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With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate inter-study comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to i) account for gender-specific differences in determining hemoglobin levels for eligibility criteria, ii) revise definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices, and iii) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks prior to study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs. non-TDA) and graded (major vs. minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.
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PURPOSE: To discuss the diagnosis and management of a rare case of endogenous endophthalmitis (EE) caused by Paenibacillus lautus mimicking granulomatous uveitis in a child, highlighting the use of 16S rRNA gene amplicon sequencing as an accurate method to identify rare pathogens. METHOD: A retrospective chart review of the clinical presentation, microbiologic workup-including microscopy, culture, antibiotic susceptibility, and polymerase chain reaction for pathogen DNA of clinical samples-and the clinical management of the case were recorded. RESULT: A 13-year-old boy presented with decreased vision in the right eye for one month. On examination, he had uveitis with hypopyon and complicated cataract. The case underwent an anterior chamber tap followed by vitrectomy and lensectomy. The culture of the vitreous aspirate grew Gram-variable bacilli that could not be identified by conventional microbiological techniques. However, PCR-based sequencing of the 16S rRNA gene was performed, and the bacterium was identified as P. lautus. The patient subsequently developed rhegmatogenous retinal detachment, for which he underwent endo laser photocoagulation and oil tamponade. Four months later, silicone oil was removed, and an intraocular lens was implanted. At six weeks follow-up, the retina remained well attached, and intraocular pressure was maintained. CONCLUSION: P. lautus can cause EE and mimic granulomatous uveitis. Techniques such as 16S rRNA gene sequencing can significantly facilitate aetiological diagnosis in cases where conventional methods fail.
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PURPOSE: To study the clinical features, causative factors and treatment outcomes in patients with infectious scleritis seen in India. METHODS: A retrospective study of all patients examined at a tertiary care center between August 2012 and March 2021. RESULTS: Forty-five patients (45 eyes; mean age 52.7 ± 17.5 years) were included in the study. The mean duration of symptoms was 3.1 ± 4.4 months. Inciting factors were found in 53.3% (injury: 33.3%; ocular surgery: 20.0%). The scleritis was predominantly anterior (97.8%), with multiple lesions in 40.0%, a solitary lesion in 31.1%, and diffuse in 28.9%. Associated features included uveitis (51.1%), keratitis (37.8%), hypopyon (15.6%), and endophthalmitis (6.7%). Causative organisms included bacteria (53.3%), fungi (35.6%), and presumed herpes virus (11.1%). All patients were treated with antimicrobial agents along with systemic corticosteroids where indicated. Surgical treatment included scleral debridement (37.8%), patch grafts (4.4%), and penetrating keratoplasty (2.2%). Complete resolution of scleritis was seen in 86.7%, with a mean duration of therapy of 2.9 ± 2.5 months. The mean follow-up was 8.3 ± 14.3 months. 51.1% of patients lost functional vision (<6/60). Causes of decreased vision included corneal scar, cataract, macular scar, glaucomatous optic atrophy, and phthisis bulbi. On bivariate analysis, poor visual acuity at presentation was associated with a worse visual outcome (p = 0.02). Other risk factors included necrotizing scleritis, multifocal scleritis, the presence of keratitis and uveitis. CONCLUSION: In our study, infectious scleritis resulted from bacterial and fungal infections. The scleritis resolved in most subjects, however, vision loss was frequent due to infection-related complications.
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BACKGROUND: For settings with low tuberculosis incidence, disease elimination is a long-term goal. We investigated pathways to tuberculosis pre-elimination (incidence <1·0 cases per 100â000 people) and elimination (incidence <0·1 cases per 100â000 people) in the USA, where incidence was estimated at 2·9 per 100â000 people in 2023. METHODS: Using a mathematical modelling framework, we simulated how US tuberculosis incidence could be affected by changes in tuberculosis services in the countries of origin for future migrants to the USA, as well as changes in tuberculosis services inside the USA. To do so, we used a linked set of transmission dynamic models, calibrated to demographic and epidemiological data for each setting. We constructed intervention scenarios representing improvements in tuberculosis services internationally and within the USA, individually and in combination, plus a base-case scenario representing continuation of current services. We simulated health and economic outcomes until 2100, using a Bayesian approach to quantify uncertainty in these outcomes. FINDINGS: Under the base-case scenario, US tuberculosis incidence was projected to decline to 1·8 cases per 100â000 (95% uncertainty interval [UI] 1·5-2·1) in the total population by 2050. Intervention scenarios produced substantial reductions in tuberculosis incidence, with the combination of all domestic and international interventions projected to achieve pre-elimination by 2033 (95% UI 2031-2037). Compared with the base-case scenario, this combination of interventions could avert 101â000 tuberculosis cases (95% UI 84â000-120â000) and 13â300 tuberculosis deaths (95% UI 10â500-16â300) in the USA from 2025 to 2050. Tuberculosis elimination was not projected before 2100. INTERPRETATION: Strengthening tuberculosis services domestically, promoting the development of more effective technologies and interventions, and supporting tuberculosis programmes in countries with a high tuberculosis burden are key strategies for accelerating progress towards tuberculosis elimination in the USA. FUNDING: US Centers for Disease Control and Prevention.
