bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delivering HIV prevention medication online: Findings from a qualitative study exploring the acceptability of an online HIV pre-exposure prophylaxis (PrEP) care pathway among service users and healthcare professionals
Authors: Kincaid Ross , Gibbs Jo , Dalrymple Jenny , Henderson Lindsay , Frankis Jamie , Estcourt Claudia 
Published: December 2023

Objective Eliminating HIV transmission worldwide could become a reality with the advent of HIV pre-exposure prophylaxis (PrEP) where people take HIV medication to prevent HIV acquisition. Incorporating digital health into PrEP provision could help services scale up and meet increasing demand. We aimed to explore the prospective acceptability of a novel online PrEP care pathway (the ePrEP clinic) among PrEP users and healthcare professionals. The ePrEP clinic is composed of online postal self-sampling for HIV and other sexually transmitted infections, an online consultation, and remote medication provision. Methods We conducted semi-structured interviews with 15 PrEP users recruited from a large sexual health service and online cohort, and focus groups with nine healthcare professionals from the same sexual health service (May to December 2021). We analysed data using framework analysis. Results Participants found the ePrEP clinic highly acceptable, anticipating that it would provide convenience, empower PrEP users, and increase capacity within sexual health services. The need for blood self-sampling was a considerable barrier for some. Participants anticipated that the ePrEP clinic would be appropriate for established PrEP users with adequate digital health literacy and no medically significant conditions requiring in-clinic monitoring. Participants highlighted the need for support, including access to in-clinic care, and the integration of the ePrEP clinic within existing services. Conclusions Our findings provide clear justification for the development of the ePrEP clinic as an addition to in-clinic PrEP care pathways and provide useful insights for those developing digital services for other conditions incorporating testing, consultations, and prescribing.
Complete Arthroscopic Posterior Knee Capsulotomy in Patients With Knee Extension Deficit: Preliminary Results of a Clinical Trial
Authors: Malinowski Konrad , Mostowy Marcin , Koźlak Magdalena , Pękala Przemyslaw A. , Kennedy Nicholas I. , LaPrade Robert F. 
Published: December 2023

Background: Guided physiotherapy and surgical arthrolysis are effective in most patients with knee extension deficit. However, in refractory cases, posterior knee capsulotomy may be needed. Purpose: To assess extension restoration, pain reduction, and functional improvement after arthroscopic complete posterior knee capsulotomy in patients with extension deficit refractory to guided physiotherapy and surgical arthrolysis. Study Design: Case series; Level of evidence, 4. Methods: Included were patients with symptomatic asymmetric extension deficit >3° refractory to at least 6 months of guided physiotherapy and initial arthrolysis (15 patients with 12-month follow-up and 8 patients with 24-month follow-up). The mean duration of extension deficit was 24.6 months. An arthroscopic complete posterior knee capsulotomy was performed with transection of the posteromedial, posterolateral and central capsule, and the posterior septum. The primary outcome measure was knee extension, with hyperextension denoted as negative knee extension values. Secondary outcome measures included visual analog scale (VAS) for pain during maximum effort and exercise, International Knee Documentation Committee (IKDC) score, and Knee injury and Osteoarthritis Outcome Score (KOOS). Results: The mean patient age was 40.0 years (range, 26-70 years); 6 out of 15 patients had developed knee contracture after isolated anterior cruciate ligament reconstruction. The mean knee extension deficit decreased from 16.9° (range, 7° to 45°) preoperatively to -0.2° (range, -5° to 5°) at 12-month follow-up ( P = .003) and to -0.3° (range, -5° to 5°) at 24-month follow-up ( P = .035). The mean VAS pain score decreased from 3.5 (range, 1-6) preoperatively to 1.1 (range, 0-2) at 12-month follow-up ( P = .004) and to 1.5 (range, 0-4) at 24-month follow-up ( P = .005). The mean IKDC increased from 37.9 (range, 21-62) preoperatively to 63.9 (range, 46-87) at 12-month follow-up ( P < .001) and to 60.9 (range, 39-80) at 24-month follow-up ( P = .003). The mean KOOS increased from 45.0 (range, 30-62) preoperatively to 75.3 (range, 49-94) at 12-month follow-up ( P < .001) and to 72.3 (range, 49-92) at 24-month follow-up ( P = .003). There were no significant differences between 12- and 24-month follow-up in extension deficit or functional outcomes. One patient had a midcalf subcutaneous hematoma 5 weeks postoperatively, requiring evacuation. Conclusion: Arthroscopic complete posterior knee capsulotomy was able to restore knee extension, reduce pain, and improve function, with 12-month follow-up results sustained at 24-month follow-up. Registration: NCT05385393 (ClinicalTrials.gov identifier).
