An expanded chronic care management approach to multiple chronic conditions in Hispanics using community health workers as community extenders in the Rio Grande Valley of Texas.

INTRODUCTION: The synergistic negative effects of type 2 diabetes (T2DM) and hypertension increases all-cause mortality and the medical complexity of management, which disproportionately impact Hispanics who face barriers to healthcare access. The Salud y Vida intervention was delivered to Hispanic adults living along the Texas-Mexico Border with comorbid poorly controlled T2DM and hypertension. The Salud y Vida multicomponent intervention incorporated community health workers (CHWs) into an expanded chronic care management model to deliver home-based follow-up visits and provided community-based diabetes self-management education. METHODS: We conducted multivariable longitudinal analysis to examine the longitudinal intervention effect on reducing systolic and diastolic blood pressure among 3806 participants enrolled between 2013 and 2019. Participants were compared according to their program participation as either higher (≥ 10 combined educational classes and CHW visits) or lower engagement (<10 encounters). Data was collected between 2013 and 2020. RESULTS: Baseline mean systolic and diastolic blood pressure were 138 and 81 mmHg respectively. There were overall improvements in systolic (-6.49; 95% CI = [-7.13, -5.85]; p < 0.001) and diastolic blood pressure (-3.97; 95% CI = [-4.37, -3.56]; p < 0.001). The higher engagement group had greater systolic blood pressure reduction at 3 months (adjusted mean difference = -1.8 mmHg; 95% CI = [-3.2, -0.3]; p = 0.016) and at 15 month follow-up (adjusted mean difference = -2.3 mmHg; 95% CI = [-4.2, -0.39]; p = 0.0225) compared to the lower engagement group. CONCLUSION: This intervention, tested and delivered in a real-world setting, provides an example of how CHW integration into an expanded chronic care model can improve blood pressure outcomes for individuals with co-morbidities.

Repurposing of rabeprazole as an anti-Trypanosoma cruzi drug that targets cellular triosephosphate isomerase.

Trypanosoma cruzi is the causative agent of American trypanosomiasis, which mainly affects populations in Latin America. Benznidazole is used to control the disease, with severe effects in patients receiving this chemotherapy. Previous studies have demonstrated the inhibition of triosephosphate isomerase from T. cruzi, but cellular enzyme inhibition has yet to be established. This study demonstrates that rabeprazole inhibits both cell viability and triosephosphate isomerase activity in T. cruzi epimastigotes. Our results show that rabeprazole has an IC50 of 0.4 µM, which is 14.5 times more effective than benznidazole. Additionally, we observed increased levels of methyl-glyoxal and advanced glycation end products after the inhibition of cellular triosephosphate isomerase by rabeprazole. Finally, we demonstrate that the inactivation mechanisms of rabeprazole on triosephosphate isomerase of T. cruzi can be achieved through the derivatization of three of its four cysteine residues. These results indicate that rabeprazole is a promising candidate against American trypanosomiasis.

Lipid Profiles of Urinary Extracellular Vesicles Released during the Inactive and Active Phases of Aged Male Mice with Spontaneous Hypertension.

Hypertension remains a major problem, especially in the elderly, as it increases the risk for cardiovascular, coronary artery, cerebrovascular, and kidney diseases. Extracellular vesicles (EVs) play a role in the aging process and contribute to pathophysiology. Our goal was to examine differences in lipid profiles of urinary EVs (uEVs) collected during the inactive and active phases of aged mice and investigate whether these EVs regulate the density of lipid rafts in mouse cortical collecting duct (mpkCCD) principal cells. Here, we demonstrate the epithelial sodium channel (ENaC) inhibitor benzyl amiloride reduced systolic blood pressure in aged male mice during the inactive and active phases. Lipidomics data demonstrate differential enrichment of lipids between the two groups. For example, there are more phosphatidylethanolamine plasmalogens, particularly in the form of alkyl phosphatidylethanolamines, that are enriched in active phase uEVs compared to inactive phase uEVs from the same mice. Amiloride-sensitive transepithelial current increased more in mpkCCD cells challenged with uEVs from the active phase group. Moreover, more ENaC alpha protein was distributed to lipid raft fractions of mpkCCD cells challenged with active phase uEVs. Taken together, the identification of bioactive lipids associated with lipid rafts that are enriched in EVs released during the active phase of aged mice may offer clues to help understand lipid raft organization in recipient principal cells after EV uptake and increased renal ENaC activity, leading to a time-of-day dependent regulation of blood pressure in an aging model.

