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1.
Journal of the American Academy of Child and Adolescent Psychiatry ; 61(10 Supplement):S149, 2022.
Article in English | EMBASE | ID: covidwho-2179855

ABSTRACT

Objectives: Mental health problems, including depression, often start in childhood or adolescence. The COVID-19 pandemic has contributed to alarming rates of child and adolescent depression. An emerging potential treatment in adults is omega-3 polyunsaturated fatty acids (PUFAs), which are naturally found in fatty fish, marine sources, and some nuts and seeds. We will determine the efficacy of omega-3 PUFAs for children and adolescents with clinical depression. Method(s): Electronic searches were conducted in several databases. Reference lists of relevant studies and grey literature were also searched for additional references. Randomized controlled trials involving supplementary omega-3 fatty acid treatment of any dose as monotherapy or adjunctive therapy among males and females who were 6 to 19 years of age with depression qualified for inclusion. All screening of citations was conducted in duplicate. Full-text citations were assessed for inclusion criteria and methodological quality from potentially relevant s. The standardized mean difference with 95% CI was determined. Result(s): This review included 6 trials involving 253 participants. Five studies involving 202 participants included in the primary outcome analysis demonstrated a moderate effect size when compared to placebo with a standardized mean difference (SMD) of -0.47 (95% CI, -1.07 to 0.13). Attrition rates were highly variable and not significant, with an OR of 0.63 (95% CI, 0.34-1.20). Conclusion(s): To date, there is insufficient evidence to determine the efficacy of omega-3 PUFAs on depressive symptoms in children and adolescents. However, this review suggests a moderate beneficial effect of omega-3 PUFAs on depressive symptoms compared to placebo, although the effect estimate is imprecise and not significant. Further research that addresses limitations in the current body of research on this topic in children and adolescents, including small sample sizes, remission, adverse events, dosage, and delivery modes, will help increase the precision in the effect estimates. DDD, TREAT Copyright © 2022

2.
JACCP Journal of the American College of Clinical Pharmacy ; 5(12):1340, 2022.
Article in English | EMBASE | ID: covidwho-2173032

ABSTRACT

Introduction: There is a paucity of literature regarding the optimal selection of combination anti-seizure medications (ASMs) for drug resistant epilepsy (DRE). The aim of this scoping review is to evaluate current evidence related to "rational polytherapy" among adults with DRE. Research Question or Hypothesis: What is the current evidence of clinical and health-related humanistic and economic outcomes of rational polytherapy with ASMs in DRE? If DRE is mentioned, is the appropriate definition applied? What are the current gaps? Study Design: Scoping review Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-SCr) guidelines, PubMed, ProQuest, CINAHL, and Cochrane databases were searched using DRE- and polytherapy-related keywords. The exclusion criteria applied included: non-English;non-human studies;non-research studies;participants less than 18 years;status epilepticus;ASM monotherapy;and certain ASMs. In Covidence, two researchers independently reviewed articles for inclusion at each phase, with a third resolving conflicts. Data were extracted, with quality appraisal using the Mixed Methods Appraisal Tool (MMAT). Result(s): Of the 6477 studies imported for screening, 33 studies were included. Clinical, humanistic, and economic outcomes were reported by 26, 12, and one study, respectively. Common efficacyrelated clinical outcomes included >=50% reduction in seizure frequency (n=14), seizure freedom (n=13), and percent reduction in seizure frequency (n=8). Common humanistic outcomes included quality of life (n=4), medication adherence (n=2), sleep-related outcomes (n=2), and physician and patient global assessments (n=2). The economic study reported quality-adjusted life years. Two studies referenced the standard definition of DRE. Five studies did not specifically define DRE. Gaps in the literature include limited generalizability, minimal reports in pregnancy, and lack of optimal ASM combinations. Conclusion(s): Strengths of the evidence include addressing a variety of outcomes. Inconsistent definitions of DRE, small sizes, and heterogeneity among studies limit the ability to draw meaningful conclusions. Optimal combinations of ASMs for rational polytherapy for DRE is unclear.

3.
Obstetric Medicine ; 15(1 Supplement):35-36, 2022.
Article in English | EMBASE | ID: covidwho-2064392

ABSTRACT

Introduction: The use of metformin in the treatment of gestational diabetes mellitus (GDM) is variable in Australia and worldwide. There is strong evidence that metformin is safe and efficacious during pregnancy in the short term.1 During the COVID-19 pandemic, Fiona Stanley Hospital offered women metformin as an alternative to insulin where clinically appropriate. Aim(s): The aim of this study was to describe the clinical characteristics of the women receiving different treatments, and assess the efficacy and safety of metformin therapy in women with GDM. Method(s): We retrospectively analysed the medical records of 157 women with GDM requiring pharmacotherapy at our site over nine months. Women were allocated to four treatment groups: metformin monotherapy (Group A), insulin monotherapy (Group B), metformin added to insulin (Group C) and insulin added to metformin (Group D). Result(s): There was no difference in the mean age (p =0.30) and ethnicity (p =0.75) of the four treatment groups. Women commenced on insulin therapy (Group B) had higher body mass index (BMI) (p =0.03) and were more likely to have previous history of GDM (p<=0.01). Eighty-three women with GDM were treated with metformin monotherapy during the study period. However, 60% of them needed addition of insulin to achieve glucose control. Sixty-six percent of women reached optimal blood sugar control with less than maximum dose of metformin. Thirteen percent of the women experienced gastrointestinal side effects, however, there were no unplanned reviews or unplanned admissions noted during the study period. This group was commenced on therapy later in the pregnancy leading to shorter mean treatment duration (6.42 weeks) compared to other groups (11.16, 11.58 and 14.62 weeks for Groups B, C and D, respectively) Group D was able to avoid insulin for a mean duration of 3.58 weeks when on metformin alone. Among the four groups there were no significant difference in neonatal complications (p=0.47), birth weight (p=0.80) and neonatal intensive care unit (NICU) (p=0.92) admissions. Fewer total maternity complications (p<=0.01) were noted in Group A but this was driven by lower postpartum haemorrhage rates. Conclusion(s): The metformin treated group had lower BMI and were at later gestational stage when metformin was commenced and there were no significant differences in neonatal outcomes as compared to the insulin group. However, 60% of women required addition of insulin and 13% had gastrointestinal side effects.

