TC-325 superiority in Malignant Gastrointestinal Bleeding - An Individual Patient Data Meta-analysis of Randomized Trials.

BACKGROUND: The efficacy of topical hemostatic agents, recommended for peptic ulcer bleeding, remains poorly characterized in malignant gastrointestinal bleeding (GIB). METHODS: We performed an individual patient data (IPD) meta-analysis assessing the efficacy of topical hemostatic agents in malignant GIB. The literature was searched using OVID MEDLINE, EMBASE, and ISI Web of Sciencedatabases (database inception to November 2023). Only randomized controlled trials (RCTs) comparing topical hemostatic agents to conventional endoscopic modalities in malignant GIB were included. Original RCT patient-level data were obtained. PRISMA guidelines were followed. Quality of the evidence was evaluated using the revised Cochrane risk of bias tool, and certainty of evidence with the GRADE approach. The primary outcome was immediate hemostasis; secondary outcomes were 30-day rebleeding and the composite measure of further bleeding (persistent bleeding or 30-day rebleeding). Other outcomes were all-cause mortality, adverse events, and need for additional non-endoscopic treatment. Odds ratios (ORs) from endpoint comparisons were pooled using logistic regression models. FINDINGS: Overall, 985 citations were identified; 3 RCTs (n=160 patients) were included with all assessing TC-325 (Hemospray™). TC-325 achieved immediate hemostasis more often than conventional endoscopic modalities (OR=46.6 (5.89; 369.1)) (low level certainty). Thirty-day rebleeding (OR=0.28 (0.11; 0.70)) and further bleeding (OR=0.11 (0.05; 0.26)) were both significantly lower with TC-325 (very low level certainty). All-cause mortality and need for additional non-endoscopic treatment did not differ between groups. No adverse events were reported. Subgroup analysis confirmed TC-325 superiority in patients with upper GIB. INTERPRETATION: TC-325 appears superior to conventional endoscopic therapy in managing patients with malignant GIB. TC-325 results in improvements in immediate hemostasis, 30-day rebleeding and further bleeding, based on very low-to-low certainties of evidence.

Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib (FREEDOM2): results from a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Most patients with myelofibrosis develop ruxolitinib intolerance or disease that is relapsed or refractory, and survival rates after ruxolitinib discontinuation are poor. We aimed to evaluate the safety and efficacy of fedratinib versus best available therapy (BAT) in patients with myelofibrosis previously treated with ruxolitinib. METHODS: FREEDOM2 was a multicentre, open-label, randomised, controlled, phase 3 trial in 86 clinics in 16 countries, in which patients aged at least 18 years with intermediate-2 or high-risk myelofibrosis that was relapsed or refractory or intolerant to ruxolitinib with Eastern Cooperative Oncology Group performance status 0-2 were stratified by spleen size by palpation, platelet count, and previous ruxolitinib treatment, and randomly assigned 2:1 by interactive response technology to receive fedratinib 400 mg per day (4 × 100 mg capsules orally once daily, open-label) or BAT. Patients received prophylactic antiemetics and thiamine supplementation, and symptomatic antidiarrhoeals as required. Primary endpoint was proportion of patients reaching spleen volume reduction (SVR) of at least 35% (SVR35) at end of cycle 6 in the intention-to-treat population. This manuscript reports the primary analysis of the trial; follow-up is ongoing. This trial is registered at clinicaltrials.gov, NCT03952039. FINDINGS: Between Sept 9, 2019 and June 24, 2022, of 316 patients screened, 201 were randomly assigned and treated (134 to fedratinib, 67 to BAT [including 52 receiving ruxolitinib]); 46 patients from the BAT group crossed over to fedratinib. Approximately half of enrolled patients were male (fedratinib 75 [56%] of 134; BAT 30 [45%] of 67) and most were White (fedratinib 106 [79%] of 134; BAT 58 [87%] of 67). At data cutoff (Dec 27, 2022), median survival follow-up was 64·5 weeks (IQR 37·9-104·9). SVR35 at end of cycle 6 was seen in 48 (36%) of 134 patients receiving fedratinib versus four (6%) of 67 patients receiving BAT (30% difference; 95% CI 20-39; one-sided p-value <0·0001). During the first six cycles 53 (40%) of 134 patients in the fedratinib group and 8 (12%) of 67 patients in the BAT group had grade 3 or greater treatment-related adverse events, most frequently anaemia (fedratinib 12 [9%] of 134; BAT 6 [9%] of 67) and thrombocytopenia (fedratinib 16 [12%] of 134; BAT 2 [3%] of 67); one patient in the fedratinib group died from acute kidney injury suspected to be related to study drug (no treatment-related deaths in the BAT group). Gastrointestinal adverse events occurred more frequently in the fedratinib group compared with the BAT group, but were mostly grade 1-2 in severity and more frequent in early cycles, and were less frequent than in prior clinical trials. A total of 28 (21%) of 134 patients in the fedratinib group and 3 (4%) of 67 patients in the BAT group had thiamine levels below lower limit of normal per central laboratory assessment, with only one case of low thiamine in the fedratinib arm after the introduction of prophylactic thiamine supplementation. INTERPRETATION: Findings from FREEDOM2 support fedratinib as a second-line Janus kinase inhibitor option to reduce spleen size after ruxolitinib failure or intolerance in patients with myelofibrosis, and shows effective strategies for management of gastrointestinal adverse events and low thiamine concentrations through prophylaxis, monitoring, and treatment. FUNDING: Bristol Myers Squibb.

