Objectives The effectiveness of trimethoprim/sulfamethoxazole (TMP/SMZ) for pneumocystis pneumonia (PCP) is limited with adverse events. Caspofungin, by inhibiting the cyst form of Pneumocystis jirovecii, may be an alternative therapy for PCP. However, the availability of clinical data about caspofungin combined with TMP/SMZ in the treatment of PCP in HIV‐infected patients is limited. Thus, we aimed to examine the clinical effectiveness and safety of caspofungin combined with TMP/SMZ as a first‐line therapy for moderate‐to‐severe PCP in HIV‐infected patients. Methods From January 2017 to December 2019, data of HIV‐infected patients with moderate‐to‐severe PCP who received either TMP/SMZ alone or caspofungin combined with TMP/SMZ as first‐line therapy were retrospectively reviewed to assess the effectiveness and safety of each regimen. The Kaplan–Meier curve and log‐rank test were used for survival analysis. Results A total of 278 patients met the criteria. The overall positive response rate of PCP treatment was 48.92%, and the overall all‐cause in‐hospital mortality rate was 33.09%. Patients who received combination therapy consisting of caspofungin and TMP/SMZ had a better positive response rate (59.44% vs. 37.78%, P < 0.001) and lower all‐cause in‐hospital mortality rate (24.48% vs. 42.22%, P = 0.003). Also, patients who received combination therapy had higher survival rate during a hospital stay (75.52% vs. 57.78%, P = 0.004), and those who received longer combination therapy were more likely to have higher survival rate (P = 0.042). We found that age (P = 0.019), CD4 cell count (P = 0.001) and therapeutic regimen (P = 0.002) were significant risk factors for all‐cause in‐hospital mortality rate in univariate analysis. In multivariate analysis, only CD4 cell count and therapeutic regimen were statistically significant factors associated with all‐cause in‐hospital mortality rate. Patients with a CD4 count of > 30 cells/µL and patients who received combination therapy consisting of caspofungin and TMP/SMZ were more likely to survive from PCP (P = 0.011 and P = 0.002, respectively). There were no additional severe adverse events caused by adding caspofungin. Conclusions For HIV‐infected patients with moderate‐to‐severe PCP, combination therapy with caspofungin and TMP/SMZ is an effective and promising first‐line therapy with no greater number of adverse events compared with TMP/SMZ monotherapy. Patients who received caspofungin had better positive response rates and lower all‐cause in‐hospital mortality rates. Also, we recommend early initiation of caspofungin.
Sophisticated cross-talk between bone marrow mesenchymal stromal cells (BM MSCs) and haematopoietic/leukaemic stem cells in patients with myelodysplastic syndromes (MDS) and myeloid leukaemia have been emphasized in previous reports. However, mesenchymal elements in patients with chronic myelomonocytic leukaemia (CMML) were poorly investigated. By utilizing a parallel RNA-sequencing method, we investigated the transcriptional profile and functional defects of primary BM MSCs from patients with CMML for the first time. Within a 24-patient cohort, transcriptional and functional analysis reveals a prominent enrichment of WNT/b-catenin signalling and multiple biology processes. Deregulated expression of WNT/b-catnin factors CTNNB1, CMYC, LEF1, and FRZB is associated with impaired proliferation, senescence phenotype, and abnormal secretion in CMML MSCs. The impaired ability to support healthy CD34 + haematopoietic stem and progenitor cells (HSPCs) correlates with activation of WNT/b-catenin signalling in CMML MSCs. Furthermore, we observed an association between WNT/b-catenin factors and treatment response to hypomethylating agents (HMAs) in a cohort of patients with MDS/myeloproliferative neoplasms (MPNs). Taken together, our study provides evidence for transcriptional and functional abnormalities in CMML MSCs, and suggests potential prognostic value of evaluating WNT/b-catenin signalling in patients with CMML.
Objectives: The present meta-analysis was performed to evaluate the efficacy, toxicities of both hypomethylating agents (decitabine and azaciticine) in the treatment of CMML patients. Methods: All available cohort studies of patients with CMML treated with decitabine and azacitidine were identified. The primary endpoints of this meta-analysis were response to hypomethylating agents. Pooled estimates of treatment response and drug-related adverse events were calculated using fixed or random effect models. Results: Fourteen studies with 600 CMML patients (decitabine: n=196; azacitidine: n=404) were identified and included for meta-analysis. HMAs yielded a pooled ORR estimate of 43% (95% CI: 36%-50%) in patients with CMML. Patients received either azacitidine or decitabine exhibited comparable incidence of ORR (43% vs. 45%, P=0.810), while significantly higher incidence of mCR was observed in patients treated with decitabine (23% vs. 10%, P=0.000). Decitabine treatment was also associated with higher incidence of transfusion independence (42% vs. 20%, P=0.044). Both HMAs led to objective hematologic or non-hematologic AEs (27%-43%), while dosage modification/delay were more frequent in patients treated with azacitidine (81% vs. 67%, P=0.021). Conclusion: This current study may provide preliminary data in evaluating the efficacy and safety of HMAs in patients with CMML. Decitabine and azacitidine are comparable effective and safe in treating CMML. However, it is necessary to point out that any comparison of decitabine and azacitidine with respect to clinical outcomes can only be done in the context of a randomized controlled trial.