Subject(s)
Models, Theoretical , Tuberculosis , Humans , Tuberculosis/epidemiology , Tuberculosis/prevention & control , United States/epidemiology , Incidence , Disease EradicationABSTRACT
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.
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OBJECTIVE: Single-photon emission computed tomography/computed tomography (SPECT/CT) is an emerging imaging modality that identifies sites of heightened bone metabolism in response to increased stresses. The relationship between sacroiliac (SI) joint radiotracer uptake and anatomic biomechanical parameters is poorly understood. METHODS: Adult patients with SPECT/CT scans performed at our institution between 2021 and 2023 for the workup of low back pain were included. Patient charts were reviewed for demographic factors including age, gender, and prior thoracolumbar fusion history. Biomechanical spinopelvic parameters were measured from standing scoliosis radiographs. SPECT/CT scans were reviewed for uptake at the SI joint. Patients were stratified into 2 cohorts; patients with SI uptake greater than iliac crest uptake were designated "hot," whereas those with less or equal uptake were labeled "cold." RESULTS: One-hundred and sixty patients met inclusion criteria. Patients were slightly more male (55%) with average age 55 ± 14.9 years. Sixty-eight patients (43%) had evidence of increased SI activity. Interrater reliability showed substantial agreement (kappa = 0.62). The hot cohort demonstrated greater pelvic incidence (54.8 ± 14.0 degrees vs. 51.0 ± 11.0 degrees, P = 0.031) and pelvic tilt (20.8 ± 9.5 degrees vs. 18.4 ± 8.6 degrees, P =0.047) compared with the cold cohort. Patients were otherwise similar between cohorts (P > 0.05). CONCLUSIONS: Increased pelvic incidence and pelvic tilt angles are associated with SPECT/CT uptake at the SI joint, which may reflect altered biomechanics at the spinopelvic junction. SPECT/CT may be a valuable tool to assess SI degeneration. Future studies are warranted to better characterize the clinical applications of these findings.
Subject(s)
Low Back Pain , Sacroiliac Joint , Single Photon Emission Computed Tomography Computed Tomography , Humans , Male , Female , Sacroiliac Joint/diagnostic imaging , Middle Aged , Single Photon Emission Computed Tomography Computed Tomography/methods , Aged , Adult , Low Back Pain/diagnostic imaging , Low Back Pain/physiopathology , Biomechanical Phenomena/physiology , Retrospective StudiesABSTRACT
Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.
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Mastocytosis, Systemic , Humans , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/therapy , Disease Management , Medical Oncology/standards , Medical Oncology/methodsABSTRACT
PURPOSE: To report a case of endogenous endophthalmitis caused by Sphingomonas paucimobilis in a young male. MATERIALS AND METHODS: A retrospective case report. RESULTS: A 25-year-old male presented with reduced vision in the right eye and recurrent past episodes of hypopyon uveitis. The right eye had vision of counting fingers close to the face with cells, flare, and hypopyon in the anterior chamber with vitritis and exudates in the fundus. Blood investigations for tuberculosis, syphilis, toxoplasma, sarcoidosis, RA, ANA, HLA B27, and HLA B29 were negative. Anterior chamber tap investigations for herpes simplex viruses, varicella-zoster virus, cytomegalovirus, and toxoplasma, as well as Mycobacterium tuberculosis, yielded negative results. Ultrasound B-scan revealed a moderate number of low-reflective dot echoes in the vitreous, along with a few membranous echoes suggestive of vitritis. Blood culture and urine culture were negative. Since there was progressive deterioration, diagnostic and therapeutic vitrectomy was done with intravitreal antibiotics. The culture of the vitreous sample grew Sphingomonas paucimobilis. In the post-operative period, the patient developed retinal detachment, and re-surgery was done with a lensectomy, and the vision improved to 6/18 with contact lenses in the follow-up. CONCLUSION: This case report describes the distinct occurrence of endogenous endophthalmitis in an immunocompetent young male, which was previously reported only in peripartum cases. The clinical course is characterized by masquerading symptoms and recurrent episodes, despite the organism being of low virulence.