4.
American Journal of Transplantation ; 22(Supplement 3):1058-1059, 2022.
Article in English | EMBASE | ID: covidwho-2063534

ABSTRACT

Purpose: To evaluate the safety and generation rate of Ab anti spike rate in SOT patients at 28 and 90 days after completing the Covid 19 vaccination scheme. Method(s): Multicenter prospective study in SOT with a complete vaccination scheme who agreed to participate in the study . Demographic , vaccination: schedule;time;adverse effects and transplant variables were collected. The generation rate of antispike antibodies was evaluated by the COVIDAR-IgG method at the Universidad de Buenos Aires School of Medicine. Result(s): 113 SOT patients were included (September 6th to October 4th). Median age was 53 (IQR 42.5-63, women 36.8%). Transplant type: 72.8% renal , 13.1% cardiac, 12.3% liver, 0.9% pancreas and 0.9% lung. Deceased donors 71.1%. The median time after transplantation to vaccination was 65 months (IQR 30 120 R 2-429). Only 7% of patients developed rejection within the year prior to vaccination and no patient rejected post vaccination. 74.3% (n 84) had triple immunosuppressive maintenance regimen (steroids + calcineurin inhibitors (ICN) + antiproliferative), 24 pts (21.1%) double regimen WITHOUT steroids and 5 (4.3%) monotherapy with IC. Vaccination schedule: Sputnik 14.5%, Sputnik-Astrazeneca 4.4%, Sputnik-Moderna 28.9%, Sinopharm 3.5%, Astrazeneca 34.2%. Vaccine-related adverse events were observed in 18.4% of patients, 82% were mild. 40% of SOT responded with Antispike Ab , with a lower response rate in kidney transplantation p <0.0007 RR 0.48 (0.32-0.71) and use of triple immunosuppressive maintenance regimen p <0.00009 RR 0.419 (0.26 -0.66). Patients previously infected with Covid-19 prior to vaccine (11.45% pts), had a higher response rate p <0.0001 RR 2.58 (1.90-3.51).No patients developed COVID-19 after vaccination. Conclusion(s): In our SOT population, a lower generation rate of anti-spike Ab was observed, compared to the reported in the general population. Renal Tx and the triple IS regimen were associated with a lower response rate. Covid-19 prior to vaccination was associated with a higher antibody response to the vaccine.

5.
American Journal of Transplantation ; 22(Supplement 3):674, 2022.
Article in English | EMBASE | ID: covidwho-2063402

ABSTRACT

Purpose: Gout in kidney transplant (KT) recipients can be severe and particularly challenging to manage. Pegloticase co-therapy with immunomodulators improved urate lowering therapy (ULT) response rates over phase 3 monotherapy trials by reducing anti-drug antibodies.1,2 This open-label trial (PROTECT NCT04087720) examined pegloticase safety and efficacy in KT patients with uncontrolled gout. Method(s): KT recipients with uncontrolled gout (serum urate [SU]>=7 mg/dL, intolerance/ inefficacy to ULT and >=1 of the following: tophi, chronic gouty arthritis, >=2 flares in past year) and functioning KT graft (eGFR>=15 ml/min/l.73m2) on stable immunosuppressive (IS) therapy (KT>l year earlier) received pegloticase (8 mg every 2 weeks for 24 weeks). SU response during Month 6 (SU <6 mg/dL for >=80% of time) and Health Assessment Questionnaire (HAQ) pain (most severe: 100) and Disability Index (HAQ-DI, max: 3) scores were evaluated. Patients discontinuing treatment before Month 6 were considered nonresponders. Patients discontinuing due to COVID-19 concerns were excluded from analysis if no data points were available in Month 6. Result(s): 20 patients enrolled (mean+/-SD;age: 53.9+/-10.9 years, 85% male, time since KT: 14.7+/-6.9 years, SU: 9.4+/-1.5 mg/dL, gout duration: 7.9+/-11.6 years;all on >=2 IS) and 14/20 completed treatment. 16/18 (88.9% [95% CI: 65.3, 98.6]) were SU responders vs 43.5% previously reported3 without immunomodulation. Substantial SU reductions during treatments were reported in 18/20 patients completing or discontinuing for non-SU monitoring rule reasons (pre-dose SU>6 mg/dL at 2 consecutive visits). No notable eGFR changes were observed up to 3 months follow-up. In patients completing treatment, HAQ-pain and HAQ-DI mean scores improved by 35.5+/-31.5 and 0.3+/-0.6, respectively, at Week 24 (n=13 and n=14). 7 serious adverse events, deemed unrelated to pegloticase, were reported in 5 patients. No anaphylaxis or infusion reaction events occurred. Conclusion(s): Pegloticase was safe and effective in treated KT patients with uncontrolled gout, achieving a higher durable response rate than in previously-reported patients not on IS therapy along with improved HAQ scores indicative of quality of life impact. These findings are consistent with other reports of immunomodulation with pegloticase.

6.
American Journal of Transplantation ; 22(Supplement 3):597, 2022.
Article in English | EMBASE | ID: covidwho-2063338

ABSTRACT

Purpose: To investigate the effect of mycophenolate mofetil (MMF) on SARSCoV- 2 vaccination response in kidney transplant recipients using the standard immunosuppressive regimen of tacrolimus (TAC) and MMF. Method(s): A randomized controlled trial in immunologically low risk kidney transplant recipients was performed (EudraCT nr.: 2014-001372-66). Patients were randomized to standard TAC/MMF or TAC monotherapy (TACmono) from 9 months onwards, without steroids. Antibody based immune responses to SARS-CoV-2 vaccination (mRNA-1273 or BNT162b2) were investigated in a central laboratory, as part of the RECOVAC Antibody study (EudraCT nr.: 2021-283 001520-18), 4-8 weeks after the second vaccination. Measurement involved the presence of antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 S-protein (IgG anti-RBD antibody) using the Sanquin anti-SARS-CoV-2 RBD IgG ELISA assay. Patients were classified as non-responders (<=50 BAU/mL), low-responders (50-300 BAU/ mL) and responders (>300 BAU/mL). Result(s): Between 2015 and 2018, 79 recipients were randomized to TAC/MMF (n=41) and TACmono (n=38). At the outbreak of the COVID-19 pandemic in early 2020, 67 patients were alive with a functioning graft (TAC/MMF n=35, TACmono n=32). In 27 patients antibody responses could be established: Ten patients were excluded from the analyses due to symptomatic COVID-19 infection and 1 due to a positive nucleocapsid test, possibly from an asymptomatic infection. The rest did not participate in the vaccination study, because of ChAdOx1-S, age >80 years or lack of informed consent. Mean age was 64 (43-75) years, median time after transplantation 4.2 (3.0-6.5) years and eGFR was 53 (36-105) ml/min/1.73m2. TAC trough levels were 6.6 (+/-0.3) mug/L in both groups, and MMF dose was 1000 mg daily (range 500- 2000) in TAC/MMF. Median SARS-CoV-2 Spike S1-specific IgG antibody levels were 37.3 BAU/ml in TAC/MMF (5 non, 7 low, 1 responder) and 715.6 BAU/ml in TACmono (1 non, 6 low, 7 responders, p =0.004, figure 1). Of note is that antibody levels of >1000 BAU/ml, as a presumed threshold for protection against Omicron (B.1.1.529), was reached in 1/13 TAC/MMF and 7/14 TACmono patients (p=0.03). Conclusion(s): In this controlled study mycophenolate mofetil on top of tacrolimus severely hampered serological COVID-19 vaccination response.

