The heart of VIALE-A: Cardiac complications of hypomethylating agents and venetoclax in acute myeloid leukaemia.

As we commemorate 50 years since the introduction of classical 7 + 3 induction chemotherapy for acute myeloid leukaemia (AML), we also embark upon new territory with the advent of novel targeted therapeutics, including BH3 mimetics. To date, we do not have much large-scale longitudinal data regarding the toxicities of such novel therapies. Johnson et al. perform a comprehensive analysis of cardiac toxicities with hypomethylating agents and venetoclax and offer valuable insight into risk-benefit analysis when considering front-line therapy for AML. Commentary on: Johnson et al. Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents. Br J Haematol 2024;204:1232-1237.

Natural history of clonal haematopoiesis seen in real-world haematology settings.

Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real-world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non-sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real-world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non-sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high-risk CH in non-sole DTA (vs. sole DTA) patients and in progressors (vs. non-progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00-52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non-progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post-CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN.

Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells.

BACKGROUND: Breast cancer cells (BCCs) can remain undetected for decades in dormancy. These quiescent cells are similar to cancer stem cells (CSCs); hence their ability to initiate tertiary metastasis. Dormancy can be regulated by components of the tissue microenvironment such as bone marrow mesenchymal stem cells (MSCs) that release exosomes to dedifferentiate BCCs into CSCs. The exosomes cargo includes histone 3, lysine 4 (H3K4) methyltransferases - KMT2B and KMT2D. A less studied mechanism of CSC maintenance is the process of cell-autonomous regulation, leading us to examine the roles for KMT2B and KMT2D in sustaining CSCs, and their potential as drug targets. METHODS: Use of pharmacological inhibitor of H3K4 (WDR5-0103), knockdown (KD) of KMT2B or KMT2D in BCCs, real time PCR, western blot, response to chemotherapy, RNA-seq, and flow cytometry for circulating markers of CSCs and DNA hydroxylases in BC patients. In vivo studies using a dormancy model studied the effects of KMT2B/D to chemotherapy. RESULTS: H3K4 methyltransferases sustain cell autonomous regulation of CSCs, impart chemoresistance, maintain cycling quiescence, and reduce migration and proliferation of BCCs. In vivo studies validated KMT2's role in dormancy and identified these genes as potential drug targets. DNA methylase (DNMT), predicted within a network with KMT2 to regulate CSCs, was determined to sustain circulating CSC-like in the blood of patients. CONCLUSION: H3K4 methyltransferases and DNA methylation mediate cell autonomous regulation to sustain CSC. The findings provide crucial insights into epigenetic regulatory mechanisms underlying BC dormancy with KMT2B and KMT2D as potential therapeutic targets, along with standard care. Stem cell and epigenetic markers in circulating BCCs could monitor treatment response and this could be significant for long BC remission to partly address health disparity.

Challenges and solutions to superior chimeric antigen receptor-T design and deployment for B-cell lymphomas.

Chimeric antigen receptor-T (CAR-T) therapies represent a major breakthrough in cancer medicine, given the ex vivo-based technology that harnesses the power of one's own immune system. These therapeutics have demonstrated remarkable success for relapsed/refractory B-cell lymphomas. Although more than a decade has passed since the initial introduction of CAR-T therapeutics for patients with leukaemia and lymphoma, there is still significant debate as to where CAR-T therapeutics fit into the management paradigm, as consensus guidelines are limited. Competing interventions deployed in subsequent lines of therapy for aggressive lymphoma include novel targeted agents, bispecific antibodies, and time-honoured stem cell transplant. In this focused review, we discuss the major obstacles to advancing the therapeutic reach for CAR-T products in early lines of therapy. Such barriers include antigen escape, "cold" tumour microenvironments, host inflammation and CAR-T cell exhaustion. We highlight solutions including point-of-care CAR-T manufacturing and early T lymphopheresis. We review the evidence basis for early CAR-T deployment for B-cell lymphomas in light of the recent Food and Drug Administration (FDA) approval of three first-in-class anti-CD3/CD20 bispecific antibodies-mosunetuzumab, epcoritamab and glofitamab. We propose practical recommendations for 2024.

