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.

ASXL1/TET2 genotype-based risk stratification outperforms ASXL1 mutational impact and is independent of mutant variant allele fractions in chronic myelomonocytic leukemia.

Not available.

Effects of Statin and Annatto-extracted Tocotrienol Supplementation on Glucose Homeostasis, Bone Microstructure, and Gut Microbiota Composition in Obese Mice.

BACKGROUND/AIM: This study examined the effects of tocotrienols (TT) in conjunction with statin on glucose homeostasis, bone microstructure, gut microbiome, and systemic and liver inflammatory markers in obese C57BL/6J mice. MATERIALS AND METHODS: Forty male C57BL/6J mice were fed a high-fat diet (HFD) and assigned into four groups in a 2 (no statin vs. 120 mg statin/kg diet)×2 (no TT vs. 400 mg TT/kg diet) factorial design for 14 weeks. RESULTS: Statin and TT improved glucose tolerance only when each was given alone, and only statin supplementation decreased insulin resistance. Consistently, only statin supplementation decreased serum insulin levels and HOMA-IR. Pancreatic insulin was also increased with statin treatment. Statin and TT, alone or in combination, reduced the levels of serum IL-6, but only TT attenuated the increased serum leptin levels induced by a HFD. Statin supplementation increased bone area/total area and connectivity density at LV-4, while TT supplementation increased bone area/total area and trabecular number, but decreased trabecular separation at the distal femur. Statin supplementation, but not TT, reduced hepatic inflammatory cytokine gene expression. Neither TT supplementation nor statin supplementation statistically altered microbiome species evenness or richness. However, they altered the relative abundance of certain microbiome species. Most notably, both TT and statin supplementation increased the relative abundance of Lachnospiraceae UCG-006. CONCLUSION: TT and statin collectively benefit bone microstructure, glucose homeostasis, and microbial ecology in obese mice. Such changes may be, in part, associated with suppression of inflammation in the host.

Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis.

The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non-transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); patients in cohort 3A/3B had stable ruxolitinib treatment prior to and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary endpoint was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary endpoint. In cohorts 1 and 3A (NTD), 27% and 50% of patients respectively had mean hemoglobin increase ≥1.5 g/dL from baseline. Among TD patients, ~50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. NCT03194542 clinicaltrials.gov.

Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in TN-MF and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. Significance: This study establishes that MYC expression is increased in TN-MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in TN-MPNs.

Etiology and Management of 800 Patients With Facial Palsy at a Private Practice Setting Over a 5-Year Period.

INTRODUCTION: Very few papers investigated the etiologic breakdown and demographic characteristics of patients with facial nerve (FN) palsy. Our paper aims to present the etiologic breakdown and demographic characteristics of patients with FN palsy, presenting at a private care center between 2014 and 2019, along with the treatment modalities that were offered to them. METHODS: Charts of 800 patients with facial palsy (FP) were reviewed. Data included the etiology of their diagnosis, family history, recurrent FP, demographic information, and treatment provided before and after presentation. RESULTS: Seventy-five percent of our study population were females. The average period between diagnosis with FP and presentation at our center was 10.8 years. The most commonly identified etiology was Bell's palsy, followed by acoustic neuroma. Eighty-one percent of the study subjects were prescribed steroids and/or antivirals. Facial neuromuscular retraining, electrical stimulation, chemodenervation, and surgical intervention were also part of some treatment plans for our population. DISCUSSION: Recommendations for the treatment of idiopathic FP include steroids with adjuvant antiviral medications. Data remains uncertain whether the combination therapy of steroids and antivirals has better results compared to steroids alone. Electrical stimulation is still a controversial therapeutic tool for facial paralysis with a potential role in exacerbating synkinesis. The difference in referral patterns between tertiary and private care centers can explain the disparity in the ranking of the etiologies between our study and what has been published. CONCLUSION: Management of FP is a complex process. The FN community must develop a common database to improve its understanding of the different presentations.

