Journal articles on the topic '530.155 7222'

ABSTRACT This study was conducted in order to (i) determine the effect of food, orange juice, or antacids on the absorption of a single oral 500-mg dose of ethionamide (ETA) in healthy volunteers, including an assessment of bioequivalence, and (ii) determine ETA population pharmacokinetic (PK) parameters. The pharmacokinetics of ETA in serum was determined for 12 healthy males and females in a randomized, four-period crossover study. Volunteers received single 500-mg doses of ETA either on an empty stomach (reference) or with food, orange juice, or antacids. Serum samples were collected for 48 h and assayed by high-performance liquid chromatography. Data were analyzed by noncompartmental and population methods. Mean test/reference ratios and 90% confidence intervals were determined. No statistically significant differences were seen in the maximum concentration of ETA (C max), time to maximum concentration (T max), or area under the concentration-time curve from 0 h to infinity (AUC0–∞) between the four treatments (P > 0.05 by analysis of variance). The least-squares mean ratios (with confidence intervals in parentheses) for C maxwere 105% (81.2 to 135%) after orange juice, 94% (72.8 to 121%) after food, and 88% (68.4 to 114%) after antacids. The least-squares mean ratios (with confidence intervals is in parentheses) for AUC0–∞ were 91% (72.7 to 115%) after orange juice, 96% (76.4 to 121%) after food, and 95% (75.5 to 120%) after antacids. The mean T max was slightly prolonged following antacid or food administration (2.3 to 2.6 h) compared to administration on an empty stomach or with juice (1.7 to 1.9 h). The median population PK parameters were as follows:K a = 0.37 to 0.48 h−1,V/F = 2.0 to 2.8 liters/kg, CL/F = 56.5 to 72.2 liters/h, and terminal half-life = 1.7 to 2.1 h, where Ka is the absorption rate constant,V is the volume of distribution, and CL is clearance. The PK behavior of ETA was not significantly modified by the different conditions studied. Mean ratios for AUC ranged from 0.91 to 0.96 for the orange juice, food, and antacid treatments, indicating a minimal effect on relative bioavailability. ETA can, therefore, be administered with food if tolerance is an issue.

FLASH radiotherapy is a new irradiation method in which large doses of ionizing radiation are delivered to tumors almost instantly (a few milliseconds), paradoxically sparing healthy tissue while preserving anti-tumor activity. Although this technique is primarily studied in the context of electron and photon therapies, proton delivery at high dose rates can also reduce the adverse side effects on normal cells. So far, no definitive mechanism has been proposed to explain the differences in the responses to radiation between tumor and normal tissues. Given that living cells and tissues consist mainly of water, we set out to study the effects of high dose rates on the radiolysis of water by protons in the energy range of 150 keV – 500 MeV (i.e., for linear energy transfer (LET) values between ∼72.2 and 0.23 keV/μm, respectively) using Monte Carlo simulations. To validate our methodology, however, we, first, report here the results of our calculations of the yields (G values) of the radiolytically produced species, namely the hydrated electron ([Formula: see text]), •OH, H•, H2, and H2O2, for low dose rates. Overall, our simulations agree very well with the experiment. In the presence of oxygen, [Formula: see text] and H• atoms are rapidly converted into superoxide anion or hydroperoxyl radicals, with a well-defined maximum of [Formula: see text] at ∼1 μs. This maximum decreases substantially when going from low-LET 500 MeV to high-LET 150 keV irradiating protons. Differences in the geometry of the proton track structure with increasing LET readily explain this diminution in [Formula: see text] radicals.

Abstract Introduction During the pandemic, healthcare workers have shared their stresses on social media, including regarding sleep disturbances. However, an assessment of sleep using validated measures among healthcare workers on social media is lacking. Methods A restricted, self-selection survey was distributed on Facebook, Twitter, and Instagram for 16 days targeting healthcare workers who were clinically active during COVID-19. In addition to demographics and career information, participants completed the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index. Poor sleep quality was defined as PSQI > 5. Moderate-to-severe insomnia was defined as an ISI > 14. Multivariate logistic regression tested the association between demographics and career characteristics and sleep outcomes. Results Of the 983 who clicked our link, 906 completed the survey. Participants were mostly white (70%), female (75%), physicians (64%). Mean sleep duration was 6.1 (SD1.2) hours. Nearly 90% experienced poor sleep (PSQI). One third reported moderate or severe insomnia. Many (60%) reported sleep disruptions due to device usage or due to bad dreams at least once per week (45%). In multivariable regression, non-physicians (OR 3.5, CI: 2.5, 5.0), Hispanic ethnicity (OR 2.2; CI: 1.44, 3.45), being single (1.5, CI: 1.03, 2.21), and youngest age group (18–24) (OR 9.9; CI: 1.44, 68.09) had increased odds of insomnia. In open-ended comments, sleep disruptions mapped to 5 categories: (1) Work demands (“The volume of calls and messages from my patient and caregiver population is through the roof”); (2) Pandemic related (“I never had sleep issues prior to the COVID-19 pandemic. Suddenly I had issues with sleep initiation.”; (3) Children and family (“COVID plus home stress plus stress over my kids, my job, my marriage.”); (4) Personal health (“Insomnia predating COVID, but worsened with COVID.”); (5) Responses to the pandemic (“I worry about how COVID is being managed by the President...This does keep me awake at night.”). Conclusion During the COVID-19 pandemic, 90% of healthcare workers surveyed on social media reported poor sleep, with over one-third of participants reporting moderate-severe insomnia. Online sleep interventions for healthcare workers are urgently needed. Support (if any):

Background Epidural clonidine produces analgesia without motor impairment, and is associated with a local anesthetic-sparing effect during labor. The authors have recently demonstrated that epidural neostigmine initiates selective labor analgesia devoid of adverse effects. Both drugs possess common analgesic mechanisms mediated through spinal acetylcholine release. This study evaluates their epidural combination in parturients. Methods At the beginning of labor, parturients were randomly allocated to one of five groups to receive one of the following after a test dose: 150 microg epidural clonidine, 750 microg neostigmine, or 75 microg clonidine combined with 250, 500, or 750 microg neostigmine. A pain score (visual analog scale, 0-100) was recorded before administration and at regular intervals until request for a supplemental injection. Subsequent analgesia was provided by continuous epidural infusion of ropivacaine. Results Parturients did not differ regarding demographic data and initial pain score. Clonidine 150 microg , neostigmine 750 microg , and 75 microg clonidine plus 250 microg neostigmine produced ineffective and short-lasting effects. Clonidine 75 microg plus 500 microg neostigmine and 75 microg clonidine plus 750 microg neostigmine presented comparable durations of 90 +/- 32 and 108 +/- 38 min (mean +/- SD), respectively, and final analgesic efficacies, with 72.2% and 84%, respectively, of the parturients reporting a visual analog scale score of less than 30 out of 100 after 30 min. Ropivacaine use was significantly reduced in all clonidine groups (average, 9.5 mg/h) in comparison with neostigmine alone (17 +/- 3 mg/h). No adverse effects were observed for 75 mug clonidine combined with any dose of neostigmine while maternal sedation (20%) and hypotension (33%) occurred with 150 microg clonidine alone. Conclusions Epidural clonidine, 75 microg , with 750 microg neostigmine is an effective combination to initiate selective labor analgesia without adverse effects. Clonidine use further reduces local anesthetic consumption throughout the course of labor.

Human inborn immune-related errors comprise a heterogeneous group of rare genetically determined diseases of the immune system caused by loss or gain of function mutations altering relevant protein functions. The 2019 International Union of Immunological Societies recently proposed the classification for such pathologies now comprising 406 distinct disorders with 430 different gene defects. Predominantly antibody deficiencies represent most common group of human inborn immune-related errors, which diagnostics poses uneasy challenge for general practitioner due to a broad range of their clinical manifestations, such as infection, allergy, autoimmunity and malignancy. In addition, patients with human immune-related inborn errors may develop a vaccine-associated disease after administering live vaccines in accordance with the Russia-wide National Vaccine Schedule. Most common among vaccine-associated diseases are vaccine-associated paralytic poliomyelitis, vaccine-associated encephalitis (1 case per 1 000 000 doses of measles, rubella, varicella vaccine), vaccine-associated meningitis (1 case per 250 000 – 500 000 doses of mumps vaccine) as well as adverse effects related to BCG immunization: local (infiltration, cold abscess – 8.6 case per 100,000 vaccinated patients) and disseminated complications (BCG lymphadenitis – 15.5 case per 100 000 vaccinated patients, BCG osteitis – 3.5 case per 100 000 vaccinated patients). Vaccine-associated paralytic poliomyelitis in vaccinated patients occurs after the first, second and rarely third oral polio vaccine dose inoculation. Incidence rate for vaccineassociated paralytic polio after 1 and 3 oral vaccine inoculation ranges from 1 case per 700 000 vaccine doses to 1 case per 3 500 000, respectively. Vaccine-associated paralytic poliomyelitis mainly emerges due to inborn mutations related to humoral immunity after primary vaccination with oral polio vaccine or close contact of unvaccinated patients with subjects vaccinated with oral polio vaccine. Here, we describe a clinical case of vaccine-associated paralytic poliomyelitis in patient with primary immunodeficiency. Our is aimed at emphasizing importance of immunological alertness with regard to detecting primary immunodeficiencies and timely apply a replacement therapy prior to verifying type of immunodeficiency.

Разработан способ определения ртути(II) с использованием пенополиуретана, модифицированного на поверхности треугольными нанопластинками серебра со средней длиной ребра 52 нм и толщиной 4 нм. Способ основан на окислении нанопластинок серебра ртутью(II). Оно сопровождается уменьшением полосы поверхностного плазмонного резонанса наночастиц, что позволяет рассматривать полученный нанокомпозитный материал в качестве твердофазного аналитического реагента для определения ртути(II). Исследовано влияние времени взаимодействия и pH раствора на чувствительность определения ртути. Предел обнаружения ртути в выбранных условиях равен 50 мкг/л, диапазон определяемых содержаний составляет 150–1000 мкг/л. Увеличение объема анализируемого раствора с 5.0 до 100.0 мл за счет концентрирования позволяет снизить предел обнаружения ртути до 5 мкг/л.

Formation of DNA adducts of chemical carcinogens is a trigger for carcinogenesis. Adducts of benzo[a]pyrene metabolites and estradiol metabolites with DNA have been found in normal and tumor cells in healthy women and patients with breast and colorectal cancer. These low-weight compounds in macromolecular complexes induce the synthesis of specific antibodies. Previously, the presence of specific antibodies against benzo[a]pyrene (IgA-Bp), estradiol (IgA-Es) and progesterone (IgA-Pg) was revealed in breast cancer patients. The aim of this study is to identify the putative features of the IgA-Bp, IgA-Es, and IgA-Pg formation in postmenopausal women with colorectal cancer, in comparison with healthy and breast cancer patients. Using a noncompetitive enzyme-linked immunosorbent assay, the content of these antibodies was studied in the blood serum of healthy women (n = 401), patients with colorectal cancer (n = 219) and breast cancer (n = 1469) using conjugates of Bp, Es, and Pg with bovine serum albumin as adsorbed antigens. When compared with healthy people, the patients with colorectal cancer exhibited higher incidence of IgA-Bp 3 (75% vs 37%, p 0.0001, OR = 5.0), as well as more common levels of individual antibody ratios: IgA-Bp/IgA-Es 1 (82% vs 41%, p 0.0001, OR = 6.5); IgA-Bp/IgA-Pg 1.5 (77% vs 20%, p 0.0001, OR = 13.4); IgA-Es/IgA-Pg 1 (89% vs 48%, p 0.0001, OR = 8.7). In breast cancer patients, compared with healthy people, high IgA-Bp values ( 3) were more common (45% vs 37%, p 0.004, OR = 1.4), as well as increased IgA-Bp/IgA-Es ratio 1 (57% vs 41%, p 0.0001, OR = 1.9), IgA-Bp/IgA-Pg 1.1 (71% vs 36%, p 0.0001, OR = 4.4) and IgA-Es/IgA-Pg 1.1 (71% vs 41%, p 0.0001, OR = 3.5). In patients with colorectal cancer, compared with patients with breast cancer we have found higher incidence of increased IgA-Bp values ( 3) (75% vs 45%, p 0.0001), IgA-Es 3 (53% vs 39%, p 0, 0001), and of IgA-Pg 2 (52% vs 44%, p = 0.025), as well as IgA-Bp/IgA- Es 1 (82% vs 57%, p 0.0001, OR = 50.8 ); IgA-Bp/IgA-Pg 1.5 (77% vs 49%, p 0.0001); IgA-Es/IgA-Pg 1.1 (85% vs 71%, p 0.0001). The apparently high serum IgA-Bp levels reflect the formation of DNA-Bp adducts at large scale in target cells in colorectal cancer compared with healthy women and breast cancer patients, due to direct exposure of colon epithelium to Bp from food. Immunoassay for IgA-Bp, IgA-Es and IgA-Pg is proposed for assessing individual risk of colorectal cancer in postmenopausal women. The ratios of IgA Bp/IgA-Pg levels 1.5 represent the most informative marker of individual risk for colorectal cancer.

90 Background: Treatment-related infertility is an important cause of distress in young women with breast cancer (YWBC) that is preventable by fertility preservation (FP) prior to initiating therapy. This study assesses FP service use by YWBC in Quebec (Canada). Methods: Administrative claims for women ≤ 40 diagnosed between 01-04-2012 and 31-03-2018 were identified using Quebec’s universal health services database (RAMQ). Access to and use of FP services were ascertained by identifying claims for a visit with an obstetrician/gynecologist (OB/GYN) ≤ 90 days of diagnosis, followed by claims for ovarian stimulation, ovule harvesting or artificial insemination. Patient, disease and treatment-related predictors were estimated using logistic regression. Results: 1 616 YWBC were treated. Mean age was 36 (SD 4.1), 72.1% had a CCI = 0, 84.5% were urban residents, and 72.2% experienced some form of socioeconomical disadvantages. Stage distribution was: 0.93%, 68.8, and 30.3% for stages 0, 1-2, and 3 respectively. 53.0% had a mastectomy, 40.8% received chemotherapy (CT), 70.7% received radiotherapy, 20.9% initiated anti-estrogen therapy. 387 YWBC consulted an OB/GYN within 90 days of diagnosis and 155 subsequently received FP services. Predictors associated with FP use included: decreased age (OR= 0.82, 95CI = 0.79-0.86), type of surgery (OR = 0.46, CI = 0.22-0.97), social isolation (OR =1.39, 95CI = 0.99-1.96) and receipt of chemotherapy (OR = 1.74, 95CI = 1.10-2.76). Conclusions: Only 23.9% of eligible YWBC in Quebec accessed FP specialists. Of these, 40.1% chose to move forward with FP. These findings raise important questions on how to optimize access to FP expertise. [Table: see text]

