dataesr/scientific-paragraphs-categorization huggingface dataset:
Cellular Therapies Several clinical trials are focused on cellular therapies such as mesenchymal stem cells (MSCs) or manipulated donor T cells which have been shown to reduce incidence of GVHD. The phase 1/2 study, NCT05152160  [26, 27]  is investigating MSCs taken from umbilical cords (UCBs) as it has been shown that both donor bone marrow-and umbilical cord-derived MSCs have immunosuppressive properties. Another approach is donor manipulated T cells. NCT03683498 and NCT05095649 are using enriched CD25hi T cells (Tregs) from CD8 and/or CD19 pre-depleted leukapheresis products, which have been shown to be an effective and safe way to prevent GVHD  [28]  for patients who did not achieve remission after ruxolitinib.
Targeted Therapies Ibrutinib inhibits Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinases (ITK) which regulate B-cell survival and activation of T cell subsets that drive immune reactivity towards health tissues  [29]. Ibrutinib is approved for the second-line treatment of cGVHD in adults and recently also for children above 1 year of age with cGVHD after failure of one or more lines of systemic therapy, based on the results of the iMAGINE (NCT03790332) and iNTEGRATE trials (NCT02959944)  [30]. JAK1/2 signaling is involved in many steps leading to inflammation, T-cell activation, and tissue damage in GVHD  [31]. Ruxolitinib, a JAK1/2 inhibitor reduces the number of circulating activated T cells in patients with cGVHD  [32] , was prospectively evaluated in a phase III randomized study including children who had glucocorticoid-refractory acute GVHD after HSCT  [33].
A total of 309 patients were included; both the response rate at 28 days and at day 56 were higher in the ruxolitinib group, as well as median free survival and overall survival. These results led to the approval of ruxolitinib for the treatment of steroid refractory cGHVD in children above 12 years of age. The NCT05121142 trial is investigating systemic ruxolitinib in children under 12 years of age with acute and chronic GVHD and the NCT03774082 in children under 18 years. TQ05105, another JAK2 inhibitor, is also being evaluate in this population (NCT04944043). Itacitinib, a JAK1 inhibitor, is being investigated in combination with cyclophosphamide and tacrolimus to prevent GVHD (NCT05364762). Belumosudil, a selective ROCK2 inhibitor which reduces follicular T helper cells by downregulating STAT3 and upregulating STAT5, has been approved for patients above 12 years of age with cGVHD after failure of at least two prior lines of treatment, based on the results of the phase II randomized study (NCT03640481) comparing two different doses (200 mg OD or 200 mg BID)  [34].
The study remains open for patients under 18 years of age and another study is also evaluating belumosudil in patients above 12 years (NCT05567406). Axatilimab (SNDX-6352) is a humanized, full-length IgG4 antibody with high affinity to CSF-1R. Axalitamab affects the migration, proliferation, differentiation, and survival of monocytes and macrophages by binding to CSF-1R and blocking its activation by its two known ligands, CSF-1 and IL-34, and may be a novel therapeutic option for treatment of patients with GVHD and has shown preliminary efficacy in adult patients  [35]. Two studies (NCT03604692, NCT04710576) are evaluating axalitamab in patients cGVHD after two or more lines of therapy. Vorinostat, an HDAC inhibitor which affects the balance of circulating T-cell subsets by increasing the regulatory T cells and decreasing Th1 and Th17 cells  [36] , will be investigated in a phase I/II clinical trial (NCT03842696) administered at three different doses.
Chemotherapeutics A phase 2 study will randomize patient to receive post-transplant cyclophosphamide in addition to anti-thymocyte globuline (ATG) given during the conditioning regimen (NCT04202835). The administration of high-dose cyclophosphamide post-HSCT in combination with MMF and tacrolimus will be evaluated in the NCT03128359 trial in patients receiving three different conditioning regiments including fludarabine combined with either melphalan, busulfan, or total body irradiation (TBI).
Other Therapies Additional experimental therapies to treat cGVHD are being investigated. NCT03083574 is investigating the impact and safety of extracorporeal photopheresis, which might affect the patient's dendritic cells by changing the antigen-specific T-cell immunity and T-cell tolerance  [37]  after HSCT. In addition, hydrogen-rich water consumption, an FDAacknowledged food additive with reactive oxygen species scavenging properties is being investigated in cGVHD patients in the NCT02918188 study.