Background Myofibroblasts (MFB), one of the major effectors of pathologic fibrosis, mainly derived from the activation of fibroblast to myofibroblast transition (FMT). Although MFBs were historically considered terminally differentiated cells, their potential for de-differentiation was recently recognized and implied with therapeutic value in treating fibrotic diseases, for instance, idiopathic pulmonary fibrosis (IPF) and post allogeneic hematopoietic stem cell transplantation bronchiolitis obliterans (BO). During the past decade, several methods were reported to block or reverse MFB differentiation, among which mesenchymal stem cells (MSC) have demonstrated potential but undetermined therapeutic values. However, the MSC-mediated regulation of FMT and underlying mechanisms remained largely undefined. Method By identifying TGF-β1 hypertension as the pivotal landmark during the pro-fibrotic FMT, TGF-β1-induced MFB and MSC co-culture models were established and utilized to investigate regulations by MSC on FMT in vitro. Methods including RNA sequencing (RNA-seq), Western blot, qPCR and flow cytometry were used. Result Our data revealed that TGF-β1 readily induced invasive signatures identified in fibrotic tissues and initiated MFB differentiation in normal FB. MSC reversibly de-differentiated MFB into a group of FB-like cells by selectively inhibiting the TGF-β-SMAD2/3 signaling. Importantly, these proliferation-boosted FB-like cells remained sensitive to TGF-β1 and could be re-induced into MFB. Conclusion Our findings highlighted the reversibility of MSC-mediated de-differentiation of MFB through TGF-β-SMAD2/3 signaling, which may explain MSC's inconsistent clinical efficacies in treating BO and other fibrotic diseases. These de-differentiated FB-like cells are still sensitive to TGF-β1 and may further deteriorate MFB phenotypes unless the pro-fibrotic microenvironment is corrected.
Hypomethylating agents (HMAs) are widely used in patients with higher-risk MDS not eligible for stem cell transplantation. However, the general response rate by HMAs is lesser than 50% in MDS patients, while the relapse rate is high. Emerging evidence indicates that demethylating effects committed by HMAs may facilitate the up-regulation of a range of immune checkpoints or cancer suppressor genes in patients with MDS, among which the programmed death protein 1 (PD-1) and its ligands are demonstrated to be prominent and may contribute to treatment failure and early relapse. Although results from preliminary studies with a limited number of enrolled patients indicate that combined administration of PD-1 inhibitor may yield extra therapeutic benefit in some MDS patients, identifications of this subgroup of patients and optimal timing for the anti-PD-1 intervention remain significant challenges. Dynamics of immune checkpoints and associated predictive values during HMA-treatment cycles remained poorly investigated. In this present study, expression levels of immune checkpoints PD-1 and its ligands PD-L1 and PD-L2 were retrospectively analyzed by quantitative PCR (Q-PCR) in a total of 135 myelodysplastic syndromes (MDS) cohort with higher-risk stratification. The prognostic value of dynamics of these immune checkpoints during HMA cycles was validated in two independent prospective cohorts in our center (NCT01599325 and NCT01751867). Our data revealed that PD-1 expression was significantly higher than that in younger MDS patients (age ≤ 60) and MDS with lower IPSS risk stratification (intermediate risk-1). A significantly up-regulated expression of PD-1 was seen during the first four HMA treatment cycles in MDS patients, while similar observation was not seen concerning the expression of PD-L1 or PD-L2. By utilizing binary logistic regression and receiver operating characteristic (ROC) models, we further identified that higher or equal to 75.9 PD-1 expressions after 2 cycles of HMA treatment is an independent negative prognostic factor in predicting acute myeloid leukemia (AML) transformation and survival. Collectively, our data provide rationales for monitoring the expression of PD-1 during HMA treatment cycles, a higher than 75.9 PD-1 expression may identify patients who will potentially benefit from the combined therapy of HMA and PD-1 inhibitors.
Hypomethylating agents (HMAs) including azacitidine (AZA) represent the only FDA-approved first-line treatments for patients with chronic myelomonocytic leukemia (CMML). However, the mechanism by which HMAs produce therapeutic responses (e.g., hematological improvement) remains unclear. Bone marrow mesenchymal stromal cells (MSCs) play a crucial role in regulating the self-renewal, survival and differentiation of hematopoietic stem and progenitor cells (HSPCs). Recently, the identified sensitivity of patient-derived MSCs to HMAs underlines a critical yet unexplored role of MSCs in regulating post-HMA efficacies. By utilizing high-throughput approaches including targeted exon sequencing, DNA methylation profiling, and RNA sequencing, our present study aims to delineate the modifications and consequences of AZA on CMML-MSCs. Demonstrated by integrated multi-omics analysis, our results reveal that cytogenetically independent CMML-MSCs exhibit strikingly high amenability to AZA. Through selectively de-methylating/methylating CpGs of 1395 sensitive genes, AZA re-activates HSPC-supportive signatures and enhances the protective effect of CMML-MSCs on healthy HSPCs. Along with the reconstitution of the dysregulated methylome/transcriptome, AZA partially restored the impaired functions of CMML-MSCs to support healthy hematopoiesis in long-term co-culture conditions. Our findings suggested a niche-dependent mechanism of post-HMA recovery of normal hematopoiesis. Identifying AZA-sensitive genes and functions may be of particular value in developing niche-targeting strategies in treating myeloid malignancies.
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