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STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) is emerging as a valuable imaging test for identifying pain generators within the lumbar spine. The relationship between radiotracer uptake on SPECT/CT and anatomic biomechanical parameters has not been previously studied. METHODS: We performed a retrospective review of all patients seen at our institution between 2021-2023 who obtained SPECT/CT scans for workup of thoracolumbar back pain. Patient data including demographic, clinical symptoms, and surgical history were collected. Radiology reports were reviewed for evidence of pathologic degeneration and increased bone metabolism on SPECT/CT. Biomechanical parameters were measured from standing scoliosis plain radiographs. Patients were stratified into two cohorts by either presence or absence of asymmetric coronal uptake on SPECT/CT. RESULTS: 160 patients met inclusion criteria. Patients were primarily male (55%) with average age 55 ± 15 years. 87 (54%) patients demonstrated asymmetric uptake on SPECT/CT. These patients were older (P < 0.001), but with similar gender, prior fusion history, sacroiliitis, adjacent segment degeneration, and pseudoarthrosis (P > 0.05). This cohort had more disc disease, facet arthropathy, and greater degree of coronal scoliosis and coronal imbalance (P < 0.001). There were significantly more sites of uptake in the asymmetric cohort, and uptake was preferentially observed in the concavity of the lumbar curve (P < 0.001). There were no significant differences in sagittal balance or spinopelvic mismatch between cohorts (P > 0.05). CONCLUSION: Asymmetric uptake on SPECT/CT was associated with coronal deformity in patients with low back pain. Further prospective studies are warranted to assess the effect of coronal deformity on pain generation.
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Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.
Subject(s)
Mutation , Tumor Suppressor Protein p53 , Humans , Male , Female , Aged , Tumor Suppressor Protein p53/genetics , Middle Aged , Aged, 80 and over , Adult , Prognosis , Treatment OutcomeABSTRACT
PURPOSE: To investigate the feasibility of diffusion tensor brain imaging at 0.55T with comparisons against 3T. METHODS: Diffusion tensor imaging data with 2 mm isotropic resolution was acquired on a cohort of five healthy subjects using both 0.55T and 3T scanners. The signal-to-noise ratio (SNR) of the 0.55T data was improved using a previous SNR-enhancing joint reconstruction method that jointly reconstructs the entire set of diffusion weighted images from k-space using shared-edge constraints. Quantitative diffusion tensor parameters were estimated and compared across field strengths. We also performed a test-retest assessment of repeatability at each field strength. RESULTS: After applying SNR-enhancing joint reconstruction, the diffusion tensor parameters obtained from 0.55T data were strongly correlated ( R 2 ≥ 0 . 70 $$ {R}^2\ge 0.70 $$ ) with those obtained from 3T data. Test-retest analysis showed that SNR-enhancing reconstruction improved the repeatability of the 0.55T diffusion tensor parameters. CONCLUSION: High-resolution in vivo diffusion MRI of the human brain is feasible at 0.55T when appropriate noise-mitigation strategies are applied.