The emerging therapeutic landscape of relapsed/refractory multiple myeloma.

From a historic lens, treatment for patients with relapsed/refractory multiple myeloma (R/R MM) has advanced significantly since the advent of immunomodulatory agents (IMiDs) in the 1990s, proteasome inhibitors in the 2000s, monoclonal antibodies in the 2010s, and CAR-T treatments in the 2020s. However, the availability of multiple new therapies has also created significant ambiguity regarding therapy selection and sequencing, as consensus guidelines are limited, and cross-trial comparisons of the novel agents are challenging. In this focused review, we discuss the novel Food & Drug Administration (FDA)-approved medications for R/R MM, including the recently approved first-in-class BCMA-directed bispecific antibody teclistamab. We highlight the seminal clinical trials data and discuss optimal sequencing considerations based on the goal of treatment, with an emphasis on the two novel CAR-T cell products. We consider the limited tolerability of certain agents, prospects for our aging population, and financial aspects of these therapies. Finally, we spotlight ongoing trials involving promising agents making their way through the pharmacologic pipeline including the BCMA-directed bispecific antibody elranatamab and the GPRC5D-directed bispecific antibody talquetamab. We summarize our recommendations based on the best available evidence as we enter 2023.

Clinico-Radio-Pathologic Correlation of Leukostasis in Acute Myeloid Leukemia with FLT3 Mutation.

The systemic complications of acute hematologic emergencies account for the high mortality rates seen during inpatient management. Perhaps the most challenging diagnostic entity among all hematologic emergencies is leukostasis. In acute myeloid leukemia, myeloid blasts are often highly adherent to the endothelial vasculature, and high peripheral blood blast count in excess of 100,000 cells per microliter can predispose patients to the pulmonary and neurologic complications, leading to rapid clinical deterioration even before a formal diagnosis of leukostasis is made. The mobilization of the appropriate healthcare personnel in the inpatient setting at inopportune times sometimes poses a major barrier to the successful treatment for patients with leukostasis, and patients often pass away quickly. In this report, we describe clinico-radio-pathologic correlations of leukostasis using pre- and post-mortem analysis in a patient with acute myeloid leukemia (AML) with a FLT3-TKD mutation, and we describe the current literature on best management approaches based on recent evidence.

Understanding Health Economics in Hand Surgery.

Rising health care costs in the United States, besides evolving payment models that place emphasis on value instead of volume, have led to an increasing number of studies evaluating hand surgery from an economic perspective. To better understand such economics-based studies, this review provides a foundational understanding of what value entails by defining its features of quality and cost. Principles of evaluating value through cost-benefit, cost-effectiveness, and cost-utility analyses are discussed. Models of discounting and clinical decision analyses are also discussed. Understanding such concepts and their evaluation in economic analyses will provide greater insight into the economic landscape of hand surgery and improving patient care.

Risk of Dislocation and Revision Following Primary Total Hip Arthroplasty in Patients With Prior Lumbar Fusion With Spinopelvic Fixation.