Single-Stage Posterior Vomerine Ostectomy, Premaxillary Setback, Bilateral Gingivoperiosteoplasties and Primary Bilateral Cheiloplasty in Patients with Protuberant Premaxilla.

Various patients with complete bilateral cleft lip and palate present with a protruded premaxilla. Several techniques have been described for correctional repair of the projection with a plethora of unsatisfactory outcomes. This poses a challenge not only for the cleft team providing care but also for the patients and their respective families. Multiple patients suffer from residual deformities after inadequate primary repair, which increase surgical, financial, and psychological burden. Premaxillary setback with posterior vomerine ostectomy and complete bilateral cleft lip repair can promote alignment of the premaxilla with the maxillary prominences. To effectively address this challenging deformity, we describe a single-stage surgical technique that includes vomerine ostectomy posterior to the vomero-premaxillary suture, bilateral gingivoperiosteoplasties with complete bilateral cleft lip repair, and primary cleft rhinoplasty. Careful surgical planning is essential for adequate matching between the length of the protruded premaxilla and the extent of ostectomy. The described technique offers several advantages for the management of complete bilateral cleft lip with a projected premaxilla. It can be applied anywhere around the world and is most beneficial in underprivileged areas where patients suffer from restricted access to healthcare, absence of presurgical orthodontics and lack of sufficient resources.

Anterior Cruciate Ligament Reconstruction Surgery Outcomes: A Comparison Between Patients Who Underwent the Procedure During the COVID-19 Pandemic and a Cohort Treated Prior to the Pandemic.

Background and objective During the coronavirus disease 2019 (COVID-19) pandemic, many elective orthopedic surgeries, including anterior cruciate ligament reconstruction (ACLR), were temporarily postponed. The purpose of this study was to compare the outcomes of ACLR in patients who underwent surgery during the COVID-19 pandemic with those in a cohort treated before the pandemic. Materials and methods This retrospective review compared patients who underwent primary ACLR during two periods: March to June 2020 (the pandemic group) and January to December 2018 (the pre-pandemic group). Matched cohorts (1:1) were created using propensity matching. Time from injury-to-first visit, injury-to-surgery, and first visit-to-surgery were calculated. Subjective and objective outcomes, minimal clinically important difference (MCID) achievement, and complication rates were recorded for up to two years postoperatively. Statistical analysis included 𝛘2 or Fisher's exact tests for categorical data, and t- or Wilcoxon signed-rank tests for continuous data with significance set at P < 0.05. Results The pandemic and pre-pandemic groups consisted of 33 and 217 patients, respectively. Matched cohorts consisted of 33 patients each. The time from injury-to-surgery and the first visit-to-surgery was prolonged in the pandemic group. When unmatched, visual analog scale (VAS) scores at three months postoperatively and Patient-Reported Outcomes Measurement Information System (PROMIS)-pain interference (PI) at six months postoperatively and at the final follow-up were higher in the pandemic group. When matched, PROMIS-PI at six months postoperatively was higher in the pandemic group, and VAS scores at one year postoperatively were higher in the pre-pandemic group. MCID achievement and complication rates did not significantly differ between the groups. Conclusions ACLR procedures were significantly delayed in the early months of the COVID-19 pandemic. While patients treated before and during the pandemic experienced varying pain levels during recovery, their functional outcomes, MCID achievement, and complication rates did not differ significantly.

Testicular histopathology and follicular stimulating hormone to predict fertility in nonobstructive azoospermia.

