The impact of cytotoxic therapy on the risk of progression and death in clonal cytopenia(s) of undetermined significance.

Clonal cytopenia of undetermined significance (CCUS) is defined by a myeloid driver mutation in the context of otherwise unexplained cytopenia. CCUS has an inherent risk of progressing to myeloid neoplasm. However, it is unknown how exposure to previous cytotoxic therapy may impact the risk of progression and survival. We stratified CCUS patients by prior exposure to DNA-damaging therapy. Of 151 patients, 46 (30%) had received cytotoxic therapy and were classified as therapy-related CCUS (t-CCUS), whereas 105 (70%) had de novo CCUS. A lower proportion of t-CCUS had hypercellular marrows (17.8% vs. 44.8%, P=0.002) but had higher median bone marrow blast percentages. After a median follow up of 2.2 years, t-CCUS had significantly shorter PFS (1.8 vs. 6.3 years, HR 2.1, P=0.007) and median OS (3.6 years vs. not reached, HR 2.3, P=0.007) compared to CCUS. Univariable and multivariable time-to-event analyses showed that exposure to cytotoxic therapy independently accounted for inferior PFS and OS. Despite the similarities in clinical presentation between CCUS and t-CCUS, we show that exposure to prior cytotoxic therapies was an independent risk-factor for inferior outcomes. This suggests that t-CCUS represents a unique clinical entity that needs more stringent monitoring or earlier intervention strategies.

Cladribine plus cytarabine plus venetoclax in acute myeloid leukemia relapsed or refractory to venetoclax plus hypomethylating agent.

Not available.

A comparative study between open pre-peritoneal approach versus laparoscopic trans-abdominal pre-peritoneal approach in recurrent inguinal hernia repair: a prospective cohort study.

BACKGROUND: The repair of recurrent inguinal hernias after prosthetic mesh repair is challenging due to the technical complexity and complications associated with it. As well as the increased risk of recurrence due to weakened tissues and distorted anatomy. The Posterior Pre-Peritoneal Approach yields significantly better results than the anterior approach due to its distance from previously scarred tissue. OBJECTIVE: To compare the open pre-peritoneal approach and Laparoscopic trans-abdominal pre-peritoneal approach in the management of recurrent inguinal hernia which was previously managed through an open anterior approach regarding their intra-operative time, the postoperative outcomes in the form of hematoma, wound infection and finally the recurrence within 1-year follow-up. PATIENTS AND METHODS: The current study is a prospective cohort study, a single-center trial conducted from June 2021 to June 2022 in the general surgery department in Ain Shams University Hospitals, which included 74 patients presented with recurrent inguinal hernia who had previous open anterior approach 68(91.8%) males and 6(8.1%) females including a 1-year follow-up postoperative. RESULTS: There were 74 patients in our study with 37 patients in each group. Group (I) underwent an open pre-peritoneal approach and group (II) underwent a Laparoscopic trans-abdominal pre-peritoneal approach. The mean age of the group (I) is 39.51 with a standard deviation of ± 3.49. While in group (II) the mean age is 39.37 with standard deviation ± 3.44 (p = 0.881). From the included 74 patients 67(91.8%) were males and 6(8.1%) were females. As regards the co-morbidities, in group (I) 17(45.9%) patients have no co-morbidities, 11(29.7%) patients have diabetes mellitus, 6(16.2%) patients have hypertension, and 3(8.1%) patients have diabetes and hypertension. Andin group (II) 26(70.3%) patients have no co-morbidities, 6(16.2%) patients have diabetes mellitus, 3(8.1%) patients have hypertension, and 2(5.4%) patients have diabetes and hypertension (p = 0.207). Regarding intra-operative time, the mean time in minutes in the group (I) is 63.33 with a standard deviation of ± 11.95. While in group (II) the mean time in minutes is 81.21 with a standard deviation of ± 18.03 (p = 0.015). The postoperative outcomes were assessed for 1-year follow-up in the form of hematoma, wound infection, and recurrence within 1 year. Regarding the hematoma occurred in 4(10.8%) patients in group (I). While in 2(5.4%) patients in group (II) (p = 0.674). The wound infection was found in 5(13.5%) patients in group(I) and zero patients in group (II) (p = 0.021). Finally, we followed up with the patients for about 1 year to detect the recurrence. Which was found in 3(8.1%) patients in group (I) and 1(2.7%) patient in group (II) (p = 0.615). CONCLUSION: The results of this study demonstrate that both the laparoscopic approach and the open posterior approach are effective for recurrent inguinal hernia following anterior approach mesh hernioplasty, with comparable results. Laparoscopy has been associated with a lower rate of recurrence and overall complications compared to open technique, however, it is difficult to draw definitive conclusions about the preferred option due to its lengthy learning curve and difficulty to perform. Furthermore, the results of this study confirm the previously reported positive results of the posterior pre-peritoneal for recurrent inguinal hernia, particularly when performed by experienced surgeons. Therefore, further prospective randomized population-based trials are necessary to better assess the decision-making for recurrent hernia management and the impact of specialization in abdominal wall surgery in terms of recurrence and complications.