BACKGROUND: The effect of spinopelvic fixation in addition to lumbar spinal fusion (LSF) on dislocation/instability and revision in patients undergoing primary total hip arthroplasty (THA) has not been reported previously. METHODS: The PearlDiver Research Program was used to identify patients aged 30 and above undergoing primary THA who received (1) THA only, (2) THA with prior single-level LSF, (3) THA with prior 2-5 level LSF, or (4) THA with prior LSF with spinopelvic fixation. The incidence of THA revision and dislocation/instability was compared through logistic regression and Chi-squared analysis. All regressions were controlled for age, gender, and Elixhauser Comorbidity Index (ECI). RESULTS: Between 2010 and 2018, 465,558 patients without history of LSF undergoing THA were examined and compared to 180 THA patients with prior spinopelvic fixation, 5,299 with prior single-level LSF, and 1,465 with prior 2-5 level LSF. At 2 years, 7.8% of THA patients with prior spinopelvic fixation, 4.7% of THA patients with prior 2-5 level LSF, 4.2% of THA patients with prior single-level LSF, and 2.2% of THA patients undergoing only THA had a dislocation event or instability (P < .0001). After controlling for length of fusion, pelvic fixation itself was associated with higher independent risk of revision (at 2 years: 2-5 level LSF + spinopelvic fixation: aHR = 3.15, 95% CI 1.77-5.61, P < .0001 vs 2-5 level LSF with no spinopelvic fixation: aOR = 1.39, 95% CI 1.10-1.76, P < .0001). CONCLUSION: At 2 years, spinopelvic fixation in THA patients were associated with a greater than 3.5-fold increase in hip dislocation risk compared to those without LSF, and an over 2-fold increase in THA revision risk compared to those with LSF without spinopelvic fixation. LEVEL OF EVIDENCE: III.

Rhino-orbito-cerebral mucormycosis: patient characteristics in pre-COVID-19 and COVID-19 period.

BACKGROUND: Rhino-orbito-cerebral-mucormycosis (ROCM), a rare and potentially fatal disease was seen in increasing numbers during the COVID-19 pandemic. This study describes and compares the patient characteristics and outcomes in COVID-19 associated mucormycosis (CAM) and non-COVID-19 mucormycosis (non-CAM). METHODOLOGY: CAM patients (24 cases) were recruited from the COVID-19 period and non-CAM (24 controls) from the pre-COVID-19 period. Clinical data of the CAM group was collected retrospectively with 3 month outcomes prospectively. The non-CAM group data was collected retrospectively. Patient characteristics were compared and risk factors for mortality in ROCM were assessed. RESULTS: Orbital symptoms [altered vision, restricted eye movements, ptosis] and intracranial involvement were higher in CAM patients on presentation. Similarly, the radiological involvement of orbit (orbital apex, superior orbital fissure) and intracranial cavity (intracranial thrombosis, cavernous sinus) was also higher in CAM patients. Newly detected diabetes was found only in CAM patients (29.2%). Although univariate analysis suggested an increased mortality risk in ROCM patients with orbital involvement, the multivariate analysis showed no increased risk with any of the parameters assessed, including COVID-19 positivity. CONCLUSIONS: Compared to the non-CAM, the disease presentation was severe in CAM with higher frequency of orbital and intracranial involvement. However, with early detection and treatment, the short term survival was comparable in both groups.

Extramedullary Acute Myeloid Leukemia of the Renal Pelvis: Insights into a Visceral Niche.

Acute myeloid leukemia (AML) is a stem cell malignancy that originates in the bone marrow and involves the peripheral blood. Extramedullary AML is rarer, but it is most commonly associated with the former French-American-British (FAB) subtypes M4 or M5 of AML. AML cells may also home to the central nervous system and other solid organs such as cortical bone and skin. Such target sites of metastasis depend on microenvironmental niche interactions, which have not been fully elucidated to date. Visceral organs usually do not represent a favorable niche for AML stem cell occupancy. Herein, we describe the case of an 80-year-old man with extramedullary AML involvement of the renal pelvis. Hypercalcemia and obstructive uropathy were presenting features. The visceral niche is a rare site of involvement of myeloid malignancy, and hypercalcemia may reflect a mechanism of extramedullary involvement. We propose a treatment paradigm for this uncommon subset of AML based on advanced age and complex karyotype.

Tumor Molecular Testing Guides Anti-PD-1 Therapy and Provides Evidence for Pathogenicity of Mismatch Repair Variants.