7.
Neuro-Oncology ; 24(Supplement 2):ii88-ii89, 2022.
Article in English | EMBASE | ID: covidwho-2062942

ABSTRACT

BACKGROUND: A novel therapeutic approach using molecularly targeted radiation is currently in development for patients with recurrent GBM. Many tumor types, including GBM, overexpress the L-type amino transporter 1 (LAT-1)4, which is able to internalize the small-molecule amino acid derivative, 4-L-[131I] iodo-phenylalanine (131I-IPA). In preclinical research, combining 131I-IPA with external radiation therapy (XRT) yielded addi- tive cytotoxic effects. Tumoral accumulation of 131I-IPA was confirmed in a proof-of-principle study using single doses of 2-7 GBq 131I-IPA as a monotherapy or in combination with XRT in patients with recurrent GBM. The objective of the IPAX-1 study was to evaluate the safety, tolerability, dosing schedule, and preliminary efficacy of 131I-IPA in combination with secondline radiotherapy in patients with recurrent GBM. METHOD(S): IPAX-1 is a multi-center, open-label, single-arm, dose-finding phase 1/2 study. Key inclusion criteria: 1. Confirmed histological diagnosis of GBM with evidence of first recurrence 2. History of GBM standard therapy 3. >= 6 months since end of first-line XRT 4. Pathologically increased amino acid tumor uptake shown by molecular imaging 5. Current indication for repeat radiation 6. Gross tumour volume of up to 4.8 cm diameter. Treatment: In phase 1 of the study patients received intravenous 131I-IPA at a dose level of 2 GBq administered in one of three different dosing regimens: single dose group with 2 GBq before radiation, 3 (f)-fractionated-parallel group: 3 x 0.67 GBq during XRT and 3 (f)-fractionated-sequential group: 0.67 GBq x 1 -> XRT -> 0.67 GBq x 2. XRT is delivered in 18 fractions of 2 Gy each. RESULT(S): 10 patients were randomized;one patient with Covid related death was withdrawn from analysis. Survival from start of TLX101 therapy showed mPFS2 of 4.33 M (95% -CI 4.18 - 4.48), PFS-6: 18 % and mOS2 of 15.97 M (95% -CI 2.9 - 29.1) at data lock 09/2021. Updated results will be presented at the meeting. CONCLUSION(S): There were no clinically relevant laboratory changes over time. Urinalysis, vital signs, and ECG did not show any clinically relevant changes from baseline. There were no notable differences in safety and tolerability between groups. Injections of single or fractionated doses of 131I-IPA containing a total activity of 2 GBq in combination with XRT in patients with recurrent GBM were safe and well tolerated. Survival data look promising;extension cohort will be treated in a phase II study in Linz;phase 1/2 study in first line setting is planned.

8.
Cardiology in the Young ; 32(Supplement 2):S57, 2022.
Article in English | EMBASE | ID: covidwho-2062104

ABSTRACT

Background and Aim: PIMS-TS often affects the cardiovascular sys-tem resulting in myocarditis and coronary artery abnormalities (CAA). Immunosuppressive therapy is the primary treatment of PIMS-TS;however, controversies on the best regimen remain. The use of anakinra as a second-line treatment in children with cardiac involvement is often proposed lately. This prospective observational study aimed to determine the incidence of cardiac involvement in PIMS-TS and to evaluate the effectiveness and safety of anakinra in its treatment Methods: From July 2020 till December 2021, we have treated 22 children with PIMS-TS (12 boys, 10 girls;aged 0,3-15,75y (median-4y). Echocardiography assessing coronary arteries and systolic function was performed at admission, during the hospitalization, at discharge and 6-8 weeks after the onset. Result(s): Fourteen(63%) of the patients had coronary artery dilata-tion (z-score: 2,1-11,8;median:2,9), 6(27%) deterioration of sys-tolic function, 5(22%) both, 20(90%) had elevated NTproBNP. Only in 2 children (9%) there was no cardiac involvement;in 3(14%) the only cardiac sign was elevated NTproBNP. Two children required admission to ICU. In the first line immuno-suppressive treatment, we administered intravenous immunoglo-bulins (IVIG) in dose 2g/kg in all patients-of which in 16 as a monotherapy, in 6 together with glucocorticosteroids (GCS) because of their severe condition. Seven patients (32%) recovered after a single IVIG infusion, 3(14%) after repeated IVIG infusions. In this subgroup all CAA normalized or got significantly smaller with the change in the median z-score from 2,8 to 1,3. In 10 (45%) patients with cardiac involvment and insufficient response (4 with previous IVIG treatment, 6 with previous IVIG+GCS treatment) we administered anakinra obtaining clinical, laboratory and echo-cardiographic improvement in all of the patients (good systolic function and normalized or significantly smaller CAA: from z-score median = 2,8 (range: 2,1-11,8) to z-score median = 1,9 (range:0-3,2)), with no side effects. The median time to introduce anakinra (for median 9 days treatment) was 4 days after the first-line treatment. In 2 patients with suboptimal effect of first-line IVIG monotherapy, but no cardiac involvement, GCS as the second-line treatment were used. Median time of hospitalization was 18 days Conclusion(s): Cardiac involvement is common in PIMS-TS. Anakinra seems to be effective and safe in its treatment.

9.
Chest ; 162(4):A1866, 2022.
Article in English | EMBASE | ID: covidwho-2060877

ABSTRACT

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Interstitial pneumonitis (ILD) is inflammation of lung interstitium leading to scarring and pulmonary fibrosis. Various etiologies include idiopathic, connective tissue disorders, sarcoidosis and drug induced1. Many chemotherapy agents have been implicated in drug related ILD such as bleomycin, taxanes. However, newer chemotherapeutic drugs such as molecular agents such as anti-VEGF, anti-EGFR (panitumumab) could be causative of drug induced ILD. CASE PRESENTATION: A 75-year-old female with stage IV sigmoid colon cancer treated with surgery, adjuvant FOLFOX chemotherapy and Panitumumab. She presented to the emergency department with shortness of breath and hypoxia after known COVID-19 exposure. Initial imaging with chest radiography showed bilateral ground glass opacities. A chest CT pulmonary embolism protocol was negative for pulmonary embolism but showed bilateral ground glass opacities (GGOs) and some interstitial thickening (L>R) not typical of COVID-19 infection. She was treated with remdesivir and dexamethasone, however her oxygen requirements continued to rapidly escalate. A repeat CT chest without contrast showed bilateral asymmetric interstitial thickening and GGOs. Given persistence of CT chest abnormalities, workup for interstitial lung disease was initiated. The results include ANA titer 1:80, otherwise negative ANCA profile, rheumatoid factor, anti-CCP, Scl-70, Sjogren antibodies. Given clinical history and imaging findings, diagnosis of ILD was suspected, and she was started on solumedrol 1 mg/kg. Her oxygen requirements decreased significantly over the next 2 days, and she was discharged home on oral steroid taper and pneumocystis pneumonia prophylaxis. DISCUSSION: Panitumumab is a fully humanized monoclonal antibody against EGFR. Approved by the US Food and Drug Administration in 2006 for advanced or recurrent colorectal cancer exhibiting wild-type KRAS mutation.2 ILD is rarely reported with panitumumab monotherapy, but higher incidence when used as a combination treatment such as with FOLFOX or FOLFIRI. A Japanese post-marketing surveillance study from 2010-2015 showed an ILD incidence of 1.3% but mortality rates of 51.3%.2 EGFR is expressed on basal cells and non-cilia cells of the bronchioles and type II cells of the alveolus. EGFR mediated mechanisms are important in tissue repair.3 Therefore inhibition of this pathway has been postulated to play a role in development of ILD. Another mechanism was decreased surfactant production by type II cells in pre-clinical study.4,5 ILD secondary to Panitumumab can occur at any point during therapy and up to 1 year after administration of drug.6 The role of infectious processes, in this case, COVID-19 pneumonia, could synergistically worsen ILD presentation. CONCLUSIONS: Although the incidence of ILD is low, the mortality rate is high, therefore early recognition and treatment is associated with improved clinical outcomes. Reference #1: Mudawi D, Heyes K, Hastings R, Rivera-Ortega P, Chaudhuri N. An update on interstitial lung disease. Br J Hosp Med (Lond). Jul 2 2021;82(7):1-14. Reference #2: Osawa M, Kudoh S, Sakai F, et al. Clinical features and risk factors of panitumumab-induced interstitial lung disease: a postmarketing all-case surveillance study. Int J Clin Oncol. Dec 2015;20(6):1063-1071. Reference #3: The FASEB Journal - 2000 - Puddicombe - Involvement of the epidermal growth factor receptor in epithelial repair in asthma.pdf. DISCLOSURES: No relevant relationships by Navitha Ramesh No relevant relationships by Uba Udeh