Exploring In Vitro Biological Cellular Responses of Pegylated ß-Cyclodextrins.

ßCDPEG5 and ßCDPEG2 are two derivatives comprising seven PEG linear chains of 5 and 2 kDa, respectively, conjugated to ßCD. As ßCDPEGs display different physicochemical properties than their precursors, they could also trigger distinct cellular responses. To investigate the biological behavior of ßCDPEGs in comparison to their parent compounds, we performed broad toxicological assays on RAW 264.7 macrophages, MC3T3-E1 osteoblasts, and MDCK cells. By analyzing ROS and NO2- overproduction in macrophages, we found that ßCDPEGs induced a moderate stress response without affecting cell viability. Although MC3T3-E1 osteoblasts were more sensitive than MDCK cells to ßCDPEGs and the parent compounds, a similar pattern was observed: the effect of ßCDPEG5 on cell viability and cell cycle progression was larger than that of ßCDPEG2; PEG2 affected cell viability and cell cycle more than ßCDPEG2; cell post-treatment recovery was favorable in all cases, and the compounds had similar behaviors regarding ROS generation. The effect on MDCK cell migration followed a similar pattern. In contrast, for osteoblasts, the interference of ßCDPEG5 with cell migration was smaller than that of ßCDPEG2; likewise, the effect of PEG2 was shorter than its conjugate. Overall, the covalent conjugation of ßCD and PEGs, particularly to yield ßCDPEG2, improved the biocompatibility profile, evidencing that a favorable biological response can be tuned through a thoughtful combination of materials. Moreover, this is the first time that an in vitro evaluation of ßCD and PEG has been presented for MC3T3-E1 and MDCK cells, thus providing valuable knowledge for designing biocompatible nanomaterials constructed from ßCD and PEGs.

A Chronic Care Management Framework Bridging Clinic, Home, and Community Care in a Mexican American Population.

Despite evidence that chronic care management improves outcomes, a framework designed for low income, uninsured populations is still needed to improve health disparities and guide further replication. We describe the Innovative Care for Chronic Conditions framework implemented by a coalition of clinics and agencies to address chronic care management for Mexican Americans with Type 2 diabetes mellitus who have low income and primarily uninsured. The core elements of the framework are described by clinic, home and community settings with community health workers playing an essential role in the delivery of community-based services that address the social determinants of health. Promising results are described. This framework expands the understanding of chronic care management approaches and contributes to further replication of the framework in diverse settings.

Technological evolution of cyclodextrins in the pharmaceutical field.

We herein disclose how global cyclodextrin-based pharmaceutical technologies have evolved since the early 80s through a 1998 patents dataset retrieved from Derwent Innovation Index. We used text-mining techniques based on the patents semantic content to extract the knowledge contained therein, to analyze technologies related to the principal attributes of CDs: solubility, stability, and taste-masking enhancement. The majority of CDs pharmaceutical technologies are directed toward parenteral aqueous solutions. The development of oral and ocular formulations is rapidly growing, while technologies for nasal and pulmonary routes are emerging and seem to be promising. Formulations for topical, transdermal, vaginal, and rectal routes do not account for a high number of patents, but they may be hiding a great potential, representing opportunity research areas. Certainly, the progress in materials sciences, supramolecular chemistry, and nanotechnology, will influence the trend of that, apparently neglected, research. The bottom line, CDs pharmaceutical technologies are still increasing, and this trend is expected to continue in the coming years. Patent monitoring allows the identification of relevant technologies and trends to prioritize research, development, and investment in both, academia and industry. We expect the scope of this approach to be applied in the pharmaceutical field beyond CDs technological applications.

Automated Osteosclerosis Grading of Clinical Biopsies Using Infrared Spectroscopic Imaging.

Osteosclerosis and myefibrosis are complications of myeloproliferative neoplasms. These disorders result in excess growth of trabecular bone and collagen fibers that replace hematopoietic cells, resulting in abnormal bone marrow function. Treatments using imatinib and JAK2 pathway inhibitors can be effective on osteosclerosis and fibrosis; therefore, accurate grading is critical for tracking treatment effectiveness. Current grading standards use a four-class system based on analysis of biopsies stained with three histological stains: hematoxylin and eosin (H&E), Masson's trichrome, and reticulin. However, conventional grading can be subjective and imprecise, impacting the effectiveness of treatment. In this Article, we demonstrate that mid-infrared spectroscopic imaging may serve as a quantitative diagnostic tool for quantitatively tracking disease progression and response to treatment. The proposed approach is label-free and provides automated quantitative analysis of osteosclerosis and collagen fibrosis.