Benefit of TKI-Treatment in CML after Failing Molecular or Cytogenetic Milestones
Authors: Hehlmann Rüdiger , Lauseker Michael , Hochhaus Andreas , Saussele Susanne 
Published: December 2023

No information is available on long-term survival of tyrosine kinase inhibitor (TKI)- treated patients failing the response milestones as defined by the European LeukemiaNet (ELN). Such information would help with decision making in failing patients when risks associated with comorbidities, drug toxicities or transplantation preclude switching to another TKI or other treatments.
To systematically analyze survival after reaching, or not reaching, ELN-response milestones, 1342 imatinib-treated patients from CML-study IV with newly diagnosed CML in chronic phase and regular molecular and cytogenetic tests were studied. Survival was analyzed by landmark analyses at 3, 6, 12 and 24 months and followed up to 14 years. In patients who failed the failure milestones (&gt;10% BCR::ABL1 IS at 6 months, &gt;1% BCR::ABL1 IS at 12 months), 10- to 12-year survival ranged around 70%, 10-20% less than in responding patients. An example is shown in Fig. 1a which depicts survival of patients reaching, or not reaching 1% BCR::ABL1 IS at 12 months. Similar survival curves were observed for the other landmarks that indicate failure. Inbetween response rates of &gt;1%-10% BCR::ABL1 IS at 12 months indicated survival probabilities similar to those of patients failing 1% BCR::ABL1 IS, whereas patients reaching &gt;1%-10% BCR::ABL1 IS at 24 months showed a survival similar to that of patients failing 10% BCR::ABL1 IS. Switching to alternative therapies, mostly to dasatinib and nilotinib, was observed in 372 patients (26.9%) and did not change the main results.
Although cytogenetic tests were increasingly replaced by molecular tests in the course of the study, sufficient cytogenetic analyses were available for comparison with molecular analyses. Complete and partial cytogenetic remissions have been shown to be roughly equivalent to 1% and 10% BCR::ABL1 IS, respectively. Wheras reaching, or not reaching cytogenetic and molecular reponse markers at 6 and 12 months was equivalent, not reaching a complete or partial cytogenetic remission at 24 months identified a small subgroup of patients (5.9%) with inferior survival (Fig. 1b).
Age (more or less than 60 years) had no major impact on survival differences, but on hazard ratios for early death. Hazard ratios at 10% BCR::ABL1 IS by 6 months were 4.0 (95%CI:2.0-8.1) for the younger patients, but only 0.9 (95% CI: 0.4-1.8) for the elderly. The reasons for early death in the younger patients were mostly CML-related, whereas the elderly primarily died of other reasons.
The data show that TKI-treated patients not reaching failure milestones still may derive benefit from continuing TKI-treatment and provide a basis for individualized decisions, if failing patients are confronted with risks of alternative treatments.
A Novel PI3K γ/δ and DNA-PK Triple Inhibitor, BR101801, for r/r PTCL: A Phase 1a/b, Multi-Center, Open-Label Clinical Trial
Authors: Kim Bong-Seog , Kim Seok Jin , Yoon Dok Hyun , Kim Jin Seok , Kim Tae Min , Lee Eunyoung , Lee Jeong-Ok , Yang Deok-Hwan , Lee Won-Sik 
Published: December 2023

Background
BR101801, a triple inhibitor of PI3Kγ/δ and DNA-PK, inhibits not only the signal affecting cell growth caused by PI3Kγ/δ but also efficiently induces cell cycle arrest and apoptosis through inhibition of DNA-PK activation, with this triple target inhibition it decreases the stability of oncogenic protein, c-Myc (AACR2020 abstract #655). BR101801 is currently being evaluated in a phase 1a/b study in advanced hematologic malignancies. In phase 1a study, BR101801 exhibited evidence of clinical activity and was established at 200mg orally once daily 28-day cycle (RP2D) in patients with r/r PTCL (ASCO2023 abstract #7551).