Corymbiform syphilis: A rare dermatological presentation.

Syphilis is often referred to as the 'great imitator' due to its diverse clinical manifestations throughout its clinical stages and polymorphic nature. We report a case of a 24-year-old man-who-has-sex-with-men presenting with an atypical syphilitic rash on the trunk, with a corymbiform appearance. This case highlights the necessity for clinicians to maintain a high index of suspicion for sexually transmitted infections, especially when there are skin manifestations of an uncertain nature.

Large ventricular myxoma causing inflow and outflow obstruction of the right ventricle; A Case Report.

BACKGROUND: Myxomas are the most common primary benign heart tumors, typically found in the left atrium, with only 2-4% occurring in the right ventricle. Clinical presentations vary widely, including congestive heart failure and systemic embolic phenomena. This case report describes a rare right ventricular myxoma causing both inflow and outflow obstruction, presenting as progressive exertional dyspnea. CASE PRESENTATION: A 23-year-old male presented with two weeks of worsening exertional dyspnea. He was stable but tachypneic with a systolic murmur over the tricuspid area. Elevated erythrocyte sedimentation rate (ESR) and C-Reactive protein (CRP) were noted, while other lab tests were normal. Imaging, including echocardiography and chest tomography scan (CT) revealed a 4 × 3.8 × 4.6 cm mass in the right ventricle extending to the pulmonary trunk. Surgical resection via right ventriculotomy was performed, and histopathology confirmed myxoma. The patient recovered uneventfully. CONCLUSION: Right ventricular myxomas, though rare, can cause significant obstruction and present with diverse symptoms. Timely diagnosis using imaging techniques like echocardiography is crucial. Surgical resection remains the definitive treatment, offering excellent outcomes and low recurrence rates. Early intervention is vital to prevent serious complications and ensure favorable patient prognosis.

Novel 3-substituted coumarins inspire a custom pharmacology prediction pipeline: an anticancer discovery adventure.

Aim: This research aims to expand the established pharmacological space of tumor-associated carbonic anhydrases (TACAs) by exploring the synthetically accessible chemical space of 3-substituted coumarins, with the help of in silico pharmacology prediction.Materials & methods: 52 novel 3-substituted coumarins were sketched, prioritizing synthetic feasibility. Their pharmacological potentials were estimated using a custom machine-learning approach. 17 compounds were predicted as cytotoxic against HeLa cells by interfering with TACAs. Those compounds were synthesized and biologically tested against HeLa cells. The three most potent compounds were assayed against multiple carbonic anhydrases, and their enzyme binding mechanism(s) were studied using molecular docking.Results: Experimental results exhibited pronounced consensus with in silico pharmacology predictions.Conclusion: Novel 3-substituted coumarins are herein dispatched to the cancer therapeutics space.

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A suprasellar Aerocele as a Complication of Endoscopic Transsphenoidal Surgery: A Case Report.