Clinico-pathologic characteristics and outcomes of the World Health Organization (WHO) provisional entity de novo acute myeloid leukemia with mutated RUNX1.

We studied the characteristics of the provisional category de novo acute myeloid leukemia (AML) with mutated RUNX1 (AML-RUNX1mut) proposed by the World Health Organization (WHO). Until now, most published studies have combined de novo and secondary AML-RUNX1mut. We compared the clinicopathologic characteristics and outcomes of WHO-defined de novo AML-RUNX1mut with de novo AML without RUNX1 alterations (AML-RUNX1wt). We performed sequential NGS to assess RUNX1 mutation stability over disease course. We identified 46 de novo AML-RUNX1mut patients [32 (70%) men, 14 (30%) women; median age, 66.5 years] with 54 RUNX1 mutations [median VAF, 32% (2-97%)]. Point mutations clustered within the runt-homology-domain and frame-shift mutations within the transactivation domain. Compared with AML-RUNX1wt, AML-RUNX1mut showed male predominance (p = 0.02), higher frequency of SRSF2 (p = 0.02), and ASXL1 (p = 0.0004) mutations and normal karyotype (p = 0.01), and absent NPM1 mutations (p = 0.0002). De novo AML-RUNX1mut showed no significant difference in overall survival (OS) compared with AML-RUNX1wt (median: 26 vs. 32 months) (p = 0.71). AML-RUNX1mut with clonal RUNX1 mutation (≥20% VAF) had shorter OS than subclonal <20% VAF (23 months vs. undefined; p = 0.04). However, the difference was not significant when compared with AML-RUNX1wt (23 vs. 32 months; p = 0.23). No significant OS difference was noted between de novo AML-RUNX1mut and AML-NOS-RUNX1wt. By sequential multigene mutation profiling, RUNX1 mutation disappeared at relapse in one of ten patients. Overall, the findings support separate categorization of this entity. However, there is no significant outcome difference compared with AML-RUNX1wt.

A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis.

Ruxolitinib (RUX)-based combinations may provide benefit for patients with myelofibrosis (MF). In this open-label, nonrandomized, prospective phase 2 study, patients with MF initially received RUX twice per day continuously in 28-day cycles for the first 3 cycles. Azacitidine (AZA) 25 mg/m2 (days 1-5) was added starting with cycle 4 and could be subsequently increased to 75 mg/m2 (days 1-5). Forty-six patients were enrolled with a median follow-up of 28 months (range, 4-50+ months). An International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response was achieved in 33 patients (72%), with a median time to response of 1.8 months (range, 0.7-19.0 months). One-fourth (7 of 33) of the IWG-MRT responses occurred after the addition of AZA. A reduction of >50% in palpable spleen length at 24 weeks and at any time on the study was achieved in 62% and 71% of the evaluable patients, respectively. Among patients who achieved a >50% reduction in spleen length at 24 weeks, 95% had maintained it at 48 weeks. Notably, improvements in bone marrow reticulin fibrosis grade occurred in 57% of the patients at 24 months. Treatment discontinuations as a result of drug-related toxicities occurred in 4 patients (9%), all as a result of cytopenias. New onset grade 3 to 4 anemia and thrombocytopenia occurred in 35% and 26% of patients, respectively. RUX and AZA were safe, with encouraging spleen response rates and improvement in bone marrow fibrosis in patients with MF. This trial was registered at www.clinicaltrials.gov as #NCT01787487.

Interventions for chronic pruritus of unknown origin.