10.
Chest ; 162(4):A855, 2022.
Article in English | EMBASE | ID: covidwho-2060708

ABSTRACT

SESSION TITLE: COVID-19 Co-Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: We present a case of Eggerthella bacteremia in a patient with COVID-19. CASE PRESENTATION: A 69-year-old woman presented to the emergency room with chief complaint of cough, dyspnea, and malaise. After testing positive with a home COVID-19 test three days earlier, she continued to have worsening respiratory status and was brought in via ambulance. She was found to be tachycardic and hypoxic, requiring high-flow oxygen to maintain saturation in the emergency department. Chest X-ray showed bilateral patchy opacities consistent with multifocal COVID-19 pneumonia, and she was admitted to the intensive care unit for acute hypoxic respiratory failure. COVID-19 drug therapy was initiated, including baricitinib, remdesivir and decadron. Shortly after hospitalization, she began to endorse worsening abdominal pain. Physical exam elicited tenderness to palpation of her right lower quadrant. Abdominal CT scan showed distal ileum fluid collection concerning for possible bowel perforation. She underwent exploratory laparotomy which confirmed perforation, and a small bowel resection with anastomosis was performed. Blood cultures were positive for gram-positive bacilli, which were further identified as Eggerthella species. She required mechanical ventilation for worsening respiratory function post-surgery but remained unresponsive on the ventilator. The patient was administered vancomycin but continued to decline and eventually expired. DISCUSSION: Eggerthella is an anaerobic, gram-positive bacilli present in the gut microflora. Eggerthella infection has most often been reported in intra-abdominal infections. However, cases of bacteremia infection remain sparse. Most infections have been associated with other gastrointestinal processes including Crohn's disease, ulcerative colitis, appendicitis, and diverticulitis abscesses. Our case involved a patient with no significant gastrointestinal history admitted for COVID-19 pneumonia infection on baricitinib complicated by bowel perforation and bacteremia. Bowel perforation is a known risk factor of baricitinib use, and these risks should be discussed with the patient before beginning therapy. Overall mortality for Eggerthella species infection remains high, with some estimates as high as 31%. Much remains unknown about the impact on gut microbiome by SARS-CoV-2, however, early research suggests a higher rate of fungal co-infection in patients with COVID-19. As the literature on COVID-19 expands, more and more unusual pathogens such as Eggerthella may be found to contribute to the morbidity and mortality of patients being treated for COVID-19. CONCLUSIONS: Unusual pathogens such as Eggerthella may complicate a patient's hospital course while undergoing treatment for COVID-19. Reference #1: Alejandra Ugarte-Torres, Mark R Gillrie, Thomas P Griener, Deirdre L Church, Eggerthella lenta Bloodstream Infections Are Associated With Increased Mortality Following Empiric Piperacillin-Tazobactam (TZP) Monotherapy: A Population-based Cohort Study, Clinical Infectious Diseases, Volume 67, Issue 2, 15 July 2018. Reference #2: Gardiner BJ, Tai AY, Kotsanas D, et al. Clinical and microbiological characteristics of Eggerthella lenta bacteremia. J Clin Microbiol. 2015. Reference #3: Lau SK, Woo PC, Fung AM, Chan K-M, Woo GK, Yuen K-Y. Anaerobic, non-sporulating, gram-positive bacilli bacteraemia characterized by 16s rrna gene sequencing. Journal of medical microbiology. 2004. DISCLOSURES: No relevant relationships by Kristin Davis No relevant relationships by Charles Peng

11.
Swiss Medical Weekly ; 152(Supplement 261):2S, 2022.
Article in English | EMBASE | ID: covidwho-2058360

ABSTRACT

Patients with inflammatory rheumatic diseases (IRD) have an increased risk for a worse COVID-19 outcome, and impaired immune responses following mRNA COVID-19 vaccines have been observed. In this prospective observational study, we compared the anti-S1 response following vaccination with BNT162b2 and mRNA- 1273 in a large cohort of IRD patients and assessed the effect of different immunomodulatory treatments. Patients from SCQM, the Swiss IRD cohort, who assented to an mRNA COVID-19 vaccine were recruited into the study between 3/2021-9/2021. Participants answered the study questionnaire via the mySCQM patient app and provided self-collected capillary blood samples at baseline, 4, 12, and 24 weeks post second vaccine dose. Samples were tested for IgG antibodies against the S1 domain of the SARS-CoV-2 spike protein using the EUROIMMUN ELISA. We examined differences in antibody titres depending on the vaccine and treatment received, while adjusting for age and history of SARSCoV- 2 infection, by applying mixed effects continuous outcome logistic regression models at each timepoint. Eligible samples were obtained from 564 IRD patients (mean age 53 y (s.d. 12 y), 66% female) with 36% RA, 37%, axSpA, 21% PsA, and 6% UA (undifferentiated arthritis), on no medication (no DMARD & no steroids 15%), csDMARD (9%), TNFi (48%), IL-6/17/23i (14%), JAKi (6%), rituximab (4%), abatacept (3%), and PDE4i (1%) in mono/combination therapy at baseline. 10% of patients had a past SARS-CoV-2 infection, 54% received BNT162b2, 46% mRNA-1273. Independently of the disease, treatment, and history of SARS-CoV- 2 infection, the odds of having higher anti-S1 titres at 4, 12, and 24 weeks post second vaccine dose were, respectively, 3.3, 3.9, and 3.8 times higher with mRNA-1273 compared to BNT162b2 for the average-aged patient of this population (p <0.0001). Moreover, with every year of age, the odds of higher anti-S1 levels increased by 3% to 5% following mRNA-1273 vs BNT162b2 vaccination (p <0.05), indicating an additional benefit for elderly IRD patients. Among monotherapies, rituximab, abatacept, JAKi, and TNFi had the highest odds of reduced anti-S1 responses compared to no medication. Patients on specific combination therapies showed significantly reduced antibody responses compared to respective monotherapies. Our results suggest that in IRD patients, vaccination with mRNA- 1273 vs BNT162b2 results in higher anti-S1 antibody titres, and has an additional benefit in elderly patients.

