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Abstract: Nonmelanoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofibrosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2 V617F , CALR ins5 or CALR del52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk., (© 2023. The Author(s).)

BACKGROUND: Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. METHODS: We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures. RESULTS: From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events. CONCLUSIONS: In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)

TNFα and NF-kB contribute in activation of pro-inflammatory signaling pathways and complications of coronary artery diseases (CAD). Current study highlights novel properties of Au (15 ± 2 nm), ZnO (77 ± 45 nm) and MgO (11 ± 4 nm) nanoparticles (NPs) as possible anti-inflammatory agents with greater efficacy and lower toxicity. Decrease in TNFα and NF-kB levels in Single Vessel Disease (SVD), Double Vessel Disease (DVD) and Triple-Vessel coronary artery disease (TVD) macrophage and lymphocyte cultures at varying concentrations of NPs has been studied to find an effective therapeutic concentration (ETC). Au and MgO NPs exhibits 5 µg/ml ETC compared to 1 µg/ml ZnO in all three CAD categories with negligible toxicity. ZnO remains most statistically significant (p < 0.001) in SVD and TVD cultures whereas MgO shows efficacy in DVD and TVD cultures with more than 50% reduction in TNFα and NF-kB levels at their respective ETCs. Au NPs exhibit prominent effect in DVD cultures. The mRNA expression results support the down-regulation of TNFα and NF-kB after NPs exposure in respective cultures. Findings of this prospective observational cohort study suggest use of NPs as an alternate anti-inflammatory agent in coronary artery and other diseases., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Background: Myelofibrosis (MF) is a blood cancer associated with splenomegaly, blood count abnormalities, reduced life expectancy and high prevalence of disease-associated symptoms. Current treatment options for MF are diverse, with limited data on management strategies in real-world practice in the United Kingdom., Methods: The REALISM UK study was a multi-center, retrospective, non-interventional study, which documented the early management of patients with MF. The primary endpoint was the time from diagnosis to active treatment., Discussion: Two hundred patients were included (63% [ n  = 126/200] with primary MF; 37% [ n  = 74/200] with secondary MF). Symptoms and prognostic scores at diagnosis were poorly documented, with infrequent use of patient reported outcome measures. 'Watch and wait' was the first management strategy for 53.5% ( n  = 107/200) of patients, while the most commonly used active treatments were hydroxycarbamide and ruxolitinib. Only 5% of patients proceeded to allogeneic transplant. The median (IQR) time to first active treatment was 46 days (0-350); patients with higher risk disease were prescribed active treatment sooner., Conclusion: These results provide insight into real-world clinical practice for patients with MF in the United Kingdom. Despite the known high prevalence of disease-associated symptoms in MF, symptoms were poorly documented. Most patients were initially observed or received hydroxycarbamide, and ruxolitinib was used as first-line management strategy in only a minority of patients., Plain Language Summary: Background: Myelofibrosis is a rare blood cancer associated with symptoms that can seriously affect a patient's daily life, such as enlarged spleen and decreased white and red blood cells. Although several treatments are available for patients with myelofibrosis, it is not clear which ones clinicians use most frequently. Methods: We aimed to review which treatments are usually given to patients with myelofibrosis in the UK, by collecting information from the medical records of 200 patients with myelofibrosis treated in different centres across the UK. Results: The results showed that the symptoms patients experienced were not always written down in the medical records. Similarly, clinical scores based on patient characteristics (which clinicians use to try to predict if a patient will respond to treatment well or not) were also missing from the medical records. Clinicians also rarely asked patients to complete questionnaires that try to measure the impact of myelofibrosis and its treatment on their health. The most common approach for patients with myelofibrosis in the UK was 'watch and wait', which over half of patients received. The most common drugs used for treatment were hydroxycarbamide and ruxolitinib; only a very small proportion of patients received a bone marrow transplant. On average, patients waited for 46 days before receiving a treatment, although patients considered to have a more aggressive type of disease received treatment sooner. Conclusion: The results of this study suggest that medical records can be missing key information, which is needed to decide which is the best way to treat a patient with myelofibrosis. They also suggest that clinicians in the UK prefer observation to treatment for a large number of patients with myelofibrosis. This could mean that the approach used for many patients with myelofibrosis does not help them to control symptoms that have an impact on their daily lives., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AJM has consulted for Novartis, Bristol Myers Squibb/Celgene, and AbbVie, has received research funding from Novartis, Bristol Myers Squibb/Celgene, and CTI BioPharma, has received honoraria from Novartis and CTI BioPharma, and has served on the speaker’s bureau for Novartis. NB has received speaker fees, advisory board and sponsored meeting attendance fees from Novartis. AW has received consulting fees and an educational grant from Novartis. JE has received speaker fees, advisory board and sponsored meeting attendance fees from Novartis. JM has received speaker fees and advisory board fees from Novartis. RB and GC are employees of Novartis. JH is an employee of OPEN VIE. TS has received consulting fees and an educational grant from Novartis. All other authors have no conflict of interest to declare., (© The Author(s), 2022.)