Methods
This is a phase 1, open-label, multi-center, dose escalation (1a), and expansion (1b) study of BR101801 in adult patients with advanced hematologic malignancies (NCT04018248). In the phase 1a study, Dose was escalated at 50, 100, 200 and 325 mg QD. PTCL-NOS, AITL, FTCL and Nodal PTCL with TFH phenotype were determined as target indications for phase 1b with the RP2D.
Results
As of Jul 19, 2023, a total of 26 patients were enrolled in dose-escalation phase (n=12) and dose-expansion phase (n=14). The median age was 66 years (range of 30-83). Histological subtypes include PTCL-NOS (n=11, 42%), AITL (n=11, 42%), DLBCL (n=2, 8%), MZL (n=1, 4%) and MF (n=1, 4%). The majority of patients had stage III or IV (92%). In the phase 1a study, Dose limiting toxicity (DLT) occurred at 325 mg; thus, 200 mg QD was determined as the maximum tolerated dose (MTD) and RP2D.
Of 19 evaluable patients with r/r PTCL (PTCL-NOS and AITL) in the phase 1 study. Patients' stage was III or IV (100%) with 47.4 % of patients having received three or more prior systemic therapies. The ORR was 31.6% (95% CI, 12.6-56.6) with 4 CRs (21.1%) and 2 PRs (10.5%), CBR was 47.4% (95% CI, 24.5-71.1). In median follow-up duration of 12.9 months, the median PFS was 7.5 months (95% CI, 1.7-NC), median OS and DoR (range of 1.9+-31.8+) has not reached. Currently, 5 patients still remain on treatment.
Safety analysis was conducted for the 26 patients; 23 patients (88.5%) experienced adverse events (AEs). The most common (≥ 20%) AEs were Rash (23.1%), AST increased (23.1%), ALT increased (23.1%) and Cough (23.1%). Grade 3/4 ADRs occurred in 12 patients (46.2%) and those were (≥ 10%, frequency) AST increased (19.2%), ALT increased (15.4%), Neutropenia (15.4%). There were no treatment related mortality observed.
Conclusion
BR101801, the triple inhibitor of PI3K γ/δ and DNA-PK, demonstrated as a promising therapeutic option for r/r PTCLs patients. Preliminary results showed the ORR of 31.6% and a CR rate of 21.1%. Phase 2 study is warranted further investigate the safety and efficacy of BR101801 in r/r PTCL and Nodal TFH cell lymphoma at 200 mg QD orally.
Mast Cell Leukemia Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database
Authors: Haddad Philip A , Chennapragada Suma Sri 
Published: December 2023

Background
Mast cell leukemia (MstCL) is a rare but aggressive variant of systemic mastocytosis (SM) which is defined by the presence of &gt;20% atypical mast cells in the bone marrow. It is further classified into leukemic and aleukemic variants based on the presence or absence of &gt;10% atypical mast cells in the peripheral blood, respectively. There is a wide variation in treatment regimens used to treat MstCL. Despite this, the prognosis remains poor. The determinants of survival outcomes in this disease are not very well defined. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies that influence survival in this disease.
Methods
To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 144 cases that fit the diagnostic criteria for MstCL. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS).
Results
A total of 144 patients with confirmed MstCL were identified. The median age was 58.5. There was a slight female preponderance with F:M of 1.2. The median duration of symptoms before diagnosis was 2 months. Involvement of lymph nodes, spleen, peripheral blood, skin, and CNS occurred in 17%, 44%, 23%, 13%, and 6%, respectively. Constitutional symptoms and hemophagocytosis occurred in 33% and 8% of the cases, respectively. The median OS and DFS of the whole group were 9 and 8 months, respectively. Patients younger than 55 had worse median OS (6 vs. 15 months, p=0.03). Hgb&lt;10g/dl (p=0.0002), Platelets&lt;100K (p=0.01), leukemic phase (p=0.02), and complex cytogenetics (p=0.02) were associated with worse OS. Furthermore, presence of hemophagocytosis had worse OS (p=0.06). Although the presence of constitutional symptoms, Tryptase&gt;200, and KIT mutations other than D816V had numerically worse OS, they did not reach statistical significance. Sex, IHC phenotype, presence of concomitant malignancy, and type of organ involvement did not impact OS. Compared to no treatment, dose-intense chemotherapy, non-dose-intense chemotherapy, novel agents, and stem cell transplant had incrementally superior OS (2 vs. 7 vs. 15 vs. 15 vs. 23 months, p&lt;0.0001). Patients who attained CR as their best response also had a superior median OS compared to responses less than CR and non-responders (NR vs. 29 vs. 8 months, p&lt;0.0001).