TKIs have also been studied in cGVHD considering their antifibrotic and anti-inflammatory properties, as inhibitors of both PDGF-R and TGFβ pathways and immunomodulatory effects, and being involved in both T-cell and B-cell responses  [47]. Only limited evidence about its use and efficacy is available in children  [48]. Local treatment with inhaled budesonide/formoterol improves FEV1 in patients with mild/severe BOS  [49]. The combination with inhaled fluticasone, azithromycin, and montelukast (also known as FAM therapy) was tested in a phase 2 trial for adults and children (NCT01307462) and was reported to halt pulmonary decline and permit reductions in systemic steroid exposure  [50]. A phase 2 study (NCT01287078) tested inhaled cyclosporine in 20 patients but only 11 completed the treatments through week 18 due to cough and bronchospasm.
Inhaled cyclosporine led to an improvement or stabilization of pulmonary function and/or a decrease in systemic immunosuppression in 9 of 11 patients  [51]. The ongoing NCT04908735 is testing whether the addition of ruxolitinib to early treatment with fluticasone/montelukast and steroids can reverse lung injury and reduce the frequency of BO. A randomized phase 3 trial (NCT04655508) is evaluating the efficacy of fluticasone and salmeterol compared to placebo on respiratory function in children above six years who underwent allo-HSCT transplantation with a decline of FEV1 ≥ 10% from pre-transplantation.
Cryptogenetic Organizing Pneumonia (COP) COP is associated with restrictive pulmonary dysfunction and, in contrast to BOS, its etiology is not strictly related to GVHD and considered as a clinico-pathologic entity of unknown etiology  [52]. COP shows a response to steroids in more than 80% of cases but relapses are common when tapering steroids  [39]. Steroids, azithromycin, montelukast, and symbicort (SAMS) therapy was tested in adults, but the trial (NCT01432080) was terminated early due to insufficient accrual. Bardoxolone, a synthetic triterpenoid, is being evaluating in adults (NCT02036970) with pulmonary hypertension (including patients with COP) due to its suppression of pro-inflammatory mediators, enhancement of nitric oxide bioavailability, and suppression of vascular proliferation, leading to prevention of tissue remodeling.
Idiopathic Pneumonia Syndrome (IPS) Lung injury in IPS occurs through two pathways, the TNF-α/LPS-dependent and IL6/IL17-dependent  [53]. Treatment is based on corticoids. Anti-TNF therapies have been tested; the randomized study of etanercept and steroids vs. placebo showed no difference in response in adults, although the study was terminated early due to low accrual. In a phase II study in children, the complete remission rate was 71% and the 1-year survival was 63%  [41]. Other agents have been addressed to the IL6/IL17 pathway, mainly tocilizumab and brodalumab  [54]. No clinical trials were identified in children in clinicaltrials. gov.
It is the only agent approved by the FDA and EMA to treat pediatric severe VOD and it is associated with higher rates of survival at day +100 compared to historical controls (38. 2 vs. 25%) when defibrotide was used in patients with established VOD/SOS  [61]. A randomized phase 3 study in children and adults with high risk for developing VOD, compared the efficacy of prophylactic defibrotide vs. best supportive care (NCT02851407). In a preliminary report, 372 patients were included; no significant differences were found between both groups regarding the VOD/SOS-free survival by day 30 (85% vs. 80%)  [62]. Pre-clinical studies have shown that antithrombin III (ATIII) has anti-inflammatory properties by binding to endothelial membranes and increasing prostacyclin synthesis, limiting platelet aggregation, and decreasing pro-inflammatory cytokine production.
To date, studies investigating prophylactic or therapeutic ATIII have produced contradictory results  [63]. A phase 2 study has evaluated the ATIII effect on children and adults with hepatic VOD post-HSCT (NCT01886248), but results are not yet available. The use of prostaglandin E1 (PGE1) in prophylaxis has shown to decrease the incidence of VOD in adults and children due to its anti-inflammatory properties  [64, 65]. Based on this premise, the NCT02338440 study has investigated its pharmacokinetic properties and the incidence of VOD after prophylactic lipo-PGE1, but the results are not yet available.
Engraftment Syndrome (ES) ES is defined as the appearance of different clinical manifestations when the first neutrophils in the peripheral blood indicate the engraftment  [66]. ES is the result of a systemic endothelial damage by the release of pro-inflammatory cytokines (IL-2, TNF-α, IFN-γ, IL-6) and products of degranulation and oxidative metabolism from neutrophils. Although the suggested therapy consists of corticosteroid therapy, controlled trials have not been performed to assess its benefit. A trial in adults is testing the prophylactic budesonide from day 5 in autologous and allogeneic stem cell transplant recipients (NCT05509933). Other approaches are cytokine targeted therapies such as tocilizumab and anakinra. In a single arm study, cord blood recipients of any age with steroid refractory ES, received tocilizumab at 4-8 mg/kg.