BACKGROUND: Pruritus is a sensation that leads to the desire to scratch; its origin is unknown in 8% to 15% of affected patients. The prevalence of chronic pruritus of unknown origin (CPUO) in individuals with generalised pruritus ranges from 3.6% to 44.5%, with highest prevalence among the elderly. When the origin of pruritus is known, its management may be straightforward if an effective treatment for the causal disease is available. Treatment of CPUO is particularly difficult due to its unknown pathophysiology. OBJECTIVES: To assess the effects of interventions for CPUO in adults and children. SEARCH METHODS: We searched the following up to July 2019: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and trials registries. We checked the reference lists of included studies for additional references to relevant trials. SELECTION CRITERIA: We sought to include randomised controlled trials and quasi-randomised controlled trials that assessed interventions for CPUO, as defined in category VI ('Other pruritus of undetermined origin, or chronic pruritus of unknown origin') of the International Forum for the Study of Itch (IFSI) classification, in children and adults. Eligible interventions were non-pharmacological or topical or systemic pharmacological interventions, and eligible comparators were another active treatment, placebo, sham procedures, or no treatment or equivalent (e.g. waiting list). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were 'Patient- or parent-reported pruritus intensity' and 'Adverse events'. Our secondary outcomes were 'Health-related quality of life', 'Sleep disturbances', 'Depression', and 'Patient satisfaction'. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We found there was an absence of evidence for the main interventions of interest: emollient creams, cooling lotions, topical corticosteroids, topical antidepressants, systemic antihistamines, systemic antidepressants, systemic anticonvulsants, and phototherapy. We included one study with 257 randomised (253 analysed) participants, aged 18 to 65 years; 60.6% were female. This study investigated the safety and efficacy of three different doses of oral serlopitant (5 mg, 1 mg, and 0.25 mg, once daily for six weeks) compared to placebo for severe chronic pruritus; 25 US centres participated (clinical research centres and universities). All outcomes were measured at the end of treatment (six weeks from baseline), except adverse events, which were monitored throughout. A pharmaceutical company funded this study. Fifty-five per cent of participants suffered from CPUO, and approximately 45% presented a dermatological diagnosis (atopic dermatitis/eczema 37.3%, psoriasis 6.7%, acne 3.6%, among other diagnoses). We unsuccessfully attempted to retrieve outcome data from study authors for the subgroup of participants with CPUO. Participants had pruritus for six weeks or longer. Total study duration was 10 weeks. Participants who received serlopitant 5 mg may have a greater rate of relief of patient-reported pruritus intensity as measured by the visual analogue scale (VAS; a reduction in VAS score indicates improvement) compared to placebo (126 participants, risk ratio (RR) 2.06, 95% confidence interval (CI) 1.27 to 3.35; low-certainty evidence). We are uncertain of the effects of serlopitant 5 mg compared to placebo on the following outcomes due to very low-certainty evidence: adverse events (127 participants; RR 1.48, 95% CI 0.87 to 2.50); health-related quality of life (as measured by the Dermatology Life Quality Index (DLQI); a higher score indicates greater impairment; 127 participants; mean difference (MD) -4.20, 95% CI -11.68 to 3.28); and sleep disturbances (people with insomnia measured by the Pittsburgh Sleep Symptom Questionnaire-Insomnia (PSSQ-I), a dichotomous measure; 128 participants; RR 0.49, 95% CI 0.24 to 1.01). Participants who received serlopitant 1 mg may have a greater rate of relief of patient-reported pruritus intensity as measured by VAS compared to placebo; however, the 95% CI indicates that there may also be little to no difference between groups (126 participants; RR 1.50, 95% CI 0.89 to 2.54; low-certainty evidence). We are uncertain of the effects of serlopitant 1 mg compared to placebo on the following outcomes due to very low-certainty evidence: adverse events (128 participants; RR 1.45, 95% CI 0.86 to 2.47); health-related quality of life (DLQI; 128 participants; MD -6.90, 95% CI -14.38 to 0.58); and sleep disturbances (PSSQ-I; 128 participants; RR 0.38, 95% CI 0.17 to 0.84). Participants who received serlopitant 0.25 mg may have a greater rate of relief of patient-reported pruritus intensity as measured by VAS compared to placebo; however, the 95% CI indicates that there may also be little to no difference between groups (127 participants; RR 1.66, 95% CI 1.00 to 2.77; low-certainty evidence). We are uncertain of the effects of serlopitant 0.25 mg compared to placebo on the following outcomes due to very low-certainty evidence: adverse events (127 participants; RR 1.29, 95% CI 0.75 to 2.24); health-related quality of life (DLQI; 127 participants; MD -5.70, 95% CI -13.18 to 1.78); and sleep disturbances (PSSQ-I; 127 participants; RR 0.60, 95% CI 0.31 to 1.17). The most commonly reported adverse events were somnolence, diarrhoea, headache, and nasopharyngitis, among others. Our included study did not measure depression or patient satisfaction. We downgraded the certainty of evidence for all outcomes due to indirectness (only 55% of study participants had CPUO) and imprecision. We downgraded outcomes other than patient-reported pruritus intensity a further level due to concerns regarding risk of bias in selection of the reported result and some concerns with risk of bias due to missing outcome data (sleep disturbances only). We deemed risk of bias to be generally low. AUTHORS' CONCLUSIONS: We found lack of evidence to address our review question: for most of our interventions of interest, we found no eligible studies. The neurokinin 1 receptor (NK1R) antagonist serlopitant was the only intervention that we could assess. One study provided low-certainty evidence suggesting that serlopitant may reduce pruritus intensity when compared with placebo. We are uncertain of the effects of serlopitant on other outcomes, as certainty of the evidence is very low. More studies with larger sample sizes, focused on patients with CPUO, are needed. Healthcare professionals, patients, and other stakeholders may have to rely on indirect evidence related to other forms of chronic pruritus when deciding between the main interventions currently used for this condition.