Conclusion
This study presents updated clinicopathologic data from a large, pooled cohort of patients with MstCL. It identifies age, anemia, thrombocytopenia, leukemic presentation, complex cytogenetics, type of therapy, and quality of response to treatment as critical determinants of OS.
Differences in Clinical Outcomes between Hydroxyurea-Resistant and -Intolerant Polycythemia Vera Patients
Authors: Kim Sung-Yong , Lee Sung-Eun , Hong Junshik , Bang Soo-Mee , Park Jinny , Choi Chul Won , Bae Sung Hwa , Kim Min Kyoung , Yoon Seug Yun 
Published: December 2023

Previous retrospective studies have revealed that a substantial portion of PV patients experience resistance to hydroxyurea (HU-R) and intolerance to HU (HU-I). Currently, the therapeutic options for both groups of patients do not differ, and most clinical trials investigating second-line therapies have enrolled patients with HU-R or HU-I without considering potential clinical distinctions between the two groups. Direct comparisons between patients with HU resistance and HU intolerance have not been conducted, and prognostic factors related to clinical outcomes, such as thrombosis, bleeding, disease progression, and survival, remain unclear for patients experiencing HU resistance or intolerance.
A total of 90 patients with HU-R/I were retrospectively anlyzed in this study. Among them, 44 and 46 patients fulfilled the ELN criteria defining resistance or intolerance to HU, respectively. Patients with HU-R were older at the time of diagnosis of PV (66.7 ± 13.2 years, vs. 59.8 ±11.2 years in the HU-I group, P = 0.016), had longer times to developing HU-R/I, and thus, were older at the time of HU-R/I development compared with those with HU-I. The majority of the study patients continued HU treatment with dose modification or intermittent discontinuation with anagrelide added to control platelet counts until disease progression or death because of limited second-line treatment options during the observed period.
The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). The type of thrombosis did not differ between the two groups (P = 0.628). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio = 5.57, 95% CI: 1.22 - 25.54, P = 0.027).
The patients in the HU-R group had significantly lower PFS (40.2% vs. 66.1% in the HU- I group, P &lt; 0.01). They also showed a trend toward lower TFS (51.0% vs. 62.1% in the HU-I group; P = 0.055) and lower OS (57.5% vs. 67.7% in the HU-I group; P = 0.060) compared to patients with HU-I. The mortality at seven years was 42.5% in the HU-R group and 32.3% in the HU-I group (P = 0.06). Higher LDH levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival.
These findings suggest that HU-resistant patients have a higher risk of hematological transformation but a comparable risk of thrombosis to HU-intolerant patients. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.
TP53 Aberrant B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Are Uniquely Sensitive to a Combination of Pyrimidine De Novo Synthesis Blockade and Replication Checkpoint Inhibition
Authors: Stoll Gawin R. , Van Ingen Schenau Dorette , Cox Willem P. J. , Tang Ziqin , Wagener Emmely M. , van der Meer Laurens T. , van Leeuwen Frank N. 
Published: December 2023

Background
Unlike most solid tumors, the incidence of TP53 aberrations in ALL is only 3% at diagnosis. However, in relapsed ALL this number increases to 12%. More importantly, at relapse, loss of p53 function is associated with therapy failure, with an overall survival of only 20%. Hence, there is a clear clinical need for more effective strategies to treat TP53 aberrant relapsed ALL. Owing to their high proliferative state, leukemic blasts show a high dependency on pyrimidines for DNA synthesis. A lack of pyrimidines leads to replication stress, causing activation of p53 and the DNA damage response pathway.
Results
We used CRISPR/Cas9 to generate TP53 deficient variants of the TP53 proficient BCP-ALL cell lines Nalm6 and RCH-ACV. We used these cell lines in a CRISPR screens and high throughput drug screen, and identified a strong synergy between the targeting of pyrimidine synthesis and DNA checkpoint kinase ATR and its downstream effectors Chk1 and Wee1 in TP53 deficient ALL. To validate these results, we tested the efficacy of a checkpoint inhibition together with Orludodstat (BAY-2402234), an inhibitor of Dihydroorotate Dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis. This clinical grade inhibitor was evaluated in either wild type or TP53 deficient BCP-ALL and T-ALL cell line models and patient derived xenografts (PDX).