PURPOSE: To examine the ability of testicular histopathology in Non-obstructive azoospermia (NOA) in predicting sperm retrieval rate (SR), sperm quality and assisted reproductive technology success. METHODS: A retrospective study recruited clinically diagnosed NOA patients between 2007 and 2015. Testicular biopsy and conventional sperm extraction (TESE) were done concomitantly. Correlation between pathological categories, SR rate, sperm quality and success of intracytoplasmic sperm injection (ICSI) was studied. FSH was measured as a predictor of fertility. RESULTS: One hundred eighteen patients were recruited. Histopathological classification was hypospermatogenesis (HS) 45 (38%), maturation arrest (MA) 22(19%), Sertoli cell only syndrome (SCOS) 34 (29%) and normal spermatogenesis (NS) 17 (14%). FSH value was above normal level in 34 (76%) of HS, 19 (86%) of MA, 32 (94%) of SCOS and 5 (29%) of NS. Positive SR was obtained in 108 (92%) patients. The highest SR rate was seen in NS group 100% and the lowest was in SCOS 26 (77%). The worst sperm quality was found in SCOS as type C represents 46%, followed by MA 40% and HS 24%. Patients had ICSI following TESE had variable success rate as success of ICSI was seen (9/15) for HS, (0/7) for MA, (5/15) for SCOS and (8/9) for NS. FSH is strongly correlated to SR, quality of sperm and success of ICSI as positive SR in normal FSH patients was obtained in 28 (100%) of normal FSH, 70 (97%) of high FSH and 10 (56%) of double high FSH (p value < 001). The success of ICSI significantly correlates with FSH value as normal FSH has 77% success ICSI rate, high FSH (52%) and double high FSH (0%) (p value < 0.001). CONCLUSIONS: Testicular biopsy and histopathology findings in NOA are strongly correlated SR rate, quality of sperms, and success of ICSI. FSH is a strong noninvasive predictor of fertility in NOA patients.

Menopausal symptom management: Fezolinetant's varied doses provide effective relief for vasomotor symptoms in women - A meta-analysis of 3291 participants.

Menopause represents the physiological transition when a woman's reproductive period ends associated with a variety of symptoms, including vasomotor symptoms, such as night sweats and hot flashes. This systematic review and meta-analysis aimed to assess the effectiveness and safety of oral Fezolinetant for treating vasomotor symptoms associated with menopause. Five electronic databases were searched from their inception until May 2023. Via the Cochrane risk of bias tool, two reviewers assessed the studies' quality. The primary outcomes were a decrease in VMSs frequency and severity and safety outcomes at 4 and 12 weeks. Data were extracted and then analyzed using RevMan software. This meta-analysis included six trials with a total of 3291 women that compared Fezolinetant to a placebo in the treatment of menopausal VMSs. After 4 and 12 weeks of therapy, fezolinetant at 30 mg QD or 45 mg QD substantially decreased the frequency and severity of VMSs per 24 hours compared to placebo. Fezolinetant at 90 mg BID, 30 mg QD, or 45 mg QD did not show a significant difference in the rate of treatment-emergent adverse events (TEAEs), headache, and TEAEs leading to permanent discontinuation compared to placebo. Fezolinetant proves to be a successful and well-tolerated remedy for menopausal women suffering from VMSs. Notably, the 45 mg daily dosage over 12 weeks exhibited significant efficacy. Nonetheless, extensive future trials are necessary to ascertain its long-term safety, effectiveness, and relative potency compared to alternative VMS treatments like hormone therapy.

La ménopause représente la transition physiologique lorsque la période de reproduction d'une femme se termine, associée à divers symptômes, notamment des symptômes vasomoteurs, tels que des sueurs nocturnes et des bouffées de chaleur. Cette revue systématique et méta-analyse visaient à évaluer l'efficacité et l'innocuité du Fezolinetant oral pour traiter les symptômes vasomoteurs associés à la ménopause. Cinq bases de données électroniques ont été consultées depuis leur création jusqu'en mai 2023. Via l'outil Cochrane sur le risque de biais, deux examinateurs ont évalué la qualité des études. Les principaux critères de jugement étaient une diminution de la fréquence et de la gravité des SVM ainsi que des critères de sécurité à 4 et 12 semaines. Les données ont été extraites puis analysées à l'aide du logiciel RevMan. Cette méta-analyse comprenait six essais portant sur un total de 3 291 femmes comparant Fezolinetant à un placebo dans le traitement des SVM ménopausiques. Après 4 et 12 semaines de traitement, le fézolinetant à la dose de 30 mg une fois par jour ou de 45 mg une fois par jour a considérablement réduit la fréquence et la gravité des SMV toutes les 24 heures par rapport au placebo. Le fézolinetant à la dose de 90 mg deux fois par jour, de 30 mg une fois par jour ou de 45 mg une fois par jour n'a pas montré de différence significative dans le taux d'événements indésirables survenus pendant le traitement (TEAE), de maux de tête et de TEAE conduisant à un arrêt définitif par rapport au placebo. Le fézolinetant s'avère être un remède efficace et bien toléré pour les femmes ménopausées souffrant de VMS. Notamment, la dose quotidienne de 45 mg sur 12 semaines a montré une efficacité significative. Néanmoins, de futurs essais approfondis sont nécessaires pour vérifier son innocuité, son efficacité et sa puissance relative à long terme par rapport aux traitements alternatifs du VMS comme l'hormonothérapie.