CSF leak-related pneumocephalus is a rare complication of endoscopic transsphenoidal surgery (ETSS) and has been reported in previous studies. We are presenting a rare case of subdural pneumocephalus, unassociated with CSF leak, that developed in the sellar and suprasellar regions. This complication was diagnosed in an adult male 1 week after the removal of a large tumor in the same site via ETSS. The patient presented with a severe headache and visual deterioration. He was diagnosed by a CT scan and managed emergently via ETSS. The headache was relieved immediately after surgery, and the recent visual deterioration was reversed the next day. As far as we have reviewed in the context of complications of ETSS, no previous study has reported such a complication of pneumocephalus unassociated with CSF leak following ETSS. As a conclusion, pneumocephalus can occur with or without CSF leakage as a complication of ETSS, and it may be avoided by a good (water-tight) sealing of the surgical site.

NCCN guideline-concordant cancer care in Sub-Saharan Africa A population-based multi-country study of five cancers.

BACKGROUND: To assess population-based quality of cancer care in Sub-Saharan Africa and to identify specific gaps and joint opportunities, we assessed concordance of diagnostic and treatment with NCCN harmonized guidelines for leading cancer types in 10 countries. METHODS: Adult patients with female breast cancer (BC), cervical cancer (CC), colorectal cancer (CRC), Non-Hodgkin lymphoma (NHL) and prostate cancer (PC) were randomly drawn from 11 population-based cancer registries. Guideline concordance of diagnostics and treatment was assessed using clinical records. In a sub-cohort of 906 patients with potentially curable cancer (stage I-III BC, CC, CRC, PC, aggressive NHL (any stage)) and documentation for >1 month after diagnosis, we estimated factors associated with guideline-concordant treatment or minor deviations (GCT). FINDINGS: Diagnostic information as per guidelines was complete for 1030 (31.7%)of 3246 patients included. In the sub-cohort with curable cancer, GCT was documented in 374 (41.3%, corresponding to 11.7% of 3246 included in the population-based cohort): aggressive NHL (59.8%/9.1% population-based), BC (54.5%/19.0%), PC (39.0%/6.1%), CRC (33.9%/9.5%), and CC (27.8%/11.6%). GCT was most frequent in Namibia (73.1% of curable cancer subset/32.8% population-based) and lowest in Kampala, Uganda (13.5%/3.1%). GCT was negatively associated with poor ECOG status, locally advanced stage, origin from low HDI countries, and a diagnosis of CRC or CC. INTERPRETATION: Quality of diagnostic workup and treatment showed major deficits, with considerable disparities among countries and cancer types. Improved diagnostic services are necessary to increase the share of curable cancer in SSA. Treatment components within NCCN guidelines synergetic for several cancers should be prioritized.

A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease.

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (ITPR1), 2 (ITPR2), and 3 (ITPR3) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical ITPR3 de novo variant-NM_002224.3:c.7570C>T, p.Arg2524Cys-causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4+ lymphopenia, a quasi-absence of naïve CD4+ and CD8+ cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg2524 to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported ITPR1-3 deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant ITPR3 variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.

Evaluation of cytotoxic potential of silver nanoparticles biosynthesized using essential oils of Jasminum sambac against breast cancer and bacterial cells.

Essential oils (EOs) which cover about 91% whole biomolecules formulated from Jasminum sambac leaves based on Gas chromatography-mass spectrometry were employed to identify structures. EOs were observed as good agents in the preparation of Silver nanoparticles (AgNPs) through the proposed mechanism that was attempted to interpret the pathway of the bio-preparation process. The characterization of EOs-AgNPs carried via ultraviolet-visible to reveal surface plasmon resonance at 420 nm, Fourier transform infrared to observe functional groups EOs compared to EOs-AgNPs. X-ray diffraction (XRD) revealed a broad chart owing to the small size of AgNPs in average size less than 10 nm calculated relying on image J software, spherical AgNPs with a small dispersive size observed by transmission electron microscopy. Quasi near spherical surface morphology of EOs-AgNPs had detected by field emission scanning electron microscope. EOs-AgNPs were assessed for their antibacterial potential against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria as suppressing bacterial agents. EOs-AgNPs had their anti-breast cancer MCF-7 cell line ability investigated by DNA fragmentation; cycle flow cytometry (apoptosis) at half maximal inhibitory concentration (IC50) was determined at 260 µg/mL which has been stated by cytotoxicity (MTT) assay. EOs-AgNPs have antibacterial and anticancer therapeutic potential, and it is safe, inexpensive, and scalable in the nanoscale range.

