Long-term dynamics of the levels of anti-SARS-CoV-2 S-protein IgG antibodies in vaccinated individuals

In the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic, it is extremely important to study immunogenicity and immune response duration in different vaccines.Aim. As part of a prospective observational study, to study the levels of anti-SARS-CoV-2 S-protein IgG antibodies in individuals vaccinated with the Gam-COVID-Vac and CoviVac vaccines.Material and methods. The data of 93 people who completed the first 3 visits were analyzed, 23 of whom were vaccinated with the Gam-COVID-Vac vaccine and 70 people — with the CoviVac vaccine. We collected blood before the injection of vaccine doses I and II, as well as 42 days after the injection of dose I in order to quantitatively determine IgG levels. The level of anti-SARS-CoV-2 S-protein IgG antibodies was determined using the SARS-CoV-2 IgG ELISA-BEST reagent kit on the InfiniteF50 TECAN system.Results. A significant increase in anti-SARS-CoV-2 S-protein IgG antibodies was observed in those vaccinated with Gam-COVID-Vac. In the group of CoviVac vaccine, an increase in the level anti-SARS-CoV-2 S-protein IgG antibodies in absolute values was recorded, however, this increase did not reach statistical significance.Conclusion. The data obtained show that the level of anti-SARS-CoV-2 S-protein antibodies 42 days after Gam-COVID-Vac vaccination is significantly higher than after CoviVac vaccination. However, an increase in the level of IgG in both groups indicates the ability of both vaccines to stimulate the production of anti-SARS-CoV antibodies.

IFN-Gamma Expression in the Tumor Microenvironment and CD8-Positive Tumor-Infiltrating Lymphocytes as Prognostic Markers in Urothelial Cancer Patients Receiving Pembrolizumab

Although immune checkpoint inhibitors have shown benefit for advanced urothelial carcinoma (aUC) patients, prognostication of treatment efficacy and response duration remains a clinical challenge. We evaluated the expression of immune markers in the tumor microenvironment and assessed their associations with response to and survival after pembrolizumab treatment in 26 aUC patients. High levels of CD8+ tumor-infiltrating lymphocytes (TILs) were associated with favorable objective responses (23.0% vs. 15.3%, p = 0.0425), progression-free survival (median, 8.8 vs 2.1 months; hazard ratio (HR), 0.24; 95% confidence interval (CI), 0.07–0.66, p = 0.0060), and overall survival (median, >24.0 vs. 5.3 months; HR, 0.17; 95% CI, 0.04–0.56, p = 0.0034) compared with low levels. High interferon-gamma (IFNγ) expression levels were associated with longer post-progression survival (median, 4.9 vs. 1.0 months; HR, 0.18; 95% CI, 0.04–0.59, p = 0.0027) compared with low expression. Multivariate analysis incorporating clinical prognosticators demonstrated that the coincidence of low CD8+ T cells/IFNγ was an independent factor for unfavorable overall survival after pembrolizumab treatment (HR, 4.07; 95% CI, 1.36–12.73; p = 0.0125). The combination of low CD8+ TILs and IFNγ expression was an independent prognostic factor with predictive ability equivalent to previously reported clinical prognosticators.

Effects of Cued and Uncued Swallowing in Patients With Dementia

Purpose: Parameters such as bolus location at swallow onset (BLSO), stage transition duration (STD), pharyngeal transition duration (PTD), pharyngeal response duration (PRD), and pharyngeal phase duration (PPD) often vary between cued and uncued swallowing conditions. Research has demonstrated that cued swallows may offer functional benefits that mitigate pathophysiological processes. However, there are limited data assessing differences between cued and uncued swallows in disordered populations, such as dementia. The purpose of this study was to evaluate if cued swallowing alters swallowing biomechanics in patients living with dementia. Method: Through a retrospective analysis of videofluoroscopic swallow studies (VFSS), 105 swallows from 26 participants living with dementia ( M age = 81 years; 14 women) were analyzed in duplicate by blinded raters using the Analysis of Swallowing Physiology, Events, Kinematics, and Timing method. Only VFSS with at least one cued and one uncued swallow were included in the analysis. Chi-square tests were used to explore differences in BLSO. Repeated-measures analyses of variance (ANOVAs) were used to explore differences in STD, PTD, PRD, and PPD. Results: Results revealed no significant differences in BLSO between cued and uncued swallows for patients living with dementia ( p = .934). Repeated-measures ANOVAs revealed no significant differences between the two types of swallows for STD ( p = .995), PTD ( p = .864), PRD ( p = .807), or PPD ( p = .660). Conclusions: This study suggests that there may be limited benefit to providing cued swallows to individuals living with dementia. Further research should investigate if this is due to impaired cognition and/or changes in motor control to volitionally complete the cued swallow.

Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10-9), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.

Intrathecal IGF2 siRNA injection provides long-lasting anti-allodynic effect in a spared nerve injury rat model of neuropathic pain

Previous studies have shown an increase of insulin-like growth factor-2 (IGF2) in animal models of neuropathic pain. We aimed to examine the hypothesis that reducing the expression of IGF2 using intrathecal IGF2 small-interfering RNA (siRNA) would attenuate the development of neuropathic pain in rats after spared nerve injury (SNI). Male Wistar rats were divided into three groups: sham-operated group, in which surgery was performed to cut the muscles without injuring the nerves; SNI group, in which SNI surgery was performed to sever the nerves; and SNI + siRNA IGF2 group, in which SNI surgery was performed, and IGF2-siRNA was administered intrathecally 1 day after SNI. The rats were assessed for mechanical allodynia and cold allodynia 1 day before surgery (baseline), and at 2, 4, 6, 8, and 10 days after siRNA treatment. The rat spinal cord was collected for quantitative polymerase chain reaction and western blot analysis. Compared with the SNI group, rats that received IGF2 siRNA showed a significantly increased SNI-induced paw-withdrawal threshold to metal filament stimulation from Day 4 to Day 10 after SNI surgery. IGF2 siRNA significantly decreased the response duration from the acetone test from Day 2 to Day 10 following SNI surgery. SNI increased IGF2 mRNA expression on Day 2 and increased IGF2 protein expression on Day 8 and Day 10 in the spinal cord of the SNI rats. However, the above-mentioned effects of IGF2 mRNA and protein expression were significantly inhibited in the SNI + IGF2 siRNA group. We demonstrated that intrathecal administration of IGF2 siRNA provided significant inhibition of SNI-induced neuropathic pain via inhibition of IGF2 expression in the spinal cord. The analgesic effect lasted for 10 days. Further exploration of intrathecal IGF2 siRNA administration as a potential therapeutic strategy for neuropathic pain is warranted.

An Analytical Method for Elastic Seismic Response of Structures Considering the Effect of Ground Motion Duration

The response to earthquake ground motion is composed of three basic elements, namely, amplitude, frequency, and duration. The seismic response of a structure is controlled by the particular combination of these three elements. The seismic response spectra reflect the earthquake ground motion’s frequency-domain features and provide the maximum response amplitude of a single-degree-of-freedom system to a given earthquake ground motion but do not consider the duration factor. However, the analysis of post-earthquake damage shows that the seismic response duration has a strong impact on the damage to structures. Therefore, it is necessary to develop a simple and practical analytical method to account for the seismic response duration. The present study was conducted based on the response spectra theory. We introduce an analytical method of elastic seismic response, which considers its duration by adding the time-domain dimension of earthquakes. The time-domain spectral matrix is used to solve the time-dependent seismic response through the vibration mode decomposition method. The time-domain vibration mode decomposition reaction spectrum not only takes into account the maximum seismic reaction of each vibration mode but also considers the seismic reaction of different vibration modes occurring at the same time, at each moment. The dynamic time duration of the structure’s seismic reaction is quantified by the time-domain seismic reaction spectrum to obtain a more accurate analysis method for the seismic reaction of the structure.