Lynch syndrome is characterized by germline abnormalities in mismatch repair (MMR) genes, leading to predisposition to multiple cancers [1]. A second hit to the unaffected allele is required for tumorigenesis. MMR proteins repair incorrectly paired nucleotides and prevent generation of insertions and deletions at microsatellites [2]. Aberrancies in these MMR proteins can be a result of germline mutations or somatic alterations. Defective MMR results in microsatellite instability (MSI) and a high mutational burden [3].The clinical implications of MSI are becoming readily apparent, as presence of MSI leads to the generation of neoantigens, stimulating tumor-associated lymphocytes [4], [5]. This has led to the use of programmed cell death protein 1 blockade for MMR-deficient tumors [6]. The U.S. Food and Drug Administration recently approved pembrolizumab for any advanced solid tumor demonstrating MSI and nivolumab for metastatic MSI colorectal cancer. However, the clinical significance of numerous MMR gene variants remains uncertain. The International Society for Gastrointestinal Hereditary Tumors classification system categorizes 2,360 MMR variants, which can be used to gauge pathogenicity [7]. There are many variants of uncertain significance (VUS; or class 3) for which clinicians are unable to provide recommendations. In this study, we employed the combination of germline testing and tumor mutational assessment to help discern the clinical relevance of VUS and guide immunotherapeutic decisions. KEY POINTS: A clinical dilemma arises when genomic testing yields variants of uncertain significance (VUS).Germline VUS were identified in two patients with gastrointestinal malignancies, but only one patient had a second-hit mutation in a mismatch repair gene leading to mismatch repair deficiency that conferred response to immunotherapy.The combination of germline testing along with tumor mutational assessment can help discern the clinical relevance of VUS and can help guide therapeutic decision-making toward individualized patient care.

Norfloxacin salts of carboxylic acids curtail planktonic and biofilm mode of growth in ESKAPE pathogens.

AIMS: To enhance the antimicrobial and antibiofilm activity of norfloxacin against the planktonic and biofilm mode of growth in ESKAPE pathogens using chemically modified norfloxacin salts. METHODS AND RESULTS: Antimicrobial testing, synergy testing and time-kill curve analysis were performed to evaluate antibacterial effect of norfloxacin carboxylic acid salts against ESKAPE pathogens. In vivo efficacy to reduce bacterial bioburden was evaluated in zebrafish infection model. Crystal violet assay and live-dead staining were performed to discern antibiofilm effect. Membrane permeability, integrity and molecular docking studies were carried out to ascertain the mechanism of action. The carboxylic acid salts, relative to parent molecule norfloxacin, displayed two- to fourfold reduction in minimum inhibitory concentration against Staphylococcus aureus and Pseudomonas aeruginosa, in addition to displaying potent bacteriostatic effect against certain members of ESKAPE pathogens. In vivo treatments revealed that norfloxacin tartrate (SRIN2) reduced MRSA bioburden by greater than 1 log fold relative to parent molecule in the muscle tissue. In silico docking with gyrA of S. aureus showed increased affinity of SRIN2 towards DNA gyrase. The enhanced antibacterial effect of norfloxacin salts could be partially accounted by altered membrane permeability in S. aureus and perturbed membrane integrity in P. aeruginosa. Antibiofilm studies revealed that SRIN2 (norfloxacin tartrate) and SRIN3 (norfloxacin benzoate) exerted potent antibiofilm effect particularly against Gram-negative ESKAPE pathogens. The impaired colonization of both S. aureus and P. aeruginosa due to improved norfloxacin salts was further supported by live-dead imaging. CONCLUSION: Norfloxacin carboxylic acid salts can act as potential alternatives in terms of drug resensitization and reuse. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study shows that carboxylic acid salts of norfloxacin could be effectively employed to treat both planktonic- and biofilm-based infections caused by select members of ESKAPE pathogens.

Financial Impact of Incentive Spirometry.