Hematopoietic cell transplantation for older acute myeloid leukemia patients in first complete remission: results of a randomized phase III study.

Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/lowdose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to five years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (n=83) or non-HCT (n=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95%CI:18.9-30.1) in the HCT and 15.6 months (95%CI:10.4-20.8) in the non-HCT arm (p=0.022) due to a decrease in cumulative relapse incidence from 91.1 (95%CI:80.7-100.0) after non-HCT to 37.8 (95%CI:27.2-48.4)% after HCT (p.

Short term effectiveness of ustekinumab versus vedolizumab in Crohn's disease after failure of anti-TNF agents: An observational comparative study design with a Bayesian analysis.

BACKGROUND: Crohn's disease (CD) is a debilitating gastrointestinal disease with complex etiology. Although effective, recipients of anti-tumor necrosis factor (TNF) agents may experience primary or secondary nonresponse, necessitating alternative treatments. This study is intended to compare the short-term effectiveness of ustekinumab and vedolizumab in treating CD after failure of multiple lines of anti-TNF therapy using real-world data. METHODS: A retrospective study was conducted at a tertiary hospital in Dammam, Saudi Arabia, including adults (≥18 years old) with CD who did not respond to anti-TNF therapy. Primary endpoints were clinical improvement per the Harvey-Bradshaw Index (HBI) scores and remission at 12 weeks on an ordinal outcome scale. Secondary endpoints included clinical, biochemical, and endoscopic remission; clinical response; corticosteroid-free days; and cumulative steroid dose. Proportional odds and logistic regression Bayesian models were used to analyze outcomes, and the probability of treatment effectiveness was calculated from the posterior distribution. RESULTS: The study included 101 patients (ustekinumab, n = 71 and vedolizumab, n = 30) with a median age of 32 years (IQR: 26.0-38.0); 54.4% were male. At 12 weeks, the HBI endpoint showed an adjusted odds ratio (aOR) = 0.60 (95% confidence interval [CI]: 0.25-1.31), favoring ustekinumab, with a 75% probability of treatment effectiveness over vedolizumab. The clinical ordinal scale had an aOR = 0.61 (95% CI: 0.26-1.35) with a 73% probability of effectiveness for ustekinumab. Ustekinumab was also associated with favorable outcomes in secondary endpoints, reaching up to a 90% probability of effectiveness. CONCLUSION: In CD patients with anti-TNF failure, ustekinumab was more effective than vedolizumab in the short term. These real-world insights contribute to understanding CD management but require validation in larger prospective studies and randomized controlled trials.

Trichoblastoma and breast carcinoma as metachronous primary tumors: Case report.

INTRODUCTION AND IMPORTANCE: The occurrence of more than one tumor originating from the same or different organs is the definition of multiple primary tumors. According to the time of diagnosis, these tumors are classified into two types: metachronous and synchronous tumors. Trichoblastoma is a rare benign skin tumor that is rarely involved in multiple primary tumors, especially in patients with breast cancer. CASE PRESENTATION: A 60-year-old male with left breast and lateral chest wall masses. Lastly, he has been diagnosed with invasive ductal carcinoma of the left breast and chest wall trichoblastoma as metachronous primary tumors with no significant genetic background. CLINICAL DISCUSSION: With the development in the medical field, such tumors are being encountered more. Some authors suggest a relationship between these tumors and genetic mutations. Although rare trichoblastomas can be transformed into malignant tumors and get metastasized. CONCLUSION: The diagnosis and management of primary tumors can be challenging in some cases. Researchers should focus on further exploration of the genetic bases and risk factors of such tumors.

Association of immune evasion in myeloid sarcomas with disease manifestation and patients' survival.