Olaparib with or without bevacizumab or bevacizumab and 5-fluorouracil in advanced colorectal cancer: Phase III LYNK-003

Oxaliplatin-based chemotherapy with a regimen such as FOLFOX with or without targeted therapy is a standard of care option for advanced colorectal cancer; however, long-term exposure to oxaliplatin is associated with cumulative toxicity. Growing evidence suggests maintenance therapy with a less intensive regimen after platinum-based induction therapy can provide continuing benefit with reduced toxicity. We describe the rationale and design of the Phase III LYNK-003 trial, which will evaluate the efficacy and safety of olaparib with or without bevacizumab compared with 5-fluoruracil plus bevacizumab in patients with unresectable or metastatic colorectal cancer that has not progressed on an induction course of FOLFOX plus bevacizumab. The primary end point is progression-free survival by independent central review; secondary end points include overall survival, objective response, duration of response and safety. Clinical trial registration: NCT04456699

LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway

Internal tandem duplications (ITD) mutation within FMS-like tyrosine kinase 3 (FLT3), the most frequent mutation happens in almost 20% acute myeloid leukemia (AML) patients, always predicts a poor prognosis. As a small molecule tyrosine kinase inhibitor, sorafenib is clinically used for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and differentiated thyroid cancer (DTC), with its preclinical and clinical activity demonstrated in the treatment of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant AML. Even though it shows a rosy future in the AML treatment, the short response duration remains a vital problem that leads to treatment failure. Rapid onset of drug resistance is still a thorny problem that we cannot overlook. Although the mechanisms of drug resistance have been studied extensively in the past years, there is still no consensus on the exact reason for resistance and without effective therapeutic regimens established clinically. My previous work reported that sorafenib-resistant FLT3-ITD mutant AML cells displayed mitochondria dysfunction, which rendered cells depending on glycolysis for energy supply. In my present one, we further illustrated that losing the target protein FLT3 and the continuously activated PI3K/Akt signaling pathway may be the reason for drug resistance, with sustained activation of PI3K/AKT signaling responsible for the highly glycolytic activity and adenosine triphosphate (ATP) generation. PI3K inhibitor, LY294002, can block PI3K/AKT signaling, further inhibit glycolysis to disturb ATP production, and finally induce cell apoptosis. This finding would pave the way to remedy the FLT3-ITD mutant AML patients who failed with FLT3 targeted therapy.

Azacytidine Treatment in Patients with Acute Myeloid Leukemia/High-Risk Myelodysplastic Syndrome: Day-Hospital Management Compared to Home Care Setting

Introduction Treatment with Hypometilating Agents (HMA) of unfit patients (pts) with Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic Syndromes (HR-MDS) is often difficult in the standard Day-Hospital (DH) setting, due to the number of hospital admissions required and the frail clinical conditions of pts. In the Viterbo province, accounting for 3612 Km 2 divided into 60 municipalities, is operative an Unit of Domiciliary Hematologic Care (UDHC) for clinical assistance to frail pts with hemopathies. Aims To evaluate the role of the UDHC compared to standard DH setting in the active frontline treatment with HMA +/- venetoclax (VTX) of pts with AML/HR-MDS. Methods All pts with newly diagnosed AML/HR-MDS unfit for intensive care and treated frontline with HMA from 1/2010 to 4/2021 were analysed. Results In this study period, 112 pts (62 AML/50 HR-MDS) received HMA (azacytidine in 105 cases and decitabine in 7 cases): six pts added VTX to HMA. As concern therapy management, 69 pts (61.6%) were treated in a standard DH setting and 43 (38.4%) were followed by UDHC: pts were allocated to DH or home care setting by responsible physician based on clinical conditions, comorbidities, caregiver availability and distance from hospital. The main features at baseline of HMA in the whole cohort and according to management are reported in the Table 1. Median interval from diagnosis to HMA initiation was 0.9 months (IQR 0.5 - 3.0). Median number of HMA cycles administered was 9 (IQR 4 - 16). The overall response rate (ORR), including complete response, partial response and hematologic improvement, was 43.7% (48/112 pts) in the whole cohort, without differences according to management [29/69 (42.0%) in DH vs 19/43 (44.1%) in home care, p=0.797]. Infections were also equally reported [46/69 pts (66.6%) in DH vs 31/43 (72.0%) in home care setting had at least 1 infection, p=0.362]. Median response duration of the whole cohort was 10.0 months (95%CI 5.7 - 14.2), without differences according to management [8.7 months (95%CI 7.0 - 10.3) in DH vs 13.0 months (95%CI 8.3 - 17.6) in home care, p=0.460]. Median Overall Survival (OS) of the whole cohort was 13.0 months (95%CI 9.7 - 16.2): median OS of pts treated in DH was 13.7 months (95%CI 9.9 - 17.4) compared to 13.0 months (95%CI 6.7 - 19.3) of pts managed by UDHC (p=0.753) (Figure 1). Conclusions Home care management of HMA for unfit AML/HR-MDS pts is feasible and effective, with results similar to those achievable in a standard DH setting: this approach is thus adequate to offer active therapies in a fraction of frail pts with AML/HR-MDS considered up to now ineligible. Figure 1 Figure 1. Disclosures Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria.