N-acetylcysteine was prospectively evaluated in a randomized phase 3 study including children (NCT03252925). A total of 140 patients were included (13% under 18 years of age). The incidence of TA-TMA at 100 days after HSCT was lower in the intervention group compared to the placebo group (7. 6% vs. 19. 5%). The complement blocker eculizumab, used in the treatment of atypical hemolytic uremic syndrome (HUS), appears to be an effective therapy for TA-TMA in children; a retrospective study showed that the use of eculizumab resulted in a significant improvement in overall survival compared to historical controls (66% vs. 16%)  [74]. The NCT03518203 trial tested eculizumab in pediatric and adult patients with high risk of developing TA-TMA, but results are not yet known. Ravulizumab is a humanized monoclonal antibody that inhibits complement protein C5, with the same indication as eculizumab for HUS but with a longer half-life  [75].
Two trials are testing Ravalizumab in patients with TA-TMA including children (NCT04557735, NCT04543591). Nomacopan inhibits terminal complement activation by binding to C5 and preventing its cleavage and activation. A trial (NCT04784455) is currently ongoing in children. Narsoplimab, an inhibitor of mannan-binding lectin-associated serine protease-2 in the alternative complement activating pathway, showed efficacy in the treatment of adult patients with TA-TMA by improvement of laboratory markers and organ function  [76] , leading to the approval in the adult population. An expanded access program is available in children (NCT04247906) and a pediatric trial of narsoplimab for TA-TMA is beginning soon.
Improvement would require the effort of large and international clinical trials, as for instance the EsPhALL2010 (NCT00287105) trial, which recommended the use of imatinib post-HSCT for Ph+ ALL or the use of FLT3 inhibitors post-HSCT in AML patients  [83]. Nevertheless, the compliance to the study recommendations is not yet known as the results are not yet available. BiTE approaches Other than blinatumomab and cell therapies have not reached the post-transplant setting. In the cGVHD setting, the examples from ibrutinib, ruxolitinib, and belumosudil that have been evaluated in parallel in adults and children within the scope of registration studies and led to regulatory approval for its use in children are definitely a way forward to accelerate the development of new drugs in children. We could only identify a few trials in children for the non-infectious pulmonary complications and endothelial complications.
The recent approval of narsoplimab in adults with TA-TMA, may lead soon to the opening of a pediatric study in this condition. An exception is represented by the VOD treatment with defibrotide, which achieved a pediatric label thanks to the results of the clinical trials including pediatric patients. We acknowledge the limitation of having missed studies that were posted in other databases different from clinicaltrials. gov. We nevertheless performed an exhaustive scrutiny of studies using the advance search including multiple and overlapping terms. We also looked for cross-references where available and performed an additional search in PubMed to minimize the possibility of missing relevant studies. In general, we have observed a paucity of clinical trials for many different conditions, such as COP, capillary leak syndrome or engraftment syndrome, and in a larger setting of post-HSCT complications.
In the absence of response, dose can be increased up to 150 mg/day in blocks of 50 mg Acute leukemia 15 Years to 60 Years Phase 2 *N-acetyl-L-cysteine N-acetyl-L-cysteine NCT03236220 35 Completed patients given orally at dosages of 400 mg three times per day from 14 days pre-allotransplant to 2 months after allotransplant.
Status Prevention of relapse including early interventions after detection of MRD positivity following HSCT in ALL and AML Cellular therapy ALL, AML 10 Years to 65 Years Phase 1 Donor γδT cell One infusion of NCT04439721 5 Active, infusion 0. 5 × 10 6-8 × 10 7 γδT/kg recruiting AML, MDS, JMML 1 Year and Older Phase 1 Cytokine-induced CIML-NK given IV on NCT04024761 50 Active, memory-like natural day 0 with IL-2, three recruiting killer (CIML-NK) cells doses of fludarabine from day -5 to -3 and two doses CP on day -4 and -4 CD19 positive B- All Phase 1 CD19/CD28 CAR T Maximum of six doses, 4 NCT02050347 40 Active, ALL/B-CLL/NHL cells derived from to 6 weeks apart, of recruiting donor CAR-T Leukemia, Up to 21 Years Phase 2 * TCRαβ-depleted CD45RA-depleted DLI NCT03849651 140 Active, lymphoma, and progenitor cell graft two weeks after recruiting myeloproliferative with additional engraftment of TCRα/β+ diseases memory T cell DLI and and CD19+-depleted, for blinatumomab CD19 pos; Blinatumomab will be given at least one-week post-DLI ALL, AML, JMML, Up to 29 Years Phase 2 Azacitidine and DLI Up to seven cycles of low NCT02458235 17 Completed MDS dose azacitidine (40 mg/m 2 IV/SC daily × 4 days) at six weekly intervals and additional cycles according to risk levels Acute leukemia 14 Years to 65 Years Phase 2/3 DLI DLI administered at a NCT02673008 206 Completed median dose of 1.