Introduction: Myeloid sarcomas (MS) comprise rare extramedullary manifestations of myeloid neoplasms with poor patients' outcome. While the clinical relevance of the tumor microenvironment (TME) is well established in many malignancies, there exists limited information in MS. Methods: The expression of the human leukocyte antigen class I (HLA-I) antigens, HLA-I antigen processing and presenting machinery (APM) components and the composition of the TME of 45 MS and paired bone marrow (BM) samples from two independent cohorts were assessed by immunohistochemistry, multispectral imaging, and RNA sequencing (RNAseq). Results: A significant downregulation of the HLA-I heavy chain (HC; 67.5%) and ß2-microglobulin (ß2M; 64.8%), but an upregulation of HLA-G was found in MS compared to BM samples, which was confirmed in a publicly available dataset. Moreover, MS tumors showed a predominantly immune cell excluded TME with decreased numbers of tissue infiltrating lymphocytes (TILs) (9.5%) compared to paired BM (22.9%). RNAseq analysis of a subset of 10 MS patients with preserved and reduced HLA-I HC expression revealed 150 differentially expressed genes and a significantly reduced expression of inflammatory response genes was found in samples with preserved HLA-I expression. Furthermore, low HLA-I expression and low TIL numbers in the TME of MS cases were linked to an inferior patients' outcome. Discussion: This study demonstrated a high prevalence of immune escape strategies in the pathogenesis and extramedullary spread of MS, which was also found in patients without evidence of any BM pathology, which yields the rational for the development of novel individually tailored therapies for MS patients.

Steady-State Versus Chemotherapy-Based Stem Cell Mobilization in Multiple Myeloma: A Single-Center Study to Analyze Efficacy and Safety.

Background: High-dose chemotherapy followed by autologous hematopoietic stem cell support is recommended in the treatment of eligible multiple myeloma (MM) patients. The aim of this study was to compare the efficacy and safety of steady-state versus chemotherapy-based stem cell mobilization in our Hungarian patient population. Methods: The subjects were 210 MM patients who underwent stem cell mobilization procedure between 2018 and 2022. Solo granulocyte colony-stimulating factor (G-CSF) was administered in 104 cases, while 106 patients received chemotherapy which was followed by G-CSF administration. We evaluated the ratio of successful mobilizations, the amount of collected stem cells, the incidence of infections and cost-effectivity in the two groups. Results: In the steady-state group, there was a significantly higher need for plerixafor (45% vs. 13%, P < 0.001), unsuccessful stem cell mobilization was more frequent (11% vs. 3%, P = 0.024) and the mean amount of collected stem cells was lower (6.9 vs. 9.8 × 106, P < 0.001) than in the chemotherapy group. However, infections were less frequent (4% vs. 27%, P < 0.001) and the number of days spent in hospital was significantly lower (6 vs. 14 days, P < 0.001). Plerixafor was more frequently administered in those who had received lenalidomide or daratumumab than in those who had been treated with other regimens (41% vs. 23%, P = 0.007 and 78% vs. 23%, P < 0.001, respectively). Conclusions: Steady-state mobilization is a safe method; however, the higher rate of plerixafor administration and unsuccessful attempts may question its superiority to chemomobilization.

Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence.

Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count <100×109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the Clonal Cytopenia Risk Score (CCRS), which stratified patients into low- (score <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's test (P <.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P =.005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

Independent Risk Factors of Failed Extubation among Adult Critically Ill Patients: A Prospective Observational Study from Saudi Arabia.

Background: Mechanical ventilation provides essential support for critically ill patients in several diagnoses; however, extubation failure can affect patient outcomes. From Saudi Arabia, no study has assessed the factors associated with extubation failure in adults. Methods: This prospective observational study was conducted in the intensive care unit of a tertiary care hospital in Riyadh, Saudi Arabia. Adult patients who had been mechanically ventilated via the endotracheal tube for a minimum of 24 hours and then extubated according to the weaning protocol were included. Failed extubation was defined as reintubation within 48 hours of extubation. Results: A total of 505 patients were included, of which 72 patients had failed extubation (14.3%, 95% CI: 11.4%-17.7%). Compared with the failed extubation group, the successfully extubated group had significantly shorter duration of mechanical ventilation (mean difference: -2.6 days, 95% CI: -4.3 to -1; P = 0.001), a slower respiratory rate at the time of extubation (mean difference: -2.3 breath/min, 95% CI: -3.8 to -1; P = 0.0005), higher pH (mean difference: 0.02, 95% CI: 0.001-0.04; P = 0.03), and more patients with strong cough (percent difference: 17.7%, 95% CI: 4.8%-30.5%; P = 0.02). Independent risk factors of failed extubation were age (aOR = 1.02; 95% CI: 1.002-1.03; P = 0.03), respiratory rate (aOR = 1.06, 95% CI: 1.01-1.1; P = 0.008), duration of mechanical ventilation (aOR = 1.08, 95% CI: 1.03 - 1.1; P < 0.001), and pH (aOR = 0.02, 95% CI: 0.0006-0.5; P = 0.02). Conclusion: Older age, longer duration of mechanical ventilation, faster respiratory rate, and lower pH were found to be independent risk factors that significantly increased the odds of extubation failure among adults.

