relatively consistent bony anatomy.

Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients.

To characterize the genomic landscape and leukemogenic pathways of older, newly diagnosed, non-intensively treated patients with AML and to study the clinical implications, comprehensive genetics analyses were performed including targeted DNA sequencing of 263 genes in 604 patients treated in a prospective Phase III clinical trial. Leukemic trajectories were delineated using oncogenetic tree modeling and hierarchical clustering, and prognostic groups were derived from multivariable Cox regression models. Clonal hematopoiesis-related genes (ASXL1, TET2, SRSF2, DNMT3A) were most frequently mutated. The oncogenetic modeling algorithm produced a tree with five branches with ASXL1, DDX41, DNMT3A, TET2, and TP53 emanating from the root suggesting leukemia-initiating events which gave rise to further subbranches with distinct subclones. Unsupervised clustering mirrored the genetic groups identified by the tree model. Multivariable analysis identified FLT3 internal tandem duplications (ITD), SRSF2, and TP53 mutations as poor prognostic factors, while DDX41 mutations exerted an exceptionally favorable effect. Subsequent backwards elimination based on the Akaike information criterion delineated three genetic risk groups: DDX41 mutations (favorable-risk), DDX41wildtype/FLT3-ITDneg/TP53wildtype (intermediate-risk), and FLT3-ITD or TP53 mutations (high-risk). Our data identified distinct trajectories of leukemia development in older AML patients and provide a basis for a clinically meaningful genetic outcome stratification for patients receiving less intensive therapies.

Guadecitabine vs treatment choice in newly diagnosed acute myeloid leukemia: a global phase 3 randomized study.

This phase 3 study evaluated the efficacy and safety of the new hypomethylating agent guadecitabine (n = 408) vs a preselected treatment choice (TC; n = 407) of azacitidine, decitabine, or low-dose cytarabine in patients with acute myeloid leukemia unfit to receive intensive induction chemotherapy. Half of the patients (50%) had poor Eastern Cooperative Oncology Group Performance Status (2-3). The coprimary end points were complete remission (19% and 17% of patients for guadecitabine and TC, respectively [stratified P = .48]) and overall survival (median survival 7.1 and 8.5 months for guadecitabine and TC, respectively [hazard ratio, 0.97; 95% confidence interval, 0.83-1.14; stratified log-rank P = .73]). One- and 2-year survival estimates were 37% and 18% for guadecitabine and 36% and 14% for TC, respectively. A large proportion of patients (42%) received <4 cycles of treatment in both the arms. In a post hoc analysis of patients who received ≥4 treatment cycles, guadecitabine was associated with longer median survival vs TC (15.6 vs 13.0 months [hazard ratio, 0.78; 95% confidence interval, 0.64-0.96; log-rank P = .02]). There was no significant difference in the proportion of patients with grade ≥3 adverse events (AEs) between guadecitabine (92%) and TC (88%); however, grade ≥3 AEs of febrile neutropenia, neutropenia, and pneumonia were higher with guadecitabine. In conclusion, no significant difference was observed in the efficacy of guadecitabine and TC in the overall population. This trial was registered at www.clinicaltrials.gov as #NCT02348489.

Case Series and Systematic Review of Electronic Scooter Crashes and Severe Traumatic Brain Injury.

OBJECTIVE: Electric scooters (e-scooters) are an increasingly popular form of transportation, but their use has also resulted in increased incidence of traumatic brain injury (TBI). Previous reports have predominantly described mild TBI with limited attention to other injury patterns. Our objective was to evaluate the impact of e-scooter use on rates of severe TBI. METHODS: We performed a multicenter retrospective case review of patients who presented with severe TBI (Glasgow Coma Scale score 3-8) related to e-scooter use and undertook a systematic literature review to identify other reports of severe TBI related to e-scooter use. RESULTS: Of the 19 patients (mean age, 38 ± 16 years; 73.7% male) included in the case series, 13 (68.4%) experienced a fall and 6 (31.6%) were involved in a collision. Various cerebral injury patterns, associated craniofacial fractures, and cervical spine injuries were also seen. Twelve patients (63.2%) underwent intracranial pressure monitor placement and 6 (31.6%) underwent a decompressive hemicraniectomy. Most patients (n = 12; 63.2%) were discharged to acute rehabilitation, with a median modified Rankin Scale score of 2 at 4.9 ± 7.7 months follow-up (52.6% had a good outcome of modified Rankin Scale score ≤2), but 4 patients died of primary injuries. The systematic review identified 18 studies with 77,069 patients between 2019 and 2021, with 37 patients who required intensive care and 6 patients who had neurosurgical intervention. CONCLUSIONS: Severe TBI after e-scooter use is associated with high morbidity and is likely underdiagnosed in the literature. Awareness and public policies may be helpful to reduce the impact of injury.