Despite largely unproven clinical effectiveness, incentive spirometry (IS) is widely used in an effort to reduce postoperative pulmonary complications. The objective of the study is to evaluate the financial impact of implementing IS. The amount of time nurses and RTs spend each day doing IS-related activities was assessed utilizing an online survey distributed to the relevant national nursing and respiratory therapists (RT) societies along with questionnaire that was prospectively collected every day for 4 weeks at a single 10-bed cardiothoracic surgery step-down unit. Cost of RT time to teach IS use to patients and cost of nurse time spent reeducating and reminding patients to use IS were used to calculate IS implementation cost estimates per patient. Per-patient cost of IS implementation ranged from $65.30 to $240.96 for a mean 9-day step-down stay. For the 566 patients who stayed in the 10-bed step-down in 2016, the total estimated cost of implementing IS ranged from $36 959.80 to $136 383.36. Using national survey workload data, per-patient cost of IS implementation costed $107.36 (95% confidence interval [CI], $97.88-$116.98) for a hospital stay of 4.5 days. For the 9.7 million inpatient surgeries performed annually in the United States, the total annual cost of implementing postoperative IS is estimated to be $1.04 billion (95% CI, $949.4 million-$1.13 billion). The cost of implementing IS is substantial. Further efficacy studies are necessary to determine whether the cost is justifiable.

The RNA-binding protein Musashi 1 stabilizes the oncotachykinin 1 mRNA in breast cancer cells to promote cell growth.

Substance P and its truncated receptor exert oncogenic effects. The high production of substance P in breast cancer cells (BCCs) is caused by the enhancement of tachykinin (TAC)1 translation by cytosolic factor. In vitro translational studies and mRNA stabilization analyses indicate that BCCs contain the factor needed to increase TAC1 translation and to stabilize the mRNA. Prediction of protein folding, RNA-shift analysis, and proteomic analysis identified a 40 kDa molecule that interacts with the noncoding exon 7. Western blot analysis and RNA supershift identified Musashi 1 (Msi1) as the binding protein. Ectopic expression of TAC1 in nontumorigenic breast cells (BCs) indicates that TAC1 regulates its stability by increasing Msi1. Using a reporter gene system, we showed that Msi1 competes with microRNA (miR)130a and -206 for the 3' UTR of exon 7/TAC1. In the absence of Msi1 and miR130a and -206, reporter gene activity decreased, indicating that Msi1 expression limits TAC1 expression. Tumor growth was significantly decreased when nude BALB/c mice were injected with Msi1-knockdown BCCs. In summary, the RNA-binding protein Msi1 competes with miR130a and -206 for interaction with TAC1 mRNA, to stabilize and increase its translation. Consequently, these interactions increase tumor growth.

A Unique Case of Bilateral Microphthalmia That May Be Related to 14q32.33.

A 2-day-old Hispanic boy was transferred to us with concerns of a small left eye. The pregnancy was uncomplicated, and both parents are healthy. Examination showed a left orbit that appeared to be empty with conjunctival tissue. The right eye had a 7 mm clear cornea, and retinal exam showed areas of thin or absent tissue and no visible optic nerve. MRI revealed a hypoplastic left orbit with an orbital cyst. The anterior-posterior diameter of the right globe was 14 mm and the left globe was 4 mm. Genetic microanalysis showed genetic abnormalities (845 kb gain) on chromosome 14 at q32.33. A diagnosis of bilateral microphthalmia with an orbital cyst was made. This is an isolated case of bilateral microphthalmia possibly associated with 14q32-33.

VITREORETINAL SURGICAL OUTCOMES PERFORMED BY SUPERVISED RETINAL FELLOWS VERSUS ATTENDING FACULTY SURGEONS.