Design, synthesis, and molecular modeling studies of novel 2-quinolone-1,2,3-triazole-α-aminophosphonates hybrids as dual antiviral and antibacterial agents.

With the aim to identify new antiviral agents with antibacterial properties, a series of 2-quinolone-1,2,3-triazole derivatives bearing α-aminophosphonates was synthesized and characterized by 1H NMR, 13C NMR, 31P NMR, single crystal XRD and HRMS analyses. These compounds were examined against five RNA viruses (YFV, ZIKV, CHIKV, EV71 and HRV) from three distinct families (Picornaviridae, Togaviridae and Flaviviridae) and four bacterial strains (S. aureus, E. feacalis, E. coli and P. aeruginosa). The α-aminophosphonates 4f, 4i, 4j, 4k, 4p and 4q recorded low IC50 values of 6.8-10.91 µM, along with elevated selectivity indices ranging from 2 to more than 3, particularly against YFV, CHIKV and HRV-B14. Besides, the synthesized compounds were generally more sensitive toward Gram-positive bacteria, with the majority of them displaying significant potency against E. feacalis. Specifically, an excellent anti-enterococcus activity was obtained by compound 4q with MIC and MBC values of 0.03 µmol/mL, which were 8.7 and 10 times greater than those of the reference drugs ampicillin and rifampicin, respectively. Also, compounds 4f, 4p and 4q showed potent anti-staphylococcal activity with MIC values varying between 0.11 and 0.13 µmol/mL, compared to 0.27 µmol/mL for ampicillin. The results from DFT and molecular docking simulations were in agreement with the biological assays, proving the binding capability of hybrids 4f, 4i, 4j, 4k, 4p and 4q with viral and bacterial target enzymes through hydrogen bonds and other non-covalent interactions. The in silico ADME/Tox prediction revealed that these molecules possess moderate to good drug-likeness and pharmacokinetic properties, with a minimal chance of causing liver toxicity or carcinogenic effects.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data is limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 comutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by ELN 2022 criteria (median OS 1.16 vs. 1.27 years, P = 0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P < 0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P = 0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P = 0.02), whereas melphalan-based conditioning was associated with a decreased relapse-risk (HR 0.02, P = 0.01). We conclude that mBCOR is a high-risk feature across MDS/AML and that alloSCT improves survival in this population.

The Efficacy of the Ponseti Method in the Management of Clubfoot: A Systematic Review.

Clubfoot is a congenital abnormality of the lower extremities, and it may be unilateral or bilateral. Left untreated, it may lead to issues with walking. Additionally, inappropriate treatment or the lack of treatment can result in functional damage. The goal of clubfoot treatment is to correct the deformities of the involved components. The Ponseti method has been regarded as the gold standard for the treatment of clubfoot as it is safe and effective. In this review, we aimed to assess the success of the Ponseti method in the treatment of clubfoot by reviewing the previous studies on this subject. We searched electronic databases, including PubMed, Scopus, Science Direct, and Google Scholar, for relevant articles spanning the period from 2018 to 2023. The keywords used in the search were "Ponseti method, Treatment, Outcomes, Success, Relapse, Failure, and Rates." The inclusion criteria were original articles in English on clubfoot patients treated with the Ponseti method. While our search yielded a total of 1,037 articles, only nine were deemed eligible for analysis based on the inclusion criteria. The articles involved a total of 537 feet of 358 patients and the age of the patients ranged from one day to five years. The success rate ranged between 55% and 100%, and the relapse rate ranged between 3.2% and 34.2%. Based on our findings, the Ponseti method has a high success rate in the treatment of idiopathic clubfoot, and hence it is an excellent conservative method of treatment. However, there are additional factors that may affect the treatment outcomes, which need to be taken into account.