12.
Coronavirus Drug Discovery: Volume 1: SARS-CoV-2 (COVID-19) Prevention, Diagnosis, and Treatment ; : 181-203, 2022.
Article in English | Scopus | ID: covidwho-2048774

ABSTRACT

The COVID-19 pandemic has brought fear and havoc into the world in ways we have never imagined. More than 10 million people have been infected and more than 500,000 have died worldwide. Until now no definite cure has been discovered and no vaccine is yet available for its prevention. Efforts and resources have been poured in to address these challenges. However, the future is still not secured, and lives and economies all over the world are still at risk of continued destruction. In this book chapter, we present the various mono and combination therapies currently being used by health professionals to combat this disease. To date, no single therapy has been shown to completely eradicate the infection, but interim data on the use of combination treatments have shown better outcome. © 2022 Elsevier Inc. All rights reserved.

13.
Middle East Journal of Digestive Diseases ; 14(2):182-191, 2022.
Article in English | EMBASE | ID: covidwho-2044374

ABSTRACT

BACKGROUND: Immunosuppressive agents used in the treatment of inflammatory bowel diseases (IBDs) could potentially increase the risk of coronavirus disease 2019 (COVID-19). We aimed to compare COVID-19 frequency in patients with IBD with their households and identify the related risk factors. METHODS: Firstly, a multi-centered, observational study on 2110 patients with IBD and 2110 age-matched household members was conducted to compare COVID-19 frequency. Secondly, the data of patients with IBD and COVID-19 who had called the COVID-19 hotline were added. Multivariable logistic regression was used to evaluate the effect of age, type and severity of IBD, the number of comorbidities, and medications on the frequency of COVID-19 among the patients with IBD. RESULTS: The prevalence of COVID-19 in patients with IBD and household groups was similar (34 [1.61%] versus 35 [1.65%];P = 0.995). The prevalence of COVID-19 increased from 2.1% to 7.1% in those with three or more comorbidities (P = 0.015) and it was significantly higher in those with severe IBD (P = 0.026). The multivariable analysis only showed a significant association with anti-TNF monotherapy (OR: 2.5, CI: 0.97-6.71, P = 0.05), and other medications were not associated with COVID-19. CONCLUSION: The prevalence of COVID-19 in patients with IBD was similar to the household members. Only patients with IBD receiving anti-TNF monotherapy had a higher risk of COVID-19 susceptibility. This finding could be attributed to the higher exposure to the virus during administration in health care facilities.

14.
Journal of Neuromuscular Diseases ; 9:S109-S110, 2022.
Article in English | EMBASE | ID: covidwho-2043401

ABSTRACT

Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders (IMIDs) treated with specific immunosuppressants and immunomodulating agents. The objective of this study is to investigate the humoral immune response after SARS-CoV-2 vaccination in patients using immunosuppressive and immunomodulating mono- and combination therapies, focussing on frequently prescribed therapies for inflammatory neuromuscular diseases. Methods: National prospective observational cohort study in selected patients with prevalent IMIDs including neuromuscular disease, and immunosuppressive or immunomodulating monotherapy (n=1273), combination therapies (n=419), patients without immunosuppressants (n=473), and healthy controls (n=174). Anti-RBD IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses, i.e. vaccination after previous SARS-CoV-2 infection, were studied as a proxy for recall responses. Findings: Sera from 1869 participants without and 470 participants with previous SARS-CoV-2 infection were analysed. We included 168 (7 2%) patients with inflammatory neuropathies and myopathies, and 127 (5 4%) patients with myasthenia gravis. Humoral responses did not differ between disorders. Anti-CD20 therapy and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks (RR) for reaching seroconversion following standard vaccination (RR: 0 32 and 0 61 respectively). The monotherapies corticosteroids, purine antagonists, methotrexate, mycophenolate mofetil and IVIg were not associated with a lower RR for reaching seroconversion (RR: 0 97, 0 98, 1 01, 0 86, and 0 99, respectively). Similarly, corticosteroids combined with either methotrexate or purine antagonists was not associated with a lower RR for reaching seroconversion (RR 0 89). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments but not for anti-CD20 therapies. Most immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that, in subgroups, did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment. Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants, most relevant for neuromuscular diseases being anti-CD20 and mycophenolate mofetil combination treatments. After standard vaccination regimens most immunosuppressants show equal seroconversion to controls although antibody titres may be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate in loss of (short term) protection. Alternatively, in immunosuppressants showing poor humoral responses after standard vaccination regimens such as, a third vaccination resulted in additional seroconversion in mycophenolate mofetil combination treatments whereas the effect for anti-CD20 therapy was limited.

15.
Journal of Oral and Maxillofacial Surgery ; 80(9):S62-S63, 2022.
Article in English | EMBASE | ID: covidwho-2041964

ABSTRACT

Problem: Clinicians treating postprocedure acute pain after third molar removal face a twofold challenge: attenuating pain levels while simultaneously limiting leftover opioid doses. Strategies for achieving the dual goals range from “letting patients decide,” which can lead to leftover doses and misuse, or “letting clinicians decide,” only prescribing opioids for those predicted to experience severe discomfort, which risks under-managing acute pain. A hybrid strategy relies on joint decision-making between the patient and clinician. The hypothesis for this IRB-approved prospective study was that a hybrid-strategy would be successful in moderating acute pain and reducing leftover opioid doses. Methods and Materials: This study included patients who met the American Society of Anesthesiologists, risk classification I or II, ages 18 to 35 years, with at least 2 mandibular third molars removed. Patients being treated for opioid addiction/abuse were excluded. All enrolled subject patients were consented and treated with a multimodal analgesic protocol consisting of intraoperative IV preventive antibiotics, dexamethasone, ketorolac, ondansetron, local anesthetics including liposomal bupivacaine and postoperative cold therapy, and scheduled ibuprofen. Patients were given 2 prescriptions (Rx), each for 4 doses of Hydrocodone/APAP 5/325, to be taken as needed for pain;1 Rx could be filled on the day of surgery, the second on any subsequent day. Opioid Rx data were retrieved from patient records and North Carolina Controlled Substances Reporting System. Pain scores and opioid-use data for each postsurgery day (PSD) were derived from a 14-day diary recorded by subjects. For the patients in this series, the goal was median pain levels ranked 1 or 2 on a 7-point scale, meaning no pain and minimal pain by postoperative day (POD) 3. Descriptive statistics were used for analyses. Results: Data were analyzed from 96 eligible patients treated consecutively from 2018 to 22, with a 15-month hiatus from COVID-19. Fifty-two patients (54%) did not fill an opioid prescription. Twenty-seven patients (28%) filled 1 opioid prescription and 17 patients (18%) filled 2 of the prescriptions. The patients who filled 1 prescription had 72 leftover doses (67% of possible doses), and the patients who filled 2 prescriptions had 50 leftover doses (74% of possible doses). Median worst pain levels reached 1 to 2 out of 7 on POD 4;median average pain on POD 3. Conclusions: The hybrid strategy reduced the number of opioid doses in circulation without compromising the patient's postoperative pain level. Decreasing the number of leftover opioid doses is an important step toward addressing opioid addiction and overdose. References: 1 Magraw CBL, Pham M, Neal T, Kendell B, Reside G, Phillips C, White RP Jr: A multimodal analgesic protocol may reduce opioid use after third molar surgery: A pilot study. Oral Surg Oral Med Oral Path Oral Radiol 126:214, 2018. 2 Pham M, Magraw C, Neal T, Kendell B, Reside G, Phillips C, White R: A Multi-modal Analgesic Protocol reduced opioid use/misuse after 3rd Molar Surgery: An Exploratory Study. Submitted Oral Surg Oral Med Oral Path Oral Radiol March 2019 3 Pham M, Magraw C, Neal T, Kendell B, Reside G, Phillips C, White R: A Multimodal Analgesic Protocol reduced acute pain levels after 3rd molar surgery. In preparation JOMS 4 White RP Jr, Shugars DA, Shafer DM, Laskin DM, Buckley MJ, Phillips C: Recovery after third molar surgery: clinical and health-related quality of life outcomes. J Oral and Maxillofacial Surgery 61:535, 2003. 5 American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 116:248, 2012 6-Savarese JJ, Tabler NG Jr: Multimodal analgesia as an alternative to the risks of opioid monotherapy in surgical pain management. J Health Care Risk Manag 37:24, 2017