5 mg/kg IV on NCT04202835 80 Active, days -2, -1, and +1 and recruiting CP at 50 mg/kg IV daily on days +3 and +4 vs. ATG alone ALL, AML, CML, 5 Years to 75 Years Phase 2 Tacrolimus, high dose CP on days 3-4, NCT03128359 38 Active, not MDS, CLL, cyclophosphamide, mycophenolate mofetil recruiting Lymphoma and MMF TID on day 5 and stopping on day 35 if no severe GVHD is present. Tacrolimus IV continuously on days 5-180 with a taper beginning on day 90 in the absence of disease progression or unacceptable toxicity.
25 mg/kg NCT03384693 25 Completed administered intravenously for 28-35 days All Phase 3 N-Acetylcysteine 50 mg/kg orally NCT03252925 170 Completed 12 Years and Older Phase 3 Ravulizumab Weight-based doses of NCT04543591 184 Active, not ravulizumab will be recruiting administered intravenously as loading dose regimen followed by maintenance dosing every 8 weeks plus best supportive care (BSC) vs. placebo.
4, 5 Current PTLD guidelines encourage sequential therapy in CD20 + polymorphic and monomorphic DLBCL-type PTLD that fail to respond to upfront RIS or if RIS is not feasible. 6 urkitt lymphoma (BL) PTLD (BL-PTLD) is a rare subtype of post-transplant lymphoma representing less than 10% of adult PTLD. 7 Its immune-competent counterpart is characterized by a highly aggressive clinical course, frequent involvement of bone marrow (BM) and central nervous system (CNS), and is biologically hallmarked by MYC gene translocation to an immunoglobulin locus. ] [10]  We conducted a multicenter retrospective study in order to better characterize these elements. Our study included adult patients diagnosed with BL-PTLD between 1989 and 2022 who were identified using the French registry of PTLD after kidney transplantation, the K-Virogref network, the Lymphopath database and the prospective German PTLD registry.
In particular, the role of chemotherapy and radiotherapy on cardiac toxicity have been investigated for years, but data on cardiovascular outcomes of radiotherapy and chemotherapy are still con icting  [14] [15] : this topic has been highlighted as a priority to prevent some potentially life-threatening side effects of cancer treatments and to improve evidence-based guidelines. Additionally, recent studies investigated the risk of stroke in women with BC, but results are controversial  [16] [17]. The aim of this study is to analyse the risk of cardiovascular and cerebrovascular diseases, particularly myocardial infarction (MI) and stroke, in women with BC, also considering potential treatment-related effect. Administrative health data from the Piedmont Longitudinal Study (PLS) were used in this analysis.
Other variables de nition The administrative nature of the study does not allow to identify other individual risk factors, such as hypertension, diabetes, body mass index (BMI), smoking, etc. However, some proxy variables have been computed using information available in health-administrative databases. Hypertension, hypercholesterolemia, and diabetes have been estimated considering the respective drug consumption. Socioeconomic Position (SEP) was well assessed thanks to the linkage with census data and it was measured using education, occupation, and material living conditions  [19]. Smoking status was impossible to retrieve, however we identi ed subjects with chronic obstructive pulmonary disease (COPD, using drug prescriptions and hospital discharges), considering this variable as a proxy for heavy smoking.
Sensitivity analyses When analysing the subset including postmenopausal women only, association between BC and MI (HR: 1. 19; 95%CI: 1. 03-1. 38) and stroke (HR: 1. 54; 95%CI 1. 33-1. 78) remained signi cant and results did not differ substantially from those obtained in the main database for all the investigated BC therapies (Table  4 ). similarity occurred for all the type of therapies investigated (Table  5 ).