Background:Upadacitinib (UPA), an oral Janus kinase inhibitor (JAKi), has demonstrated efficacy in the phase 3 SELECT clinical program, conducted across a range of patients (pts) with rheumatoid arthritis (RA).1–6 Real-world data for UPA, including in pts previously treated with a JAKi, have not yet been reported since global approvals beginning in 2019.Objectives:To assess the characteristics of US-based pts receiving UPA and its effectiveness in clinical practice at 3 months.Methods:This observational study included US-based pts from the United Rheumatology Normalized Integrated Community Evidence (UR-NICE) database who initiated UPA 15 mg once daily from FDA approval (August 2019) to July 31, 2020 and had ≥6-month pre-baseline data available. Effectiveness was assessed in pts with a reported Clinical Disease Activity Index (CDAI) score at 3 months after UPA initiation and included proportions of pts achieving CDAI remission (≤2.8), CDAI low disease activity (≤10), other disease activity measures, and pt-reported outcomes. A subgroup analysis assessed UPA effectiveness in pts with or without prior tofacitinib (TOFA) treatment.Results:This analysis included 252 pts treated with UPA 15 mg, of whom 98 (38.9%) received UPA monotherapy and 154 (61.1%) received UPA combined with conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs). 64.3% of pts were from the Southern region of the USA. 86.1%, 72.2%, and 47.6% of pts had been previously treated with csDMARDs, biologic DMARDs, and JAKis, respectively. Baseline characteristics were largely similar between UPA monotherapy and combination therapy groups and those with or without prior TOFA treatment (Table 1). Pts with prior TOFA treatment had a longer duration of RA since diagnosis and higher steroid use versus those without. UPA 15 mg improved disease activity scores (including CDAI) and pt-reported outcomes (including physical function and pain) after 3 months of treatment (Figure 1). Similar effectiveness was observed with UPA 15 mg in pts with or without prior TOFA treatment.Conclusion:In the UR-NICE real-world database of US-based pts, improvements in clinical and pt-reported outcomes were observed at 3 months in UPA-treated pts with RA, including those with or without prior TOFA treatment, despite the treatment-refractory population included in this dataset.References:[1]Burmester GR, et al. Lancet 2018;391:2503–12.[2]Smolen JS, et al. Lancet 2019;393:2303–11.[3]Fleischmann R, et al. Arthritis Rheumatol 2019;71:1788–800.[4]Genovese MC, et al. Lancet 2018;391:2513–24.[5]van Vollenhoven R, et al. Arthritis Rheumatol 2020;72:1607–20.[6]Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21.Table 1.Baseline characteristicsn (%), unless otherwise statedFull analysis set(n=252)Pts with prior TOFA treatment(n=113)Pts without prior TOFA treatment (n=139)Mean (SD) exposure, days219.7 (112.1)215.7 (116.7)222.9 (108.5)Female199 (79.0)85 (75.2)114 (82.0)Age ≥65 years75 (29.8)34 (30.1)41 (29.5)Oral steroid use140 (55.6)70 (61.9)70 (50.4)Prior csDMARDs217 (86.1)102 (90.3)115 (82.7)Prior TOFA113 (44.8)113 (100.0)0Prior biologic DMARDs182 (72.2)86 (76.1)96 (69.1)Tumor necrosis factor inhibitor147 (58.3)66 (58.4)81 (58.3)Interleukin-6 receptor inhibitor87 (34.5)47 (41.6)40 (28.8)nMean (SD)nMean (SD)nMean (SD)Duration of RA diagnosis, years1884.0 (3.0)895.1 (2.9)993.1 (2.8)Methotrexate dose, mg/week8817.0 (5.1)2817.8 (5.0)6016.6 (5.2)SJC282394.8 (5.7)1084.5 (5.0)1315.0 (6.2)TJC282376.5 (6.7)1076.5 (6.8)1306.5 (6.6)CDAI22520.4 (13.4)10520.2 (13.5)12020.6 (13.3)Routine assessment of patient index data 31654.2 (2.3)724.2 (2.4)934.3 (2.2)Disease Activity Score in 28 joints based on C-reactive protein1673.9 (1.5)833.9 (1.5)843.9 (1.5)Health Assessment Questionnaire-Disability Index1702.5 (2.1)742.4 (2.2)962.5 (2.1)Pain(0–10)22956.5 (28.5)10456.9 (29.3)12556.1 (28.0)SD, standard deviation; S/TJC, swollen/tender joint countAcknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Hilary Wong, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Allan Gibofsky Shareholder of: AbbVie, Amgen, Johnson & Johnson, and Pfizer, Consultant of: AbbVie, Celgene, Eli Lilly, Flexion, Pfizer, Relburn Pharma, and Samumed. Paid consultant with investment analysts on behalf of the Gerson Lehrman Group, Bhavna Dhillon Shareholder of: May own stock or options in United Rheumatology, Employee of: United Rheumatology, Mark E. Pearson Shareholder of: May own AbbVie stock or options, Namita Tundia Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Kendall Dunlap Shareholder of: May own stocks or shares in AbbVie, Employee of: AbbVie, Grace Wright Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Exagen, Myriad Autoimmune, Novartis, Sanofi/Regeneron, UCB, and Vindico, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Exagen, Gilead, Janssen, Myriad Autoimmune, Novartis, Pfizer, Sanofi/Regeneron, and UCB, Employee of: President and Founder of the Association of Women in Rheumatology

Abstract Background: CDK4/6 inhibitors combined with endocrinotherapy (ET) represent an essential part of the treatment for HR-positive and HER2-negative breast cancer (BC). However, the role of angiogenesis inhibitors, such as bevacizumab, in these patients (pts) is controversial. While it has been demonstrated to improve progression-free survival (PFS), it has failed to show a significant overall survival (OS) benefit in HER2-negative BC. Several preclinical studies have explored the combination of anti-angiogenesis multi-targeted receptor tyrosine kinase inhibitors (TKIs) and CDK4/6 inhibitors in other cancers, suggesting a synergistic effect. Our phase Ib/II trial (NCT05176080, ChiCTR2100053950) aims to evaluate the safety and efficacy of a novel anti-angiogenesis TKI famitinib (F) added to dalpiciclib (D) and ET in advanced HR-positive and HER2-negative BC. Here we report the results of Phase Ib. Methods: A 3+3 de-escalation design was used in this dose-exploring phase (phase Ib). Pts with HR-positive and HER2-negative BC, who had no more than two prior chemotherapies in the advanced setting, were enrolled and administered F (orally, at doses of 15 mg/d, 10 mg/d, or 15 mg qod), D (orally, at doses of 150, 125 or 100 mg/d, 21 days on and 7 days off) and fulvestrant (intramuscularly, at a fixed dose of 500 mg every four weeks) until progression, unaccepted toxicities, or withdrawal. The initial dose level (Level 1) was set as F 15 mg daily and D 150 mg/d. The primary endpoints were recommended phase 2 dose (RP2D) and safety. Results: From December 2021 to June 2022, 18 pts were enrolled, and 3, 6, 3, and 6 pts were assigned to Level 1 (F 15 mg + D 150 mg), Level 2 (F 10 mg + D 125 mg), Level 3 (F 15 mg qod + D 125 mg), and Level 4 (F 10 mg + D 100 mg), respectively. 14 (77.8%) pts had visceral metastasis, and 7 (38.9%) had prior systemic therapies in the advanced setting. 13 (72.2%) pts had received ET, and 11 (61.1%) were resistant to ET before enrolled. A total of 6 dose-limiting toxicities (DLTs) were observed, including 3 Grade 4 thrombopenia (2 in Level 1, 1 in Level 2) and 3 Grade 4 neutropenia (2 in Level 3, 1 in Level 4), 4 of which were serious adverse events (AEs). The most common (≥20%) treatment-related AEs of Grade 3 or above were neutropenia (100.0%), leukopenia (88.9%), thrombocytopenia (33.3%), anemia (27.8%), lymphopenia and hypertension (both 22.2%). No death was reported. Overall 10 pts (55.6%) achieved confirmed partial responses and 16 (88.9%) achieved clinical benefits. Confirmed objective response rates (ORRs), clinical benefit rates (CBRs), and DLTs in different dose levels were shown in Table 1. Considering the efficacy and safety profiles, Level 4 was selected as RP2D. Conclusion: The anti-angiogenesis multi-targeted receptor TKI famitinib combined with CDK4/6i and fulvestrant has shown antitumor effects in advanced HR-positive and HER2-negative BC, and no new safety signals were observed. Citation Format: Min Yan, Mengwei Zhang, Limin Niu, Huimin Lv, Zhenzhen Liu, Huiai Zeng, Shengnan Zhao, Huihui Sun, Jing Wang, Yajing Feng, Huajun Li. Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-01.

ObjectiveTo investigate the clinical outcomes of myocarditis associated with mRNA vaccines against the SARS-CoV-2 virus compared with other types of myocarditis.DesignPopulation based cohort study.SettingNationwide register data from four Nordic countries (Denmark, Finland, Norway, and Sweden), from 1 January 2018 to the latest date of follow-up in 2022.ParticipantsThe Nordic myocarditis cohort; 7292 individuals aged ≥12 years who had an incident diagnosis of myocarditis as a main or secondary diagnosis, in a population of 23 million individuals in Denmark, Finland, Norway, and Sweden.Main outcome measuresHeart failure, or death from any cause within 90 days of admission to hospital for new onset myocarditis, and hospital readmission within 90 days of discharge to hospital for new onset myocarditis. Clinical outcomes of myocarditis associated with SARS-CoV-2 mRNA vaccination, covid-19 disease, and conventional myocarditis were compared.ResultsIn 2018-22, 7292 patients were admitted to hospital with new onset myocarditis, with 530 (7.3%) categorised as having myocarditis associated with SARS-CoV-2 mRNA vaccination, 109 (1.5%) with myocarditis associated with covid-19 disease, and 6653 (91.2%) with conventional myocarditis. At the 90 day follow-up, 62, nine, and 988 patients had been readmitted to hospital in each group (vaccination, covid-19, and conventional myocarditis groups, respectively), corresponding to a relative risk of readmission of 0.79 (95% confidence interval 0.62 to 1.00) and 0.55 (0.30 to 1.04) for the vaccination type and covid-19 type myocarditis groups, respectively, compared with the conventional myocarditis group. At the 90 day follow-up, 27, 18, and 616 patients had a diagnosis of heart failure or died in the vaccination type, covid-19 type, and conventional myocarditis groups, respectively. The relative risk of heart failure within 90 days was 0.56 (95% confidence interval 0.37 to 0.85) and 1.48 (0.86 to 2.54) for myocarditis associated with vaccination and covid-19 disease, respectively, compared with conventional myocarditis; the relative risk of death was 0.48 (0.21 to 1.09) and 2.35 (1.06 to 5.19), respectively. Among patients aged 12-39 years with no predisposing comorbidities, the relative risk of heart failure or death was markedly higher for myocarditis associated with covid-19 disease than for myocarditis associated with vaccination (relative risk 5.78, 1.84 to 18.20).ConclusionsCompared with myocarditis associated with covid-19 disease and conventional myocarditis, myocarditis after vaccination with SARS-CoV-2 mRNA vaccines was associated with better clinical outcomes within 90 days of admission to hospital.

Background. Blood transfusion is an essential component in the care of patients with sickle cell disease (SCD), but it might be associated with serious acute and delayed complications. This study was aimed to describe red cell transfusion patterns and indications among hospitalized SCD children in a low-resource setting. Patients and Methods. A retrospective, descriptive study of all children (≤16 years) with SCD who received blood transfusion therapy during their hospital admissions in the pediatric department at Al-Sadaqa Teaching Hospital in Aden, Yemen, for a period of one year. Results. Out of 217 hospitalized children with SCD, 169 (77.9%) were transfused and received 275 RBC transfusion episodes. The mean age of transfused children was 6.9 ± 4.6 years and 103 (60.9%) were males, with a male/female ratio of 1.6 : 1 (p=0.004). Hemoglobin (Hb) levels were significantly lower in the transfused than in the nontransfused (Hb 5.5 ± 1.5 vs. 7.7 ± 1.5 g/dL, p=0.03). Pretransfusion Hb levels were ˂7.0 g/dL in 86.2% and ˂5.0 g/dL in 39.3% of patients. Single transfusion was given to 122 (72.2%) and 5 or more transfusions in 9 (4.15%) of patients on different occasions. Simple (top-up) transfusion was used in all transfusion events. Commonest indications for transfusion were anemic crises (41.1%), vasoocclusive crises (VOC) (13.8%), VOC with anemic event (11.3%), acute chest syndrome (8.7%), and stroke (7.3%). Conclusion. Intermittent blood transfusion remains a common practice for the management of children with acute SCD complications. Main indications were acute anemic crises, severe pain crises, ACS, and stroke. In limited resource settings, such as Yemen, conservative transfusion policy appears to be appropriate.

The purpose of the research was to study the impact of age on the incidence of disanapsis in children and adolescents with bronchial asthma (BA) taking into consideration the anthropometric features of the patients as well. Materials and methods used: a single-center observational cross-sectional pilot study was conducted with data obtained from 334 patients with atopic BA aged 7 to 17 years old (12.0 [9.0; 14.0] y/o), of which 241 (72.2%) were boys. All of the participants have undergone the spirometry and the diagnostics for disanapsis. Results: the incidence of disanapsis was higher in prepubertal children compared to adolescents, 57.0% (77 of 135) and 30.7% (61 of 199), respectively (p<0.001). These patterns were also typical for children with normal body weight (BW): 53.0% (44 of 83) vs. 22.3% (23 of 103); and for patients with excessive BW: 68.6% (24 of 35) vs. 33.3% (22 of 66) (p<0.001 and p<0.001, respectively). Incidence of disanapsis in patients with obesity was comparable in prepubertal age: 52.9% (9 of 17); and adolescence: 53.3% (16 of 30) (p=0.980). Conclusion: the incidence of disanapsis is higher in prepubertal age than in adolescence in patients with both normal and excessive BW. Incidence of disanapsis is comparable in prepubertal age and adolescence in patients with BA coupled with the obesity.

This study was carried out to analyzed the socio-economic and institutional characteristics of wheat farmers in Jigawa State, Nigeria. Multi-stage sampling procedure was used to select 503 wheat farmers (352 men and 151 women) from the study area. Data were collected through the use of structured questionnaire and analyzed; using descriptive and inferential statistics (Tobit regression). The result revealed that Majority (70%) of the respondents were male and 30% were female. About 56.0% male and 49.0% women respondents were within the age bracket of 30-39 years and 20-29 years respectively. It was revealed that 91.5% male and 95.4% female respondents were married. Furthermore, 58.3% of the female respondents had primary level of education. Meanwhile, 55.4% male and 56.3% female respondents had a household size between 6-10 persons and 1-5 persons respectively. Majority (64.2%) of the female respondents had a farm size between 0.5-1.0 hectares. About 54.8% male and 67.5% female respondents had 6-10 years and 1-5 years of farming experience. Furthermore, 68.5% of the male respondents had access to extension from Jigawa Agricultural and Rural Development Authority (JARDA) while, 51.7% women had no contact. On the other hand, 32.4% of male had extension contact twice a year while 32.5% female had contact once a year. The result further revealed that 64.9% female respondents practice mixed cropping. 52,0% male practice bed drill method of sowing. The result further shows that majority (63.3% males and 67.5% female) respondents use the LCRIWHIT-4 (Atilla-Gan-Atilla) variety of wheat, 53.0% of female respondents applied organic manure to their farmland and 72.2% of the female respondents used machine in processing the wheat grains. Majority (68%) female respondents used wheat to prepare traditional dishes. The result further shows that 61.6% of the female respondents believed that high quality wheat variety is rewarded by substantial price premium. Tobit regression estimate of the extent of participation in wheat farming had a chi-square of 54.43 and significant at P≤0.01 level and Log likelihood of 364. Men and women participated in wheat farming, except that, on average male respondents had better access to land, inputs and extension services than the female wheat farmers. Policy makers should ensure that farmers receive the latest information on wheat agronomy through regular trainings.

e20654 Background: Cancer incidence is increasing in elderly but specific treatment data in this population is not often available. The objectives of this study were to evaluate the effectiveness and safety of darbepoetin alfa (DA) administered once every 3 weeks (Q3W) for the treatment of chemotherapy-induced anaemia (CIA) in elderly within routine clinical practice. Methods: Prospective, observational, single-arm, multicentre study performed in 28 centres across Spain. Eligible patients (pts):≥65 years, anaemic (haemoglobin [Hb] 11 g/dl), with non-myeloid malignancies, and scheduled to receive ≥9 weeks (wks) of chemotherapy. Pts were treated with a fixed dose of DA 500 μg Q3W and treatment stopped if Hb levels exceeded 13g/dl. Primary endpoint was hematopoietic response (Hb increase ≥2g/dl or Hb ≥12g/dl without transfusions in the previous 28 days). Secondary endpoints included percentage of pts achieving target Hb (>11g/dl from wk 5 till end of treatment without red blood cell transfusion within 28 days), changes in the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale and the incidence of adverse reactions. Results: Data were prospectively collected from 153 pts: women (56.86%), mean (SD) age 73.43 (5.77) years, ECOG Performance Status 0–1 (65.36%) with solid tumors (66.67%) and lymphoproliferative malignancies (33.33%) and stage III/IV (63.40%). Most pts (90.20%) had baseline Hb levels between 9–11g/dL. DA was administered for a median of 9.0 wks (range: 1–22.57). The Kaplan-Meier percentage (KM; 95% CI) of pts who achieved hematopoietic response was 69.70% (56.06–83.34) and 72.22% (57.5–86.94) for pts who achieved target Hb (>11g/dL). FACT-F median score at baseline was 29.00 and 33.00 at the end of the study. Only one (0.7%) non-serious adverse reaction (cutaneous eruption) was reported. Conclusions: These results suggest that DA given at 500 μg Q3W to elderly pts with non-myeloid malignancies is an effective and well-tolerated treatment for CIA. [Table: see text]

Background and Objectives: Total hip arthroplasty (THA) is considered the most successful surgical procedure in orthopedics. However, dislocation remains the main indication for surgical revision. New designs of dual mobility cups (DMC) have lowered the classical complications and have extended the indications of DMC in elective surgeries. Our aim is to assess the trend of DMC indications in THA as well as the incidence of their dislocation. Materials and Methods: We retrospectively reviewed all patients undergoing THA with DMC during the years 2015 and 2021. The original indication for DMC included patients sustaining neck of femur fractures (NOF#) and associated risk factors for dislocations. Five years later, DMC was considered our standard of care in total hip arthroplasty. The approach (anterolateral or posterolateral) was chosen by the surgeon according to his/her preferences, as was the implant. Data collected included patients’ demographics, diagnosis, admission time, surgical approach, cup models, and inclination and complications. Patients sustaining a hip dislocation were prospectively reviewed and assessed for treatment received, new dislocations, and need for surgical revision. Two groups were created for the analysis according to the presence or absence of dislocation during follow-up. Results: In the analysis, 531 arthroplasties were included (mean age 72.2 years) with a mean follow-up of 2.86 years. The trend of indications for DMC increased from 16% of THA in 2015 to 78% of THA in 2021. We found a total of 8 dislocations (1.5%), none of them associated with elective surgery. Closed reduction was unsatisfactory in four cases (50%). There was one case of intraprosthetic dislocation. Dislocations were associated to smaller heads (22 mm) (1.5% vs. 25%, p = 0.008) and cups (51.2 mm vs. 48.7 mm, p = 0.038) and posterior approach (62.5% vs. 37.5%, p = 0.011). Conclusion: Dual mobility cups are a great option to reduce the risk of dislocation after a THA both in the neck of femur fractures and elective cases. The use of an anterolateral approach in THA after a neck or femur fracture might considerably decrease the risk of dislocation.