PURPOSE: To evaluate common vitreoretinal surgeries performed by retinal fellows under direct faculty supervision, compared with experienced faculty members. METHODS: Retrospective study analyzing 592 consecutive eyes undergoing retinal surgery from 2009 to 2011 at Retina Consultants of Alabama/University of Alabama at Birmingham, Department of Ophthalmology. Vitreoretinal surgeries included macular hole, macular pucker, retinal detachment, diabetic vitreous hemorrhage, and diabetic tractional retinal detachment. Three fellows performed 390 cases (divided into first or second year fellows), while 4 faculty members performed 202 cases. All 390 fellow-performed cases were under direct supervision. Chi-square analysis was used to compare outcomes. RESULTS: There were no baseline differences between the groups. The mean postoperative visual improvement was statistically significant and equal in all groups, as well as between each physician (P ≤ 0.0001). Complications occurred in 29/592 cases (4.8%), whereas reoperations occurred in 21/592 cases (3.5%) and were equally distributed across groups. There were no differences in complications and reoperations when comparing first-year with second-year fellows. CONCLUSION: With proper supervision, vitreoretinal fellows can achieve an equally high visual improvement with low complication and reoperation rates compared with experienced faculty. The year of fellowship does not significantly influence outcomes or complications. Quality outcomes after vitreoretinal surgery can be obtained throughout fellowship training.

Impact of COVID-19 on emergency oral health care in New Jersey.

BACKGROUND: The COVID-19 pandemic led to reduced services of private dental practices. The public emergency clinic of Rutgers School of Dental Medicine (RSDM) (Newark, NJ) faced changing demands during various periods of the pandemic. METHODS: Records of patients visiting the emergency clinic at RSDM during 3 distinct periods (prelockdown, lockdown, teledentistry) from January 10, 2020, through June 30, 2020, were retrospectively reviewed. Qualitative and quantitative attributes pertaining to patient encounters were reviewed and analyzed. RESULTS: A total of 1,799 records were included in this study. Patient visits increased during the early lockdown but were reduced after the implementation of teledentistry. Trends were noted in patient volume, reasons for visits, treatment needs, symptoms, diagnostic methodology, prescription use, and final disposition of patients. CONCLUSIONS: The lockdown affected emergency dental clinic services at RSDM. Teledentistry visits played a key role in screening patients and in facilitating the delivery of oral health care and timely follow-ups to patients who needed urgent in-person emergency visits. PRACTICAL IMPLICATIONS: Data gathered will lead to a better understanding of patients seen in the emergency clinic and can help with long-term planning for both institutional and smaller outpatient clinics during public health emergencies.

Translational insights into the genetics and immunobiology of relapsed/refractory follicular lymphoma.

Although follicular lymphoma (FL) is traditionally classified as an indolent subtype of B cell non-Hodgkin lymphoma, clinical trajectories are often diverse based on unique disease biology, and many patients will eventually experience relapse of their disease. Furthermore, progression of disease within 24 months is associated with increased mortality rates for FL. In the last five years, we have witnessed an upsurge in the commercial availability of targeted therapies for relapsed/refractory (R/R) FL, including chimeric antigen receptor-T (CAR-T) products, bispecific T cell engagers (BiTEs), epigenetic modifier therapies, and next-generation Bruton tyrosine kinase (BTK) inhibitors. Furthermore, clinical trial options have increased tremendously and now include combinatorial strategies that exert synergy against malignant germinal center B cells. Here, we provide a 2024 update of novel therapeutic agents whose development has been informed by recent advances in the genetics and immunobiology of R/R FL. Specifically, we emphasize high-value targeted therapeutics, including anti-CD3 x anti-CD20 BiTEs and adoptive T cell therapies. We discuss prospects on selection and sequencing of BiTEs and CAR-T therapies for patients with R/R FL. We underscore the principles of FL pathobiology that are paving way for future drug discovery and shed insight into therapeutic targeting within nodal basins based on our increasing understanding of the FL microenvironment. Finally, we summarize how a greater knowledge of FL immunobiology can inform risk stratification and therapy selection on a personalized basis for R/R FL in 2025.