Incidence, risk factors, and treatment of retroprosthetic membranes following Boston keratoprosthesis eyes and the impact of glaucoma surgery.

PURPOSE: To assess incidence, risk factors, and treatment of retroprosthetic membrane (RPM) formation in eyes following Boston keratoprosthesis (Kpro) implantation and their correlation with glaucoma drainage device placement (GDD). METHODS: A retrospective review was performed on eyes that underwent Kpro type I or II implantation between 2005 and 2020 at a tertiary academic center. Multiple variables were collected including preoperative characteristics, presence of RPM, management of RPM, and outcomes including corrected visual acuity (VA). A Fischer's exact test was used to evaluate the significance of risk factors of RPM formation and an odds ratio was calculated for each possible risk factor. A Mann-Whitney U test was used to evaluate comparisons between outcomes and qualitative analyses. RESULTS: Of the 87 eyes identified, 37 (43%) developed an RPM within an average of 1.5 years (range, 31 days-7.5 years) following Kpro implantation. Mean follow-up duration was 4.3 years. Eyes that developed RPM had significantly worse preoperative VA compared to those that did not (logMAR 2.55 vs. 2.28, p = 0.022). The mean number of prior penetrating keratoplasty procedures trended higher in eyes that developed RPM (2.46 vs. 2.18, p = 0.44) but was not significant. GDD placement after Kpro implantation was associated with an increased risk of RPM formation (RR = 1.69 p = 0.026). Of the 37 eyes that developed an RPM following Kpro, 17 (47%) were treated with Nd:YAG laser, and four of those 17 (21%) also underwent pars plana vitrectomy (PPV). Seven of 37 eyes (19%) underwent PPV without Nd:YAG. Comparisons between RPM occurrence and final VA were not significant. CONCLUSIONS: The incidence of RPM formation following Kpro implantation was 43%. Eyes that developed RPM had significantly worse preoperative VA. GDD placement after Kpro implantation increased the risk of developing RPM. Final VA and occurrence of RPM were not significantly different between the Nd:YAG and PPV treatment groups.

A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma.

Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities to adult glioma, it is increasingly recognized as a molecularly distinct, yet highly heterogeneous disease. In this study, we longitudinally profiled a molecularly diverse cohort of 16 pHGG patients before and after standard therapy through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of the tumor microenvironment during progression following treatment. We found that the canonical neoplastic cell phenotypes of adult glioblastoma are insufficient to capture the range of tumor cell states in a pediatric cohort and observed differential tumor-myeloid interactions between malignant cell states. We identified key transcriptional regulators of pHGG cell states and did not observe the marked proneural to mesenchymal shift characteristic of adult glioblastoma. We showed that essential neuromodulators and the interferon response are upregulated post-therapy along with an increase in non-neoplastic oligodendrocytes. Through in vitro pharmacological perturbation, we demonstrated novel malignant cell-intrinsic targets. This multiomic atlas of longitudinal pHGG captures the key features of therapy response that support distinction from its adult counterpart and suggests therapeutic strategies which are targeted to pediatric gliomas.

Hypomethylating Agents and Venetoclax for Acute Myeloid Leukemia Relapsed After Hematopoietic Stem Cell Transplant.