Abstract Objective: Genetic testing (GT) and counseling (GC) are important aspects of comprehensive cancer care, yet persistent equity challenges exist. We aim to characterize the evolving utilization of GT and GC services for potential hereditary breast, ovarian, pancreatic, and prostate cancers (HBOPP). Methods: We performed a retrospective single-institution chart review of a balanced racial subset of HBOPP patients who met National Comprehensive Cancer Network (NCCN) criteria diagnosed from 2019-2013. Data were analyzed using chi-squared test and multivariable logistic regression. Results: 503 HBOPP patients were studied. GT was discussed with 50.5% (n=254) of patients, 42.3% (n=213) completed GT, but only 8.7% had GC (n=44) (Table 1). Patients who were younger, had managed care, or had a family history of cancer were significantly more likely to have a GT discussion and complete GT (all p&lt;0.01). Pancreatic cancer (RR 0.11; 95% CI 0.05-0.21) and prostate cancer patients (RR 0.05; 95% CI 0.02-0.10) were less likely to have a GT discussion with their provider than breast cancer patients. HBOPP patients had a lower likelihood of having a GT discussion with each additional year of age at diagnosis (RR 0.95; 95% CI 0.93-0.98). Among patients who had a GT discussion, prostate cancer patients (RR 0.14; 95% CI 0.04-0.47) and Black patients (RR 0.25; 95% CI 0.09-0.71) were less likely to complete GT. Ovarian cancer patients (RR 12.1; 95% CI 5.19-28.5) and patients with a family history of cancer (RR 2.26; 95% CI 1.05-4.86) were more likely to have GC. Conclusions: Inequities persist in GT and GC. NCCN-eligible patients who were older or had prostate or pancreatic cancer were less likely to have GT discussion. We found that Black patients were less likely than White patients to complete GT. GC rates were low across all groups except patients with ovarian cancer. Multilevel and systemic interventions are needed to improve equity in cancer genetic services. Access to, completion, and outcomes of genetic testing and counseling, by cancer type. Breast (n=212) Ovarian (n=48) Pancreatic (n=105) Prostate (n=138) Total (n=503) Test (p) Was there evidence a provider discussed and/or offered genetic testing? Yes 172 (81.1%) 36 (75.0%) 26 (24.8%) 20 (14.5%) 254 (50.5%) &lt;0.001 No 40 (18.9%) 12 (25.0%) 79 (75.2%) 118 (85.5%) 249 (49.5%) Is there any evidence that the patient received genetic testing? Yes 155 (90.1%) 32 (88.9%) 18 (69.2%) 8 (42.1%) 213 (84.2%) &lt;0.001 No 17 (9.9%) 4 (11.1%) 8 (30.8%) 11 (57.9%) 40 (15.8%) What were the patients results? Mutation positive 25 (16.3%) 5 (15.6%) 2 (11.1%) 0 (0.0%) 32 (15.2%) 0.095 Mutation negative 83 (54.2) 12 (37.5%) 13 (72.2%) 3 (37.5%) 111 (52.6%) Variant of unknown significance 43 (28.1%) 13 (40.6%) 3 (16.7%) 4 (50.0%) 63 (29.9%) No info available/cannot find 2 (1.3%) 2 (6.2%) 0 (0.0%) 1 (12.5%) 5 (2.4%) Was there evidence of any genetic counseling encounter? No 195 (92.4%) 27 (57.4%) 102 (97.1%) 133 (96.4%) 457 (91.2%) &lt;0.001 Yes 16 (7.6%) 20 (42.6%) 3 (2.9%) 5 (3.6%) 44 (8.8%) Citation Format: Ariana Naaseh, Hannah Rice, Isabel Temosihue, Natasha Zimmermann, Erin Linnenbringer. From provider discussion to test completion: Evaluating cancer genetic services in a diverse academic comprehensive cancer care population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7333.

Introduction: Data on blood-borne viral infections in some regions in Saudi Arabia remain scarce. This study investigates the prevalence of serological markers and nucleic acid for blood-borne viruses among blood donors in Al-Baha, Kingdom of Saudi Arabia. Methodology: In this cross-sectional study, 2,807 donors who donated blood between January 2009 and November 2011 were investigated for blood-borne viral serological markers including HBsAg, anti-HBc, anti-HBs, anti-HCV, anti-HIV, and anti-HTLVI/III in addition to viral nucleic acid. Results: All donors were males between 16 to 66 years of age (mean: 31.5 ± 9.3 years). Viral nucleic acid and/or serological markers were detected in a total of 36 (1.3%) donors; of them, 26 (72.2%) had nucleic acid concomitant with serological markers, 6 (16.7%) had only viral nucleic acid, while 4 (11.1%) had only serological markers. Of all donors, 22 (0.8%) had HBsAg, 227 (8.0%) had anti-HBc, 157 (5.0%) had anti-HBs, 2,577 (91.8%) had no HBV markers, 2 (0.07%) had anti-HIV, 1 (0.04%) had anti-HCV, and 1 (0.04%) had anti-HTLVI/II. The donors who were born during HBV vaccination era showed no HBsAg (0.0%; p = 0.052), lower rates of anti-HBc (1.5%; p < 0.001) and anti-HBs (0.7%; p < 0.001), while the majority had no HBV markers (98.5%; p < 0.001). Conclusions: Combined viral nucleic acid and serological testing of donated blood enhances blood safety. The absence of HBV markers among donors suggests susceptibility or declined anti-HBs levels. Thus, HBV revaccination or a vaccine boost among adolescents and adults might be indispensable.

The objective of this study was to compare the efficiency of cloprostenol and fenprostalene in synchronizing estrus. Before treatment, estrus was detected during 4.5 d for multiparous cows in exp. 1 (n = 105) and 7.5 d for primiparous and nulliparous females in exp. 2 (n = 86). Females that were not in estrus (exp. 1: n = 74 and exp. 2: n = 58) received at random, either 500 μg of cloprostenol (i.m.) or 1 mg of fenprostalene (s.c). Cattle synchronized with cloprostenol or fenprostalene that presented estrus within 5 d showed similar fertility rates (exp. 1: 86.1% vs. 88.0% and exp. 2: 89.3% vs. 72.2% for cloprostenol and fenprostalene, respectively) and PGF2α-estrus intervals (exp. 1: 68 h vs. 73 h and exp. 2: 57 h vs. 57 h). However, the incidence of synchronization (exp. 1: 97.3% vs. 67.6%, P < 0.001; and exp. 2: 93.3% vs. 64.3%, P < 0.01) and pregnancy rates (exp. 1: 83.8% vs. 59.5%, P < 0.05; and exp. 2: 83.3% vs. 46.4%, P < 0.01) were statistically higher for cloprostenol than for fenprostalene. In exp. 2, primiparous cows and heifers obtained similar reproductive performances. The fertility rate of cattle treated with cloprostenol in exp. 2 was higher than that of untreated cattle (89.3% vs. 50.0%, P < 0.001, n = 56). In exp. 1, the variance of interval to estrus was similar for both analogues, but in exp. 2, it was less variable after the administration of cloprostenol (P < 0.05). Intervals between cloprostenol injection and estrus (0–10 and 0–15 d) were shorter (P < 0.05) and less variable (P < 0.001) than fenprostalene–estrus intervals. These results indicate that cloprostenol has a better potential for estrus synchronization than fenprostalene. Key words: Cloprostenol, fenprostalene, estrus synchronization, prostaglandin F2α, beef cattle

The role of angiotensin-converting enzyme (ACE) in the metabolism of bradykinin (BK) has been studied in several tissues. However, and contrary to angiotensin I, the metabolism of BK at the cardiac level has not been investigated. In this study, we define the participation of ACE in the carboxy-terminal degradation of BK in heart membranes of the dog, human, rabbit, and rat. The calculation of the kinetic parameters characterizing the metabolism of BK and the generated des-Arg9-BK can be summarized as follows: the half-life ( t 1/2) of BK [dog (218 ± 32 s) > human (143 ± 9 s) = rat (150 ± 4 s) > rabbit (22 ± 2 s)] and of des-Arg9-BK [dog (1,042 ± 40 s) > human (891 ± 87 s) > rat (621 ± 65 s) > rabbit (89 ± 8 s)] both showed significant differences according to species. Enalaprilat, an ACE inhibitor, significantly prevented the rapid degradation of BK and des-Arg9-BK in all species studied, whereas retrothiorphan, a neutral endopeptidase inhibitor, and losartan, an angiotensin II type I receptor antagonist, did not affect this metabolism. The relative importance of ACE in the cardiac metabolism of BK was species related: dog (68.4 ± 3.2%) = human (72.2 ± 2.0%) > rabbit (47.7 ± 5.0%) = rat (45.3 ± 3.9%). ACE participation in the metabolism of des-Arg9-BK was as follows: rabbit (57.0 ± 4.0%) > dog (39.9 ± 8.8%) = human (25.4 ± 5.5%) = rat (36.0 ± 7.0%). The participation of cardiac kininase I (carboxypeptidase M) in the transformation of BK into des-Arg9-BK was minor: human (2.6 ± 0.1%) > dog (0.9 ± 0.1%) = rabbit (1.0 ± 0.1%) = rat (1.0 ± 0.1%). These results demonstrate that ACE is the major BK-degrading enzyme in cardiac membranes. However, the metabolism of exogenous BK by heart membranes is species dependent. Our observations could explain some discrepancies regarding the contribution of kinins in the cardioprotective effects of ACE inhibitors.

Abstract Introduction: Although advances in care have allowed individuals with SCD to live further into adulthood, treatment of adult SCD pts is challenging due to increased rates of comorbidities and complications. Here we present clinical outcomes and treatment patterns from a prospective registry of pediatric and adult pts with SCD at 3 y to better characterize disease and treatment patterns in adult pts. Methods: Pts ≥2 y old with HbSS, HbSC or HbS/β-thalassemia were enrolled from 57 US centers and assessed every 6 mo until 3 y. Differences between pediatric (<18 y) and adult pts at 3 y are reported. Results: Among 498 pts (317 pediatric; 181 adults) completing baseline visit, 74.1% had HbSS, 15.3% HbSC and 10.4% HbS/β-thalassemia; 61 pts discontinued the study. At baseline, pediatric pts had more asthma/airway reactive disease, dactylitis, and splenic sequestration (Table 1). Adults had significantly poorer performance status (P<0.0001) and more avascular necrosis (AVN), gallbladder disease (GBD), leg ulcers, and pulmonary hypertension (PAH). The most common SCD crisis was pain, both in the 5 y prior to study (86.2% of adults, 72.2% of children) and during study (64.1% of adults, 69.4% of children; Table 2). During study, more pediatric pts had respiratory conditions, including acute chest syndrome (ACS). More than half of all pts were hospitalized; key reasons were pain, fever, and ACS. Significantly more pediatric pts were hospitalized due to fever (P<0.0001) and significantly more adult pts were hospitalized for transfusion/chelation (P=0.0336). Absenteeism from school/work was frequent prior to and during study. Conclusions: Patterns of disease and complications differed between children and adults. Adults had more hospitalizations due to transfusions/chelation and more classic chronic conditions (eg, AVN, GBD and PAH). Absenteeism from school/work was common in both groups. Limitations included the observational study design, variation in time from diagnosis, and lack of mandatory data collection. TABLE 1. Baseline Characteristics of Pediatric vs Adult Pts with SCD at 3 Y <18 y(n=317) ≥18 y(n=181) Age, y, mean±SD 8.9±4.43 35.2±12.52* Males, % 56.8 47.0† SCD genotype, n (%) HbSS 242 (76.3) 127 (70.2) HbSC 43 (13.6) 33 (18.2) HbS/β-thalassemia 32 (10.1) 20 (11.0) Karnofsky performance status, n (%) 100% 105 (33.1) 26 (14.4)* 90% 64 (20.2) 54 (29.8)* ≤80% 22 (6.9) 63 (34.8)* Medical history, n (%) Aplastic episode 31 (9.8) 15 (8.3) Asthma/reactive airway disease 97 (30.6) 29 (16.0) AVN 10 (3.2) 61 (33.7) CNS Abnormal TCD 28 (8.8) 7 (3.9) Seizure 15 (4.7) 13 (7.2) Silent infarct 23 (7.3) 11 (6.1) Stroke (lifetime) 33 (10.4) 27 (14.9) Dactylitis 75 (23.7) 12 (6.6) GBD 48 (15.1) 80 (44.2) Leg ulcer 0 18 (9.9) PAH 3 (0.9) 19 (10.5) Splenic sequestration 75 (23.7) 15 (8.3) *P<0.0001 † P<0.05 CNS, central nervous system; TCD, transcranial Doppler TABLE 2. Clinical Complications and Treatment Patterns in Pediatric vs Adult Pts with SCD at 3 Y <18 y(n=317) ≥18 y(n=181) <18 y (n=317) ≥18 y (n=181) Clinical Complications Pts with SCD crises in 5 y prior to study, n (%) Pain 229 (72.2) 156 (86.2) Infections (≥1) 135 (42.6) 62 (34.3) ACS/pneumonia 135 (42.6) 40 (22.1) Stroke (lifetime) 33 (10.4) 27 (14.9) Priapism 14 (4.4) 14 (7.7) Pts with SCD crises in 3 y during study, n (%) Pain 220 (69.4) 116 (64.1) Infections (≥1) 113 (35.6) 53 (29.3) ACS/pneumonia 62 (19.6) 18 (9.9) Stroke 9 (2.8) 2 (1.1) Priapism 8 (2.5) 3 (1.7) Pts hospitalized in 3 y during study, n (%) 212 (66.9) 111 (61.3) Number of hospitalizations in 3 y during study, n Causesµ Pain 135 91 Fever‡ 63 13 ‡ ACS/pneumonia 70 28 Transfusion/chelation 14 17 * Infections 8 7 Treatments Pts transfused, n (%) During 12 mo prior to study 138 (43.5) 96 (53.0)* During 3 y on study 172 (54.3) 93 (51.4) Chelation therapy, n (%) Pts ever chelated prior to study 63 (19.9) 59 (32.6) † During 3 y on study 40 (12.6) 19 (10.5) Pts used hydroxyurea, n (%) Prior to study 146 (46.1) 88 (48.6) During 3 y on study 156 (49.2) 78 (43.1) Absenteeism from school/work Missed school, n (%) Prior to study (>20 d in last 12 mo) 28 (14.7) 5 (25.0) During study (>20 d since last visit) 4 (2.5) 0 Missed work, n (%) Prior to study (>20 d in last 12 mo) 0 12 (22.2) During study (>20 d since last visit) 0 4 (9.5) ACS, acute chest syndrome *P<0.05 † P<0.01 ‡ P<0.0001 µUp to 3 discharge diagnoses may be listed for any hospital admission Disclosures Heeney: Novartis: Research Funding. Adams-Graves:Novartis Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Paley:Novartis Pharma: Employment. Esposito:Novartis Pharma: Employment. McNamara:Novartis Pharmaceuticals Corporation: Employment. Vichinsky:Novartis : Consultancy, Research Funding, Speakers Bureau.