The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia.

BACKGROUND: Phenotypic characterization of immune cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) is lacking. METHODS: T-cell infiltration was quantified on BM biopsies from 13 patients with AML, and flow cytometry was performed on BM aspirates (BMAs) from 107 patients with AML who received treatment at The University of Texas MD Anderson Cancer Center. The authors evaluated the expression of inhibitory receptors (programmed cell death protein 1 [PD1], cytotoxic T-lymphocyte antigen 4 [CTLA4], lymphocyte-activation gene 3 [LAG3], T-cell immunoglobulin and mucin-domain containing-3 [TIM3]) and stimulatory receptors (glucocorticoid-induced tumor necrosis factor receptor-related protein [GITR], OX40, 41BB [a type 2 transmembrane glycoprotein receptor], inducible T-cell costimulatory [ICOS]) on T-cell subsets and the expression of their ligands (41BBL, B7-1, B7-2, ICOSL, PD-L1, PD-L2, and OX40L) on AML blasts. Expression of these markers was correlated with patient age, karyotype, baseline next-generation sequencing for 28 myeloid-associated genes (including P53), and DNA methylation proteins (DNA methyltransferase 3α, isocitrate dehydrogenase 1[IDH1], IDH2, Tet methylcytosine dioxygenase 2 [TET2], and Fms-related tyrosine kinase 3 [FLT3]). RESULTS: On histochemistry evaluation, the T-cell population in BM appeared to be preserved in patients who had AML compared with healthy donors. The proportion of T-regulatory cells (Tregs) in BMAs was higher in patients with AML than in healthy donors. PD1-positive/OX40-positive T cells were more frequent in AML BMAs, and a higher frequency of PD1-positive/cluster of differentiation 8 (CD8)-positive T cells coexpressed TIM3 or LAG3. PD1-positive/CD8-positive T cells were more frequent in BMAs from patients who had multiply relapsed AML than in BMAs from those who had first relapsed or newly diagnosed AML. Blasts in BMAs from patients who had TP53-mutated AML were more frequently positive for PD-L1. CONCLUSIONS: The preserved T-cell population, the increased frequency of regulatory T cells, and the expression of targetable immune receptors in AML BMAs suggest a role for T-cell-harnessing therapies in AML.

Ring sideroblasts in chronic phase of polycythemia vera identifies a subset of patients with an increased risk of progression to blast phase.

Blast phase of PV is often associated with a complex karyotype (CK) and bilineage dysplasia. We hypothesized that BM morphologic abnormalities detected in the Chronic phase (CP) can identify patients with an increased risk of developing blast phase (BP). We also compared cases of BP PV to a group of acute myeloid leukemia cases with JAK2 mutation (AML-JAK2mut). We collected morphological, cytogenetics (CG), and molecular information at the time of diagnosis and at time of diagnosis of BP. We evaluate the presence of splicing factor mutations at BP. A total of 60/477 (12.5%) patients with diagnosis of BP of PV were identified, 17 of them had BM sample available during CP. Ten patients with PV CP were used as control group. We found that dyserythropoiesis during evolution were more frequent in patients who develop BP than in patients who remain in CP (13/17 vs. 3/10; P = .0402). Similarly, ring sideroblast (RS) increase during CP were more frequent in patients who develop BP (8/16 vs. 0/10. P = .0095). By ELN risk stratification for CG risk in BP all patients had adverse or intermediate risk; in AML-JAK2mut 2/11 patients (18%) had favorable as risk category. TP53 mutations were significantly more frequent in BP than in AML-JAK2mut (7/14 vs. 1/11, P = .0421). Mutation analysis for splicing factor at BP was performed on 13 patients. Only 2 patients with >15% RS had SRSF2 (2 patients) and SF3B1 (1 patient) mutations. The other patients were wild type. Dyserythropoiesis and the acquisition of RS precede other markers of disease progression to BP. CK and TP53 mutation are more frequent in BP than in AML-JAK2mut. SF3B1 mutations are rare in BP.