Subject(s)
Brain , Diffusion Tensor Imaging , Feasibility Studies , Image Processing, Computer-Assisted , Signal-To-Noise Ratio , Humans , Brain/diagnostic imaging , Diffusion Tensor Imaging/methods , Male , Adult , Reproducibility of Results , Female , Image Processing, Computer-Assisted/methods , Algorithms , Healthy VolunteersABSTRACT
ABSTRACT: Progression of myeloproliferative neoplasms (MPNs) to accelerated or blast phase is associated with poor survival outcomes. Since 2017 there have been several therapies approved for use in acute myeloid leukemia (AML); these therapies have been incorporated into the management of accelerated/blast-phase MPNs (MPN-AP/BP). We performed a multicenter analysis to investigate outcomes of patients diagnosed with MPN-AP/BP in 2017 or later. In total, 202 patients were identified; median overall survival (OS) was 0.86 years. We also analyzed patients based on first-line treatment; the 3 most common approaches were intensive chemotherapy (n = 65), DNA methyltransferase inhibitor (DNMTi)-based regimens (n = 65), and DNMTi + venetoclax-based regimens (n = 54). Median OS was not significantly different by treatment type. In addition, we evaluated response by 2017 European LeukemiaNet AML criteria and 2012 MPN-BP criteria in an effort to understand the association of response with survival outcomes. We also analyzed outcomes in 65 patients that received allogeneic hematopoietic stem cell transplant (allo-HSCT); median OS was 2.30 years from time of allo-HSCT. Our study demonstrates that survival among patients with MPN-AP/BP is limited in the absence of allo-HSCT even in the current era of therapeutics and underscores the urgent need for new agents and approaches.
Subject(s)
Myeloproliferative Disorders , Humans , Myeloproliferative Disorders/therapy , Myeloproliferative Disorders/mortality , Myeloproliferative Disorders/drug therapy , Female , Middle Aged , Male , Aged , Adult , Treatment Outcome , Hematopoietic Stem Cell Transplantation , Aged, 80 and over , Blast Crisis/therapy , Blast Crisis/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
BACKGROUND: This study aimed to determine whether the presence of distinct glioma margins on preoperative imaging is correlated with improved intraoperative identification of tumor-brain interfaces and overall improved surgical outcomes of non-enhancing gliomas. METHODS: This is a retrospective study of all primary glioma resections at our institution between 2000-2020. Tumors with contrast enhancement or with final pathology other than diffuse infiltrative glial neoplasm (WHO II or WHO III) were excluded. Tumors were stratified into two groups: those with distinct radiographical borders between tumor and brain, and those with ill-defined radiographical margins. Multivariate analysis was performed to determine the impact of clear preoperative margins on the primary outcome of gross-total resection. RESULTS: Within the study period, 59 patients met inclusion criteria, of which 31 (53%) had distinct margins. These patients were predominantly younger (37.6 vs. 48.1 years, P=0.007). Tumor and other patient characteristics were similar in both cohorts, including gender, laterality, size, location, tumor type, grade, and surgical adjuncts utilized (P>0.05). Multivariate regression identified that distinct preoperative margins correlated with increased rates of gross total resection (P=0.02). Distinct margins on preoperative neuroimaging also correlated positively with surgeon identification of intra-operative margins (P<0.0001), fewer deaths over the study period (P=0.01), and longer overall survival (P=0.03). CONCLUSIONS: Distinct glioma-parenchyma margins on preoperative imaging are associated with improved surgical resection for diffuse gliomas, as distinct margins may correlate with distinguishable glioma-brain interfaces intraoperatively. Further prospective studies may discover additional clinical uses for these findings.
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PURPOSE: Hospital at Home (HaH) services are expanding to provide acute multidisciplinary care in an individual's home. In this pilot study, we interviewed HaH staff to understand challenges and opportunities for service development. METHODS: We conducted 23 semi-structured interviews with multidisciplinary staff working across three HaH services in Scotland. The questions focussed on service strengths and challenges. RESULTS: Four themes emerged: raising referral awareness, service design and efficiency, staff security on home visits, and sustainability. HaH staff described Emergency Department posters, experience days for non-HaH staff, and daily communication of virtual bed capacity to raise awareness for referrals. Ideas for maximising clinician time were prioritised to improve service efficiency and investment in electric vehicles was strongly supported to mitigate climate impact. CONCLUSION: We found high job satisfaction and engagement amongst HaH staff. Our interviews suggest enthusiasm for further development of HaH while raising important challenges to address during service expansion.