Acknowledgments Some authors belong to the  SGR program  of " Generalitat de Catalunya " ( 2021-SGR-00187 REMAR Group ), and the  RICORS 2040 (kidney Disease)  ( Redes de Investigación Cooperativa Orientadas a Resultados en Salud) ,  IDI-2021-000080  or  RD21/ 0005/0009  and  RD21/0005/0013 ,  ISCIII ,  Instituto de Salud Carlos III, Spain.
Eliminating or reducing the need for RBC transfusions could improve the overall health-related quality of life of patients with LR-MDS while also reducing health care resource use and associated costs. However, very few therapeutic options are available to these patients after failure of erythropoiesis-stimulating agents (ESAs). Alternative treatments are a priority, one of which is luspatercept, a first-in-class recombinant fusion protein that binds select transforming growth factor β superfamily ligands thus inhibiting downstream Smad2/3 signaling, which enables late-stage erythroid blast differentiation and erythroid maturation  [17] [18] [19]. In the phase 3 MEDALIST study (NCT02631070), luspatercept treatment resulted in RBC-TI for 8 weeks or longer in 38% of patients treated with luspatercept versus 13% of patients treated with placebo by week 25 (p < 0.
The cumulative mean number of RBC transfusion units or RBC transfusion visits required was estimated using Nelson-Aalen nonparametric estimators with robust variance estimate for each treatment group with a 95% confidence interval. This post hoc analysis also evaluated the effect of continuing luspatercept treatment beyond the first 24 weeks. Assessment of clinical benefit was conducted up to the data cutoff date of July 1, 2019 (144 weeks of treatment). Clinical benefit indicators included RBC transfusion burden, hemoglobin and serum ferritin levels, and hematologic improvement-erythroid (HI-E) response. HI-E response was assessed per modified IWG 2006 criteria  [24]  and was defined as a reduction in RBC transfusions of ≥ 4 units/8 weeks for patients with baseline RBC transfusion burden of ≥ 4 units/8 weeks, and an increase in hemoglobin level of ≥ 1.
Low baseline RBC transfusion burden was defined as having < 6 RBC transfusion units over 8 weeks and high baseline RBC transfusion burden was defined as having ≥ 6 RBC transfusion units over 8 weeks. Cumulative mean function estimated using nonparametric method with robust variance estimate. The efficacy cutoff date is defined as the minimum date among death date, study discontinuation date, last dose date + 20, and database cut date. RBC, red blood cell.
Clinical outcomes in patients who did not achieve RBC-TI at ≥ 8 weeks but continued luspatercept treatment beyond week 25 Weeks   (A, B ) and RBC transfusion visits (C, D) by baseline RBC transfusion burden (low vs high) by luspatercept response at week 25. Low baseline RBC transfusion burden was defined as having < 6 RBC transfusion units over 8 weeks and high baseline RBC transfusion bur-den was defined as having ≥ 6 RBC transfusion units over 8 weeks. Cumulative mean function estimated using nonparametric method with robust variance estimate. The efficacy cutoff date is defined as the minimum date among death date, study discontinuation date, last dose date + 20, and database cut date. RBC, red blood cell relative to baseline. In this group, the mean change (standard deviation (SD)) from baseline in the RBC units transfused was -3.
In the real-world setting, clinicians' assessment of improvement in clinical features and, critically, how their patients perceive the balance between burden of treatment and benefit, in terms of reduced anemia and transfusion burden, should guide decisions regarding continuation of treatment. In line with prescribing guidelines, most of those patients going on to achieve benefit after week 25 in the MEDAL-IST study did so on the highest dose of luspatercept, making maximal titration, when tolerated, a key consideration before discontinuation. A strength of this analysis is that the patient-level data were obtained from a large multinational phase 3 randomized, placebo-controlled trial. Limitations include its nature as a post hoc analysis focused on a subgroup of patients not attaining a response, resulting in the loss of statistical inference attainable from a randomized population.
PURPOSE BRAF V600 mutations occur in many childhood cancers, including approximately 20% of low-grade gliomas (LGGs). Here, we describe a phase I/II study establishing pediatric dosing and pharmacokinetics of trametinib with or without dabrafenib, as well as efficacy and safety in a disease-specific cohort with BRAF V600-mutant LGG; other cohorts will be reported elsewhere. METHODS This is a four-part, phase I/II study (ClinicalTrials. gov identifier: NCT02124772) in patients age , 18 years with relapsed/refractory malignancies: trametinib monotherapy dose finding (part A) and disease-specific expansion (part B), and dabrafenib 1 trametinib dose finding (part C) and disease-specific expansion (part D). The primary objective assessed in all patients in parts A and C was to determine pediatric dosing on the basis of steadystate pharmacokinetics.