Structural Requirements of N-alpha-Mercaptoacetyl Dipeptide (NAMdP) Inhibitors of Pseudomonas Aeruginosa Virulence Factor LasB: 3D-QSAR, Molecular Docking, and Interaction Fingerprint Studies.

The zinc metallopeptidase Pseudomonas elastase (LasB) is a virulence factor of Pseudomonas aeruginosa (P. aeruginosa), a pathogenic bacterium that can cause nosocomial infections. The present study relates the structural analysis of 118 N-alpha-mercaptoacetyl dipeptides (NAMdPs) as LasB inhibitors. Field-based 3D-QSAR and molecular docking methods were employed to describe the essential interactions between NAMdPs and LasB binding sites, and the chemical features that determine their differential activities. We report a predictive 3D-QSAR model that was developed according to the internal and external validation tests. The best model, including steric, electrostatic, hydrogen bond donor, hydrogen bond acceptor, and hydrophobic fields, was found to depict a three-dimensional map with the local positive and negative effects of these chemotypes on the LasB inhibitory activities. Furthermore, molecular docking experiments yielded bioactive conformations of NAMdPs inside the LasB binding site. The series of NAMdPs adopted a similar orientation with respect to phosphoramidon within the LasB binding site (crystallographic reference), where the backbone atoms of NAMdPs are hydrogen-bonded to the LasB residues N112, A113, and R198, similarly to phosphoramidon. Our study also included a deep description of the residues involved in the protein-ligand interaction patterns for the whole set of NAMdPs, through the use of interaction fingerprints (IFPs).

Bone marrow findings in blast phase of polycythemia vera.

Approximately 10% of patients with polycythemia vera (PV) transform to acute leukemia (blast phase) at 10 years after initial diagnosis of PV. The bone marrow pathologic, cytogenetic, and molecular features of blast phase have not been well characterized. In this study, we reviewed 422 PV patients over a period of 11 years and identified 58 patients who developed acute myeloid leukemia (blast phase) during the course of disease. We found that blast phase of PV was characterized by overt myelodysplasia (n = 51, 88%); moderate to severe myelofibrosis (33 of 45, 73%); an abnormal karyotype (n = 51, 88%) that was often complex karyotype (n = 42, 72%); and gene mutations involving TP53 (55%), TET2 (27%), and DNMT3A (25%). Patients with blast phase of PV had an aggressive clinical course, with a median overall survival of 4 months after onset of blast phase. Eleven patients had close follow-up from polycythemic phase to blast phase: Four patients showed dysplastic changes in the polycythemic phase, and three of them transformed to blast phase without a "middle phase" of post-PV myelofibrosis.We conclude that blast phase of PV is characterized by myelodysplasia, moderate to severe fibrosis, a high frequency of an abnormal and often complex karyotype, and frequentTP53mutation.

A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms.

Ruxolitinib and azacytidine target distinct disease manifestations of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs). Patients with MDS/MPNs initially received ruxolitinib BID (doses based on platelets count), continuously in 28-day cycles for the first 3 cycles. Azacytidine 25 mg/m2 (Day 1-5) intravenously or subcutaneously was recommended to be added to each cycle starting cycle 4 and could be increased to 75 mg/m2 (Days 1-5) for disease control. Azacytidine could be started earlier than cycle 4 and/or at higher dose in patients with rapidly proliferative disease or with elevated blasts. Thirty-five patients were treated (MDS/MPN-U, n =14; CMML, n =17; aCML, n =4), with a median follow-up of 15.2 months (range, 1.0-41.5). All patients were evaluable by the 2015 international consortium proposal of response criteria for MDS/MPNs (ICP MDS/MPN) and 20 (57%) responded. Nine patients (45%) responded after the addition of azacytidine. A greater than 50% reduction in palpable splenomegaly at 24 weeks was noted in 9/14 (64%) patients. Responders more frequently were JAK2-mutated (P = .02) and had splenomegaly (P = .03) compared to nonresponders. New onset grade 3/4 anemia and thrombocytopenia occurred in 18 (51%) and 19 (54%) patients, respectively, but required therapy discontinuation in only 1 (3%) patient. Patients with MDS/MPN-U had better median survival compared to CMML and aCML (26.5 vs 15.1 vs 8 months; P = .034). The combination of ruxolitinib and azacytidine was well-tolerated with an ICP MDS/MPN-response rate of 57% in patients with MDS/MPNs. The survival benefit was most prominent in patients with MDS/MPN-U.