Background. Considering decreasing age of patients with prostate cancer, increasing cancer alertness of first-line doctors as well as increased frequency of radical prostatectomies (RP), the problem of preservation of erectile function (EF) is vitally important (erectile dysfunction develops in 25–75 % of all patients who underwent surgery).The study objective is to analyze preservation of EF after RP depending on the type of endoscopic access and nerve preservation.Materials and methods. Between February of 2015 and February of 2016, in the Urology Clinic of the Sechenov University, 507 RPs were performed; the retrospective single-center study included 231 patients with localized prostate cancer. Surgery was performed with the following accesses: laparoscopic, extraperitoneal laparoscopic, and robotic. Indications for nerve preservation were formulated based on the Briganti nomogram, Partin table as well as patient’s desire to preserve EF. Further evaluation of EF was performed using the International Index of Erectile Function (IIEF5), evaluation of quality of life – using the QoL (Quality of Life) scale.Results. RP with nerve preservation was performed in 150 patients. Surgical time and blood loss did not significantly differ for surgeries with and without nerve preservation (р = 0.064 and р = 0.073 respectively). Pathomorphological examination showed that in all cases (n = 231) integrity of the prostatic capsule and negative surgical margin were achieved. Frequent significant erectile dysfunction and full loss of EF were observed in patients after RP without nerve preservation compared to the group with preserved neurovascular bundles (5.0 (0.0–10.0) points compared to 6.5 (0.8–19.0) points per the IIEF5 scale, р = 0.271): 96.2 % versus 72.2 % (p <0.001). Nerve preservation significantly improved quality of life: 1.63 ± 1.16 points versus 1.88 ± 1.02 points per the QoL scale (р = 0.035).Conclusions. The best results were achieved in the robotic access group. Surgery with nerve preservation decreased frequency of EF loss. This benefit in conjunction with the radical nature of the operative intervention allows to consider RP techniques with nerve preservation as reasonable approach to erectile dysfunction prevention in patients with localized prostate cancer.

Background The COVID-19 disease burden continues to be high worldwide and vaccines continue to be developed to help combat the pandemic. Acceptance and risk perception for COVID-19 vaccines is unknown in Botswana despite the government’s decision to roll out the vaccine nationally. Objectives This study aims to assess the acceptance rate and risk perception of COVID-19 vaccines amongst the general population in Botswana. Methods We interviewed 5300 adults in Botswana from 1–28 February 2021 using self-administered questionnaires. The main outcomes of the study were vaccine acceptance and hesitancy rates. Demographic, experiential and socio-cultural factors were explored for their association with outcome variables. Results Two-thirds of the participants were females (3199), with those aged 24–54 making the highest proportion (61%). The acceptance rate of COVID-19 vaccine was 73.4% (95% CI: 72.2%-74.6%) with vaccine hesitancy at 31.3% (95% CI: 30.0%-32.6%). When the dependent variable was vaccine acceptance, males had higher odds of accepting the vaccine compared to females (OR = 1.2, 95% CI: 1.0, 1.4). Individuals aged 55–64 had high odds of accepting the vaccine compared to those aged 65 and above (OR = 1.2, 95% CI: 0.6, 2.5). The odds of accepting the vaccine for someone with primary school education were about 2.5 times that of an individual with post graduate level of education. Finally, individuals with comorbidities had higher odds (OR = 1.2, 95% CI: 1.0, 1.5) of accepting the vaccine compared to those without any underlying conditions. Conclusion This study demonstrated a high acceptance rate for the COVID-19 vaccine and a low risk perception in Botswana. In order to achieve a high vaccine coverage and ensure a successful vaccination process, there is need to target populations with high vaccine hesitancy rates. A qualitative study to assess the factors associated with vaccine acceptance and hesitancy is recommended to provide an in-depth analysis of the findings.

ImportanceMismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti–programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor.ObjectiveTo assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors.Design, Setting, And ParticipantsThe GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017. Participants had advanced or recurrent dMMR and microsatellite instability–high (MSI-H) or polymerase epsilon (POLE)–altered solid tumors. The data cut for this interim analysis was from November 1, 2021, with median follow-up of 27.7 months.InterventionsPatients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal.Main Outcomes and MeasuresThe primary objective was to evaluate objective response rate and duration of response in patients with dMMR solid tumors by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.ResultsThe efficacy population included 327 patients (median [range] age, 63 [24-85] years; 235 [71.9%] female; 7 [2.1%] Asian, 6 [1.8%] Black, and 206 [63.0%] White patients), with 141 patients (43.1%) with dMMR endometrial cancer, 105 patients (32.1%) with dMMR colorectal cancer, and 81 patients (24.8%) with other dMMR tumor types. All patients had at least 1 previous line of therapy. Objective response rate assessed per blinded independent central review for dMMR solid tumors was 44.0% (95% CI, 38.6% to 49.6%). Median duration of response was not reached (range, ≥1.18 to ≥47.21 months); 72.2% of responders (104 of 144) had a response lasting 12 or more months. Median progression-free survival was 6.9 months (95% CI, 4.2 to 13.6 months); probability of progression-free survival at 24 months was 40.6% (95% CI, 35.0% to 46.1%). Median overall survival was not reached (95% CI, 31.6 months to not reached). The most frequent immune-related adverse events were hypothyroidism (25 [6.9%]), alanine aminotransferase increase (21 [5.8%]), and arthralgia (17 [4.7%]). No new safety concerns were identified.Conclusions And RelevanceIn this nonrandomized controlled trial, dostarlimab was a well-tolerated treatment option with rapid, robust, and durable antitumor activity in patients with diverse dMMR solid tumors. These findings suggest that dostarlimab provides meaningful long-term benefit in a population with high unmet need.Trial RegistrationClinicalTrials.gov Identifier: NCT02715284

Abstract Background In MDS, cytogenetic aberrations play an important role for classification and prognostication. The original IPSS and the revised IPSS classifiers have clearly demonstrated the prognostic impact of distinct cytogenetic abnormalities. The vast majority of chromosome aberrations in MDS are gains or losses of chromosomal material while balanced rearrangements are rare. However, more than 50% of MDS and even more in low risk MDS harbor a normal karyotype. Chromosome banding analysis can only detect gains and losses of more than 10 Mb size due to its limited resolution and is dependent on proliferation of the MDS clone in vitro to obtain metaphases. Array CGH has a considerably higher resolution and does not rely on proliferating cells. Aims In this study we addressed the question whether MDS with normal karyotype harbor cytogenetically cryptic gains and losses. Patients and Methods 520 MDS patients with normal karyotype were analyzed by array CGH (Human CGH 12x270K Whole-Genome Tiling Array, Roche NimbleGen, Madison, WI). For all patients cytomorphology and chromosome banding analysis had been performed in our laboratory. The cohort comprised the following MDS subtypes: RA (n=22), RARS (n=43), RARS-T (n=27), RCMD (n=124), RCMD-RS (n=111), RAEB-1 (n=104), and RAEB-2 (n=89). Median age was 72.2 years (range: 8.9-90.1 years). Subsequently, recurrently deleted regions detected by array CGH were validated using interphase-FISH. Results In 52/520 (10.0%) patients copy number changes were identified by array CGH. Only eight cases (1.5%) harbored large copy number alterations >10 Mb in size, as such generally detectable by chromosome banding analysis. These copy number alterations were confirmed by interphase-FISH. They were missed by chromosome banding analysis due to small clone size (n=2), insufficient in vitro proliferation (n=3) or poor chromosome morphology (n=3). In the other 44 patients with submicroscopic copy number alterations 18 gains and 32 losses were detected. The sizes ranged from 193,879 bp to 1,690,880 bp (median: 960,176 bp) in gained regions and 135,309 bp to 3,468,165 bp (median: 850,803 bp) in lost regions. Recurrently deleted regions as confirmed by interphase-FISH encompassed the genes TET2 (4q24; n=9), DNMT3A (2p23; n=3), ETV6 (12p13; n=2), NF1 (17q11; n=2), RUNX1 (21q22; n=2), and STAG2 (Xq25, deleted in 2 female patients). No recurrent submicroscopic gain was detected. In addition, we performed survival analysis and compared the outcome of patients with normal karyotype also proven by array CGH (n=462) to patients with aberrant karyotype as demonstrated by array CGH (n=52). No differences in overall survival were observed. However, overall survival in 35 patients harboring deletions detected solely by array CGH was significantly shorter compared to all others (median OS: 62.1 vs 42.4 months, p=0.023). Conclusions 1. Array CGH detected copy number changes in 10.0% of MDS patients with cytogenetically normal karyotype as investigated by the gold standard method, i.e. chromosome banding analysis. 2. Most of these alterations were submicroscopic deletions encompassing the genes TET2, ETV6, DNMT3A, NF1, RUNX1, and STAG2. 3. Interphase-FISH for these loci can reliably pick up these alterations and is an option to be easily performed in routine diagnostics in MDS with normal karyotype. 4. Patients harboring deletions detected solely by array-CGH showed worse prognosis. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Zenger:MLL Munich Leukemia Laboratory: Employment. Staller:MLL Munich Leukemia Laboratory: Employment. Roller:MLL Munich Leukemia Laboratory: Employment. Raitner:MLL Munich Leukemia Laboratory: Employment. Holzwarth:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Abstract Background Investigation of liver disease is recommended in the ECCO Guidelines for Extraintestinal Manifestations in Inflammatory Bowel Disease (IBD). The aim of this study was to analyse the prevalence of liver disease in IBD patients, to examine the frequency of different aetiologies, and to investigate a possible correlation between the severity of liver disease and IBD. Methods Cross-sectional descriptive study including all patients with inflammatory bowel disease (IBD) of nine hospitals in Spain. The study of liver disease was carried out in two phases: patients with FIB-4 greater than 1.3 (greater than 2 in those aged 65 years or more), as well as those with APRI greater than 0.5 and/or elevated transaminases were selected as those at risk of liver disease. In the second phase, these patients underwent a medical history, comprehensive blood tests, abdominal ultrasound with SWE elastography and Fibroscan® (including transitional elastography (TE) and Controlled Attenuation Parameter (CAP)). Results In total, 5302 patients were enrolled and 1640 (31%) were identified as at risk for liver disease. The University Hospital of Burgos has completed the second phase of the study in patients diagnosed with IBD between 2010 and 2021 (n=151). Of these patients, 72.2% were male and the median age was 61 years. Ulcerative colitis (57%) was the most common type of IBD and 62% of the patients were overweight or obese, while 12% of the patients had high-risk alcohol consumption. Metabolic hepatic steatosis was the most frequent cause of liver disease (35%). Moderate/severe steatosis was detected in 44.3% of patients by CAP and 24% by ultrasound. The prevalence of advanced fibrosis was 10.6% and 12% when assessed by ET and SWE, respectively. Notably, 12.6% displayed ultrasound signs of chronic liver disease. A positive correlation was found between the ET and the SWE for liver fibrosis, with a correlation coefficient of ĸ = 0.663. On univariate analysis, an increased risk of significant fibrosis (p=0.011) and moderate/severe steatosis (p=0.00) was found only in those who were overweight or obese. However, no association with severity of liver disease was found for perianal disease, use of immunosuppressants or history of previous surgery. Conclusion The incidence of unrecognised liver disease in IBD patients is substantial, with metabolic hepatic steatosis being the most common cause. The severity of liver disease in these patients cannot be ignored, with one in ten patients having advanced fibrosis. In the univariate study, only obesity was found to correlate with the severity of steatosis and fibrosis, while IBD severity showed no significant association with liver disease severity.

Abstract Background: Elotuzumab (elo) is a humanized monoclonal antibody, which has been approved by the FDA for use in combination with lenalidomide (lena) and dexamethasone (dexa) in patients (pts) with relapsed and refractory multiple myeloma (RRMM). Elotuzumab is effective as a single agent, as well as in combination for multiple myeloma treatments, supporting the use of elo in pts with RRMM and newly diagnosed multiple myeloma (NDMM) pts. Method: After review of literature using database searches was done on 6/27/18 (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), 9 prospective and 1 retrospective study with 1128 enrolled pts met the inclusion criteria to date in RRMM and 2 clinical trials including 123 pts in NDMM (Table 1). CMA software v.3 was used for meta-analysis. A random-effect model was applied. Result: Regimens used in RRMM: Based on pooled analysis (95% CI), an overall response rate (ORR) of 66% (54-76.2) was calculated in 685 evaluable pts treated with elo based regimens in RRMM (Figure 1). Most common grade (G) ≥ 3 hematological adverse events (HAE) and non-hematological adverse events (NHAE) based on regimen were calculated using pooled analysis in RRMM pts (Table 2). Anemia was noted in 12.1% ( 7.7-18.6) in 559 pts, while neutropenia in 14.5% (7.5-26.4) out of 591 pts and thrombocytopenia (tcp) in 11.9% (7.9-17.4) in 198 evaluable pts. Diarrhea 5.5% (3.6-8.3), pyrexia 2.4% (1.5-4), peripheral neuropathy (PN) 8.4% (3.8-17.8) were measured in 626, 668 and 143 pts respectively. Elotuzumab as monotherapy: 1 study (n=34) evaluated the efficacy of elo as single agent in RRMM. The median age, time from diagnosis and number of prior therapies were 64.5 years (y) (46-87), 4.4 y (0.9-12.8) and 4.5 y (2-10) respectively. It produced an ORR of 1.4% (0.1-19.1 95% CI) in 34 evaluable pts. Adverse events recorded were pyrexia and fatigue in 17.6% and 8.8% pts respectively. Elotuzumab in two drug regimen: In RRMM, 2 clinical trials (n=49) evaluated the efficacy (95% CI) of elo, ORR of 25% (4.1-72.3) was calculated. The best PFS (progression free survival) produced was in combination of elo 20 mg with bortezumib (bort) 1.3mg/m2 of 9.46 months as compared to 1.8 months when elo10mg/kg + dexamethasone (dexa) 28mg was used. In our analysis for safety, common G≥ 3 HAE calculated were, thrombocytopenia 8.7% (3.3-21.1) n=49, neutropenia 10.7 % (3.5-28.4) n=28 pts and anemia 7.1% (1.8-24.5) n=28 pts. NHAE included diarrhea 1.7% (0.1-22.3), PN 10.7% (3.5-28.4), pyrexia 1.7% (0.1-22.3) in 28 evaluable pts each. Elotuzumab in three drug regimen: In RRMM, 10 clinical trials including 602 pts evaluated the efficacy of elo as a part of triple drug regimen, producing an ORR of 72.2% (54-76.2). The best results were produced with the combination of elo 10-20mg/kg + lenalidomide (lena) 25mg + dexa 40mg producing a PFS of 32.2 mo and 28.62 mo in its phase I and II cohorts respectively. Based on pooled analysis (95% CI) common HAE calculated were neutropenia 17.5% (7.6-35.4) in n=563, thrombocytopenia 12.7% (8.2-19.4) in n=149 and anemia 13% (8-20.5) in n=531 pts. Common G ≥ 3 NHAE estimated were diarrhea 5.7% (3.7-8.6), PN 6.6% (2-19.2), pyrexia 2.5% (1.5-4.1) in 598, 115 and 640 pts respectively. Elotuzumab based regimen in NDMM: A currently ongoing clinical trial NCT02272803 has produced promising results in NDMM pts. As a part of three drug regimen with dose of elo 10mg/kg-20mg/kg, lena 25mg, dexa 20mg in 40 pts produced an ORR of 87.5% (73.2-95.8) versus control group of lena 25mg plus dexa 40mg in 42 pts with an ORR of 73.8% (58-86.1). The PFS rate recorded at 1 year was 93% (79-98%) and 91% (73-97%) respectively. The HAE G ≥ 3 included, neutropenia 18% and leukopenia 15%. In another study with 41 pts, elo was used in combination with lena, bort and dexa producing an ORR of 100% and greater than grade 3 adverse events including Tcp 15%, PN 2%. Conclusion: Results produced in our study suggest that elotuzumab is highly effective when used in pts with RRMM and NDMM. Combination regimens for elo produces an ORR ranging from 79-83% with elo + lena+ dexa, proving that the best results were produced by three drug regimens. Large prospective studies are required to evaluate efficacy and safety of elotuzumab in combination therapies. Disclosures No relevant conflicts of interest to declare.