Background: Population based data suggest the proportion of patients failing imatinib in chronic myeloid leukaemia (CML) is higher than the reported one-third of patients in clinical trials. Clinical trials have demonstrated second generation tyrosine kinase inhibitors (TKI) dasatinib and nilotinib can restore complete cytogenetic remission (CCR) and major molecular response (MMR) to many patients failing imatinib, but their impact in the general population is not clear., Design and Methods: We report CML outcome in a population of 2.3 million people in a geographically contiguous area of North West England and North Wales., Results: Between 2003 and 2009, 192 new CML cases were diagnosed, of whom 184 were in chronic phase and 160 started on imatinib. The maximal CCR rate was 65% at 24 months and the maximal MMR rate was 50% at 36 months. Patients diagnosed since second generation TKI became available for imatinib failure had a more rapid cumulative CCR and MMR rate and a significantly improved progression free survival (p=0.022) than those diagnosed before this time., Conclusion: The study indicates that second generation TKI have improved CML outcome in the general population., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Iron-palladium nanoalloy in the particle size range of 15-30 nm is synthesized by the relatively low temperature thermal decomposition of coprecipitated [Fe(Bipy)(3)]Cl(2) and [Pd(Bipy)(3)]Cl(2) in an inert ambient of dry argon gas. The silvery black Fe-Pd alloy nanoparticles are air-stable and have been characterized by EDX-RF, XRD, AFM, TEM, magnetometry, (57)Fe Mössbauer and impedance spectroscopy. This Fe-Pd nanoalloy is in single phase and contains iron sites having up to 11 nearest-neighboring atoms. It is superparamagnetic in nature with high magnetic susceptibility, low coercivity and hyperfine field.

The BCR-ABL fusion protein is characteristic of chronic myeloid leukaemia and may be an effective tumour-specific antigen. CD8+ T cell responses to BCR-ABL fusion peptides have been reported in normal subjects and CML patients but CD4+ T cell responses have been less well characterised. Here, the 23-mer e14a2 fusion peptide VHSATGFKQSSKALQRPVASDFE has been used to stimulate T cell responses. Most normal subjects and CML patients showed no proliferative responses to this peptide, with stimulation indices not significantly greater than 1.0. Following a second stimulation with the same peptide, small proliferative responses were obtained in normal subjects but not CML patients. These responses were not improved following a third stimulation with 23-mer peptide, nor by using mature autologous dendritic cells to present the peptide. Intracellular interferon-gamma production by CD4+ T cells was also not induced by the 23-mer e14a2 peptide. Hence, this e14a2 peptide does not stimulate CD4+ T cell proliferation in vitro in most normal subjects or CML patients. The precise sequence of amino acids may be critical in defining immunogenicity for CD4+ T cell responses against BCR-ABL peptides.

Background and Objectives: The fusion oncoprotein bcr-abl that characterizes chronic myeloid leukemia (CML) is a leukemia-specific antigen, which may be immunogenic in vivo. KQSSKALQR and GFKQSSKAL, peptide sequences spanning the b3a2 bcr-abl junction, have affinity for HLA-A3 and HLA-B8, respectively, and we have shown the presence of KQSSKALQR on the surface of CML cells. We analyzed the existence of bcr-abl-specific T cells in vivo and correlated their presence to contemporary disease burden., Design and Methods: We investigated circulating CD8+ T lymphocytes directed against the bcr-abl junction, using fluorochrome-labeled tetramers of HLA-A3 with KQSSKALQR and of HLA-B8 with GFKQSSKAL, and flow cytometry analysis. Using chromium-release assays and interferon-g ELISPOT assays, we also studied the functionality of these expanded T cells., Results: Eight of 12 b3a2+ HLA-A3+ and/or HLA-B8+ CML patients studied serially on at least three occasions had bcr-abl junction-specific CD8+ T cells. Specific T cells were more likely to be found in patients with a low leukemic burden (p=0.03). Three of 18 HLA-A3+ and/or HLA-B8+ healthy donors had bcr-abl junction-specific T cells, though these were not detected in any of 13 subjects who were HLA-A3- and HLA-B8-. Bcr-abl-specific T cells were expandable in vitro in three of seven healthy donors and five of seven CML patients., Interpretation and Conclusions: Bcr-abl-specific T cells are detectable in CML patients, and might contribute to leukemic control. The occurrence of specific CD8+ T cells in some healthy donors might represent an immune response to occult BCR-ABL rearrangements.