16.
Annals of Oncology ; 33:S1050, 2022.
Article in English | EMBASE | ID: covidwho-2041544

ABSTRACT

Background: The value of increased HER2 gene copy number (GCN) in NSCLC is unclear. In this study we defined its frequency and characterized a cohort of patients harboring it. Methods: Patients with stage IIIB/IV NSCLC enrolled in the Gustave Roussy MSN study (NCT02105168) between Oct. 2009 and Feb. 2016 were screened by FISH (positivity defined as HER2 GCN to centromeres ratio ≥ 2) and tested for other molecular alterations. Descriptive analyses of clinical-pathological data were performed, progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Results: HER2 FISH tested positive in 22 of 250 screened patients (9%). Median age was 60 years (range 47-80), 68% (n=15) were male, 91% (n=20) were current or former tobacco smokers (median exposure 47 pack-year), 64% (n=14) had adenocarcinoma, 18% (n=4) squamous cell and 18% (n=4) large cell carcinoma. 91% (n=20) had an ECOG PS of 0 or 1. Stage IV with extra-thoracic involvement was the most common clinical presentation (64%, n=14). Overall, 95% of patients (n=21) had 1 or 2 metastatic sites at diagnosis (bone 32%, lung 27%, nodes 18%, liver 18%, brain 18%). In 9 patients (41%) 12 concurrent molecular alterations were detected: 5 KRAS mutation (3 G12C, 1 G12D, 1 G61H), 2 HER2 exon 20 insertion, 1 EGFR exon 19 deletion, 1 BRAF V600E mutation, 1 ALK rearrangement, 1 FGFR1 and 1 MET amplification. 18 patients received first-line platinum-based chemotherapy, with 33% (95% CI 16-56) objective response rate and 83% (95% CI 61-94) disease control rate. After a median follow-up of 28 months (95% CI 23-45), median PFS and OS were 5.9 (95% CI 3.4-11.0) and 15.3 (95% CI 10.3-NR) months, respectively. Median PFS was longer in patients with higher GCN. As further line of treatment, 5 patients received trastuzumab: 4 in combination with chemotherapy and 1 as monotherapy, with 1 stabilization of disease as best response. 3 patients received nivolumab (1 partial response and 1 stable disease) and 3 a targeted therapy (anti ALK, EGFR, BRAF). Conclusions: Increased HER2 GCN was found in 9% of patients with unresectable NSCLC, was not correlated to particular clinical characteristics, but frequently occurred with other molecular alterations. Its clinical actionability and the correlation with protein expression deserve further characterization. Clinical trial identification: NCT02105168. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: M. Tagliamento: Other, Personal, Other, Travel grants: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly;Other, Personal, Writing Engagements, Honoraria as medical writer: Novartis, Amgen. E. Auclin: Financial Interests, Personal, Advisory Board: Amgen, Sanofi. E. Rouleau: Financial Interests, Institutional, Advisory Board: AstraZeneca, Roche, Amgen, GSK;Financial Interests, Institutional, Invited Speaker: Clovis, BMS;Financial Interests, Institutional, Funding, Data base: AstraZeneca. A. Bayle: Non-Financial Interests, Institutional, Other, Principal/Sub-Investigator of Clinical Trials: AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, BicycleTx Ltd, Non-Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi;Financial Interests, Institutional, Other, drug supplied: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, GSK, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. F. Barlesi: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Seattle Genetics, Takeda;Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd. D. Planchard: Financial I terests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen;Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen;Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre;Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, EISAI, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Research Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. All other authors have declared no conflicts of interest.