How do I manage refractory invasive pulmonary aspergillosis.

BACKGROUND: Invasive aspergillosis is associated with significant morbidity and mortality in patients with haematologic malignancies and haematopoietic cell transplant recipients. The prognosis is worse among patients who have failed primary antifungal treatment. OBJECTIVES: We aim to provide guidance on the diagnosis and management of refractory invasive pulmonary aspergillosis. SOURCES: Using PubMed, we performed a review of original articles, meta-analyses, and systematic reviews. CONTENT: We discuss the diagnostic criteria for invasive pulmonary aspergillosis and the evidence on the treatment of primary infection. We outline our diagnostic approach to refractory disease. We propose a treatment algorithm for refractory disease and discuss the role of experimental antifungal agents. IMPLICATIONS: For patients with worsening disease while on antifungal therapy, a thorough diagnostic evaluation is required to confirm the diagnosis of aspergillosis and exclude another concomitant infection. Treatment should be individualized. Current options include switching to another triazole, transitioning to a lipid formulation of amphotericin B, or using combination antifungal therapy.

Venetoclax and hypomethylating agent combination therapy in newly diagnosed acute myeloid leukemia: Genotype signatures for response and survival among 301 consecutive patients.

Venetoclax + hypomethylating agent (Ven-HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND-AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND-AML was to identify molecular predictors of treatment response to Ven-HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, "favorable" predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and "unfavorable" TP53 (40% vs. 67%), FLT3-ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy-related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow-up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5-4.8), adverse karyotype (1.6, 1.1-2.6), TP53 mutation (1.6, 1.0-2.4), and absence of IDH2 mutation (2.2, 1.0-4.7); these risk factors were subsequently applied to construct an HR-weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low (n = 130; median survival 28.9 months), intermediate (n = 105; median 9.6 months), and high (n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3-tiered, CR/CRi-based, and genetics-enhanced survival model for AML patients receiving upfront therapy with Ven-HMA.

Venetoclax plus hypomethylating agents in DDX41-mutated acute myeloid leukaemia and myelodysplastic syndrome: Mayo Clinic series on 12 patients.

Venetoclax (VEN) is an FDA-approved selective inhibitor of B-cell leukaemia/lymphoma-2 (BCL-2), used for treating elderly or unfit acute myeloid leukaemia (AML) patients unable to undergo intensive chemotherapy. Combining VEN with hypomethylating agents (HMAs) has shown impressive response rates in high-risk myelodysplastic syndromes (MDS) and relapsed/refractory AML. However, the efficacy of VEN and HMAs in treating DDX41-mutated (mDDX41) MDS/AML patients remains uncertain. Despite the favourable prognostic nature of mDDX41 MDS/AML patients, there is a lack of clinical experience regarding their response to different treatment regimens, leading to an unknown optimal therapeutic approach.

Determinants of outcomes and advances in CD19-directed chimeric antigen receptor therapy for B-cell acute lymphoblastic leukemia.

Relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive B-cell neoplasm associated with poor outcomes. Conventional multiagent chemotherapy and bispecific antibody therapy may induce remission; however, relapse rates remain high and overall survival is poor. Chimeric antigen receptor T-cell (CAR-T) therapy provides durable, deep complete remission, and long-term cures in relapsed and refractory B-ALL. However, with this new treatment modality, 10%-30% of patients do not achieve remission, and over 50% experience relapse after therapy. Currently, there are two approved CD19-specific CAR-T cell constructs in B-ALL, Tisagenlecleucel and Brexucabtagene Autoleucel by the United States Food and Drug Administration, and the European Medicines Agency (EMA). In this review, we discuss patients, disease, and CAR-T predictors of outcomes in B-ALL. We describe the two approved CD19-directed CAR-T cell products, review the current literature, and discuss factors associated with high risks of therapy failure and future direction in CAR-T cell therapy for B-ALL.

Venetoclax duration (14 vs. 21 vs. 28 days) in combination with hypomethylating agent in newly diagnosed acute myeloid leukemia: Comparative analysis of response, toxicity, and survival.