We studied the iron status of 32 evaluable adult acute myeloid leukaemia (AML) survivors who were entered into the UK Medical Research Council acute myeloid leukaemia (AML) 10 and 12 trials at our institution between 1988 and 1998. Patients were required to have been independent of all blood products for at least 3 years. As a group, the median first serum ferritin level was 1323 mug/l (NR 19-300 mug/l) at a median of 1321 days from the last transfusion confirming the presence of significant iron overload persisting for some years after completion of all therapy and blood products. There was a general trend for the serum ferritin level to fall with time, but the fall was less pronounced in men and carriers of the C282Y mutation. Recipients of autologous stem cell transplantation (SCT) had a higher median first serum ferritin level (3245 mug/l) than patients who received chemotherapy alone (1148 mug/l) or allogeneic SCT (1334 mug/l) because of increased use of transfused blood. Nine of the 10 recipients of autologous SCT underwent venesection. No evidence of end organ damage was seen in any patient. Serial monitoring of serum ferritin and assessment of the C282Y status may be useful in all long-term AML survivors, especially autograft recipients.

We report our experience of CD34 positive selection as a means of graft T-cell depletion (TCD) in 14 consecutive HLA-identical Peripheral blood stem cells (PBSC) allografts as prophylaxis against graft versus host disease (GVHDp). CD34 positive selection was performed by immunomagnetic separation achieving a median CD34 and T-cell dose of 4.17 (range 1.4-8.50) x 10(6)/kg and 1.89 (range 0.92-13.18) x 10(4)/kg, respectively, in the graft. This represents 4-log depletion of T-cells. The median time to achieve a neutrophil count of 0.5 x 10(9)/l was 15 days and to achieve a platelet count of 50 x 10(9)/l was 20 days. Only four patients developed acute GVHD at a median of 41 days but this was exclusively mild grade I cutaneous disease and settled with oral steroids. Four patients, all of whom had AML, relapsed or progressed after transplant at a median of 161 (range 109-311) days. One of these had been transplanted in early relapse (9% blasts) whilst another was in second remission. The remaining 10 patients are alive and well. The median progression free survival for the whole population is 69% at 686 days. We conclude that CD34 positive selection by immunomagnetic separation in HLA-identical PBSC allografting achieves significant TCD with clinically trivial acute GVHD, prompt engraftment and an acceptable disease relapse risk.

Peptide extracts of rat brain powerfully inhibited the cyclic AMP phosphodiesterase activity of rat brain homogenate. Similar extracts of ox brain showed comparable although less potent activity. Preliminary investigation of the physicochemical properties of brain extracts indicated that the rat brain extract contained an active peptide of low molecular weight (about 1400), whereas ox brain contained two such peptides (about 1400 and 900). These studies indicate that endogenous oligopeptides that inhibit cyclic AMP phosphodiesterase are present in brain. Experiments on several pure peptides known to be present in brain. Experiments on several pure peptides known to be present in the CNS showed that the majority were inactive against brain phosphodiesterase, but ACTH(1-24), somatostatin, substance P and Lys8-vasopressin, in descending order of potency, were active. To help distinguish the peptides found in rat and ox brain extracts from known peptides, preliminary analyses of amino acid composition were performed. These suggested that the peptides found in brain extracts were distinct from known peptides having the ability to inhibit cyclic AMP phosphodiesterase.

Of 7 phosphodiesterase inhibitors tested for ability to induce a quasi-morphine withdrawal syndrome (QMWS) in opiate-naive rats, five were effective in a dose-related way. These, in descending order of potency, were IBMX, ICI-63197, RO-201724, theophylline and caffeine. Their potencies in inducing a QMWS correlated significantly (P less than 0.05) with those in inhibiting low Km cyclic AMP phosphodiesterase of rat brain homogenate. There was no correlation with potencies in inhibiting cyclic GMP phosphodiesterase.

Mammalian serum and plasma contain an endogenous inhibitor of prostaglandin synthetase (EIPS). Human plasma fractions rich in EIPS show anti-inflammatory activity in vivo. In rats, glucocorticoids raise EIPS activity of plasma and serum. These findings suggest the existence of a natural mechanism of controlling prostaglandin synthesis, possibly related to corticosteroid action.