ImportanceThe US Food and Drug Administration’s Center for Tobacco Products (CTP) prioritized its enforcement efforts against nontobacco, nonmenthol (ie, sweet)–flavored cartridge e-cigarettes in February 2020. Within-person e-cigarette initiation, continuation, and switching behaviors among youth are unknown following CTP’s prioritized enforcement efforts.ObjectiveTo describe transitions in youths’ e-cigarette flavor/device combination use, brand use, nicotine use, and frequency of use following CTP’s e-cigarette enforcement prioritization.Design, Setting, and ParticipantsThe US population-based, nationally representative Population Assessment of Tobacco and Health cohort study included data collected in 2019 and 2021 from youth aged 12 to 17 years. The data were analyzed from February to June 2023.Exposuree-cigarette use (past 30 days), flavor/device combination used, brand used, nicotine use, and frequency of use.Main Outcomes and MeasuresTransitions in e-cigarette use, flavor/device combination used, brand used, nicotine use, and frequency of use between 2019 and 2021 among 9088 youth aged 12 to 17 years in 2019; prevalence of e-cigarette use, flavor/device combination used, and brand used in 2019 (n = 8771) and 2021 (n = 5574) among youth aged 14 to 17 years in each year.ResultsThe 2019 sample included 8771 youth. The population of those aged 12 to 17 years was 49.0% female (95% CI, 48.7%-49.3%) and 51.0% male (95% CI, 50.8%-51.3%). Participants were 15.4% Black (95% CI, 15.0%-15.7%), 24.1% Hispanic (95% CI, 23.9%-24.4%), 75.9% non-Hispanic (95% CI, 75.6%-76.1%), 69.1% White (95% CI, 68.5%-69.8%), and 15.5% another race (95% CI, 14.9%-16.1%). Among youth ages 12 to 17 years who did not use e-cigarettes in 2019, 531 (6.5%) initiated use in 2021 (95% CI, 5.9%-7.1%); among them, 415 (76.8%) initiated with a combination other than a sweet cartridge (95% CI, 72.2%-80.8%). Among youth ages 12 to 17 who used e-cigarettes in 2019, 360 (47.8%) continued use in 2021 (95% CI, 44.0%-51.1%). Continuation rates were similar for those who used sweet-cartridge e-cigarettes (144 [51.5%]; 95% CI, 45.7%-57.3%) and those who used other combinations (204 [47.6%]; 95% CI, 42.8%-52.4%) in 2019. Among those who continued e-cigarette use in 2021, 121 (84.0%) of those who used sweet-cartridge e-cigarettes in 2019 switched to a different combination (95% CI, 77.0%-89.2%). Overall, among youth who used e-cigarettes in 2021, 177 (53%) used a sweet-disposable combination, 32 (11%) used a sweet-cartridge, and no individual brand was used by more than 10%.Conclusions and RelevanceThe results of this longitudinal cohort study of youth in the US suggest that most youth who initiated or continued e-cigarette use in 2021 used flavor/device combinations that were excluded from CTP’s enforcement priorities. Restrictions and enforcement efforts that only cover a subset of products may be ineffective at preventing youth flavored e-cigarette use.

In the cell, all-trans retinoic acid (ATRA), a vitamin A metabolite, binds to retinoic acid-receptor (RAR), whereas the ATRA isomere 9-cis-retinoic acid (9-cis-RA) binds to both RAR and the retinoid X receptor (RXR). Synthetic compounds such as LG100268 (LG; Ligand Laboratories) are highly specific to bind RXR, which allows to differentially study the RAR and RXR pathways. In previous work morulae treated with LG for 48 h showed to improve blastocyst development and to activate pro-apoptotic genes (in press), whereas ATRA for 24 h increased cell numbers in the inner cell mass (ICM) and the trophectoderm (TE) (Rodr�guez et al. 2006 Hum. Reprod. 21, 2149–2157). However, LG and ATRA were never both compared for 24 in medium with BSA, which is thought to be more appropriate to produce embryos for cryopreservation than serum-containing medium. In this work we analyze development, quality, and viability of morulae cultured with RAR and RXR agonists. Cumulus–oocyte complexes from slaughterhouse ovaries were matured and fertilized in vitro. Presumptive zygotes were cultured in synthetic oviduct fluid (SOF) +3 gL–1 BSA. On day 6, morulae were treated for 24 h with ATRA 0.7 µm, LG 0.1 µm, or no additives. Blastocyst development was monitored up to day 8. Differential cell counts were made on hatched blastocysts on days 7 and 8. Apoptosis and necrosis (TUNEL + nuclear histology) were made on day 8 expanded and hatched blastocysts. Data were analyzed by GLM and Duncan's test, expressed as LSM � SE, and development rates were expressed as percentages of cultured morulae (replicates [R] = 14 for development; R = 9 for cell counts; R = 4 for apoptosis; n = 1647 morulae). ATRA yielded more blastocysts on day 8 than LG and controls (72.2 � 2.2 v. 60.0 � 2.3 and 65.6 � 2.4, respectively; P < 0.02), and more expanded blastocysts than LG (48.6 � 2.3 v. 36.6 � 2.4; P < 0.02), but no more than controls (43.5 � 2.5). Day-7 and day-8 hatched blastocysts cultured with ATRA showed more total cells than day-7 controls (163.5 � 8.0 and 161.5 � 5.4 v. 137.7 � 8.9, respectively; P < 0.05). However, in the presence of ATRA, day-8 blastocysts showed a strong cell reduction in the inner cell mass (ICM), whereas their day-7 counterparts conserved ICM/total cells proportions comparable to day-7 controls (11.0 � 1.2 v. 19.7 � 1.7 and 20.6 � 1.9, respectively; P < 0.03). The LG increased apoptotic index (AI) and necrotic index (NI) in the ICM (AI: 14.5 � 2.4 v. 6.4 � 1.5 and 6.4 � 1.4; NI: 5.0 � 1.2 v. 0.9 � 0.8 and 1.6 � 0.7; for LG, ATRA, and controls, respectively; P < 0.02). Embryos produced with ATRA showed improved development and cell distribution without increasing apoptosis and necrosis. Vitrification of excellent day-7 and day-8 blastocysts is in course to evaluate cryosurvival and further embryo transfer to determine full developmental competence. Grant Support: MEC, project AGL2005-04479. M. Muñoz is sponsored by FICYT.

Abstract Background: Medical financial hardship, encompassing material, behavioral, and psychologic domains, is becoming an increasingly common consequence of illness in cancer patients. Identifying at-risk patients is the first step to develop proactive approaches to mitigate this problem. To try and address this need, Mayo Clinic Breast Disease Registry (MCBDR) is prospectively collecting data about financial concerns in addition to the usual sociodemographic and clinical information. Methods: We used data from Mayo Clinic Breast Disease Registry, a prospective cohort of consenting patients seen at Mayo Clinic Rochester within one year of initial breast cancer diagnosis. Participants completed baseline and annual follow-up surveys rating their financial concerns on a linear analogue scale from 0 (“none”) to 10 (“constant concerns”). We compared patient-reported financial concern at baseline to that on each patient’s most recent survey, with worsening concerns defined as a 1+-point increase. Logistic regression evaluated for predictors of worsening financial concerns. Results: 1,957 participants responded to financial concern questions on a baseline and at least one follow-up survey between 2015 and 2020. Mean age was 58.5 years (SD 12.5), and mean time between diagnosis and the most recent follow-up was 25.6 months (SD 16.2). 357 (18.2%) reported worsening financial concerns. Only lower baseline financial status was associated with a greater likelihood of worsening financial concerns (see Table). Conclusions: More than one in seven breast cancer survivors develop worsening financial concerns within 5-years of diagnosis, and those with less financial security at baseline appear to be most vulnerable. Funding: Breast Cancer Research Foundation (CLL) and NR015259 (KJR). Patient and tumor characteristics, compared by whether financial status worsened over time Full Cohort (n=1957) Worsening, ≥ 1-point change (n=357) Stable/Improved (n=1600) p value Full Cohort (n=1957) Worsening, ≥ 1-point change (n=357) Stable/Improved (n=1600) p value Age at diagnosis II or III 502 (25.7%) 98 (27.5%) 404 (25.3%) 0.239 ≤ 50 546 (27.9%) 105 (29.4%) 441 (27.6%) IV 67 (3.4%) 17 (4.8%) 50 (3.1%) 0.086 51-64 757 (38.7%) 136 (38.1%) 621 (38.8%) 0.562 Unknown 351 (17.9%) 65 (18.2%) 286 (17.9%) 0.536 ≥65 654 (33.4%) 116 (32.5%) 538 (33.6%) 0.506 ER and/or PR positive Race No/Unknown 482 (24.6%) 92 (25.8%) 390 (24.4%) White 1863 (95.2%) 337 (94.4%) 1526 (95.4%) Yes 1475 (75.4%) 265 (74.2%) 1210 (75.6%) 0.580 Non-white 24 (1.2%) 5 (1.4%) 19 (1.2%) 0.729 Her2 positive Other/Unknown/Choose not to respond 70 (3.6%) 15 (4.2%) 55 (3.4%) 0.478 No/Unknown 1746 (89.2%) 314 (88.0%) 1432 (89.5%) Educational status Yes 176 (9.0%) 37 (10.4%) 139 (8.7%) 0.321 Less than bachelor’s degree 880 (45.0%) 168 (47.1%) 712 (44.5%) Borderline 35 (1.8%) 6 (1.7%) 29 (1.8%) 0.898 Bachelor's degree or higher 1065 (54.4%) 187 (52.4%) 878 (54.9%) 0.384 Radiation Unknown 12 (0.6%) 2 (0.6%) 10 (0.6%) 0.832 No/Unknown 781 (39.9%) 140 (39.2%) 641 (40.1%) Financial status near time of diagnosis Yes 1176 (60.1%) 217 (60.8%) 959 (59.9%) 0.768 Pay bills, money for special things 1412 (72.2%) 244 (68.3%) 1168 (73.0%) Chemotherapy/targeted therapy Pay bills, no money for special things 367 (18.8%) 80 (22.4%) 287 (17.9%) 0.046 No/Unknown 1264 (64.6%) 221 (61.9%) 1043 (65.2%) Pay bills by making cuts 102 (5.2%) 19 (5.3%) 83 (5.2%) 0.729 Yes 693 (35.4%) 136 (38.1%) 557 (34.8%) 0.241 Unable to pay bills 56 (2.9%) 10 (2.8%) 46 (2.9%) 0.911 Hormone/endocrine therapy Unknown 20 (1.0%) 4 (1.1%) 16 (1.0%) 0.750 No/Unknown 710 (36.3%) 141 (39.5%) 569 (35.6%) Employment status at time of diagnosis Yes 1247 (63.7%) 216 (60.5%) 1031 (64.4%) 0.163 Employed full-time 462 (23.6%) 83 (23.2%) 379 (23.7%) Surgery type Employed part-time/unemployed/retired 525 (26.8%) 92 (25.8%) 433 (27.1%) 0.856 Lumpectomy 846 (43.2%) 145 (40.6%) 701 (43.8%) Not available 970 (49.6%) 182 (51.0%) 788 (49.3%) 0.716 Mastectomy 903 (46.1%) 165 (46.2%) 738 (46.1%) 0.535 Stage at time of diagnosis None/Unknown 208 (10.6%) 47 (13.2%) 161 (10.1%) 0.069 0 or I 1037 (53.0%) 177 (49.6%) 860 (53.8%) Citation Format: Michael H. Storandt, Urshila Durani, Daniela Stan, Nicole Larson, Charles Loprinzi, Fergus Couch, Janet E. Olson, Nandita Khera, Kathryn J. Ruddy. Financial hardship in breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1012.

Abstract Abstract 2926 Background: RAS proteins are encoded by 3 proto-oncogenes (K-RAS, N-RAS, and H-RAS) and regulate the growth and differentiation of many cellular types, including the myeloid compartment. Codons 12, 13, and 61 (in N-RAS and K-RAS) have been reported to be common targets of mutations. These mutations result in constitutive activation of the RAS pathway by increasing intracellular RAS GTP levels, which result in activation of the RAS/MEK and the RAS/PI3K pathways. Its prognostic significance in MDS is yet to be clarified. Because the potential prognostic and therapeutic implications of RAS mutations in MDS, we decided to study the impact of RAS mutations in patients (pts) with MDS. Methods: Mutation analysis of KRAS and NRAS codons 12, 13, and 61 was performed by Pyrosequencing using biotinylated reverse primers. All pts referred to MD Anderson between 2000–2009 were reviewed. In addition to standard clinical characteristics, including karyotyping, mutational status of Flt3, c-Kit and JAK2 was also analyzed. Overall survival was calculated based on Kaplan-Meier. Results: Of the 1067 pts with MDS of age above 17 evaluated for RAS mutation, 43 pts (4%) were positive. Seventy nine percent of RAS mutations were of N-RAS type (codon12 (55%), codon 13 (12%), codon 61(12%)) with K-RAS 12 comprising the rest (21%). Median age was 68 years (range, 18–94) with 66% being males (703 pts). Their median white blood cell (WBC) was 3.3×109/L (range, 0.3–72.2), hemoglobin 9.8 (range, 3–17.5), and platelets 73×109/liter (range, 1–1040). Median bone marrow blast was 5% and 77 pts (7%) had leukemic transformation. More than half of the pts had RAEB or RAEB-t (44% and 9 % respectively) which translated into fewer patients in the low IPSS category (19%). The median age was 66 years (range 26–84) in the RAS mutated (muRAS) group compared to 68 in the wild type (wtRAS). WBC was higher in the muRAS group compared to wtRAS (6.8 ×109/L vs. 3.2 ×109/L, p<0.001 by Mann-Whitney median test (M-W-T)). Percent of bone marrow blasts was higher (9%) in muRAS group compared to 5% in wtRAS (p<0.001 by M-W-T). High (Int-2 and high) risk by IPSS was more frequent in muRAS 51% compared to 40% in wtRAS group (p=0.11). Leukemic transformation was 9% and 7% (p=0.61) in both muRAS and wtRAS groups respectively. RAS mutation was detected more frequently in the CMML subgroup (12/80 (15%) pts). There were no differences in terms of response to DNA methylating inhibitors (CR in 41% in muRAS versus 40% in wtRAS). ARA-C-based regimens resulted in better CR in wtRAS than muRAS (59% vs 25%); however, the size of muRAS group was too small (1 out 4 pts).There was a trend towards shorter overall survival (OS) in the muRAS group compared to wtRAS (395 vs. 500 days, p value=0.057). MuRAS RAEB (325 vs. 450 days, p= 0.13) and RAEB-t (125 vs. 375 days, p= 0.27) subgroups showed a trend towards worse OS compared to wtRAS group. There was a significant OS decrease in RCMD (150 vs. 700 day, p= 0.015). Surprisingly, muRAS CMML group showed a trend towards better OS compared to wtRAS (728 vs. 687 days, p=0.44). Additionally we analyzed patients for presence of Flt3 mutation. These were present in only 18 of the pts (4%) but none of them had also a RAS mutation. There was no c-Kit mutations found in this cohort of pts, compared to 9/37 (24%) pts tested positive for JAK2V617F. Conclusion: MuRAS occurs in 4% of pts with MDS. In the muRAS group, pts tended to have higher risk disease and risk of transformation to acute leukemia compared with wtRAS. OS tended to be worse in some subgroups in muRAS. Although the prognostic impact of RAS mutations in MDS appears to be limited, mutations could be used to develop targeted therapeutic interventions. Disclosures: No relevant conflicts of interest to declare.

Abstract HER2DX genomic assay in triple-negative breast cancer (TNBC) patients treated with 12-weeks of neoadjuvant chemotherapy: a correlative analysis from WSG-ADAPT-TN phase II trial Background: Biomarkers for de-escalation and escalation of systemic therapy in early-stage TNBC are needed. HER2DX is a standardized prognostic (risk-score) and predictive (pathological complete response [pCR]-score) assay based on clinical and gene expression-based data. Here we aimed to test the value of HER2DX assay in early TNBC. Methods: Standardized HER2DX was evaluated centrally using RNA from baseline FFPE tumor biopsies from the WSG-ADAPT-TN study (NCT01815242), a multicenter phase II trial that randomized 336 patients with stage I–III early TNBC to 12-weeks of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 d1,8 every 3 weeks (arm A) versus nab-paclitaxel 125 mg/m2 plus carboplatin AUC2 day 1,8 every 3 weeks (arm B). The primary aim was to test the ability of HER2DX pCR and risk-score models to predict pCR (ypT0/isN0) and survival endpoints, respectively, such as invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). Secondary objectives were to assess the association of the i) HER2DX immune signature score and ii) percentage (%) of stromal tumor infiltrating lymphocytes (sTILs) with efficacy endpoints. Uni- and multi-variable logistic regression and Cox models tested the association of each variable with each endpoint. Results: HER2DX was evaluated in 126 (37.5%) baseline pre-treatment tumors. Mean age was 52.1 (range 26-76). cT1 represented 40.5% of cases and 72.2% were cN0. Overall, pCR rate was 34.1% (95%CI 26.1 – 43.2) and median follow-up was 5.0 years. Median sTILs at baseline was 31.6% (range 0-90) and moderately correlated with the IGG signature (coefficient=0.57). The % of HER2DX high-, medium- and low-pCR groups was 41.3%, 47.6% and 11.1%, respectively. HER2DX pCR score (as a continuous variable) was significantly associated with pCR in univariate (odds ratio [OR per 10-unit increase]=1.31, 1.06-1.64, p=0.016) and after adjusting by treatment arm (OR=1.31, 1.06-1.65, p=0.015). Overall, the pCR rates in HER2DX pCR-high, -medium and -low groups were 46.2%, 26.7% and 21.4%, respectively (high vs medium/low OR=2.48, 1.17-5.34, p=0.018). In arm B (n=51), the pCR rates in HER2DX pCR-high, -medium and -low groups were 47.8%, 25.0% and 0.0% respectively (high vs medium/low OR=3.36, 1.02-12.0, p=0.051). In terms of the risk-score, the % of HER2DX low-risk and high-risk groups was 60.3% and 39.7%, respectively. HER2DX risk score as a continuous variable was significantly associated with iDFS, DDFS and OS (p&lt; 0.001 in all univariate analysis), and after adjusting by variables such as arm and pCR status (all p&lt; 0.05). sTILs were not associated with any survival endpoint (all p &gt;0.35). The HER2DX immune signature was significantly associated with iDFS (p=0.012), DDFS (p=0.022) and OS (p=0.012). Conclusion: The HER2DX genomic test in TNBC provides valuable insights into the response and survival following neoadjuvant taxane-based chemotherapy in the absence of immunotherapy. The development of a tailored genomic assay for TNBC is currently in progress. Citation Format: Oleg Gluz, Fara Brasó-Maristany, Ulrike Nitz, Laia Paré, Matthias Christgen, Guillermo Villacampa, Benedetta Conte, Sherko Kuemmel, Ronald Kates, Cornelia Kolberg-Liedtke, Eva-Maria Grischke, Helmut Forstbauer, Michael Braun, Mathias Warm, John Hackmann, Christoph Uleer, Bahriye Aktas, Claudia Schumacher, Ana Vivancos, Rachel Wuerstlein, Joel S. Parker, Monika Graeser, Charles M. Perou, Christine zu Eulenburg, Patricia Villagrasa, Hans-Heinrich Kreipe, Aleix Prat, Nadia Harbeck. HER2DX genomic assay in triple-negative breast cancer (TNBC) patients treated with 12-weeks of neoadjuvant chemotherapy: a correlative analysis from WSG-ADAPT-TN phase II trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-15-07.

