Effect of non-pharmacological interventions on symptoms and quality of life in patients with hematological malignancies - A systematic review.

BACKGROUND: Non-pharmacological interventions have the potential to enhance health-related quality of life (HRQoL) through symptom management. This systematic review aims to identify, collate, and assess randomized controlled trials investigating the effect of non-pharmacological interventions on symptoms and HRQoL within hematology. METHODS: MEDLINE/PUBMED, EMBASE, CINAHL, PSYCINFO and COCHRANE were searched up to April 2021. Outcomes were changes in symptoms and HRQoL. RESULTS: Sixty-five studies were categorized into five intervention types: Mind/body (n=9), Web-based (n=9), Music/art (n=6), Consultation-based (n=4), and Physical activity (n=37). We found significantly reduced fatigue (n=12 studies), anxiety (n=8) and depression (n=7), with 11 studies showing significant improvements in HRQoL. CONCLUSIONS: The evidence for non-pharmacological interventions shows substantial variation in efficacy and methodological quality. While specific symptoms and HRQoL outcomes significantly favored the intervention, no particular intervention can be emphasized as more favorable, given the inability to conduct a meta-analysis.

Detailed Long-Term Follow-Up of Patients Who Relapsed After the Nordic Mantle Cell Lymphoma Trials: MCL2 and MCL3.

Mantle cell lymphoma (MCL) is an incurable disease with a highly variable clinical course. The prognosis after relapse is generally poor, and no standard of care exists. We investigated the postrelapse outcomes of 149 patients who were initially treated in the Nordic Lymphoma Group trials, MCL2 or MCL3, both representing intensive cytarabine-containing frontline regimens including autologous stem cell transplant. Patients with progression of disease before 24 months (POD24, n = 51, 34%) displayed a median overall survival of 6.6 months compared with 46 months for patients with later POD (n = 98, 66%; P < 0.001). MCL international prognostic index, cell proliferation marker, blastoid morphology, and TP53 mutations showed independent prognostic value irrespective of POD24, and in a combined, exploratory risk score, patients with 0, 1, 2-3, or 4-5 high-risk markers, respectively, displayed a 5-year overall survival of 62%, 39%, 31%, and 0%. By a comparison of median progression-free survival of the different salvage therapies in the relapse setting, bendamustine-rituximab was superior to all other combination chemotherapy regimens; however, it was also associated with longer responses to last line of therapy. Collectively, we confirm the prognostic impact of POD24 and highlight the relevance of other biomarkers, and we emphasize the importance of novel therapies for patients with high-risk features at first POD.

Apheresis principles in a patient with chronic myeloid leukemia during pregnancy: challenges in cell separation and assessing transcript levels.

BACKGROUND: Chronic myeloid leukemia (CML) is rarely diagnosed in pregnant women. CASE REPORT: We report a case of a pregnant woman who presented with a leukocyte count of 250 × 109 cells/L at gestational age (GA) 26 weeks and was diagnosed with CML in the chronic phase. Because the patient deliberately opted out of interferon α and tyrosine kinase inhibitor treatment, the main goal was to reduce the leukocyte count to postpone delivery beyond the number of weeks considered severely premature and avoid thromboembolic complications while continuously evaluating the clinical safety of the mother and fetus. Hence therapeutic leukapheresis was initiated, and we report the first application of an apheresis approach for this procedure using the Spectra Optia instrument without sedimentation agents. Leukapheresis was conducted 2 to 4 times per week for 9 weeks. RESULTS: During treatment the leukocyte count decreased remarkably, and the patient developed lymphopenia together with a paradoxical increase in her blood platelet count. Premature labor was induced at GA 35 weeks, and a healthy boy was delivered. Thereafter, the patient initiated imatinib treatment and was in major molecular and complete cytogenetic remission after 1 year. Despite the remarkable reduction of the leukocyte count, we observed a pronounced increase in expression of BCR-ABL1 transcripts, implying the need for close monitoring of patients with CML during pregnancy. CONCLUSIONS: We report a pregnant woman who was diagnosed with CML and treated solely with apheresis procedures using the Spectra Optia instrument for 9 weeks, ensuring the safe delivery of her child.

NSP4 is stored in azurophil granules and released by activated neutrophils as active endoprotease with restricted specificity.

Whereas neutrophil elastase, cathepsin G, and proteinase 3 have been known as granule-associated serine proteases of neutrophils for decades, a fourth member, called neutrophil serine protease 4 (NSP4), was just recently described and provisionally characterized. In this study, we identified NSP4 as a novel azurophil granule protein of neutrophils by Western blot analyses of subcellular fractions as well as by RT-PCR analyses of neutrophil precursors from human bone marrow. The highest mRNA levels were observed in myeloblasts and promyelocytes, similar to myeloperoxidase, a marker of azurophil granules. To determine the extended sequence specificity of recombinant NSP4, we used an iterative fluorescence resonance energy transfer-based optimization strategy. In total, 142 different peptide substrates with arginine in P1 and variations at the P1', P2', P3, P4, and P2 positions were tested. This enabled us to construct an α1-proteinase inhibitor variant (Ile-Lys-Pro-Arg-/-Ser-Ile-Pro) with high specificity for NSP4. This tailor-made serpin was shown to form covalent complexes with all NSP4 of neutrophil lysates and supernatants of activated neutrophils, indicating that NSP4 is fully processed and stored as an already activated enzyme in azurophil granules. Moreover, cathepsin C was identified as the activator of NSP4 in vivo, as cathepsin C deficiency resulted in a complete absence of NSP4 in a Papillon-Lefèvre patient. Our in-depth analysis of NSP4 establishes this arginine-specific protease as a genuine member of preactivated serine proteases stored in azurophil granules of human neutrophils.

MicroRNA-130a-mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-ß1 stimulation in granulocytic precursors.

Smad4 is important in the TGF-ß pathway and required for transcriptional activation and inhibition of cell growth after TGF-ß1 stimulation. We demonstrate that miR-130a is differentially expressed during granulopoiesis and targets Smad4 mRNA. The transcript for Smad4 is present throughout neutrophil maturation, but Smad4 protein is undetectable in the most immature cells, where miR-130a is highly expressed. Two miR-130a binding sites were identified in the 3'-untranslated region of the Smad4 mRNA. Overexpression of miR-130a in HEK293, A549, and 32Dcl3 cells repressed synthesis of Smad4 protein without affecting Smad4 mRNA level. Repression of Smad4 synthesis in a granulocytic cell line by miR-130a reduced its sensitivity to TGF-ß1-induced growth inhibition. This effect was reversed by inhibiting the activity of miR-130a with an antisense probe or by expressing a Smad4 mRNA lacking miR-130a binding sites. High endogenous miR-130a and Smad4 mRNA levels and low expression of Smad4 protein were found in the t(8;21)(q22;q22) acute myelogenous leukemia-derived cell line Kasumi-1. When miR-130a was inhibited by an antisense RNA, the amount of Smad4 protein increased in Kasumi-1 cells and rendered it susceptible for TGF-ß1-mediated cell growth inhibition. Our data indicate that miR-130a is involved in cell cycle regulation of granulocytic cells through engagement of Smad4 in the TGF-ß pathway.