17.
Annals of Oncology ; 33:S904-S905, 2022.
Article in English | EMBASE | ID: covidwho-2041538

ABSTRACT

Background: CSCC is highly immune-responsive;a prior pilot study demonstrated a high rate of pathologic complete response (pCR) or major pathologic response (MPR, ≤10% viable tumor), using cemiplimab anti-programmed death 1 (PD-1) therapy in the neoadjuvant setting. Here, we present the primary analysis of a confirmatory, open-label, multicenter, Phase 2, single-arm trial of neoadjuvant cemiplimab in pts with resectable Stage II–IV (M0) CSCC. Methods: Pts received cemiplimab 350 mg IV q3W for up to 4 doses before surgery. The primary endpoint was pCR rate per independent central pathologic review (ICPR). Key secondary endpoints included MPR rate per ICPR, objective response rate (ORR;complete response [CR] + partial response [PR]) per RECIST v1.1, investigator-assessed pCR and MPR, safety and tolerability. Results: At data cutoff date of 01 Dec 2021, 79 pts were enrolled (67 male;median age 73.0 yrs [range, 66.0–81.0];ECOG performance status 0 (n=60) and 1 (n=19) with stage II (n=5), III (n=38), or IV(M0) (n =36) disease;62 pts received all 4 doses (median number of doses given (Q1:Q3), 4 (4:4);70 pts underwent surgery. The study met its primary endpoint: pCR was observed in 40 (50.6%) pts (95% confidence interval [CI], 39.1–62.1%). MPR was observed in an additional 10 (12.7%) pts (95% CI, 6.2–22.0%). ORR was 68.4% (95% CI, 56.9–78.4) (5 CR, 49 PR, 16 stable disease, 8 progressive disease (PD), 1 non evaluable. Reasons 9 pts did not have surgery: 3 responders declined surgery, 2 lost to follow-up or noncompliance, 2 had inoperable PD, 2 due to AE. Fourteen (17.7%) pts experienced Grade ≥3 AE. Four pts died due to AEs: 1 exacerbation of cardiac failure, 2 myocardial infarctions, and 1 COVID-19 pneumonia. The most common AEs regardless of attribution (all grades) were fatigue (30.4%), rash maculo-papular (13.9%), diarrhea (13.9%) and nausea (13.9%). Conclusions: The pCR + MPR of 63.3% by ICPR in pts with Stage II–IV (M0) CSCC is the highest observed in a multicenter anti-PD-1 neoadjuvant monotherapy study for any solid tumor type. The safety profile of neoadjuvant cemiplimab is consistent with previous anti-PD-1 monotherapy experience. Ongoing follow-up will describe disease-free survival. Clinical trial identification: NCT04154943. Editorial acknowledgement: Medical writing support was provided by John G Facciponte, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc., and Sanofi. Legal entity responsible for the study: Regeneron Pharmaceuticals, Inc., and Sanofi. Funding: Regeneron Pharmaceuticals, Inc., and Sanofi. Disclosure: N. Gross: Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Advisory Board: PDS Biotechnology, Shattuck Labs and Genzyme;Financial Interests, Personal, Advisory Role: PDS Biotechnology, Shattuck Labs and Genzyme. D.M. Miller: Financial Interests, Personal, Advisory Role: Castle Biosciences, EMD Serono, Merck KGaA, Merck Sharpe & Dome, Pfizer, Regeneron, Sanofi Genzyme;Financial Interests, Personal, Ownership Interest: Checkpoint Therapeutics;Financial Interests, Personal, Research Grant: Kartos Therapeutics, NeoImmune Tech, Inc., Regeneron Pharmaceuticals, Inc. N. Khushanlani: Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc., Bristol Myers Squibb, HUYA Bioscience International, Merck, Novartis, GlaxoSmithKline, Celgene, Amgen;Financial Interests, Personal, Advisory Board: EMD Serono, Regeneron Pharmaceuticals, Inc., Genentech, AstraZeneca (data safety monitoring committee), Merck, Array Biopharma, Jounce Therapeutics, Immunocore, Bristol Myers Squibb, HUYA Bioscience International;Financial Interests, Personal, Other, honoraria: Sanofi;Financial Interests, Personal, Stocks/Shares: Bellicum Pharmaceuticals, Mazor Robotics, Amarin, Transenetrix. V. Divi: Financial Interests, Institutional, Research Grant: Genentech. E.S. Ruiz: Financial Interests, Personal, Advisory Board: Genentech, Leo Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi;Financial Int rests, Personal, Advisory Role, consulting fees: Genentech, Leo Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi;Financial Interests, Personal, Member of the Board of Directors: Checkpoint Therapeutics. E.J. Lipson: Financial Interests, Personal, Other, Advisory board and consulting fees: Bristol Myers-Squibb, Eisai, Genentech, Immunocore, Instil Bio, MacroGenics, Merck, Natera, Nektar Therapeutics, Odonate Therapeutics, OncoSec, Pfizer, Rain Therapeutics, Regeneron, Sanofi;Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Merck, Regeneron. F. Meier: Financial Interests, Personal, Other, Travel support, speaker’s fees or advisor’s honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche and Sanofi;Financial Interests, Personal, Research Grant: Novartis and Roche. P.L. Swiecicki: Financial Interests, Institutional, Research Grant: Ascentage Pharma, Pfizer;Financial Interests, Personal, Advisory Board: Prelude Therapeutics, Elevar Therapeutics, Regeneron Pharmaceuticals. J.L. Atlas: Financial Interests, Personal, Advisory Role: Regeneron Pharmaceuticals, Inc., Sanofi, and Bristol Myers Squibb. J.L. Geiger: Financial Interests, Institutional, Research Grant: Alkermes, Debio, Merck, Regeneron Pharmaceuticals, Inc., and Roche/Genentech;Financial Interests, Personal, Advisory Role: Exelixis, Merck and Regeneron Pharmaceuticals, Inc. A. Hauschild: Financial Interests, Personal and Institutional, Other, Institutional grants, speaker’s honoraria and consultancy fees: Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Provectus and Roche;Financial Interests, Institutional, Other, Institutional grants and consultancy fees: EMD Serono, Philogen and Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Advisory Role: OncoSec Medical. J.H. Choe: Financial Interests, Personal, Advisory Role: Exelixis, Coherus Biosciences, Regeneron Pharmaceuticals, Inc. B.G.M. Hughes: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer and Roche;Financial Interests, Institutional, Research Grant: Amgen. S. Yoo: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. K. Fenech: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.D. Mathias: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. H. Han: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.G. Fury: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. D. Rischin: Financial Interests, Institutional, Research Grant: Regeneron Pharmaceuticals, Inc., Genentech, Sanofi, Kura Oncology, Roche, Merck Sharp & Dohme, Merck KGaA, Bristol Myers Squibb, GlaxoSmithKline, ALX Oncology;Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, Bristol Myers Squibb;Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, Bristol Myers Squibb. All other authors have declared no conflicts of interest.

18.
Annals of Oncology ; 33:S759, 2022.
Article in English | EMBASE | ID: covidwho-2041531

ABSTRACT

Background: ICI revolutionized solid tumor treatment, however, in many tumors only partial response is achieved. Here we investigated the anti-tumoral effect of Allocetra—OTS cellular therapy, in solid tumor models. Methods: Allocetra-OTS is manufactured from enriched mononuclear fractions and induced to undergo early apoptosis.Balb/c mice were inoculated in the peritoneal cavity with AB12 (mesothelioma) stably transduced with pLenti-PGK-V5-Luc-Neo for IVIS visualization and treated with anti-CTLA4, anti-PD1, or cisplatin, with or without Allocetra-OTS (also administered as monotherapy). Kaplan-Meier log rank test was done for survival. CAR T model was induced in SCID-Bg mice were inoculated intraperitoneally with human HeLa-CD19, followed by treatment with 10×109 cells of Allocetra-OTS or vehicle, and 1×107 CD19-CAR T cells or mock T cells. Results: Anti-CTLA4 therapy significantly improved survival from mean 34±9 to 44.9 ±20 days (p<0.05). However, Allocetra-OTS monotherapy improved survival to 52.3 ±20 days (p<0.02) and anti-CTLA4 + Allocetra-OTS combination therapy to 86.7±20 days (p<0.0001) with complete cancer remission in 60-100% of mice. Similar results were seen in combination therapy with either anti-PD1 or cisplatin. In the CAR-T model, SCID-Bg mice survived 30±5 days (range 27–37) and were sacrificed or died from tumor progression. Results were verified using IVIS of intraperitoneal HeLaCD19-Luc cells. CAR T cell therapy significantly improved survival to 55±11 days (p < 0.05 vs MOCK) but Alloctra-OTS further improved survival to 75±10 (p < 0.001) with 20-40% complete remission. Conclusions: During intraperitoneal tumor progression, Allocetra-OTS as monotherapy or in combination with ICI, cisplatin or CAR-T therapy, significantly reduced tumor size and resulted in complete remission in up to100% treated mice. Based on excellent safety profile in > 40 patients treated in prior clinical trials for sepsis and COVID-19, phase I/II clinical trial of Allocetra-OTS plus chemotherapy is planned for Q3 2022, and a second phase I/II clinical trial of Allocetra-OTS plus anti-PD1, as a second- and third-line therapy in various cancers, is planned for Q4 2022. Legal entity responsible for the study: The authors. Funding: Enlivex Therapeutics Ltd. Disclosure: D. Mevorach: Financial Interests, Personal, Royalties, Founder & CSO: Enlivex Therapeutics LTD. E. Yalon, E. Regev, C. Ankri, O. Hershkovitz, Y. Shabat, B. Reicher: Financial Interests, Personal, Full or part-time Employment: Enlivex Therapeutics LTD.