Objectives: Acute myeloid leukemia (AML) patients with biallelic mutations of CEBPA (bi CEBPA) have a 30-50% relapse rate after standard chemotherapy. This study established the value of multiparameter flow cytometric measurable residual disease (MFC-MRD) detection, mutations based on next-generation sequencing (NGS), and compares the outcomes of risk stratification treatment in adult bi CEBPA AML patients. Methods: From March 2014 to December 2018, 124 patients with newly diagnosed acute myeloid leukemia with bi CEBPA were treated with chemotherapy. Out of these, 93 patients were analyzed further by a sensitive NGS assay for mutations in 87 candidate genes. MRD was detected in all patients by MFC after each cycle of induction and consolidation chemotherapy and every 3 months later. Results: Among these patients, 73 patients were male (58.9%), and median age was 37.5 (16-69) years. The expression of CD34, CD117, CD7, HLA-DR, CD15, CD33 and CD13 in 124 patients were 120 (96.8%), 123 (99.2%), 112 (90.3%), 107 (86.3), 93 (75.0%), 115 (92.7%) and 107 (86.3%) respectively. The most common co-occurring mutations were found in the GATA2 (n=29/93, 31%), WT1 (n=20/93, 21.7%), NRAS (n = 13/93, 14.0%), CSF3R (n = 12/93, 12.9%), and TET2 (n = 9/93, 9.6%) genes. All patients (100%) achieved complete remission (CR) including 114 patients (91.9%) who achieved it with only 1 induction course. The median follow-up was 33.5 (4-69) months. The 3-year Cumulative incidence of relapse (CIR), disease-free survival (DFS) and overall survival (OS) were 32.8%, 64.7%, and 84.3%, respectively. Univariate analysis results shown that WT1 Wild-type was favorable factor of 3-year CIR (23.3% vs. 47.0%, P=0.022) and 3-year DFS (75.5% vs 53.0%; P=0.031), GATA2 Wild-type had good trend for lower CIR and longer DFS and CSF3R Wild-type had inferior trend for higher CIR and shorter DFS. Patients with sustained positive MRD status after 2 consolidation cycles and MRD negative status loses in any time defined as "MRD high risk" had higher CIR (3-year CIR, 100% vs 25.5%; P&lt;0.001; 81.5% vs 6.4%; P&lt;0.001, respectively) and worse DFS and OS (3-year DFS, 0% vs 71.5%; P&lt;0.001; 16.8% vs 90.2%; P&lt;0.001, respectively; 3-year OS, 39.0% vs 89.8%; P&lt;0.001; 72.2% vs 96.5%; P=0.001, respectively ) than those with persistent negative MRD status that defined as "MRD low risk" (Figure). Multivariate analysis showed that MRD low risk was the only favorable factor of CIR, DFS and OS (CIR: HR=37.3, 95%CI: 8.6-161.3, P&lt;0.001;. DFS: HR=24.6, 95%CI: 7.2-84.0, P&lt;0.001; HR=28.2, 95%CI: 2.1-374.1, P=0.011; respectively). Thirty-two (91.4%) MRD high risk patients (P&lt;0.001) relapsed at a median time of 8 months (range: 3-32 months) include 21 patients of MRD negative status loses in any time and 11 patients with positive MRD status after 2 consolidation cycles. In totally 35 relapsed patients, 3 patients give up, 19 (61.3%) patients achieved CR2 after induction again. 15 CR2 and 4 non-remission patients underwent allo-HSCT achieved superior 3-year OS (83.0% vs 5.1%; p= 0.034; 75.0% vs 0%; p=0.006; respectively) than chemotherapy. To assess the role of risk stratification treatment by transplant or non-transplant, the124 patients were divided into 2 groups by the unique risk factor: MRD high risk group (n=43, 34.7%) and MRD low risk group (n=81, 65.3%). In the MRD low risk group (median follow-up: 35 months; range: 4-65 months), there was no significant difference in probabilities of 3-year OS (92.3% vs. 96.9%, P=0.428) between the transplant and non-transplant cohorts. In the MRD high risk group (median follow-up: 30 months; range: 7-69 months), 3-year OS was significantly better in the transplant cohort than in the non-transplant cohort (84.0% vs. 44.3%, p=0.007).Conclusions: MRD high risk may better predict the outcome rather than mutations based on NGS in AML with bi CEBPA, and allo-HSCT may achieve superior survival in MRD high risk patients. Key words: Acute myeloid leukemia with biallelic CEBPA mutations; next-generation sequencing; multiparameter flow cytometric measurable residual disease; allogeneic stem cell transplantation; Chemotherapy Disclosures No relevant conflicts of interest to declare.

GOM Lease Sale Generates $121 Million in High Bids; Shell Offshore Takes Top Spot Regionwide US Gulf of Mexico (GOM) Lease Sale 256 generated $120,868,274 in high bids for 93 tracts in federal waters. The sale on 18 November featured 14,862 unleased blocks covering 121,875 square miles. With $27,877,809 spanning 21 high bids, Shell Offshore Inc. took the top spot among 23 competing companies. A total of $135,558,336 was offered in 105 bids. Among the majors, Shell, Equinor, BP, and Chevron submitted some of the highest bids. Each company claimed high bids of over $17 million, signaling the GOM remains a priority in their portfolios. Last year was a record year for American offshore oil production at 596.9 million bbl, or 15% of domestic oil production, and $5.7 billion in direct revenues to the government. Offshore oil and gas supported 275,000 total domestic jobs and $60 billion total economic contributions in the US. “The sustained presence of large deposits of hydrocarbons in these waters will continue to draw the interest of industry for decades to come,” Deputy Secretary of the Interior Kate MacGregor said. Still, as Mfon Usoro, senior research analyst at Wood Mackenzie, noted, “Although bidding activity increased by 30% from the March 2020 sale, the high bid amount of $121 million still trends below the average high bid amount seen in previous regionwide lease sales, proving that companies are still being conservative with exploration spend.” Although the Bureau of Ocean Energy Management has proposed another regionwide GOM lease sale in March 2021, Usoro predicted that Lease Sale 256 “could potentially be one of the last lease sales.” “With the Biden administration set to inaugurate next year and possibly ban future lease sales, a massive land grab might have ensued,” he continued. “But companies are constrained by tight budgets due to the prevailing low oil price. Additionally, companies in the region have existing drilling inventory to sustain them in the near term. The best blocks with the highest potential reserves are likely already leased. As a result, we do not expect a potential ban on leasing to materially impact production in the region until the end of the decade.” This was the seventh offshore sale held under the 2017–2022 National Outer Continental Shelf Oil and Gas Leasing Program; two sales a year for 10 total regionwide lease sales are scheduled for the gulf. Nine Areas on Norwegian Continental Shelf Open for Bids The 25th licensing round on the Norwegian Continental Shelf, comprising eight areas in the Barents Sea and one in the Norwegian Sea, has been announced by the Norwegian Ministry of Petroleum and Energy. Known for being a country with some of the greenest credentials and policies in the world, Norway surprised observers in June by announcing plans for a licensing round that signaled further oil exploration in the Norwegian sector of the Arctic Sea. In this round, 136 blocks/parts of blocks will be available: 11 in the Norwegian Sea and 125 in the Barents Sea. The application deadline for companies is 23 February 2021. New production licenses will be awarded in Q2 2021. Johan Sverdrup Capacity Increased to Half Million B/D Following positive results in a November capacity test, the Johan Sverdrup field is set to increase daily production capacity. Capacity will rise from today’s 470,000 to around 500,000 B/D in the second increase since the field came on stream just over a year ago. The move will increase the field’s total production capacity by around 60,000 bbl more than the original basis when the field came on line. Overall, the field is estimated to have resources of 2.7 billion BOE. “The field has low operating costs, providing revenue for the companies and Norwegian society, even in periods with low prices,” said Jez Averty, Equinor’s senior vice president for operations south in development and production, Norway. The Johan Sverdrup field uses water injection to secure high recovery of reserves and maintain production at a high level. An increase in the water-injection capacity should further increase production capacity by mid-2021, according to Rune Nedregaard, vice president for Johan Sverdrup operations. Phase 2 production starting in Q4 2022 will raise the Johan Sverdrup full-field plateau production capacity from 690,000 to around 720,000 B/D. Equinor operates the field with 42.6% stake; other partners include Lundin Norway (20%), Petoro (17.36%), Aker BP (11.57%), and Total (8.44%). ConocoPhillips Makes Significant Gas Discovery Offshore Norway ConocoPhillips announced a new natural-gas condensate discovery in production license 1009, located 22 miles northwest of the Heidrun oil and gas field and 150 miles offshore Norway in the Norwegian Sea. The wildcat well 6507/4-1 (Warka) was drilled in 1,312 ft of water to a total depth of 16,355 ft. Preliminary estimates place the size of the discovery between 50 and 190 million BOE. Further appraisals will determine potential flow rates, the reservoir’s ultimate resource recovery, and plans for development. “The Warka discovery and potential future opportunities represent very low cost-of-supply resource additions that can extend our multi-decade success on the Norwegian Continental Shelf,” said Matt Fox, executive vice president and chief operating officer. The drilling operation, which was permitted to ConocoPhillips in August 2020, was performed by the Transocean-managed Leiv Eiriksson semisubmersible rig. ConocoPhillips Skandinavia AS is the main operator of the license with a 65% working interest; PGNiG Upstream Norway AS holds the remaining stake. Lundin Energy Completes Barents Sea Exploration Well, Comes Up Dry Lundin Energy has completed exploration well 7221/4-1, targeting the Polmak prospect in licenses PL609 and PL1027, in the southern Barents Sea. The well was meant to prove hydrocarbons in Triassic-aged sandstones within the Kobbe formation of the Polmak prospect. After finding indications of hydrocarbons in a 9-m interval in poor-quality reservoir in the targeted formation, the well was classified as dry. The well was drilled 30 km east of the Johan Castberg discovery, by the Seadrill-operated West Bollsta semisubmersible rig. Lundin Energy, operator of Polmak, holds a 47.51% working interest. Partners are Wintershall DEA Norge AS (25%), Inpex Norge AS (10%), DNO Norge AS (10%), and Idemitsu Petroleum Norge AS (7.5%). Polmak is the first of Lundin’s three high-impact exploration prospects drilled this quarter in the Barents Sea; the wells target gross unrisked prospective resources of over 800 million bbl of oil. The West Bollsta rig will now proceed to drill the Lundin Energy-operated Bask prospect in PL533B. Well 7219/11-1 will target Paleocene-aged sandstones, estimated to hold gross unrisked prospective resources of 250 million bbl of oil. Tullow Sells Remaining Stake in Ugandan Oil Field Tullow Oil has completed the 10 November sale of its assets in Uganda to French giant Total for $500 million. Tullow will also receive $75 million when a final investment decision is taken on the development project, calculated to hold 1.7 billion bbl of crude oil. Contingent payments are payable after production begins if Brent crude prices rise above $62/bbl. The completion of this transaction marks Tullow’s exit from its licenses in Uganda after 16 years of operations in the Lake Albert basin. The deal is designed to strengthen Tullow’s balance sheet, as tumbling crude prices combined with exploration setbacks have created problems for the company. In September, the company reported that it had lost $1.3 billion in the first 6 months of 2020 as falling oil prices forced it to write down the value of its assets. The deal cut Tullow’s net debt to $2.4 billion; it has $1 billion in cash.

Abstract Introduction: PIK3CA (encoding phosphatidylinositol 3-kinase alpha [PI3Kα]) is a driver oncogene mutated (mut) in ~40% of HR+, HER2- ABCs, leading to endocrine therapy (ET) resistance and poor prognosis. Alpelisib (ALP) is the first oral α-selective PI3K inhibitor and degrader approved in this patient (pt) population. Primary analyses of Cohorts A and B from BYLieve, an ongoing Phase II noncomparative study, demonstrated efficacy and a consistent safety profile of ALP + ET (fulvestrant [FUL] or letrozole [LET]) in pts with PIK3CA-mut, HR+, HER2- ABC in the post CDK4/6i setting. Post hoc analyses of ALP benefit in pts with centrally confirmed PIK3CA mut, based on median duration of prior CDK4/6i, supported the efficacy of ALP + ET in CDK4/6i-resistant, HR+, HER2- ABC. Here we assessed whether those who achieved a short duration of disease control (6-month [mo] cutoff), with prior CDK4/6i + ET received clinical benefit with ALP + ET. Methods: In Cohorts A and B, pts with PIK3CA-mut, HR+, HER2- ABC had received CDK4/6i + aromatase inhibitor (AI) or FUL, respectively, as immediate prior therapy (majority in first line). Pts in Cohort A received ALP 300 mg PO QD + FUL 500 mg IM Q28D + C1D15; pts in Cohort B received ALP 300 mg PO QD + LET 2.5 mg PO QD. Within each cohort, pts were divided based on duration of prior CDK4/6i therapy (≤6 mo or &gt;6 mo), and the association of progression-free survival (PFS) with this covariate was analyzed using a stratified log-rank test and Cox Proportional Hazards model. A 6-mo cutoff was selected based on the ESO-ESMO ABC5 cutoff for primary ET resistance, as current guidelines do not specify cutoffs for CDK4/6i resistance. This analysis is based on the PFS endpoint and included pts for whom duration of prior CDK4/6i therapy was known. Results: Of the 121 pts in Cohort A with centrally confirmed PIK3CA-mut disease (modified full analysis set, mFAS), 120 had duration of prior CDK4/6i available; 26 had CDK4/6i for ≤6 mo and 94 for &gt;6 mo, with similar demographics/disease characteristics between subgroups. The hazard ratio (HR) of median PFS (mPFS) between the ≤6-mo group and &gt;6-mo group was 0.50 (95% confidence interval [CI], 0.27-0.94), indicating a lower risk of progression in the ≤6-mo group, with mPFS 10.0 mo (95% CI, 5.55-not estimable) and 6.0 mo (95% CI, 5.16-8.31), respectively. Grade ≥3 adverse events (AEs) were experienced by 67.5% (n=85) of all pts (safety set) in Cohort A and by 76.9% (n=20)/65.0% (n=65) in the ≤6-mo/&gt;6-mo subgroups, respectively. Of the 115 pts in Cohort B with centrally confirmed PIK3CA-mut disease (mFAS), 113 had duration of prior CDK4/6i available; 31 had CDK4/6i for ≤6 mo and 82 for &gt;6 mo, with similar demographics/disease characteristics between subgroups. The HR of mPFS between the ≤6-mo and &gt;6-mo groups was 0.76 (95% CI, 0.47-1.23), with the wide CI indicating no difference in risk of progression between subgroups, and mPFS was 5.9 mo (95% CI, 3.55-10.97) and 5.6 mo (95% CI, 3.68-7.10), respectively. Grade ≥3 AEs were experienced by 69.9% (n=86) of all pts (safety set) in Cohort B and by 63.6% (n=21)/72.2% (n=65) in the ≤6-mo/&gt;6-mo subgroups, respectively. Conclusions: This demonstrates that pts with PIK3CA-mut, HR+, HER2- ABC who achieved ≤6-mo duration of disease control with prior CDK4/6i had a numerically longer PFS in Cohort A, and almost the same clinical efficacy in Cohort B, to ALP + ET vs pts with &gt;6-mo duration of disease control, with a comparable safety profile. This confirms targeting PI3Kα with ALP provides clinical benefit in pts with CDK4/6i-resistant ABC, including early progressors, and supports consideration of ALP + ET as an immediate next-line option in this setting, possibly delaying chemotherapy. Citation Format: Stephen Chia, Eva M Ciruelos, Hope S Rugo, Florence Lerebours, Manuel Ruiz-Borrego, Pamela Drullinsky, Aleix Prat, Thomas Bachelot, Nicholas Turner, Ennan Gu, Christina Arce, Murat Akdere, Dejan Juric. Effect of duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy (≤6 mo or &gt;6 mo) on alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) from BYLieve [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-08.