MoReLife - real-life data support the potential of momelotinib as a safe and effective treatment option for cytopenic myelofibrosis patients.

Recurrent problems of patients with myelofibrosis (MF) are cytopenias, debiliating disease-related symptoms and splenomegaly. Whereas the latter are usually addressed by the JAK1/2 inhibitors ruxolitinib and fedratinib, cytopenias often remain critical. Momelotinib, a JAK1/2 inhibitor recently approved for the treatment of anemic MF patients, was shown to improve anemia via a direct inhibition of activin A receptor type I. In this German-wide, multicenter, retrospective analysis the safety and efficacy profile of momelotinib was evaluated in a real world setting within a cohort of 60 MF patients independent of pre-treatment. The median duration of treatment was 12 weeks. As a new, but manageable safety finding, creatinine increase (CTC°1-2) was detected in 10/60 patients (17%). Interestingly, not only hemoglobin levels increased in 84% of patients, but also platelet values (67%). In the cohort of transfusion-dependent individuals (n = 38), transfusion requirement improved in 15 patients (39%) with 8 reaching transfusion independency (21%). Transfusion independency was achieved within a median of 4 weeks (range 2-12). Spleen size decreased in 13/53 individuals (25%) with a median response time of 6 weeks. Thereof, 11 patients had been pre-treated with JAK inhibitor(s) (85%). Clinical improvement was detected in 24/51 symptomatic individuals (47%) with a median response time of 4 weeks. 5 patients stopped treatment due to side effects (8%), 6 patients due to a worsening of clinical symptoms (10%). Taken together, the MoReLife analysis identifies momelotinib as potent and safe therapeutic option also for heavily pre-treated cytopenic MF patients under real world conditions.

Comparative Performance of 4 Penicillin-Allergy Prediction Strategies in a Large Cohort.

BACKGROUND: A safe and pragmatic guide for labelling and delabelling patients with suspected penicillin allergy is mandatory. OBJECTIVE: To compare the performance of 4 penicillin-allergy prediction strategies in a large independent cohort. METHODS: We conducted a retrospective study for subjects presenting between January 2014 and December 2021 at the University Hospital of Montpellier, with a history of hypersensitivity to penicillins. The outcome targeted by the study was a positive penicillin-allergy test. RESULTS: Of the 1,884 participants included, 382 (20.3%) had positive penicillin-allergy tests. The ENDA (European Network on Drug Allergy) and Blumenthal strategies yielded relatively high sensitivities and low specificities and, by design, did not misclassify any positive subjects with severe index reactions. The PEN-FAST <3 score had a negative predictive value of 90% (95% confidence interval [95% CI] 88%-91%), with a sensitivity of 66% (95% CI 62%-71%) and a specificity of 73% (95% CI 71%-75%), and incorrectly delabelled 18 subjects with anaphylaxis and 15 with other severe nonimmediate reactions. For the adapted Chiriac score, the specificity corresponding to 66% sensitivity was 73% (95% CI 70%-75%). Conversely, at a 73% specificity threshold, the sensitivity was 65% (95% CI, 61%-70%). Attempts to improve these prediction algorithms did not substantially enhance performance. CONCLUSIONS: The ENDA and Blumenthal strategies are safe for high-risk subjects, but their delabelling effectiveness is limited, leading to unnecessary avoidance. Conversely, the PEN-FAST and Chiriac scores are performant in delabelling, but more frequently misclassify high-risk subjects with positive penicillin-allergy tests. Selection of the most appropriate tool requires careful consideration of the target population and the desired goal.