BACKGROUND: Hypomethylating agent + venetoclax is an effective frontline combination for acute myeloid leukemia, but its efficacy and safety in post-allogeneic hematopoietic cell transplant (alloHCT) relapse remain underexplored. Outcomes have been poor for this population, with no standard treatment. PATIENTS AND METHODS: We retrospectively analyzed 72 Ven-naïve patients who received hypomethylating agents + venetoclax at relapse following alloHCT and aimed to evaluate the rates of complete remission with or without hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity, CR/CRi duration, and overall survival. We leveraged our larger sample to analyze the impact of cytogenetic/molecular features on the odds of CR/CRi. RESULTS: CR/CRi was achieved among 32 of 67 (48%) patients, and MRD negativity was recorded among 10 of 12. NPM1 and IDH 1 or 2 mutations increased the odds of CR/CRi, as did increasing time from alloHCT to relapse. Fourteen patients subsequently received donor lymphocyte infusions or a second alloHCT. Responses lasted a median of 17.8 months (95% CI, 7.2 months to not reached), and responders had a greater median overall survival of 19.7 months (95% CI, 7.6-51.5 months) compared to 2.9 months among nonresponders (95% CI, 1.8-4.4 months; log-rank P < .01). Treatment was well tolerated, but prolonged cytopenias were common and most patients required reduction in the number of venetoclax days per cycle. CONCLUSION: These data support the efficacy of this combination in the alloHCT relapse setting where we report responses among nearly half of patients, with possibly greater benefit for NPM1 and IDH 1/2-mutated cases. These responses can be durable and profound as evidenced by conversion to MRD negativity.

Retraction: Cecal Lipoma: A Rare Etiology of Acute Appendicitis in Adults.

[This retracts the article DOI: 10.7759/cureus.19423.].

Raspberry polyphenols target molecular pathways of heart failure.

Approximately 650,000 new cases of heart failure (HF) are diagnosed annually with a 50% five-year mortality rate. HF is characterized by reduced left ventricular (LV) ejection fraction and hypertrophy of the LV wall. The pathophysiological remodeling of the heart is mediated by increased oxidative stress and inflammation. Raspberries are rich in polyphenols which may favorably impact enzymes involved in redox homeostasis while also targeting inflammatory signaling. Thus, the objective of this study was to investigate whether raspberry polyphenols could attenuate HF. Sprague Dawley rats consumed a 10% (w/w) raspberry diet for 7 weeks. At week 3, HF was surgically induced via coronary artery ligation. Hemodynamics and morphology of the heart were assessed. Expression of cardiac proteins involved in oxidative stress, inflammation, apoptosis, and remodeling were examined, and histological analysis was conducted. Additionally, human cardiomyocytes were treated with raspberry polyphenol extract (RBPE) followed by CoCl2 to chemically induce hypoxia. Redox status, apoptosis, and mitochondrial dysfunction were measured. Raspberries attenuated reductions in cardiac function and reduced morphological changes which coincided with reduced toll-like receptor (TLR)4 signaling. Reductions in oxidative stress, apoptosis, and remodeling occurred in vivo. Incubation of cardiomyocytes with RBPE attenuated CoCl2-induced oxidative stress and apoptosis despite pronounced hypoxia-inducible factor (HIF)-1α expression. These data indicate that consumption of raspberries can reduce the underlying molecular drivers of HF; thus, leading to the observed improvements in cardiac functional capacity and morphology. This dietary strategy may be an effective alternative strategy for treating HF. However, further investigation into alternative models of HF is warranted.

Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. METHODS: In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). FINDINGS: Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. INTERPRETATION: Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. FUNDING: Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.

Weakly Supervised Deep Learning Predicts Immunotherapy Response in Solid Tumors Based on PD-L1 Expression.