19.
HemaSphere ; 6:1096-1097, 2022.
Article in English | EMBASE | ID: covidwho-2032152

ABSTRACT

Background: Infectious complications are a major cause of morbidity and mortality in Chronic Lymphocytic Leukaemia (CLL). Therapeutic approaches that deplete CLL cells also affect normal B-cells. Optimal treatment would result in eradication of CLL cells and recovery of normal immune function. FLAIR (ISRCTN01844152) is a phase III trial for previously untreated CLL comparing ibrutinib plus rituximab (IR) with fludarabine, cyclophosphamide and rituximab (FCR) and subsequently amended to also compare ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR. Measurable residual disease (MRD) and normal B-cell levels were assessed at multiple timepoints. Aims: To assess the depletion of normal B-cells during treatment and recovery after end of treatment. Methods: Participants aged under 75 years with <20% TP53-deleted cells were initially randomised to FCR or IR and subsequently to FCR, IR, I+V or I with the IR arm closed after randomisation of 771 participants to FCR/IR. FCR was given for 6 cycles, while treatment in the IR, I and I+V arms continued for up to 6 years except in participants attaining <0.01% MRD who continued treatment for the time taken to achieved MRD <0.01% and then stopped if MRD remained <0.01%. Month (M) 24 was earliest permitted stopping point. MRD flow cytometry was performed according to ERIC guidelines (panel: CD19/5/20/43/79/81+ROR1, acquisition of 0.5-2.2 million cells, BD Biosciences Lyric). Additional analysis of normal B-cell subsets was performed in a cohort of >500 patients (panel: CD19 to identify B-cells, CD20/5/79b+ROR1 and CD3 to exclude CLL & contaminating cells, with CD27/ 38/IgD/IgM to characterise normal B-cell subsets using a Coulter Cytoflex LX). Results: Normal B-cells were undetectable during FCR treatment and only rarely detectable until 12 months after last FCR cycle. Circulating normal B-cells were reduced in number or undetectable in participants receiving ibrutinibcontaining regimens with greater depletion in the I+V and IR arms relative to I monotherapy. B-progenitors persist through FCR treatment but were depleted during I, I+R or I+V treatment. Normal B-cell levels at 24 and 36 months after randomisation, with time off-treatment if applicable, are shown in Figure 1. In the ibrutinib-containing arms (IR, I, and I+V), there was a trend towards fewer COVID-associated SAE at any time point for participants with detectable B-cells at 24M (4/181, 2.2%) compared to those with no detectable B-cells (14/344, 4.1%) and COVID-associated SAEs were not observed in FCR-treated participants who had recovered any level of normal B-cells by 24M (0/215). However, the data on COVID infections are limited and there was no apparent association between normal B-cell levels at 24M with the proportion of participants experiencing an infectious SAE overall. Assessment of normal B-cell subsets during ibrutinib-based treatment demonstrated a mix of naïve and memory B-cells. Serological response to COVID infection/vaccination in this cohort is currently being performed. Participants stopping I+V treatment at 24-30 months post-randomisation due to MRD eradication showed rapid recovery of normal naive B-cells within 6-12 months after end of treatment in the vast majority (>95%) of evaluable cases. Summary/Conclusion: Normal circulating B-cells are depleted during treatment with rituximab but can persist at a low level during I, IR or I+V treatment. Most patients in remission after treatment with FCR or I+V show recovery of normal B-cells at 12 months of stopping treatment.

20.
HemaSphere ; 6:1059-1060, 2022.
Article in English | EMBASE | ID: covidwho-2032148

ABSTRACT

Background: In the largest study of Baliakas et al. (2019) the presence of at least 5 abnormalities, was associated with dismal clinical outcome, independently of the somatic hypermutation status and TP53 status. The presence of 3 or 4 aberrations is defined as clinically relevant in the absence of TP53. Studies by Kittai (2021) and Al-Sawaf (2020) showed the impact of karyotypic complexity on survival in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib or venetoclax. The complex karyotype (CK) is a topic that is being intensively researched, both in the aspect of increasing karyotypic complexity stratification and clonal evolution. Optimal therapy for patients with CLL has not yet been developed. The combination therapy of ibrutinib and venetoclax was superior to chlorambucil and obinutuzumab in terms of undetectable minimal residual disease (MRD) responses according to data from the GLOW trial (Tunir, 2021). The importance of achieving a complete response with undetectable MRD as the goal of therapy in CLL was proposed (Montserrat, 2005). Aims: The aim of our study is to evaluate the effectiveness of therapy with ibrutinib and venetoclax in combination for the patients with CLL and CK. Methods: This ambilinear observational study included patients with CLL with high genetic complexity (high-CK), defined as >=5 aberrations or CK (>=3 aberrations) in combination with a 17p deletion (CK+del17p). The first retrospective cohort included patients treated with ibrutinib monotherapy (Imono) to progression or intolerable toxicity since May 2015. The second prospective cohort included patients receiving ibrutinib in combination with venetoclax (IVen) since July 2019. Venetoclax therapy was started at the 3rd month of ibrutinib (from the escalation phase). Combination therapy was continued until a complete response, defined as three consecutive PET-CT-negative and MRD-negative results 3 months apart. If this criterion was not achieved at 24th month of therapy, venetoclax was discontinued and ibrutinib continued indefinitely. Results: Seventy-nine patients are included in the study. Twenty-nine patients in the first cohort and 50 patients in the second cohort. The characteristic is presented in Table. At the current follow-up periods, there were no significant differences in PFS and OS regarding a follow-up period <= 24 months (with the exception of death from COVID-19, since patients were not observed at parallel time intervals). In the group of patients treated with Imono, the majority of patients achieved partial remission or partial remission with lymphocytosis by 12 months. In 21 patients from Iven group, with a median follow-up of 7.4 months, a complete remission was achieved (72.4%);of these, 8 had unmeasurable MRD. Four patients did not complete the escalation period. There was a significant difference in the median MRD response achieved between 3 (log10>10) and 12 (log10<0,1) months in IVen group (p=0,03). In 2 patient from the IVen group progression of the disease was noted. Summary/Conclusion: Combination therapy with ibrutinib and venetoclax is an effective oral regimen for high-risk patients with complex karyotype disorders. PFS in both groups is currently not significantly different, which is obviously due to the short follow-up period. Patients receiving the IVen regimen achieve a significantly better response, which paves the way for allogeneic transplantation in these patients.

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