Abstract Abstract 2772 Background: Thrombocytopenia, found in 40–65% of MDS patients, is an independent risk factor for survival. Romiplostim increases platelet production, with 46% of MDS patients in a phase 1/2 study having a durable platelet response [Kantarjian JCO 2010, 28:437–444]. MDS patients who completed a romiplostim clinical study could enroll in this open-label extension study. Interim results are reported to provide an update on continued, long-term romiplostim treatment in MDS patients. Methods: MDS patients who completed a prior romiplostim study with platelets ≤50×109/L and no evidence of disease progression were eligible to enroll. Prior studies were as follows: (1) romiplostim only for up to 52 weeks [Kantarjian JCO 2010, 28:437–444], (2) romiplostim or placebo plus decitabine for ≥4 cycles [Greenberg ASH 2009], (3) romiplostim or placebo plus lenalidomide for ≥4 cycles [Lyons ASH 2009], or (4) 58-week placebo-controlled study. The primary endpoint was adverse event incidence; secondary endpoints were bleeding event incidence, platelet transfusions, and platelet response duration. Based on previous dosing, patients received romiplostim at 250, 500, 750, 1000, or 1500 mcg weekly or biweekly, adjusting for platelet counts. If no response was observed after 4 weeks at 1000 mcg/week, treatment was discontinued. Results: As of May 31, 2011, 72 patients had enrolled; previous treatments were romiplostim or placebo (60), romiplostim with decitabine (7), or with lenalidomide (5). Patients (56% male) had median age 71.0 (Q1-Q3: 65.0–76.5) years, median baseline platelet count of 27×109/L (Q1-Q3:14–42×109/L), MDS subtypes: RA (22 patients), RARS (1), RAEB-1 (6), RAEB-2 (1), RCMD (25), RCMD-RS (2), and MDS-U (15), and IPSS status at prior study baseline: low (22), int-1 (44), int-2 (4), and unknown (2). Median duration of MDS (until last contact or AML progression) was 3.1 years (Q1-Q3:1.7–5.2 years). Median treatment duration during this extension study was 28 weeks (range: 2–181 weeks); for those patients who received romiplostim in prior studies, there was additional exposure for a median of 52 weeks (range: 7–74 weeks). The median average weekly dose was 750 mcg (Q1-Q3: 669–923 mcg). Romiplostim was well tolerated; the most common adverse events were epistaxis (32%), cough (25%), and fatigue (24%). No neutralizing antibodies to romiplostim or thrombopoietin were detected. Five cases of AML progression occurred (Table). There were a total of 11 deaths, 4 on-study and 7 post-study. The on-study deaths included cardiac arrest and intestinal obstruction after 83 weeks, congestive heart failure after 17 weeks, progressive muscle dystrophy after 153 weeks, and pulmonary fibrosis in a patient with a history of chronic obstructive pulmonary disease and congestive heart failure after 35 weeks. This last death was considered to be related to romiplostim by the investigator. The post-study deaths included four due to AML, one due to respiratory causes, one due to cerebral hemorrhage, and one due to unknown causes. The annual rate of AML or death was 14.3% (95% CI: 8.1%-25.2%). Fifty-two (72.2%) patients reported ≥1 bleeding event(s); the incidence rate was 23.3/100 patient-weeks; 23 patients (32%) reported ≥1 clinically significant bleeding event(s). The proportion of patients with significant bleeding events decreased over time. Platelet transfusions occurred in 32 (44%) patients, with none after 48 weeks of romiplostim. From Week 3 onwards, the median platelet count was ≥50×109/L; 60 patients (83%) had a platelet response (per IWG 2006). The median time to first platelet response was 2.1 weeks (Q1-Q3: 1.1–3.7 weeks) and the median platelet response duration was 20 weeks (Q1-Q3: 6.5–72 weeks). Shortly after this data cutoff, all patients were discontinued from romiplostim treatment and moved into the long-term observation portion of the study. Conclusion: In this study, long-term treatment of MDS patients with romiplostim for up to 3.5 years (5 years with prior studies) was well tolerated and resulted in platelet responses in 83% of patients. Among patients in this extension study, AML progression occurred at expected rates. Disclosures: Fenaux: Merck: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Off Label Use: Use of romiplostim, which is indicated for ITP, will be discussed in patients with MDS. Kantarjian:Amgen: Research Funding. Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. Lyons:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Larson:Amgen: Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Becker:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jia:Amgen: Employment, Equity Ownership. Yang:Amgen: Employment, Equity Ownership.

Abstract Abstract 3967 Multiple myeloma (MM) is characterized by the presence of osteolytic bone disease. Periostin, previously known as osteoblast-specific factor, is a matricellular protein, which is expressed in the periosteum after mechanical stress and is involved in bone formation. Periostin expression is up-regulated by several members of the TGF-β superfamily, including activin-A, which has been recently found to be elevated in MM by our group. Periostin expression and circulating levels were elevated in solid tumors with bone metastases, like breast cancer but there is no information for its role in MM. To address this issue we evaluated periostin in the supernatants of six myeloma cell lines (LR5, MR20, L363, U261, H929, and JJN3) and four ovarian cancer cell lines (A2780, C30, OVCA3 and SKOV3) before and after incubation for 24h and 48h with stromal cell line HS5. Furthermore, we measured periostin in the bone marrow plasma and the serum of 72 consecutive, newly diagnosed, patients with symptomatic MM (37M/35F, median age 70 years) before the administration of any kind of therapy and in the serum of 245 MM patients (106M/92F, median age 73 years) at different phases of the disease: 33 patients had asymptomatic myeloma (AMM) at diagnosis, 152 symptomatic MM at diagnosis (including the 72 with marrow plasma measurement), 30 “plateau” phase MM and 30 relapsed MM after previous response to therapy. Periostin was also measured in the bone marrow plasma and the serum of 23 patients with MGUS and in the serum of 30, gender- and age-matched, healthy controls. In all patients and controls, we also measured bone marrow plasma and serum activin-A, and serum C-telopeptide of collagen type-I (CTX, a bone resorption marker) and bone-specific alkaline phosphatase (bALP, a bone formation marker). Evidence of bone involvement in all patients was documented using plain radiographs and MRI of the spine. The periostin levels in the supernatants of the myeloma cell lines were higher than those found in the supernatants of the ovarian cancer cell lines (mean±SD: 17.2±6.14 ng/ml vs. 2.98±1.92 ng/ml; p=0.001; levels of periostin in the RPMI+FBS was 0.595 ng/ml). There was no difference regarding periostin concentrations among the different myeloma cell lines or among the different ovarian cancer cell lines. After incubation for 24h and 48h with stromal cell line HS5 (periostin level in the HS5 supernatant was 0.227 ng/ml), there was no alteration in the periostin levels of the supernatants of the myeloma cell lines. On the contrary, the ovarian cancer cell lines showed a dramatic increase in the periostin concentration after incubation with HS5 after 48h (18.3±16.3 ng/ml, p=0.023) but not after 24h (1.54±0.50 ng/ml). The mean periostin levels of the bone marrow plasma of the 72 patients were 3406 ng/ml (±5320 ng/ml) almost 5-fold higher that the respective values of MGUS patients (703±320 ng/ml; p<0.001). The serum periostin concentrations of symptomatic MM patients at diagnosis (2385±4690 ng/ml) were increased compared to controls (537±190 ng/ml; p<0.001), to AMM patients at diagnosis (601±351 ng/ml; p<0.001) and to MGUS patients (633±271 ng/ml; p<0.002). Patients with MM at plateau phase had reduced serum periostin concentrations (729±360 ng/ml) compared to symptomatic MM patients at diagnosis (p=0.002) but they continued to have increased levels compared to controls (p=0.013). Patients with relapsed MM had also increased circulating periostin (938±847 ng/ml) compared to controls (p=0.016), MGUS (p=0.04) and AMM patients (p=0.04). Periostin in both the marrow plasma and the serum were markedly elevated in patients with fractures compared to all others (p<0.001 for both comparisons), while bone marrow plasma periostin were elevated in patients with diffuse MRI pattern compared to all others (5352±7221 ng/ml vs. 3252±4943 ng/ml, p<0.05). In symptomatic MM patients at diagnosis, serum periostin negatively correlated with bALP (r=-0.464, p<0.001), while marrow plasma levels positively correlated with activin-A (r=0.478, p<0.001). In the 72 patients with measurements in both bone marrow plasma and serum, there was a correlation between the two values (r=0.225, p=0.05). Our data suggests that periostin is elevated in MM patients and correlates with bone fractures, diffuse MRI pattern, reduced bone formation and increased activin-A levels, supporting a significant role of this molecule into the biology of myeloma-related bone disease. Disclosures: No relevant conflicts of interest to declare.

Background:In PALACE 4, DMARD-naive patients (pts) with moderately active (ModDA) psoriatic arthritis (PsA) at baseline (BL) were more likely to achieve Clinical Disease Activity Index for PsA (cDAPSA) treatment targets (cDAPSA remission [REM] or low disease activity [LDA]) at Week 52 with continued apremilast 30 mg BID (APR) treatment than pts with high disease activity (HDA) at BL. Pts who achieved cDAPSA treatment targets also had no or mild articular and extra-articular disease activity by Week 52. Whether specific PsA manifestations other than arthritis impact the achievement of cDAPSA treatment targets in this population is unknown.Objectives:To assess the predictive value of BL clinical disease status on achieving cDAPSA treatment targets in DMARD-naive pts in PALACE 4 with PsA in ModDA or HDA who exhibited manifestations of skin involvement, enthesitis, and/or dactylitis at BL.Methods:This post hoc analysis included APR-treated pts in ModDA or HDA with available cDAPSA data at BL and Week 52 who exhibited any of the PsA manifestations at BL, including skin-involved body surface area (BSA) ≥3%, Maastricht Ankylosing Spondylitis Entheses Score (MASES) >0, or dactylitis count >0. Pts were divided into 4 subgroups based on number of manifestations: ≥1, only 1, any 2, or all 3. The proportions of pts who shifted across ModDA (>13 to ≤27) and HDA (>27) cDAPSA categories at BL to REM (≤4) and LDA (>4 to ≤13) treatment targets at Week 52 were calculated (data as observed).Results:In 176 PALACE 4 pts with PsA receiving APR, 165 had involvement in ≥1 PsA manifestation in addition to peripheral arthritis (ie, skin/enthesitis/dactylitis) at BL. This population had a mean age of 48.8 years, PsA duration of 3.6 years, Psoriasis Area and Severity Index (PASI) score of 6.6, MASES of 3.8, and dactylitis count of 3.5 (Table 1). Within this subgroup, 32.7% had only 1 of these non-arthritic PsA manifestations, 50.9% had any 2, and 16.4% had all 3. In pts with ≥1 manifestation, a greater proportion in ModDA achieved REM/LDA at Week 52 than those in HDA (66.7% vs 32.2%; risk difference: 0.34) (Figure 1). Similarly, greater rates of treatment target achievement were observed in subgroups of pts in ModDA vs HDA and only 1 (72.2% vs 39.1%; risk difference: 0.33), any 2 (57.1% vs 28.6%; risk difference: 0.29), or all 3 (75.0% vs 33.3%; risk difference: 0.42) PsA manifestations (Figure 1).Conclusion:In DMARD-naive pts exhibiting various non-arthritic manifestations of active PsA (ie, skin/enthesitis/dactylitis), those in ModDA at BL were more likely to achieve cDAPSA REM or LDA at Week 52 of APR treatment than pts in HDA. This observation was consistent whether pts had only 1 or multiple manifestations. These findings are consistent with the probability of achieving treatment targets demonstrated in the overall population in PALACE 4 (61.7% ModDA vs 28.2% HDA).Table 1.BL Demographics and Disease Characteristics in Pts With ≥1 Manifestations of PsA (Skin Involvement, Enthesitis, and/or Dactylitis) Treated With APR (N = 165)Age*, years48.8 (12.5)Women, n (%)87 (52.7)BMI*, kg/m229.9 (6.5)Duration of PsA*, years3.6 (5.0)Duration of psoriasis*, years15.5 (13.3)cDAPSA (0-154)*39.4 (19.7)Swollen joint count (0-66)*10.3 (7.7)Tender joint count (0-68)*18.5 (12.9)Pt’s Assessment of Pain (VAS 0-100 mm)*52.8 (21.5)Pt’s Global Assessment (VAS 0-100 mm)*53.8 (20.1)Physician’s Global Assessment (VAS 0-100 mm)*52.2 (17.6)PASI score (0-72)*,†6.6 (5.1)MASES (0-13)*,‡3.8 (3.0)Dactylitis count (0-20)*,§3.5 (3.3)Corticosteroid use, n (%)13 (7.9)NSAID use, n (%)126 (76.4)*Mean (SD).†In pts with BSA ≥3% at BL.‡In pts with enthesitis at BL.§In pts with dactylitis at BL.Acknowledgements:This study was funded by Celgene. Additional analyses were funded by Amgen Inc. Writing support was funded by Amgen Inc. and provided by Kristin Carlin, RPh, MBA, of Peloton Advantage, LLC, an OPEN Health company.Figure 1.Disclosure of Interests:Philip J Mease Speakers bureau: AbbVie, Amgen Inc., Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen Inc., Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Galapagos, GSK, Novartis, Pfizer, Sun, and UCB, Grant/research support from: AbbVie, Amgen Inc., Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Galapagos, GSK, Novartis, Pfizer, Sun, and UCB, Arthur Kavanaugh Grant/research support from: AbbVie, Amgen Inc., AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Alexis Ogdie Consultant of: AbbVie, Amgen Inc., BMS, Celgene, Corrona, Eli Lilly, Gilead, Novartis, Pfizer, and UCB, Grant/research support from: Novartis and Pfizer, Alvin F. Wells Speakers bureau: AbbVie, Alexion, Amgen Inc., BMS, Celgene, Horizon, Lilly, Novartis, and UCB, Consultant of: AbbVie, Alexion, Amgen Inc., BMS, Celgene, Horizon, Lilly, Novartis, and UCB, Grant/research support from: AbbVie, Celgene, and Lilly, Martin Bergman Shareholder of: Johnson & Johnson, Speakers bureau: AbbVie, Amgen Inc., Novartis, Pfizer, and Sanofi, Consultant of: AbbVie, BMS, Celgene, Genentech, Janssen, Merck, Novartis, Pfizer, and Sanofi, Dafna D Gladman Consultant of: AbbVie, Amgen, BMS, Celgene Corporation, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, BMS, Celgene Corporation, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB, Frank Behrens Speakers bureau: AbbVie, Biotest, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly, Genzyme, Janssen, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Chugai, Janssen, Roche, and Pfizer, Yuri Klyachkin Employee of: Amgen Inc., Sven Richter Employee of: Amgen Inc., Lichen Teng Employee of: Amgen Inc., Josef S. Smolen Speakers bureau: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, MSD, Novartis, Pfizer, Roche, Samsung, Sanofi, and UCB, Consultant of: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, MSD, Novartis, Pfizer, Roche, Samsung, Sanofi, and UCB, Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Medimmune, Pfizer, and Roche.