Programmed death-ligand 1 (PD-L1) IHC is the most commonly used biomarker for immunotherapy response. However, quantification of PD-L1 status in pathology slides is challenging. Neither manual quantification nor a computer-based mimicking of manual readouts is perfectly reproducible, and the predictive performance of both approaches regarding immunotherapy response is limited. In this study, we developed a deep learning (DL) method to predict PD-L1 status directly from raw IHC image data, without explicit intermediary steps such as cell detection or pigment quantification. We trained the weakly supervised model on PD-L1-stained slides from the non-small cell lung cancer (NSCLC)-Memorial Sloan Kettering (MSK) cohort (N = 233) and validated it on the pan-cancer-Vall d'Hebron Institute of Oncology (VHIO) cohort (N = 108). We also investigated the performance of the model to predict response to immune checkpoint inhibitors (ICI) in terms of progression-free survival. In the pan-cancer-VHIO cohort, the performance was compared with tumor proportion score (TPS) and combined positive score (CPS). The DL model showed good performance in predicting PD-L1 expression (TPS ≥ 1%) in both NSCLC-MSK and pan-cancer-VHIO cohort (AUC 0.88 ± 0.06 and 0.80 ± 0.03, respectively). The predicted PD-L1 status showed an improved association with response to ICIs [HR: 1.5 (95% confidence interval: 1-2.3), P = 0.049] compared with TPS [HR: 1.4 (0.96-2.2), P = 0.082] and CPS [HR: 1.2 (0.79-1.9), P = 0.386]. Notably, our explainability analysis showed that the model does not just look at the amount of brown pigment in the IHC slides, but also considers morphologic factors such as lymphocyte conglomerates. Overall, end-to-end weakly supervised DL shows potential for improving patient stratification for cancer immunotherapy by analyzing PD-L1 IHC, holistically integrating morphology and PD-L1 staining intensity. SIGNIFICANCE: The weakly supervised DL model to predict PD-L1 status from raw IHC data, integrating tumor staining intensity and morphology, enables enhanced patient stratification in cancer immunotherapy compared with traditional pathologist assessment.

The Effect of Diabetes Mellitus on Cardiac Remodeling and Overall Clinical Outcomes in Patients With Acute Myocardial Infarction: A Single-Center Retrospective Study in Saudi Arabia.

BACKGROUND: Diabetes mellitus (DM) is a major chronic condition that is considered a strong indicator of poor cardiovascular outcomes, such as recurrent infarction and heart failure (HF), in individuals with acute myocardial infarction (AMI). However, the concept of left ventricular remodeling (LVR) following AMI in DM patients is not well understood and studied in Saudi Arabia. Thus, the aim of this study is to assess the association between LVR and DM in patients presenting with ST-elevation myocardial infarction (STEMI) who had reperfusion therapy with optimal medical therapy after percutaneous coronary intervention (PCI). METHODS: In this retrospective cohort study, 171 patients diagnosed with AMI who visited King Faisal Cardiac Center in King Abdulaziz Medical City, National Guard Hospital, Jeddah, Saudi Arabia, were chosen via the convenience sampling method. The study included patients with AMI who received echocardiograms upon admission and during a follow-up period of six to 12 months. The patients were divided into two groups based on their diabetic status: diabetic (DM) and non-diabetic (non-DM). To collect the data, trained medical students supervised by the principal investigator used the patients' medical records. RESULTS: The study showed that DM patients were more likely to have a history of hypertension, dyslipidemia, smoking, and stress hyperglycemia and had a higher hospitalization rate compared to the non-DM group. Although there was no statistically significant difference (p=0.253), both groups had a higher incidence of the left main trunk and/or left anterior descending artery affected. Regarding the echocardiographic finding, there were no significant differences between the two groups in terms of left ventricular ejection fraction, left ventricular internal diameter at end-diastole, left ventricular internal diameter at end-systole, and interventricular septum thickness. CONCLUSION: This paper suggests that there is no significant correlation between DM and non-DM patients in terms of LVR after AMI. However, DM patients had a statistically significant increased risk of developing HF and valvular heart disease compared to non-DM patients after AMI.

Time-to-Surgery and Short-Term Outcomes of Trimalleolar Ankle Fracture During the COVID-19 Pandemic.

