Long COVID affects many individuals following acute coronavirus disease 2019 (COVID-19), and hematological changes can persist after the acute COVID-19 phase. This study aimed to evaluate these ...hematological laboratory markers, linking them to clinical findings and long-term outcomes in patients with long COVID. This cross-sectional study selected participants from a 'long COVID' clinical care program in the Amazon region. Clinical data and baseline demographics were obtained, and blood samples were collected to quantify erythrogram-, leukogram-, and plateletgram-related markers. Long COVID was reported for up to 985 days. Patients hospitalized in the acute phase had higher mean red/white blood cell, platelet, and plateletcrit levels and red blood cell distribution width. Furthermore, hematimetric parameters were higher in shorter periods of long COVID than in longer periods. Patients with more than six concomitant long COVID symptoms had a higher white blood cell count, a shorter prothrombin time (PT), and increased PT activity. Our results indicate there may be a compensatory mechanism for erythrogram-related markers within 985 days of long COVID. Increased levels of leukogram-related markers and coagulation activity were observed in the worst long COVID groups, indicating an exacerbated response after the acute disturbance, which is uncertain and requires further investigation.
Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Postremission maintenance ...therapy that prolongs MRD negativity or converts MRD+ patients to MRD− status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged ≥55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (≥0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed oral-AZA significantly improved OS and RFS vs placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher rate of conversion from MRD+ at baseline to MRD− during treatment: 37% vs 19%, respectively. In the oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. Although presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with oral-AZA maintenance therapy compared with placebo, independent of patients' MRD status at baseline. Registered at clinicaltrials.gov as #NCT01757535.
•Oral-AZA significantly improved overall and RFS vs placebo independent of baseline MRD status.•Rate of MRD+ to MRD− conversion was higher with oral-AZA; one-fourth of MRD responders achieved MRD negativity >6 months after starting oral-AZA.
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Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, ...in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia.
Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI).
Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 10
/L, and absolute neutrophil count was 1.3 × 10
/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (
= .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4%
4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3%
6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3
16.2 months;
= .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 10
/L.
CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.
Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response pathway factors, such as ataxia telangiectasia-mutated ...(ATM)/ataxia telangiectasia and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content γ-H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break (DSB) repair and rely on compensatory repair pathways for survival. Therefore, impairing ATR activity may selectively sensitize cancer cells to killing. ATR inhibition in an ATM-deficient context results in phosphorylation of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) and leads to induction of γ-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-of-function mantle cell lymphoma (MCL) compared with ATM wild-type cancer cells. In summary, single-agent ATR inhibitors have therapeutic utility in the treatment of cancers, like MCL, in which ATM function has been lost.
These data suggest that single-agent ATR inhibitors have therapeutic utility and that ATR uses a complex and coordinated set of proteins to maintain genomic stability that could be further exploited.
Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes ...with a different selectivity profile. The key to achieve these objectives was to couple a structure-based design approach with intensive pharmacologic evaluation of selected compounds during the medicinal chemistry optimization process. Here, we report on the biologic characterization of the 2-morpholino pyrimidine derivative pan-PI3K inhibitor NVP-BKM120. This compound inhibits all four class I PI3K isoforms in biochemical assays with at least 50-fold selectivity against other protein kinases. The compound is also active against the most common somatic PI3Kα mutations but does not significantly inhibit the related class III (Vps34) and class IV (mTOR, DNA-PK) PI3K kinases. Consistent with its mechanism of action, NVP-BKM120 decreases the cellular levels of p-Akt in mechanistic models and relevant tumor cell lines, as well as downstream effectors in a concentration-dependent and pathway-specific manner. Tested in a panel of 353 cell lines, NVP-BKM120 exhibited preferential inhibition of tumor cells bearing PIK3CA mutations, in contrast to either KRAS or PTEN mutant models. NVP-BKM120 shows dose-dependent in vivo pharmacodynamic activity as measured by significant inhibition of p-Akt and tumor growth inhibition in mechanistic xenograft models. NVP-BKM120 behaves synergistically when combined with either targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide. The pharmacological, biologic, and preclinical safety profile of NVP-BKM120 supports its clinical development and the compound is undergoing phase II clinical trials in patients with cancer.
Purpose: Chk1 kinase is a critical regulator of both S and G 2 -M phase cell cycle checkpoints in response to DNA damage. This study aimed to evaluate the biochemical, cellular, and antitumor
effects ...of a novel Chk1 inhibitor, CHIR124.
Experimental Design: CHIR-124 was evaluated for its ability to abrogate cell cycle checkpoints, to potentiate cytotoxicity, and to inhibit Chk1-mediated
signaling induced by topoisomerase I poisons in human tumor cell line and xenograft models.
Results: CHIR-124 is a quinolone-based small molecule that is structurally unrelated to other known inhibitors of Chk1. It potently
and selectively inhibits Chk1 in vitro (IC 50 = 0.0003 μmol/L). CHIR-124 interacts synergistically with topoisomerase poisons (e.g., camptothecin or SN-38) in causing
growth inhibition in several p53-mutant solid tumor cell lines as determined by isobologram or response surface analysis.
