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The current standard‐of‐care for treatment of myelofibrosis (MF) comprises inhibitors of the Janus kinase (JAK)/signal transducers and activators (STAT) pathway; however, despite their ability to alleviate symptoms, they do not appear to modify underlying disease and have not demonstrated substantial survival benefit. Allogeneic‐hematopoietic stem cell transplantation remains the only curative option for patients with MF but is limited to a subset of high‐risk and fit patients. Early disease modification could positively affect disease trajectory for lower risk patients with MF as well as those with conditions that can precede MF, such as polycythemia vera and essential thrombocythemia. Here, the authors discuss critical unmet needs in the MF treatment paradigm, including: the need for safe, impactful therapies for lower risk patients, thus allowing intervention when success is most likely; better development of first‐line therapies (likely highly novel or combination strategies) for intermediate‐risk/higher risk patients; and approved drugs to manage cytopenia. Finally, a consensus definition of disease modification is needed that informs trial design, allowing the development of clinical end points that enable understanding of therapies and responses and that facilitate the development of therapies that work according to this definition. Through close collaboration between clinicians, patients, and the pharmaceutical industry, better efforts to define benefit and identify patients most likely to benefit from a particular combination or treatment strategy should enable the development of more effective and safe treatments to extend and improve quality of life for patients with MF. Early disease modification could positively affect the disease trajectory for patients with myelofibrosis. Herein, the authors discuss critical unmet needs in the myelofibrosis treatment paradigm, including safe therapies for lower risk patients, better development of first‐line therapies for intermediate‐risk/higher risk patients, approved drugs to manage cytopenia, and a consensus definition of disease modification. [ABSTRACT FROM AUTHOR]

Copyright of Journal der Deutschen Dermatologischen Gesellschaft is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: Pruritus is a cross‐disciplinary leading symptom of numerous diseases and represents an interdisciplinary diagnostic and therapeutic challenge. In contrast to acute pruritus, chronic pruritus (CP) is a symptom of various diseases that is usually difficult to treat. Scratching and the development of scratch‐associated skin lesions can alter the original skin status. In the presence of an itch‐scratch‐cycle, even secondary diseases such as chronic prurigo can develop. Chronic pruritus leads to considerable subjective suffering of those affected, which can result in restrictions on the health‐related quality of life such as sleep disturbances, anxiety, depressiveness, experience of stigmatization and/or social withdrawal up to clinically relevant psychic comorbidities. Medical care of patients should therefore include (a) interdisciplinary diagnosis and therapy of the triggering underlying disease, (b) therapy of the secondary symptoms of pruritus (dermatological therapy, sleep promotion, in the case of an accompanying or underlying psychological or psychosomatic disease an appropriate psychological‐psychotherapeutic treatment) and (c) symptomatic antipruritic therapy. The aim of this interdisciplinary guideline is to define and standardize the therapeutic procedure as well as the interdisciplinary diagnosis of CP. This is the short version of the updated S2k‐guideline for chronic pruritus. The long version can be found at www.awmf.org. [ABSTRACT FROM AUTHOR]

Hereditary pyrimidine 5‐nucleotidase (P5′N‐1) deficiency is a very rare disorder. Here, we describe a new mutation in a Turkish family. Although functional tests have not been performed, our findings confirm that the homozygous mutational state leads to clinical manifest P5′N‐1 deficiency, while heterozygosity does not lead to hemolysis or anemia. [ABSTRACT FROM AUTHOR]

Summary: Dyskeratosis Congenita (DKC) is a systemic disorder caused by mutations resulting in impaired telomere maintenance. Clinical features include bone marrow failure and an increased risk of developing hematological malignancies. There are conflicting data whether androgen derivatives (AD) can elongate telomeres in vivo and whether AD treatment enhances the risk of gaining myelodysplastic syndrome‐related mutations. Seven TERC or TERT‐mutated DKC patients underwent AD treatment. All patients revealed hematological response. Telomere length of lymphocytes and granulocytes increased significantly and no MDS‐related mutations were detected. Pending longer follow‐up, treatment with AD seems to represent an efficient and safe therapy for DKC patients. [ABSTRACT FROM AUTHOR]

COVID‐19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID‐19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental "cytokine storm", such as Janus‐activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55‐yo patient with proven COVID‐19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in‐label for co‐existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID‐19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS‐CoV‐2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID‐19 pneumonia, preventing cytokine storm and ARDS. [ABSTRACT FROM AUTHOR]