Overall survival and response rates of 270 patients with newly diagnosed acute myeloid leukemia receiving venetoclax (Ven) plus hypomethylating agent, stratified by Ven dosing schedule (Cycle 1 Ven 14 vs. 21 vs. 28 days).

Molecular Identification of Candida albicans and C. dubliniensis Using Small Subunit rRNA Gene Sequence in Kerbala, Iraq.

This study was conducted to confirm the phenotypic diagnosis of two Candida species, including Candida albicans (C. albicans) and Candida dubliniensis (C. dubliniensis). They were previously isolated in another study from cases of oral candidiasis using polymerase chain reaction and determining the nitrogenous base sequences of the 18 SrRNA product duplication using the NS1 and NS8 primers. The sequences of the multiple bases were analyzed using the Basic Local Alignment Search Tool program (BLAST), which proved that the two diagnosed Candida strains belong to two species, including C. albicans and C. dubliniensis, respectively. Additionally, the comparison of these sequences to the data available in the National Center for Biotechnology Information (NCBI) database showed that C. albicans strains in this study were 99% similar to the universal strains of C. albicans from Japan, Brazil, the United States, Germany, India, China, Pakistan, and Egypt. The C. dubliniensis strains in this study also had the highest genetic similarity rate of 99% to the C. dubliniensis strains isolated from the United States, Netherlands, France, and Germany. The study strains were recorded in the GenBank database with the sequence codes MZ574137 and MZ574410.1 for C. albicans and C. dubliniensis, respectively. The results of the 18 SrRNA region's duplication also showed variations between C. albicans and C. dubliniensis, represented by the presence of three mutations of the first type and two mutations in the second type at different sequence sites.

U2AF1 pathogenic variants in myeloid neoplasms and precursor states: distribution of co-mutations and prognostic heterogeneity.

We have previously recognized the genotypic and prognostic heterogeneity of U2AF1 mutations (MT) in myelofibrosis (MF) and myelodysplastic syndromes (MDS). In the current study, we considered 179 U2AF1-mutated patients with clonal cytopenia of undetermined significance (CCUS; n = 22), MDS (n = 108), MDS/acute myeloid leukemia (AML; n = 18) and AML (n = 31). U2AF1 variants included S34 (60%), Q157 (35%), and others (5%): corresponding mutational frequencies were 45%, 55%, and 0% in CCUS; 57%, 39%, and 4% in MDS; 61%, 33%, and 6% in MDS/AML; and 55%, 35% and 10% in AML (P = 0.17, 0.36 and 0.09), respectively. Concurrent mutations included ASXL1 (37%), BCOR (19%), RUNX1 (14%), TET2 (15%), DNMT3A (10%), NRAS/KRAS (8%), TP53 (8%), JAK2 (5.5%) and SETBP1 (5%). The two most frequent U2AF1 MT were S34F (n = 97) and Q157P (n = 46); concurrent MT were more likely to be seen with the latter (91% vs 74%; P = 0.01) and abnormal karyotype with the former (70% vs 62%; P = 0.05). U2AF1 S34F MT clustered with BCOR (P = 0.04) and Q157P MT with ASXL1 (P = 0.01) and TP53 (P = 0.03). The median overall survival (OS) in months was significantly worse in AML (14.2) vs MDS/AML (27.3) vs MDS (33.7; P = 0.001); the latter had similar OS with CCUS (30.0). In morphologically high-risk disease (n = 49), defined by ≥10% blood or bone marrow blasts (i.e., AML or MDS/AML), median OS was 14.2 with Q157P vs 37.1 months in the presence of S34F (P = 0.008); transplant-adjusted multivariable analysis confirmed the detrimental impact of Q157P (P = 0.01) on survival and also identified JAK2 MT as an additional risk factor (P = 0.02). OS was favorably affected by allogeneic hematopoietic stem cell transplantation (HR: 0.16, 95% CI; 0.04-0.61, P = 0.007). The current study defines the prevalence and co-mutational profiles of U2AF1 pathogenic variants in AML, MDS/AML, MDS, and CCUS, and suggests prognostic heterogeneity in patients with ≥10% blasts.

Modelling the trident SME-bank relationship.