CHIR-124 abrogates the SN-38–induced S and G 2 -M checkpoints and potentiates apoptosis in MDA-MD-435 breast cancer cells. The abrogation of the G 2 -M checkpoint and induction of apoptosis by CHIR-124 are enhanced by the loss of p53. We have also shown that CHIR-124 treatment
can restore the level of cdc25A protein, which is normally targeted by Chk1 for degradation following DNA damage, indicating
that Chk1 signaling is suppressed in the presence of CHIR-124. Finally, in an orthotopic breast cancer xenograft model, CHIR-124
potentiates the growth inhibitory effects of irinotecan by abrogating the G 2 -M checkpoint and increasing tumor apoptosis.
Conclusions: CHIR-124 is a novel and potent Chk1 inhibitor with promising antitumor activities when used in combination with topoisomerase
I poisons.
Oral azacitidine (oral-Aza) treatment results in longer median overall survival (OS) (24.7 vs. 14.8 months in placebo) in patients with acute myeloid leukemia (AML) in remission after intensive ...chemotherapy. The dosing schedule of oral-Aza (14 days/28-day cycle) allows for low exposure of Aza for an extended duration thereby facilitating a sustained therapeutic effect. However, the underlying mechanisms supporting the clinical impact of oral-Aza in maintenance therapy remain to be fully understood. In this preclinical work, we explore the mechanistic basis of oral-Aza/extended exposure to Aza through in vitro and in vivo modeling. In cell lines, extended exposure to Aza results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to Aza, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of Aza induces differentiation and depletes CD34+CD38- LSC. Mechanistically, LSC differentiation is driven in part by increased myeloperoxidase (MPO) expression. Inhibition of MPO activity either by using an MPO-specific inhibitor or blocking oxidative stress, a known mechanism of MPO, partly reverses the differentiation of LSC. Overall, our preclinical work reveals novel mechanistic insights into oral-Aza and its ability to target LSC.
A significant proportion of patients experience a wide range of symptoms following acute coronavirus disease 2019 (COVID-19). Laboratory analyses of long COVID have demonstrated imbalances in ...metabolic parameters, suggesting that it is one of the many outcomes induced by long COVID. Therefore, this study aimed to illustrate the clinical and laboratory markers related to the course of the disease in patients with long COVID. Participants were selected using a clinical care programme for long COVID in the Amazon region. Clinical and sociodemographic data and glycaemic, lipid, and inflammatory screening markers were collected, and cross-sectionally analysed between the long COVID-19 outcome groups. Of the 215 participants, most were female and not elderly, and 78 were hospitalised during the acute COVID-19 phase. The main long COVID symptoms reported were fatigue, dyspnoea, and muscle weakness. Our main findings show that abnormal metabolic profiles (such as high body mass index measurement and high triglyceride, glycated haemoglobin A1c, and ferritin levels) are more prevalent in worse long COVID presentations (such as previous hospitalisation and more long-term symptoms). This prevalence may suggest a propensity for patients with long COVID to present abnormalities in the markers involved in cardiometabolic health.
•Patients in remission treated with Oral-AZA had better OS and RFS vs placebo regardless of NPM1 or FLT3 mutational status at AML diagnosis.•Oral-AZA conferred OS and/or RFS benefits in patients with ...favorable (NPM1mut, no MRD) or adverse (FLT3mut, MRD+) prognostic AML features.
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The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (ClinicalTrials.gov identifier: NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplantation. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days per 28-day cycle. We evaluated relapse-free survival (RFS) and overall survival (OS) in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1 mutations (NPM1mut), 66 patients (14.1%) had FLT3 mutations (FLT3mut; with internal tandem duplications ITD, tyrosine kinase domain mutations TKDmut, or both), and 30 patients (6.4%) had NPM1mut and FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (hazard ratio HR, 0.63; 95% confidence interval CI, 0.41-0.98) and 45% (HR, 0.55; 95% CI, 0.35-0.84), respectively, vs placebo. Median OS was improved numerically with Oral-AZA among patients with NPM1mut whether without MRD (48.6 months vs 31.4 months with placebo) or with MRD (46.1 months vs 10.0 months with placebo) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR, 0.63; 95% CI, 0.35-1.12) and 49% (HR, 0.51; 95% CI, 0.27-0.95), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 months vs 16.2 months, respectively, for patients with FLT3mut and without MRD and 24.0 months vs 8.0 months for patients with FLT3mut and MRD. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.
Background
The transfemoral approach is an extensile surgical approach that is performed routinely to facilitate cement and implant removal and improve exposure for revision stem implantation. ...Previous studies have looked at clinical results of small patient groups. The factors associated with fixation failure of cementless revision stems when using this approach have not been examined.
Questions/purposes
We determined (1) the clinical results and (2) complications of the transfemoral approach and (3) factors associated with fixation failure of revision stems when using the transfemoral approach.
Patients and Methods
We retrospectively examined all our patients in whom femoral stem revision was performed through a transfemoral approach between December 1998 and April 2004 and for whom a minimal followup of 2 years was available. One hundred patients were available for this study. The mean (± SD) postoperative followup was 5 years (± 1.64 years).
Results
The average Harris hip score improved from 45.2 (± 14.02) preoperatively to 83.4 (± 11.86) at final followup. Complete radiographic bony consolidation of the osteotomy site was observed in 95% of patients. Dislocations occurred in 9% of patients. Four revision stem fixation failures were observed, all occurring in patients with primary three-point fixation. Three-point fixation was associated with short osteotomy flaps and long revision stems.
Conclusions
The transfemoral approach is associated with a high rate of osteotomy flap bony healing and good clinical results. When using the transfemoral approach, a long osteotomy flap should be performed and the shortest possible revision stem should be implanted.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
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