Assessment of telomere length (TL) in peripheral blood leukocytes is part of the diagnostic algorithm applied to patients with acquired bone marrow failure syndromes (BMFSs) and dyskeratosis congenita (DKC). Monochrome multiplex–quantitative polymerase chain reaction (MM–qPCR) and fluorescence in situ hybridization (flow‐FISH) are methodologies available for TL screening. Dependent on TL expressed in relation to percentiles of healthy controls, further genetic testing for inherited mutations in telomere maintenance genes is recommended. However, the correct threshold to trigger this genetic workup is still under debate. Here, we prospectively compared MM–qPCR and flow‐FISH regarding their capacity for accurate identification of DKC patients. All patients (n = 105) underwent genetic testing by next‐generation sequencing and in 16 patients, mutations in DKC‐relevant genes were identified. Whole leukocyte TL of patients measured by MM–qPCR was found to be moderately correlated with lymphocyte TL measured by flow‐FISH (r² = 0.34; P < 0.0001). The sensitivity of both methods was high, but the specificity of MM–qPCR (29%) was significantly lower compared with flow‐FISH (58%). These results suggest that MM–qPCR of peripheral blood cells is inferior to flow‐FISH for clinical routine screening for suspected DKC in adult patients with BMFS due to lower specificity and a higher rate of false‐positive results. [ABSTRACT FROM AUTHOR]

Copyright of Research Synthesis Methods is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post-ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin. [ABSTRACT FROM AUTHOR]

Key Clinical Message Acquired von Willebrand syndrome may be related to plasma cell dyscrasia and can cause severe bleeding complications. Treatment, for example, with intravenous immunoglobulins may be indicated in selected cases. Physicians treating plasma cell dyscrasia have to be aware of bleeding complications in these patients, and clarification is necessary. [ABSTRACT FROM AUTHOR]

The randomized, double-blind, double-dummy, phase 3b RELIEF trial evaluated polycythaemia vera ( PV)-related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV-related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID ( n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm -symptom assessment form total symptom score cytokine symptom cluster ( TSS-C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib- and hydroxycarbamide-treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82-4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13-16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening-to-baseline TSS-C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV-related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement. [ABSTRACT FROM AUTHOR]

A robust method for the synthesis of benzo[ c]isothiazole 2-oxides has been developed providing a range of functionalized derivatives starting from anilines and DMSO. The reaction sequence can be performed on a gram scale and leads to products that can easily be modified by standard cross-coupling reactions. [ABSTRACT FROM AUTHOR]

The transcription factor RUNX1 is essential to establish the haematopoietic gene expression programme; however, the mechanism of how it activates transcription of haematopoietic stem cell (HSC) genes is still elusive. Here, we obtained novel insights into RUNX1 function by studying regulation of the human CD34 gene, which is expressed in HSCs. Using transgenic mice carrying human CD34 PAC constructs, we identified a novel downstream regulatory element (DRE), which is bound by RUNX1 and is necessary for human CD34 expression in long-term (LT)-HSCs. Conditional deletion of Runx1 in mice harbouring human CD34 promoter-DRE constructs abrogates human CD34 expression. We demonstrate by chromosome conformation capture assays in LT-HSCs that the DRE physically interacts with the human CD34 promoter. Targeted mutagenesis of RUNX binding sites leads to perturbation of this interaction and decreased human CD34 expression in LT-HSCs. Overall, our in vivo data provide novel evidence about the role of RUNX1 in mediating interactions between distal and proximal elements of the HSC gene CD34. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article on therapy for severe immune thrombocytopenia in a previous issue of the journal.

Summary. We report the development of secondary acute myeloid leukaemia (AML) with monosomy 7 in identical twins, both at the age of 52 years. In the first twin, induction therapy resulted in complete remission (CR). At relapse 9 months later monosomy 7 was found. The patient died of sepsis 11 months after diagnosis. The other twin presented with leucopenia and thrombocytopenia and refractory anaemia (RA) was diagnosed. During follow-up, fluorescence in situ hybridization analysis demonstrated a monosomy 7 in 11% of the cells. Twenty-eight months following diagnosis the patient progressed to RA with excess blasts in transformation and induction chemotherapy was initiated without achieving CR. Three months later an allogeneic stem cell transplantation from a niece was performed, resulting in CR of the secondary AML. [ABSTRACT FROM AUTHOR]