Relationship banking (RB) with SMEs has been approached as a one-size-fits-all where no differences exist between micro, small, and medium businesses. Nevertheless, recent research has clearly identified three distinct levels of RB depending on variables such as the size and complexity of the business and the amount of borrowing. In this study, we create an original model of this fundamental trident, presented as a system of postulates and inferences in mathematical terms, to capture the structure and dynamics of the three RB levels from the supply/bank side. The model systematically shows the existence of and describes the three RB levels. Further, it highlights how each of these levels is dependent on the determinant variables and how a comparison between the three levels is possible based on the per-capita contribution of each of the determinant variables, in turn, to the per-capita RB service production. Our model provides an analytical framework that can assist banks and researchers to rigorously assess and study each level separately or in comparison to the others. It is also beneficial as it can be used to calculate the optimal allocation of the bank's limited resources among the three levels of RB and to achieve maximum value creation for all stakeholders.

The establishment of national diagnostic reference levels for adult SPECT-CT in Saudi Arabia.

This study aims to introduce national diagnostic reference levels (NDRLs) for adult hybrid single photon emission computed tomography (SPECT-CT) in nuclear medicine (NM) departments in the Kingdom of Saudi Arabia. The administered activity (AA) of radiopharmaceuticals, volume-weighted computed tomography dose index (CTDIvol) and dose length product (DLP) for ten hybrid SPECT/CT examinations were collected and analysed for one year. The median of AA, CTDIvoland DLP for each dose quantity was derived and the suggested national DRLs were determined based on the 75thpercentile for all identified SPECT-CT examinations. A comparison of the defined adult NDRLs in Saudi Arabia with the published data of other countries was performed. Although there are no significant variations of the proposed NDRL of AA between countries, the proposed NDRLs of the integrated CT metrics exceed the published data in most procedures. NM departments are urged to consider optimisation for both image quality and radiation protection.

Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations.

PURPOSE OF REVIEW: CCAAT enhancer binding protein A (CEBPA) gene mutation is one of the common genetic alterations in acute myeloid leukemia (AML), which can be associated with sporadic and familial AML. RECENT FINDINGS: Due to the recent advances in molecular testing and the prognostic role of CEBPA mutation in AML, the definition for AML with CEBPA mutation (AML-CEBPA) has significantly changed. This review provides the rationale for the updates on classifications, and the impacts on laboratory evaluation and clinical management for sporadic and familial AML-CEBPA patients. In addition, minimal residual disease assessment post therapy to stratify disease risk and stem cell transplant in selected AML-CEBPA patients are discussed. Taken together, the recent progresses have shifted the definition, identification, and management of patients with AML-CEBPA.

Clinical and molecular correlates of somatic and germline DDX41 variants in patients and families with myeloid neoplasms.

The diagnosis of germline predisposition to myeloid neoplasms (MN) secondary to DDX41 variants is currently hindered by the long latency period, variable family histories and the frequent occurrence of DDX41 variants of uncertain significance (VUS). We reviewed 4,524 consecutive patients who underwent targeted sequencing for suspected or known MN and analyzed the clinical impact and relevance of DDX41VUS in comparison to DDX41path variants. Among 107 patients (44 [0.9%] DDX41path and 63 DDX41VUS [1.4%; 11 patients with both DDX41path and DDX41VUS]), we identified 17 unique DDX41path and 45 DDX41VUS variants: 24 (23%) and 77 (72%) patients had proven and presumed germline DDX41 variants, respectively. The median age was similar between DDX41path and DDX41VUS (66 vs. 62 years; P=0.41). The median variant allele frequency (VAF) (47% vs. 48%; P=0.62), frequency of somatic myeloid co-mutations (34% vs 25%; P= 0.28), cytogenetic abnormalities (16% vs. 12%; P=>0.99) and family history of hematological malignancies (20% vs. 33%; P=0.59) were comparable between the two groups. Time to treatment in months (1.53 vs. 0.3; P=0.16) and proportion of patients progressing to acute myeloid leukemia (14% vs. 11%; P=0.68), were similar. The median overall survival in patients with high-risk myelodysplastic syndrome/acute myloid leukemia was 63.4 and 55.7 months in the context of DDX41path and DDX41VUS, respectively (P=0.93). Comparable molecular profiles and clinical outcomes among DDX41path and DDX41VUS patients highlights the need for a comprehensive DDX41 variant interrogation/classification system, to improve surveillance and management strategies in patients and families with germline DDX41 predisposition syndromes.