Introduction During the coronavirus disease 2019 (COVID-19) pandemic, a rapid and significant transformation in patient management occurred across the healthcare system in order to mitigate the spread of the disease and address resource constraints. Numerous surgical cases were either postponed or canceled, permitting only the most critical and emergent cases to proceed. The impact of these modifications on patient outcomes remains uncertain. The purpose of this study was to compare time-to-surgery and outcomes of open reduction and internal fixation for trimalleolar ankle fractures during the pandemic to a pre-pandemic group. We hypothesized that the pandemic group would have a prolonged time-to-surgery and worse outcomes compared to the pre-pandemic cohort. Materials and methods This retrospective cohort study was conducted within a single healthcare system, examining the treatment of trimalleolar ankle fractures during two distinct periods: April to July 2020 (COVID-19 group) and January to December 2018 (2018 group). Cases were identified using Current Procedural Terminology code 27822. Information on demographics, fracture characteristics, and outcomes was obtained through chart review. Outcomes analyzed included time-to-surgery, mean visual analog scale scores, ankle strength and range of motion, and complications. Results COVID-19 and 2018 groups consisted of 32 and 100 patients, respectively. No significant difference was observed in group demographics and comorbidities (p > 0.05). Fracture characteristics were similar between groups apart from tibiofibular syndesmosis injury, 62.5% (20/32) in COVID-19 vs 42.0% (42/100) in 2018 (p = 0.03). Time-to-surgery was not significantly different between the two groups (8.84 ± 6.78 days in COVID-19 vs 8.61 ± 6.02 days in 2018, p = 0.85). Mean visual analog scale scores, ankle strength, and ankle range of motion in plantarflexion were not significantly different between the two groups at three and six months postoperatively (p > 0.05). Dorsiflexion was significantly higher in the COVID-19 group at three months (p = 0.03), but not six months (p = 0.94) postoperatively. No significant difference in postoperative complication was seen between groups, 25.0% (8/32) COVID-19 group compared to 15.0% (15/100) 2018 group (p = 0.11). Conclusions Patients who underwent surgery during the early months of the COVID-19 pandemic did not experience prolonged time-to-surgery and had similar outcomes compared to patients treated prior to the pandemic.

Fracture strength of endocrown maxillary restorations using different preparation designs and materials.

PURPOSE: This study investigated the impact of preparation design and material types on fracture strength in maxillary premolars endocrowns after thermodynamic aging. MATERIALS AND METHODS: Eighty two-rooted maxillary premolar crowns underwent endodontic treatment (N = 80, n = 10). The teeth were categorized into ten groups (4-mm deep with no intracanal extension lithium disilicate glass ceramic & multilayer zirconia endocrowns (LE0 & ZE0); 4-mm deep with 4-mm intracanal extension in one canal (LE1 & ZE1); 4-mm deep with 2-mm intracanal extensions in both canals (LE2 & ZE2); flat overlays with no endocore (LO & ZO); glass fiber reinforced post & core and crown (LC & ZC)). After cementation, all specimens were subjected to 1500 thermocycles and 1,200,000 chewing cycles with an axial occlusal load of 49 N. A static loading test was performed at a non-axial 45° loading using a universal testing machine and failure modes (Type I: restoration debonding; Type II: restoration fracture; Type III: restoration/tooth complex fracture above bone level; Type IV: restoration/tooth complex fracture below bone level) were evaluated using a stereoscope. Data were ananalzed using 2-way ANOVA and Tukey's tests (alpha = 0.05). RESULTS: The endocrowns manufactured from multilayered zirconia and pressed lithium disilicate glass ceramic exhibited a fracture load ranging between 1334 ± 332 N and 756 ± 150 N, with ZC presenting the highest and LE2 the lowest values. The differences were not statistically significant (p > 0.05). CONCLUSION: All endocrowns tested in this study performed similar considering the different designs and materials tested. The distribution of fracture modes did not differ significantly depending on the design of the restoration and the type of material used.