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OPINION STATEMENT: A majority of patients with lower-risk myelodysplastic syndrome (MDS) will present with or develop anemia. Anemia in MDS is associated with decreased quality of life and may correlate with decreased progression-free survival and overall survival. In this state of the art review we summarize current risk stratification approaches to identify lower-risk MDS (LR-MDS), the natural history of the disease, and meaningful clinical endpoints. The treatment landscape of LR-MDS with anemia is also rapidly evolving; we review the role of supportive care, erythropoietin stimulating agents, lenalidomide, luspatercept, hypomethylating agents (HMAs), and immunosuppressive therapy (IST) in the management of LR-MDS with anemia. In patients with deletion 5q (del5q) syndrome lenalidomide has both efficacy and durability of response. For patients without del5q who need treatment, the management approach is impacted by serum erythropoietin (EPO) level, SF3B1 mutation status, and ring sideroblast status. Given the data from the Phase III COMMANDS trial, we utilize luspatercept in those with SF3B1 mutation or ring sideroblasts that have an EPO level < 500 U/L; in patients without an SF3B1 mutation or ring sideroblasts there is equipoise between luspatercept and use of an erythropoietin stimulating agent (ESA). For patients who have an EPO level ≥ 500 U/L or have been previously treated there is not a clear standard of care. For those without previous luspatercept exposure it can be considered particularly if there is an SF3B1 mutation or the presence of ring sideroblasts. Other options include HMAs or IST; the Phase III IMERGE trial supports the efficacy of the telomerase inhibitor imetelstat in this setting and this may become a standard option in the future as well.
Subject(s)
Anemia , Disease Management , Myelodysplastic Syndromes , Humans , Myelodysplastic Syndromes/therapy , Myelodysplastic Syndromes/etiology , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/drug therapy , Anemia/etiology , Anemia/diagnosis , Anemia/therapy , Anemia/drug therapy , Treatment Outcome , Disease Susceptibility , Risk FactorsABSTRACT
Not available.
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Human Carbonic anhydrase IX (hCA IX) is found to be an essential biomarker for the treatment of hypoxic tumors in both the early and metastatic stages of cancer. Due to its active function in maintaining pH levels and overexpression in hypoxic conditions, hCA IX inhibitors can be a potential candidate specifically designed to target cancer development at various stages. In search of selective hCA IX inhibitors, we developed a pharmacophore model from the existing natural product inhibitors with IC50 values less than 50â¯nm. The identified hit molecules were then investigated on protein-ligand interactions using molecular docking experiments followed by molecular dynamics simulations. Among the zinc database 186 hits with an RMSD value less than 1 were obtained, indicating good contact with key residues HIS94, HIS96, HIS119, THR199, and ZN301 required for optimum activity. The top three compounds were subjected to molecular dynamics simulations for 100â¯ns to know the protein-ligand complex stability. Based on the obtained MD simulation results, binding free energies are calculated. Density Functional Theory (DFT) studies confirmed the energy variation between the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO). The current study has led to the discovery of lead compounds that show considerable promise as hCA IX inhibitors and suggests that three compounds with special molecular features are more likely to be better-inhibiting hCA IX. Compound S35, characterized by a higher stability margin and a smaller energy gap in quantum studies, is an ideal candidate for selective inhibition of CA IX.
Subject(s)
Antigens, Neoplasm , Carbonic Anhydrase Inhibitors , Density Functional Theory , Molecular Docking Simulation , Molecular Dynamics Simulation , Humans , Antigens, Neoplasm/metabolism , Antigens, Neoplasm/chemistry , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Ligands , Molecular Structure , PharmacophoreABSTRACT
BACKGROUND: A 54-year-old Hispanic OPos female with known history of anti-Rh17 antibodies was diagnosed with Philadelphia-Chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Rh17, also known as Hr0, is a high-frequency antigen composed of several epitopes on the RhCE protein. Anti-Rh17 antibodies can be made by individuals with missing or varied C/c, E/e antigens. Anti-Rh17 antibodies are clinically significant given multiple case reports of hemolytic disease of the fetus and newborn (HDFN). Finding compatible units for patients with anti-Rh17 can be particularly difficult given that only 1 in 100,000 people are Rh17 negative. STUDY DESIGN AND METHODS: Search for compatible units was conducted by the American Rare Donor Program (ARDP) with no leads. After chemotherapy induction and despite erythropoiesis stimulating agent administration, the patient's hemoglobin continued to trend down to a nadir of 2.8 g/dL. Here we report transfusion of incompatible pRBC to this patient with critically symptomatic anemia. HBOC-201 (Hemopure) was obtained and administered under an emergency compassionate/expanded access designation from the Food and Drug Administration (FDA) under an emergency Investigational New Drug (IND) application. RESULTS AND DISCUSSION: Overall difficulties in this case included the challenge of finding compatible units, dilemma of transfusing incompatible units in a patient with severe anemia and obtaining alternatives to blood products. This case report demonstrates the successful use of HBOC-21 in treating life-threatening anemia.