A strong apoptotic response was observed when Orludodstat was combined with the ATR inhibitor Berzosertib, most notably in TP53 deficient ALL. This p53 dependency was confirmed using ex vivo cultures of patient derived xenografts (PDX) of diagnosis and relapse pairs, where each diagnostic sample was wild type for TP53, and the relapse carried a TP53 aberration. While little or no synergy was observed in the diagnostic samples, a strong efficacy of the combination was observed in the matched TP53 deficient relapsed samples (Figure 1 A).
Preliminary results from i n vivo experiments using p53 deficient patient derived xenografts indicate that the combination of Orludodstat and Berzosertib is well tolerated, while significantly delaying leukemic growth (Figure 1 B).
Conclusion
Together, our findings suggest that the combined targeting of de novo pyrimidine synthesis and ATR signaling may present a specific and non-genotoxic vulnerability for TP53 aberrant ALL.
ATG or Post-Transplant Cyclophosphamide to Prevent Gvhd in Matched Unrelated Stem Cell Transplantation? - a Registry Analysis By the EBMT Transplant Complications Working Party
Authors: Penack Olaf , Abouqateb Mouad , Peczynski Christophe , Boreland William , Kröger Nicolaus , Stelljes Matthias , Gedde-Dahl Tobias , Wolfgang Blau Igor , Schroeder Thomas , Salmenniemi Urpu , Kulagin Aleksandr , Peffault De Latour Regis , Mielke Stephan , Finke Jürgen , Moiseev Ivan Sergeevich , Schoemans Helene , Koenecke Christian , Peric Zinaida 
Published: December 2023

T
There is a considerable risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when matched unrelated donors (MUD) are used. Prophylaxis with either rabbit anti-thymocyte globulin (rATG, also termed anti-T-lymphocyte globulin) or post-transplantation Cyclophosphamide (PTCy) is in standard clinical use. The unresolved question is whether to prefer PTCy or rATG in this setting. So far, two randomized trials, several retrospective studies and a meta-analysis comparing PTCy to rATG in MUD alloSCT gave contradictory results. Current data from large registry cohorts has not been published.
To improve the evidence base, we analyzed outcomes of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen MUD between Jan 2018 and June 2021 in the EBMT database. We performed multivariate analyses using Cox cause-specific hazard models, adjusting for known risk factors, and variables that showed significant difference between the two comparison groups.
Overall 8764 patients were included, treatment- and patient characteristics are shown in Table 1. Patients receiving PTCy (n=1039) were younger, had undergone alloSCT more recently, and had a lower disease risk compared to patients receiving rATG (n=7725). Median follow up was 2.1 years in both groups. Outcomes graphs are shown in figure 1. All outcomes are given starting from alloSCT (with 95% CI): NRM (fig 1A) was higher in the rATG arm (2-years NRM: PTCy 12.4% [10.2 - 14.7] vs. rATG 16.1% [15.3 - 17]; HR 0.72, p=0.016), same for Relapse incidence, (2-years RI: PTCy 22.8% [19.9 - 25.8] vs. rATG 26.6% [25.5 - 27.7]; HR 0.87, p=0.046), Overall survival (fig 1B) was better in the PTCy arm (2-years OS: PTCy 73.1% [70 - 76] vs. rATG 65.9% [64.7 - 67.1]; HR 0.82, p=0.001), same for Progression free survival (fig 1C) (2-years PFS: PTCy 64.9% [61.4 - 68.1] vs. rATG 57.2% [56 - 58.5]; HR 0.83, p&lt;0.001), Chronic GVHD was lower in the PTCy arm (2-years cGVHD: PTCy 28.4% [25.2 - 31.7] vs. rATG 31.4% [30.3 - 32.6]; HR 0.77, p=0.012), whereas acute GVHD grades II-IV was not significantly different between the two arms (100-day aGVHD: PTCy 24.1% [21.3 - 27] vs. rATG 26.5% [25.5 - 27.6]; HR 0.85, p=0.11)
In conclusion, we found a lower NRM, lower incidence of chronic GVHD as well as higher survival outcomes in adult recipients of peripheral blood alloSCTs from MUD receiving PTCy compared to rATG. The current analysis improves the evidence basis for decision making on GVHD prophylaxis in MUD alloSCT.