Anethole alleviates Doxorubicin-induced cardiac and renal toxicities: Insights from network pharmacology and animal studies.

Doxorubicin (Dox) is widely used as a chemotherapy drug, while anethole (AN) is primarily known as the main aromatic component in various plant species. This research focused on the impact of AN on the cardiac and renal toxicity induced by Dox and to understand the underlying mechanisms. For cardiac toxicity, Wistar rats were categorized into four groups: a Control group; a Dox group, where rats received 2.5 mg/kg of Dox intraperitoneally every other day; and two Dox + AN groups, where animals were administered Dox (2.5 mg/kg/every other day, IP) along with 125 mg/kg or 250 mg/kg of AN, respectively. The renal toxicity study included similar groups, with the Dox group receiving a single dose of 20 mg/kg of Dox intraperitoneally on the tenth day, and the Dox + AN groups receiving 125 mg/kg and 250 mg/kg of AN for two weeks, alongside the same dose of Dox (20 mg/kg, IP, once on the 10th day). Parameters assessed included ECG, cardiac injury markers (CK, CK-MB, and LDH), and kidney function tests (Cr, BUN, uric acid, LDL, Kim-1, NGAL, and CysC). Antioxidant activity, lipid peroxidation, inflammation, and apoptotic markers were also monitored in heart and renal tissues. Gene expression levels of the TLR4/MyD88/NFκB pathway, along with Bax and Bcl-2, were evaluated. Dox significantly altered ECG, elevated cardiac injury markers, and renal function markers. It also augmented gene expressions of TLR4/MyD88/NFκB, amplified oxidative stress, inflammatory cytokines and apoptotic markers. Conversely, AN reduced cardiac injury markers and kidney function tests, improved ECG, diminished TLR4/MyD88/NFκB gene expression, and alleviated oxidative stress by increasing antioxidant enzyme activities and reducing inflammatory cytokines. AN also enhanced Bcl-2 levels and inhibited Bax and the cleavage of caspase-3 and 9. AN countered the lipid peroxidation, oxidative stress, inflammation, and apoptosis induced by Dox, marking it as a potential preventive strategy against Dox-induced nephrotoxic and cardiotoxic injuries.

Consistency of Spleen and Symptom Reduction Regardless of Cytopenia in Patients With Myelofibrosis Treated With Pacritinib.

BACKGROUND: Pacritinib is a JAK2/IRAK1/ACVR1 inhibitor that is approved in the United States for the treatment of patients with myelofibrosis who have a platelet count < 50 × 109/L. Phase 3 clinical studies of pacritinib included patients across a wide range of baseline platelet and hemoglobin levels. PATIENTS AND METHODS: In order to assess the impact of baseline blood counts on pacritinib efficacy, an analysis of efficacy outcomes by baseline platelet and hemoglobin levels was performed using data pooled from 2 Phase 3 studies of pacritinib in patients with MF (PERSIST-1 and PERSIST-2). RESULTS: Of 276 patients evaluable for spleen response, spleen volume reduction occurred consistently across platelet subgroups (< 100 × 109/L or ≥ 100 × 109/L) and hemoglobin subgroups (< 8 g/dL, ≥ 8 to < 10 g/dL, or > 10 g/dL), with no diminution in treatment effect in patients with severe thrombocytopenia or anemia. Among 159 patients evaluable for symptoms response, improvement in total symptom score (TTS) was similar across platelet subgroups. A ≥ 50% improvement of TSS occurred more frequently in patients with baseline hemoglobin < 8 g/dL compared with those with baseline hemoglobin ≥ 8 to < 10 g/dL or > 10 g/dL. Patients with baseline hemoglobin < 8 g/dL also experienced improved hemoglobin sustained over 24 weeks, whereas subgroups with less severe anemia had stable hemoglobin levels over time. Symptom improvement as assessed using the Patient Global Impression of Change instrument was generally consistent across platelet and hemoglobin subgroups. CONCLUSION: Pacritinib demonstrates consistent efficacy in patients with MF regardless of baseline platelet and hemoglobin counts.