Publicamos una pequeña serie de monedas, relacionadas con las piezas conocidas inicialmente como de ejemplares “tipo Auriol”. Se trata de varias imitaciones greco-massaliotas, relacionadas con el ciclo numismático griego del Occidente mediterráneo. La importante novedad de las mismas se fundamenta en el lugar de hallazgo, pues este se ha producido en una zona interior de la Península Ibérica, donde hasta el momento no se había documentado el descubrimiento de numismas de este tipo. Palabras clave: moneda, imitaciones, edetanosTopónimos: Massalia, Emporion, AuriolPeriodo: Edetanos ABSTRACTThe text presents a small series of coins, similar to those initially known as "Auriol type". These are various Greek-Massalian imitations, related to the Greek numismatic cycle of the Western Mediterranean. What makes these coins particularly interesting is their place of discovery, since they were found in an inland area of the Iberian Peninsula, where the appearance of specimens of this type had not previously been documented. Keywords: coin, imitations, AuriolPlace names: Massalia, Emporion,Period: edetans REFERENCIASAmorós, J. V. (1934), Les monedes emporitanes anteriors a les dracmes, Barcelona, Gabinet Numismàtic de Catalunya.Arévalo González, A. (2002), “La moneda griega foránea en la Península Ibérica”, en Actas del X Congreso Nacional de Numismática, Madrid, Museo Casa de la Moneda, pp. 1-15.Babelon, E. C. F. (1901), Traité des monnaies grecques et romaine, vol. 1, Paris, Ernest Leroux Editeur.Benezet, J., Delhoeste, J. Lentillon, J.-P. (2003), “Une monnaie du “type d´Auriol” dans la plaine roussillonnaise”, Cahiers Numismatiques, 158, pp. 5-8.Blancard, M. 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Abstract We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve patients with locally advanced/metastatic urothelial carcinoma. TAS0313 9 mg was administered subcutaneously followed by pembrolizumab 200 mg on Day 1, and as monotherapy on Day 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Biomarkers of response were assessed. In 36 patients enrolled, the ORR was 33.3% (complete response: 7 patients; partial response: 5 patients). Median PFS was 5.0 months; 6- and 12-month progression free rates (PFRs) were 46.4% and 36.5%, respectively. Median OS was not reached; 6-, 12- and 24-month OS rates were 83.3%, 72.2%, and 55.1%, respectively. In post-hoc analysis, patients with a tumor infiltrating CD8+ lymphocyte (CD8+ TIL) count ≥99 and/or programmed cell death protein 1 (PD-L1) Combined Positive Score (CPS) ≥50 and lymphocyte count &gt;1380 cells/μL had higher ORRs and prolonged PFS versus patients with a CD8+ TIL count &lt;99, PD-L1 CPS &lt;50, and lymphocyte count ≤1380 cells/μL. Thirty-four (94.4%) patients receiving combination therapy experienced treatment-related adverse events (AEs), with pyrexia (n=15, 41.7%), injection-site reactions (n=15, 41.7%), injection-site induration (n=6, 16.7%), and malaise (n=6, 16.7%) the most common. No grade ≥3 treatment-related AEs occurred in ≥10% of patients. TAS0313 plus pembrolizumab combination therapy showed promising efficacy and manageable safety in locally advanced/metastatic urothelial carcinoma.

IntroductionThe current study was carried out with the hypothesis that foliar application of plant-derived smoke water (PDSW) and karrikinolide (KAR1) might enhanced the plant growth, physiology, and essential oil production of the Mentha arvensis L. Karrikinolide (KAR1) is one of the most important bioactive constituents of PDSW. MethodsMint (Mentha arvensis L.) was grown in natural conditions in the net-house. Different concentrations of PDSW (1:125, 1:250, 1:500 and 1:1000 v/v) and KAR1 (10-9 M, 10-8 M, 10-7 M and 10-6 M) were used as foliar-spray treatments, using double-distilled water as control. The PDSW was prepared by burning the dried wheat-straw that acted as a growth-promoting substance.ResultsFoliar-spray treatment 1:500 v/v of PDSW and 10-8 M of KAR1 proved optimal for enhancing all morphological, physiological, and essential-oil yield related parameters. In comparison with the control, 1:500 v/v of PDSW and 10-8 M of KAR1 increased significantly (p ≤ 0.05) the height of mint plant (19.23% and 16.47%), fresh weight (19.30% and 17.44%), dry weight (35.36% and 24.75%), leaf area (18.22% and 17.46%), and leaf yield per plant (28.41% and 23.74%). In addition, these treatments also significantly increased the photosynthetic parameters, including chlorophyll fluorescence (12.10% and 11.41%), total chlorophyll content (25.70% and 20.77%), and total carotenoid content (29.77% and 27.18%). Likewise, 1:500 v/v of PDSW and 10-8 M of KAR1 significantly increased the essential-oil content (37.09% and 32.25%), essential oil productivity per plant (72.22% and 66.66%), menthol content (29.94% and 25.42%), menthyl acetate content (36.90% and 31.73%), and menthone content (44.38% and 37.75%). Furthermore, the TIC chromatogram of the GCMS analysis revealed the presence of 34 compounds, 12 of which showed major peak areas. DiscussionTreatment 1: 500 v/v of PDSW proved better than the treatment 10-8 M of KAR1 with regard to most of the parameters studied. The outcome of the study can be used as a recommendation tool for agricultural and horticultural crops, since it costs much lesser than that of KAR1. In fact, the foliar application of PDSW proved economical and played bioactive role at very low concentrations.

Background aimsB-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). However, CAR-T-related tumor lysis syndrome (TLS) has been observed. We aimed to elucidate the incidence, clinical and laboratory characteristics, and prognosis of CAR-T cell-related TLS.MethodsPatients (n=105) with r/r MM treated with BCMA-targeted CAR-T cell therapy were included. Patient characteristics, laboratory parameters, and clinical outcomes were assessed.ResultsEighteen (17.1%) patients developed TLS after BCMA-targeted CAR-T cell therapy. The median time till TLS onset was 8 days. Patients with TLS had steep rise in uric acid (UA), creatinine, and lactate dehydrogenase (LDH) within 6 days following CAR-T cell infusion and presented earlier and persistent escalation of cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-γ [IFN-γ], and ferritin levels). All 18 patients had cytokine release syndrome (CRS), of which 13 (72.2%) developed grade 3–4 CRS. Three of 18 patients (16.7%) developed immune effector cell-associated neurotoxicity syndrome (ICANS): two patients with grade 1 ICANS and one with grade 2 ICANS. TLS development had a negative effect on the objective response rate (77.8% in the TLS group vs. 95.4% in the non-TLS group, p&lt;0.01). During the median follow-up of 15.1 months, the median PFS was poorer of patients with TLS (median: 3.4 months in the TLS group vs. 14.7 months in the non-TLS group, p&lt;0.001, hazard ratio [HR]=3.5 [95% confidence interval [CI] 1.5–8.5]). Also, TLS development exhibited significant effects on OS (median: 5.0 months in the TLS group vs. 39.8 months in the non-TLS group, p&lt;0.001, hazard ratio [HR]=3.7 [95% CI 1.3–10.3]). TLS was associated with a higher tumor burden, elevated baseline creatinine and UA levels, severe CRS, pronounced CAR-T cell expansion, and corticosteroid use.ConclusionTLS is a frequently observed CAR-T therapy complication and negatively influences clinical response and prognosis. Close monitoring for TLS should be implemented during CAR-T cell therapy, especially for those at high TLS risk.

Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD (<8.20, 8.20–10.49, 10.50–13.19, and ≥13.20 mm Hg), hazard ratios (HRs) for all adverse events were significantly high in the highest quartile compared with the lowest quartile (HR, 2.00, 95% CI, 1.15–3.49, P =0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36–4.97, P =0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11–3.07, P =0.018 for all‐cause death) after adjusting for components of the CHA 2 DS 2 ‐VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP‐coefficient of variation was used instead of BP‐SD. Conclusions Systolic BP visit‐to‐visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique Identifier: UMIN000001569.

The cerebrovascular response to incremental aerobic exercise is comparable between males and females. Whether this response can be found in moderately-trained athletes remains unknown. We aimed to examine the effect of sex on the cerebrovascular response to incremental aerobic exercise until volitional exhaustion in this population. Twenty-two moderately-trained athletes (11 M/11 F; age: 25 ± 5 vs. 26 ± 6 years, p=0.6478; peak oxygen consumption: 55.8± 5.2 vs. 48.3 ± 4 mL/kg/min; p=0.0011; training volume: 532 ± 173 vs. 466 ±151 min/week, p=0.3554) performed a maximal ergocycle exercise test. Systemic and cerebrovascular hemodynamics were measured. At rest, middle cerebral artery mean blood velocity (MCAvmean; 64.1 ± 12.7 vs. 72.2 ± 15.3 cm.s-1; p=0.2713) was not different between groups, while partial pressure of end-tidal carbon dioxide (PETCO2, 42 ± 3 vs. 37 ± 2 mmHg, p=0.0002) was higher in males. During the MCAvmean ascending phase, changes in MCAvmean (intensity: p<0.0001, sex: p=0.3184, interaction: p=0.9567) were not different between groups. Changes in cardiac output (Q) (intensity: p<0.0001, sex: p<0.0001, interaction: p<0.0001) and PETCO2 (intensity: p<0.0001, sex: p<0.0001, interaction: p<0.0001) were higher in males. During the MCAvmean descending phase, changes in MCAvmean (intensity: p<0.0001, sex: p=0.5522, interaction: p= 0.4828) and Q (intensity: p= 0.0504, sex: p= 0.0003, interaction: p= 0.2715) were not different between groups. Changes in PETCO2 (intensity p<0.0001, sex: p<0.0001, interaction: p= 0.0280) were higher in males. These results suggest the MCAvmean response during exercise is comparable between moderately-trained males and females notwithstanding differences in the response of key CBF determinants.

BackgroundCognitive impairment is common after stroke. So is cortical- and subcortical atrophy, with studies reporting more atrophy in the ipsilesional hemisphere than the contralesional hemisphere. The current study aimed to investigate the longitudinal associations between (I) lateralization of brain atrophy and stroke hemisphere, and (II) cognitive impairment and brain atrophy after stroke. We expected to find that (I) cortical thickness and hippocampal-, thalamic-, and caudate nucleus volumes declined more in the ipsilesional than the contralesional hemisphere up to 36 months after stroke. Furthermore, we predicted that (II) cognitive decline was associated with greater stroke volumes, and with greater cortical thickness and subcortical structural volume atrophy across the 36 months.MethodsStroke survivors from five Norwegian hospitals were included from the multisite-prospective “Norwegian Cognitive Impairment After Stroke” (Nor-COAST) study. Analyses were run with clinical, neuropsychological and structural magnetic resonance imaging (MRI) data from baseline, 18- and 36 months. Cortical thicknesses and subcortical volumes were obtained via FreeSurfer segmentations and stroke lesion volumes were semi-automatically derived using ITK-SNAP. Cognition was measured using MoCA.ResultsFindings from 244 stroke survivors [age = 72.2 (11.3) years, women = 55.7%, stroke severity NIHSS = 4.9 (5.0)] were included at baseline. Of these, 145 (59.4%) had an MRI scan at 18 months and 72 (49.7% of 18 months) at 36 months. Most cortices and subcortices showed a higher ipsi- compared to contralesional atrophy rate, with the effect being more prominent in the right hemisphere. Next, greater degrees of atrophy particularly in the medial temporal lobe after left-sided strokes and larger stroke lesion volumes after right-sided strokes were associated with cognitive decline over time.ConclusionAtrophy in the ipsilesional hemisphere was greater than in the contralesional hemisphere over time. This effect was found to be more prominent in the right hemisphere, pointing to a possible higher resilience to stroke of the left hemisphere. Lastly, greater atrophy of the cortex and subcortex, as well as larger stroke volume, were associated with worse cognition over time and should be included in risk assessments of cognitive decline after stroke.

ObjectiveThe acceptance of drug treatment for younger children with attention-deficit/hyperactivity disorder (ADHD) in China remains low. Here, we explored the clinical benefits of a non-pharmaceutical intervention method combining a group and executive function training and an online parent training program, termed group executive functioning and online parent training (GEF-OPT), for school-aged students with ADHD through a randomized controlled trial.MethodA total of 145 children (aged 6–8 years) were formally registered and randomized to the intervention group (n = 73) and waitlist group (n = 72). The enrolled children received eight sessions of GEF-OPT treatment, which consists of a hospital-based children executive function (EF) training program and an online parent training program. Treatment outcome was assessed by a parent/teacher report questionnaire and neurophysiological experiment.ResultsAfter eight sessions of intervention, children in the intervention group showed a significant improvement in inattentive symptom compared to the waitlist group (14.70 ± 4.35 vs. 16.03 ± 2.93; p = 0.024), but an insignificant difference in hyperactive-impulsivity (9.85 ± 5.30 vs. 10.69 ± 5.10; p = 0.913). Comorbid oppositional defiant disorder was significantly reduced in the intervention group (7.03 ± 4.39 vs. 8.53 ± 4.41; p = 0.035). Children in the intervention group had greater reduction in the scores of behavioral regulation index (inhibition, emotional control) and metacognition index (working memory, planning/organization, monitoring) in executive function than those in the waitlist group (p &lt; 0.05). Significant effects were also found in learning problem of Weiss Functional Impairment Scale–Parent form and parental distress between two groups at post-treatment (p &lt; 0.05). In line with this, the result of go/no-go task showed significant improvements in accuracy change (4.45 ± 5.50% vs. 1.76 ± 3.35%; p = 0.001) and reaction time change (47.45 ± 62.25 s vs. 16.19 ± 72.22 s; p = 0.007) in the intervention group compared with the waitlist group.ConclusionWe conclude that participants in the GEF-OPT program improved outcomes for inattentive symptom, executive function, learning problems, and parental distress. GEF-OPT is a promising non-pharmaceutical therapeutic option for younger children.Trial RegistrationChiCTR2100052803.

Background: The CREST trial demonstrated that for patients at standard risk of surgical complications, there was no significant difference in the primary composite outcome of periprocedural death, MI, or stroke, or late ipsilateral stroke between carotid artery stenting (CAS) and carotid endarterectomy (CEA), although CAS had a higher rate of stroke, and CEA had a higher rate of MI. The economic implications of these two strategies are unknown. Methods: We performed a prospective health economic study alongside the CREST trial. Costs were assessed from the perspective of the US health care system in 2008 dollars using a combination of resource-based and event-based methods. Costs for carotid revascularization procedures were based on measured resource use and unit costs derived from a sample of study hospitals. Non-procedural costs for these hospitalizations were estimated using hospital billing data (charges) and cost-center-specific cost-to-charge-ratios. Costs for follow-up events were estimated using national average DRG reimbursements. The primary analysis was based on a modified intention-to-treat population for which the assigned procedure was attempted (n=1212 CAS; 1193 CEA). Results: CAS was associated with higher total procedural costs (Δ=$675, see Table), driven mainly by higher costs for disposable supplies. Length of stay was shorter for CAS, with associated reductions in non-procedural hospital costs (Δ = -$436). Total cost for the index hospitalization remained slightly higher for CAS (Δ=$239) with similar differences at 1 year. Conclusions: For patients at standard risk of surgical complications, total 1-year costs are slightly higher for CAS vs. CEA, driven largely by higher initial procedural costs. Cost-utility analysis will be performed to determine whether differences in quality of life observed in CREST render CAS an economically attractive strategy. CAS (n= 1212) CEA (n=1193) Δ CAS - CEA (95% CI via bootstrap) Index Procedure Costs, $ Excluding MD Fees 6782 ± 1412 5743 ± 1370 1039 (926, 1148) MD Fees 1114 ± 240 1478 ± 108 -364 (-379, -349) Total 7896 ± 1551 7221 ± 1450 675 (555, 800) Index Hospital Stay 7159 ± 5108 7595 ± 7482 -436 (-951, -59) TOTAL Index Hosp Costs 15055 ± 5539 14816 ± 7709 239 (-302, 778) Index Hosp LOS (days) ICU LOS 0.7 ± 1.1 0.8 ± 1.4 -0.1 (-0.24, -0.04) Non-ICU LOS 1.9 ± 3.2 2.2 ± 4.1 -0.2 (-0.55, 0.06) TOTAL LOS 2.6 ± 3.3 3.0 ± 4.5 -0.4 (-0.7, -0.06) 1-year Rehosp Costs: Repeat Revasc - CAS 295 ± 2097 273 ± 2126 -21 (-142, 201) Repeat Revasc - CEA 287 ± 2088 477 ± 2510 -190 (-371, -11) Ipsilateral Stroke 556 ± 3273 384 ± 2580 172 (-75, 402) TIA 48 ± 520 33 ± 487 16 (-25, 56) Death 63 ± 846 45 ± 779 18 (-49, 85) TOTAL Rehosp costs 1321 ± 4827 1293± 4502 28 (-334, 396) TOTAL 1-year costs 16375 ± 7730 16108 ± 9030 267 (-366, 961)

To achieve high therapeutic efficacy in the patient, information on pharmacokinetics, pharmacodynamics, and pharmacogenetics is required. With the development of science and technology, especially genetic sequencing technology, more and more research on pharmacogenomics has been conducted. The relationship between the genome and the response of a person to drugs is being explored to support personalized medicine, which shows efficacy in clinical treatment. In particular, the IL28B gene polymorphisms have been studied and shown to have impacts on drug responses in the treatment of many diseases, such as chronic hepatitis C, chronic hepatitis B, and myeloproliferative neoplasms. 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