Characteristics and clinical significance of cytogenetic abnormalities in polycythemia vera.

Up to 20% of patients with polycythemia vera have karyotypic abnormalities at the time of the initial diagnosis. However, the cytogenetic abnormalities in polycythemia vera have not been well characterized and their prognostic impact is largely unknown. In this study, we aimed to address these issues using a large cohort of polycythemia vera patients with cytogenetic information available. The study included 422 patients, 271 in polycythemic phase, 112 with post-polycythemic myelofibrosis, 11 in accelerated phase, and 28 in blast phase. Abnormal karyotypes were detected in 139 (33%) patients, ranging from 20% in those in the polycythemic phase to 90% among patients in accelerated/blast phase. Different phases harbored different abnormalities: isolated del(20q), +8 and +9 were the most common abnormalities in the polycythemic phase; del(20q) and +1q were the most common abnormalities in post-polycythemic myelofibrosis; and complex karyotypes were the most common karyotypes in accelerated and blast phases. Patients with an abnormal karyotype showed a higher frequency of disease progression, a shorter transformation-free survival and an inferior overall survival compared with patients with a normal karyotype in the same disease phase. Cytogenetics could be effectively stratified into three risk groups, low- (normal karyotype, sole +8, +9 and other single abnormality), intermediate- (sole del20q, +1q and other two abnormalities), and high-risk (complex karyotype) groups. We conclude that cytogenetic changes in polycythemia vera vary in different phases of disease, and carry different prognostic impacts.

Morphologic and Molecular Characteristics of De Novo AML With JAK2 V617F Mutation.

Background:JAK2 V617F mutation (mut) in acute myeloid leukemia (AML) is rare. We describe the clinicopathologic findings of a single-institution series of 11 de novo AML cases with JAK2 V617. Methods: We identified cases of de novo AML with JAK2 V617F over a 10-year period. We reviewed diagnostic peripheral blood and bone marrow (BM) morphologic, cytogenetic, and molecular studies, including next-generation sequencing. The control group consisted of 12 patients with JAK2 wild-type (wt) AML matched for age, sex, and diagnosis. Results: We identified 11 patients (0.5%) with JAK2 V617F, with a median age at diagnosis of 72.5 years (range, 36-90 years). Ten neoplasms were classified as AML with myelodysplasia-related changes and 1 as AML with t(8;21)(q22;q22). All JAK2mut AML cases showed at least bilineage dysplasia, 7 of 11 showed fibrosis, 8 of 11 had an abnormal karyotype, and 5 had deletions or monosomy of chromosomes 5 and 7. Using the European LeukemiaNet (ELN) classification, 9 patients (82%) with JAK2mut AML were intermediate-2 and adverse risk. Cases of JAK2mut AML did not have mutations in other activating signaling pathways (P=.013); 7 (64%) showed additional mutations in at least one gene involving DNA methylation and/or epigenetic modification. Patients with JAK2mut AML had a significantly higher median BM granulocyte percentage (12% vs 3.5%; P=.006) and a higher frequency of ELN intermediate-2 and adverse risk cytogenetics (P=.04) compared with those with JAK2wt AML. JAK2mut AML showed higher circulating blasts, but this difference was not significant (17% vs 5.5%; P=not significant). No difference was seen in the median overall survival rate of patients with JAK2mut AML versus those with JAK2wt AML (14 vs 13.5 months, respectively). Conclusions: De novo JAK2mut AML is rare and frequently found in patients with dysplasia, BM fibrosis, and abnormal karyotype with intermediate- or high-risk features; gene mutations in DNA methylation and epigenetic-modifying pathways; and absence of gene mutations in activating signaling pathways.

An exploratory clinical trial of bortezomib in patients with lower risk myelodysplastic syndromes.

Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis and an increased risk of transformation. Few effective therapies are available for lower risk MDS patients, especially after the failure of hypomethylating agents. MDS progenitor cells are dependent on the nuclear factor-κB (NF-κB) for survival, which makes it an attractive therapeutic target. As a proteosomal inhibitor, bortezomib is thought to have inhibitory activity against NF-κB. We designed a proof-of-principle study of subcutaneous (SC) bortezomib in lower risk MDS patients with evidence of NF-κB activation in their bone marrow. Fifteen patients were treated, their median age was 71 (range 56-87), 33% were low and 67% int-1 by IPSS, median number of prior therapies was 2, all patients were transfusion dependent. Baseline median pp65 percentage was 31% and 11 patients had evidence of ring sideroblasts (RS). SC bortezomib was safe, well tolerated with no excess toxicity. Three patients out of the 15 (20%) had evidence of response with hematologic improvement (HI-E). Bortezomib caused a decrease in pp65 levels in 7 out of 13 evaluable patients (54%, P = .025). Of interest, unexpectedly, we observed a significant decrease in RS in 7 out of 10 (70%) evaluable patients during treatment. In conclusion, this study suggests that NF-κB activation, measured by pp65 levels, may be a useful biomarker in MDS. Bortezomib is safe in this patient population but has modest clinical activity. The role of the proteasome in the genesis of RS needs further study.

Donor-Derived T-Cell Large Granular Lymphocytic Leukemia in a Patient With Peripheral T-Cell Lymphoma.

T-cell large granular lymphocytic (T-LGL) leukemia after hematopoietic stem cell transplantation (SCT) is rare and its natural history and clinical outcome have not been well described. We report the clinical, morphologic, immunophenotypic, and molecular features of a case of donor-derived T-LGL leukemia in a 16-year-old man who received allogeneic SCT for peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). The patient presented with persistent neutropenia and splenomegaly 9 months after SCT when the chimerism study showed a 100% donor pattern. A splenectomy revealed T-LGL leukemia. Flow cytometric analysis showed an aberrant T-cell population positive for CD3, CD5 (dim, subset), CD7, CD8, CD16 (subset), CD57, CD94 (dim, partial), and T-cell receptor (TCR) αß, and negative for CD4, CD26, CD56, and TCRγδ. Molecular studies showed monoclonal TCRß and TCRγ gene rearrangements. Both the immunophenotype and molecular profile of the T-LGL leukemia were different from the pre-SCT PTCL. Sequencing analysis for STAT3 exon 21 did not reveal any mutation in both pre-SCT and post-SCT specimens. The patient did not receive any treatment for T-LGL leukemia; however, his count progressively increased after splenectomy, despite the presence of persistent T-LGL leukemia in the bone marrow. There was no evidence of recurrent PTCL. We propose an algorithm to diagnose this rare post-SCT neoplasm.

Insights into bonding interactions and excitation energies of 3d-4f mixed lanthanide transition metal macrocyclic complexes.

In this contribution, a computational study of equatorial bound tetranuclear macrocycle (butylene linked) [LnZn(HOMBu)]3+ (Ln = La3+, Ce3+) complexes was carried out. Here, the electronic structure, bonding interaction and excitation energies were studied within the relativistic density functional theory framework. From the electronic structure analysis, the frontier molecular orbitals (FMOs) were strongly localized in the d-orbitals of the Zn centers and the f-orbitals of the lanthanide ions. Besides, the inner MOs were found to exhibit a π-character from the organic part of the macrocyclic chain. EDA-NOCV was used as a tool for evaluating the bonding interaction, taking the trinuclear metallomacrocycle (ZnHOMBu) and the lanthanide center as fragments. This analysis showed that the interaction between these fragments was slightly covalent; with this covalency being the result of a charge transfer from the metallomacrocyclic ring to the lanthanide. This phenomenon was observed in the deformation density channels obtained from the EDA-NOCV study; in which π- and σ-charge transfer was observed. Finally, the TD-DFT study of the excitation energies evidenced three sets of bands: the first set with the highest intensity represented the ligand to metal charge transfer bands; the second set could be attributed to the 3d-4f electronic transitions between the metal centers; and the third set represented the f-f bands found for the open-shell cerium complex. This class of complexes accomplishes the "antenna effect" principle, which states that highly absorptive transition-metal (TM) complexes can be used to enhance the luminescence of poorly emissive systems, and are introduced in this study as self-sensitizer bimetallic d-f systems with potential applications in near infra-red (NIR) technologies.