Long Term Follow up of the Resort Study (E4402): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma

BACKGROUND: E4402 was a randomized phase III study comparing two different rituximab dosing strategies for patients with previously untreated, low tumor burden follicular lymphoma (FL). The primary endpoint was time to treatment failure. The initial publication (Kahl, JCO 2014) demonstrated that a retreatment strategy utilized less drug and produced comparable time to treatment failure compared to a maintenance strategy. Here we provide long term follow up results, focusing on response duration, time to first cytotoxic therapy, overall survival, and risk of histologic transformation. METHODS: Eligible patients had untreated, low tumor burden (GELF criteria) FL. Patients received R 375 mg/m 2 weekly x 4 and responders were randomized to maintenance rituximab (MR) (single dose R q 3 months) or retreatment rituximab (RR) (R weekly x 4 doses at disease progression). Each strategy was continued until treatment failure. The primary endpoint, time to treatment failure, was defined as progression within 6 months of last R, no response to R retreatment, initiation of alternative therapy, or inability to complete protocol therapy. Secondary endpoints included time to first cytotoxic therapy, quality of life and safety. The ECOG Data Monitoring Committee recommended release of study results at a planned interim analysis in September 2011 and patients and providers were notified of results. Time to treatment failure data collection halted with release of the results but limited data collection on time to first cytotoxic therapy, response duration, and risk of histologic transformation continued. INITITIAL RESULTS: From 11/03 to 9/08, 384 patients with FL were enrolled. Complete or partial response was achieved in 289 patients (71%), who were then randomized to MR (n=146) or RR (n=143). Demographic features were similar in the two arms: median age 59 years; ECOG PS 0-1 in all patients, and FLIPI low-risk (14.9 vs. 16.4%), intermediate-risk (46.3 vs. 42.9%) and high-risk (38.8 vs. 40.7%) for MR vs. RR, respectively. At initial publication, with a median follow-up of 3.8 years, the time to treatment failure was 3.9 years for MR vs. 3.6 years for RR (p=NS). LONG TERM FOLLOW UP RESULTS: Immunoglobulin levels and risks for serious infections/late complications in MR patients will be updated at the annual meeting. For the endpoint of time to first cytotoxic therapy, the median follow up is 8.7 years. At 7 years, 83% of MR and 63% of RR remained free from first cytotoxic therapy (HR 2.37; 95% CI 1.50 - 3.76) [Figure 1]. For the endpoint of response duration, the median follow up is 12.1 years. At 10 years, 66% of the MR patients remained in their 1 st remission compared to 30% of the RR patients who remained in their 1 st remission [Figure 2]. The median response duration for RR patients receiving a single 4-week course of rituximab was 3.25 years. There was no difference in the overall survival at 10 years, 84% for MR vs. 83% for RR. There was a trend towards a lower risk of histologic transformation for patients receiving MR (n = 4) compared to RR (n = 11) (p = 0.11). CONCLUSIONS: With long term follow up, the RESORT data indicates that in previously untreated, low tumor burden, follicular lymphoma, MR was superior to RR for delaying time to first cytotoxic therapy and for response duration, with a trend towards reducing the risk of histologic transformation. MR did not improve the overall survival. The original publication concluded that the time to treatment failure is similar between the two dosing strategies. Due to study design, time to treatment failure could not be analyzed in this long term follow up analysis. Compared to the historical benchmark of 3 years median time to first cytotoxic therapy when watch and wait is utilized, single agent rituximab, administered by either dosing strategy, was highly effective at delaying the time to first cytotoxic therapy. Figure 1 Figure 1. Disclosures Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Habermann: Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Seagen: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding. Fenske: TG Therapeutics: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy; Seattle Genetics: Speakers Bureau; Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; MorphoSys: Consultancy; Kite (Gilead): Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy.