European Stop Tyrosine Kinase Inhibitor Trial (EURO-SKI) in Chronic Myeloid Leukemia: Final Analysis and Novel Prognostic Factors for Treatment-Free Remission.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The European Stop Kinase Inhibitors (EURO-SKI) study is the largest clinical trial for investigating the cessation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in stable deep molecular remission (DMR). Among 728 patients, 434 patients (61%; 95% CI, 57 to 64) remained in major molecular response (MMR) at 6 months and 309 patients of 678 (46%; 95% CI, 42 to 49) at 36 months. Duration of TKI treatment and DMR before TKI stop were confirmed as significant factors for the prediction of MMR loss at 6 months. In addition, the type of BCR::ABL1 transcript was identified as a prognostic factor. For late MMR losses after 6 months, TKI treatment duration, percentage of blasts in peripheral blood, and platelet count at diagnosis were significant factors in multivariate analysis. For the entire study period of 36 months, multiple logistic regression models confirmed duration of treatment, blasts, and transcript type as independent factors for MMR maintenance. In addition to the duration of treatment, transcript type as well as blasts in peripheral blood at diagnosis should be considered as important factors to predict treatment-free remission.

Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis: A retrospective analysis of the DRST and GREM registries.

We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia [MCL]) in two national registries (DRST/GREM) who received an allogeneic hematopoietic cell transplantation (alloHCT) performed in Germany from 1999-2021. Median overall survival (OS) of ASM/SM-AHN (n = 30, 45%), SM-AML (n = 28, 39%) and MCL ± AHN (n = 13, 19%) was 9.0, 3.3 and 0.9 years (P = 0.007). Improved median OS was associated with response of SM (17/41, 41%; HR 0.4 [0.2-0.9], P = 0.035) and/or of AHN (26/43, 60%, HR 0.3 [0.1-0.7], P = 0.004) prior to alloHCT. Adverse predictors for OS included absence of KIT D816V (10/61, 16%, HR 2.9 [1.2-6.5], P < 0.001) and a complex karyotype (9/60, 15%, HR 4.2 [1.8-10.0], P = 0.016). HLA-match, conditioning type or transplantation at centers reporting above-average alloHCTs (≥7) had no impact on OS. Taking into account competing events at years 1, 3 and 5, relapse-related mortality and non-relapse mortality rate were 15%/23%, 20%/30% and 23%/35%, respectively. Irrespective of subtype, subsequent treatment response was achieved in 13/30 (43%) patients and was highest on midostaurin/avapritinib (7/9, 78%). We conclude that outcome of alloHCT in AdvSM is more affected by disease phenotype and treatment response prior to transplant than by transplant characteristics.

Poor Applicability of Currently Available Prognostic Scoring Systems for Prediction of Outcome in KIT D816V-Negative Advanced Systemic Mastocytosis.

Within our nationwide registry, we identified a KIT D816V mutation (KIT D816Vpos.) in 280/299 (94%) patients with advanced systemic mastocytosis (AdvSM). Age, cytopenias and the presence of additional somatic mutations confer inferior overall survival (OS). However, little is known about the characteristics of KIT D816V-negative (D816Vneg.) AdvSM. In 19 D816Vneg. patients, a combination of clinical, morphological and genetic features revealed three subgroups: (a) KIT D816H- or Y-positive SM (KIT D816H/Ypos., n = 7), predominantly presenting as mast cell leukemia (MCL; 6/7 patients), (b) MCL with negative KIT sequencing (KITneg. MCL, n = 7) and (c) KITneg. SM with associated hematologic neoplasm (KITneg. SM-AHN, n = 5). Although >70% of patients in the two MCL cohorts (KIT D816H/Ypos. and KITneg.) were classified as low/intermediate risk according to prognostic scoring systems (PSS), treatment response was poor and median OS was shorter than in a KIT D816Vpos. MCL control cohort (n = 29; 1.7 vs. 0.9 vs. 2.6 years; p < 0.04). The KITneg. SM-AHN phenotype was dominated by the heterogeneous AHN (low mast cell burden, presence of additional mutations) with a better median OS of 4.5 years. We conclude that (i) in MCL, negativity for D816V is a relevant prognostic factor and (ii) PSS fail to correctly classify D816Vneg. patients.

Treatment with the apoptosis inhibitor Asunercept reduces clone sizes in patients with lower risk Myelodysplastic Neoplasms.

In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described as possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement in a clinical phase I trial for low-risk MDS patients (NCT01736436; 2012-11-26). In the current study we aimed to evaluate the effect of Asunercept therapy on the clonal bone marrow composition to identify potential biomarkers to predict response. Bone marrow samples of n = 12 low-risk MDS patients from the above referenced clinical trial were analyzed by serial deep whole exome sequencing in a total of n = 58 time points. We could distinguish a mean of 3.5 molecularly defined subclones per patient (range 2-6). We observed a molecular response defined as reductions of dominant clone sizes by a variant allele frequency (VAF) decrease of at least 10% (mean 20%, range: 10.5-39.2%) in dependency of Asunercept treatment in 9 of 12 (75%) patients. Most of this decline in clonal populations was observed after completion of 12 weeks treatment. Particularly early and pronounced reductions of clone sizes were found in subclones driven by mutations in genes involved in regulation of methylation (n = 1 DNMT3A, n = 1 IDH2, n = 1 TET2). Our results suggest that APG101 could be efficacious in reducing clone sizes of mutated hematopoietic cells in the bone marrow of Myelodysplastic Neoplasms, which warrants further investigation.

A clinical, morphological and molecular study of 70 patients with gastrointestinal involvement in systemic mastocytosis.

In 70 patients with KIT D816V positive systemic mastocytosis (SM) including 36 patients with advanced SM (AdvSM), we correlated the extent of reported mucosal mast cell ([m]MC) infiltration of the upper and/or lower gastrointestinal tract (UGIT, n = 63; LGIT, n = 64; both, n = 57) with symptoms and markers of MC burden/subtype. GI symptoms were reported by all patients (mean 2.1 number of symptoms). A strong mMC infiltration was identified in 24 patients (UGIT, 17/63, 27%; LGIT, 19/64, 30%). Concurrent involvement of UGIT and LGIT (n = 12) correlated with female gender (75%) and a higher symptom burden (mean 2.7) but not with MC burden or subtype. Significant differences between non-AdvSM and AdvSM were reported regarding food intolerance (54% vs. 17%), cramping (54% vs. 22%) and weight loss (0% vs. 64%). KIT D816V was identified in 54/56 (96%) available biopsies. In 46 patients, digital PCR revealed a correlation with low albumin levels (r = - 0.270, P = 0.069) and the KIT D816V VAF in peripheral blood (r = 0.317, P = 0.036) but not with the extent of mMC infiltration or markers of MC burden/subtype. Although MC mediator triggered GI symptoms have a substantial impact on the quality of life, correlation to objective disease parameters is lacking thus making its systematic assessment challenging.

Analysis of Burnout Prevalence among German Physicians Working in a Palliative Care Setting: A Survey of the AIO Quality of Life Working Group.

INTRODUCTION: Palliative care physicians (Pcps) face special challenges caring for terminally ill patients. We conducted this study to evaluate the burnout (bo) prevalence among pcps and sought to identify risk as well as protective factors as a basis for the development of preventive measures. METHODS: Participants (Pcs) were invited via e-mail to complete an online survey between May and June 2022. Besides the Oldenburg Burnout Inventory assessing the bo dimensions of exhaustion (exh) and disengagement (dis), sociodemographic data were collected. RESULTS: The study found that 58% (cut-off mean value [M] ≥2.18) or more specifically, 38% (cut-off M ≥2.5) of the pcs showed increased scores in the exh subscale as a key dimension of bo. All dimensions were correlated with the level of medical and palliative care training, with higher scores for physicians in training. Furthermore, pcs without preventive measures like employee appraisals at work were more likely to be considered exhausted, disengaged, or burned out. The discrepancy between high exh and low dis scores shows that the polled pcps, despite feeling exh, nevertheless considered their work meaningful. CONCLUSION: Bo prevalence among pcps exceeds that of the general population and other specialties, whereas inexperienced pcps might be at high risk of shifting from exh to bo and could therefore benefit from tailored support. Further preventive measures including individual and organizational aspects are necessary to prevent bo and promote health among medical staff, thereby preserving quality of patient care. Elementary preventive measures such as employee appraisals can have a protective effect against bo.

Hemodynamic and Stress Response After Sound Intervention with Different Headphone Systems: A Double-Blind Randomized Study in Healthy Volunteers Working in the Health Care Sector.

Objectives: Two headphone systems using different sound systems were compared to investigate the effects of a sound intervention on cardiovascular parameters, indicators of stress, and subjective feelings. Methods: One hundred volunteers who work in the health care sector reporting elevated workplace-related stress were enrolled and randomized to a 12-min sound intervention (classical music) with either conventional headphones ("MEZE 99 Classic") or with the same-but internally modified-headphone (called "Lautsaenger"). Cardiovascular parameters were measured with the VascAssist2.0, both before and after sound interventions. In addition, participants were asked to complete questionnaires on burnout risk and emotions/stress. Results: The study population consisted mainly of female participants (n = 83), with the majority being students (42%). Median age was 32.5 years (range 21-71). In terms of cardiovascular parameters, a significant reduction in aortic pulse wave velocity, as measure of arterial stiffness, and heart rate was observed within both treatment arms. Both systolic blood pressure and arterial flow resistance were reduced by sound intervention, while these effects were only documented with Lautsaenger. Treatment groups were comparable in terms of subjective feedback by participants: a significant increase in emotional wellbeing was achieved with both headphone systems. Conclusions: A single short-term sound intervention seems to be able to achieve objective cardiovascular improvements in healthy volunteers reporting subjective symptoms of workplace-related stress, using two different headphone systems. Moreover, significant emotional improvement was reported within both arms. Trial Registration: ISRCTN registry 70947363, date of registration August 13, 2021.

Prospective analysis of the attendance behaviour of the participants of a facilitated support group for patients after allogeneic hematopoietic cell transplantation.

PURPOSE: Support groups might help survivors of allogeneic hematopoietic cell transplantations (HCT) to cope with medical, psychological, and social challenges. The aim of this project was (1) to establish a facilitated post-HCT support group and (2) to assess the participation behaviour. METHODS: From 11/2013 until 7/2017, all adult patients who had received a HCT at our centre were invited to participate in a professionally facilitated support group. The format of the group was unstructured without any rules regarding regular attendance. The attendance was prospectively minuted by the facilitator. Reasons for non-attendance were assessed by a survey. RESULTS: During the observation period, 53 group meetings were scheduled. Nine meetings were cancelled because of low attendance. Altogether 23 different patients (F: n=10; M: n=13) and 10 spouses (F: n=9; M: n=1) participated. Median participation was 5 [range 2-11]. With respect to all HCT patients who had the theoretical opportunity to attend, the mean participation rate was 7%. Thirteen patients and four spouses attended more than one meeting. The median count of participations among those participants was 8 [2-32]. The median interval from the first until the last participation was 16 months. The main reason reported for non-participation was the effort to get to the venue of the support group. CONCLUSIONS: To our knowledge, this is the first analysis on the attendance behaviour of the participants of a support group for HCT survivors. The results provide guidance for the organization of future support groups and indicate what participation rates can be expected and how they might be increased.

ASXL1 mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms.

Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMAs) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5- AZA could also extend the rationale of this treatment concept to high-risk MDS. In this study, we performed a comprehensive in vitro assessment of alvocidib and 5-AZA effects in n=45 high-risk MDS patients. Our data revealed additive cytotoxic effects of the combination treatment. Mutational profiling of MDS samples identified ASXL1 mutations as predictors of response. Further, increased response rates were associated with higher gene-expression of the pro-apoptotic factor NOXA in ASXL1 mutated samples. The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.

Reverse Transcription Can Critically Impact the Diagnostic Outcome of BCR::ABL1 Quantitative Real-Time RT-PCR.

Reverse transcriptases (RT) are essential tools in BCR::ABL1 fusion transcript monitoring in chronic myeloid leukemia (CML). The RT type and cDNA priming method may impair the stoichiometry of cDNA synthesis, thereby potentially introducing a bias in BCR::ABL1 qRT-PCR data. Using the Acrometrix™ BCR::ABL1 reference panel and 37 clinical specimens, we have comparatively investigated the performance of the RTs MLV and SuperScript IV with random hexamer vs. target-specific priming. Quantitative RT-PCR results identified the priming type and RT type as major factors for diagnostic data variation, mainly due to the different efficacies of processing BCR::ABL1 low-copy-numbers (<50) compared to GUSB or ABL1 high-copy targets. The impairment of SuperScript IV in processing low- and high-copy-number RNA targets equally was not reflected by the diagnostically relevant Log (BCR::ABL1/GUSB%) values. Therefore, the correct representation of housekeeping and BCR::ABL1 target genes should have priority when aiming at as high a number of housekeeping gene copies as possible. Our data suggest that for improving BCR::ABL1 assay sensitivity, increased RNA/cDNA amounts and the use of distinct RT/priming combinations are advantageous. However, for inter-laboratory harmonization, the proper conversion factor according to the CML international standard (IS) has to be reevaluated each time the grade of RT is changed.

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: reevaluation of the defining characteristics in a registry-based cohort.

In a registry-based analysis of 135 patients with "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-TK; FIP1L1::PDGFRA, n = 78; PDGFRB, diverse fusions, n = 26; FGFR1, diverse, n = 9; JAK2, diverse, n = 11; ETV6::ABL1, n = 11), we sought to evaluate the disease-defining characteristics. In 81/135 (60%) evaluable patients, hypereosinophilia (>1.5 × 109/l) was observed in 40/44 (91%) FIP1L1::PDGFRA and 7/7 (100%) ETV6::ABL1 positive patients but only in 13/30 (43%) patients with PDGFRB, FGFR1, and JAK2 fusion genes while 9/30 (30%) patients had no eosinophilia. Monocytosis >1 × 109/l was identified in 27/81 (33%) patients, most frequently in association with hypereosinophilia (23/27, 85%). Overall, a blast phase (BP) was diagnosed in 38/135 (28%) patients (myeloid, 61%; lymphoid, 39%), which was at extramedullary sites in 18 (47%) patients. The comparison between patients with PDGFRA/PDGFRB vs. FGFR1, JAK2, and ETV6::ABL1 fusion genes revealed a similar occurrence of primary BP (17/104, 16% vs. 8/31 26%, p = 0.32), a lower frequency (5/87, 6% vs. 8/23, 35%, p = 0.003) of and a later progression (median 87 vs. 19 months, p = 0.053) into secondary BP, and a better overall survival from diagnosis of BP (17.1 vs. 1.7 years, p < 0.0008). We conclude that hypereosinophilia with or without monocytosis and various phenotypes of BP occur at variable frequencies in MLN-TK.

Assessment and Evaluation of Psychosocial Distress in Outpatients with Cancer at a University Hospital in Germany.

INTRODUCTION: Cancer patients (pts) suffer from a significant amount of psychosocial distress related to tumor disease itself or straining treatments. Despite recommendations on how to screen for and to deal with psychosocial distress in cancer pts, data about implementation of psycho-oncological interventions (poi) in outpatient settings of cancer pts are scarce. The aim of this study was to identify outpatients with cancer in need of poi and to evaluate different assessment instruments. METHODS: N = 200 outpatients with hemat-/oncological malignancies were interviewed between October 2015 and December 2017 at the University Hospital Mannheim using the Basic Documentation for Psycho-Oncology (PO-Bado) and the Hornheider Screening Instrument (HSI) - both clinician-administered assessment tools - followed by descriptive, univariate, and agreement analysis. RESULTS: N = 61 cancer pts (31%) were identified to be in need for poi considering the results of both questionnaires. The number of identified pts in need of poi was lower when analyzing the results of the PO-Bado (n = 42, 21%) and the HSI (n = 39, 20%) separately. The degree of agreement between the results of PO-Bado and HSI was low (kappa = 0.3655). Several factors like gender, age and diagnosis were identified to have significant impact on the need for poi (p ≤ 0.05). CONCLUSION: Our study underlines that different screening instruments for psychosocial distress may identify disparate populations of cancer pts. The study data also revealed significant characteristics that might be associated with elevated levels of psychosocial distress and a clear indication for poi. However, further analyses on larger populations of cancer pts are needed to provide information how to transfer positive screening to poi in clinical routine.

Significant improvement of bone marrow-derived MSC expansion from MDS patients by defined xeno-free medium.

BACKGROUND: Robust and reliable in vitro and in vivo models of primary cells are necessary to study the pathomechanisms of Myelodysplastic Neoplasms (MDS) and identify novel therapeutic strategies. MDS-derived hematopoietic stem and progenitor cells (HSPCs) are reliant on the support of bone marrow (BM) derived mesenchymal stroma cells (MSCs). Therefore, isolation and expansion of MCSs are essential for successfully modeling this disease. For the clinical use of healthy MSCs isolated from human BM, umbilical cord blood or adipose tissue, several studies showed that xeno-free (XF) culture conditions resulted in superior growth kinetics compared to MSCs cultured in the presence of fetal bovine serum (FBS). In this present study, we investigate, whether the replacement of a commercially available MSC expansion medium containing FBS with a XF medium is beneficial for the expansion of MSCs derived from BM of MDS patients which are often difficult to cultivate. METHODS: MSCs isolated from BM of MDS patients were cultured and expanded in MSC expansion medium with FBS or XF supplement. Subsequently, the impact of culture media on growth kinetics, morphology, immunophenotype, clonogenic potential, differentiation capacity, gene expression profiles and ability to engraft in immunodeficient mouse models was evaluated. RESULTS: Significant higher cell numbers with an increase in clonogenic potential were observed during culture of MDS MSCs with XF medium compared to medium containing FBS. Differential gene expression showed an increase in transcripts associated with MSC stemness after expansion with XF. Furthermore, immunophenotypes of the MSCs and their ability to differentiate into osteoblasts, adipocytes or chondroblasts remained stable. MSCs expanded with XF media were similarly supportive for creating MDS xenografts in vivo as MSCs expanded with FBS. CONCLUSION: Our data indicate that with XF media, higher cell numbers of MDS MSCs can be obtained with overall improved characteristics in in vitro and in vivo experimental models.

Gene Expression Pattern of ESPL1, PTTG1 and PTTG1IP Can Potentially Predict Response to TKI First-Line Treatment of Patients with Newly Diagnosed CML.

The achievement of major molecular response (MMR, BCR::ABL1 ≤ 0.1% IS) within the first year of treatment with tyrosine kinase inhibitors (TKI) is a milestone in the therapeutic management of patients with newly diagnosed chronic myeloid leukemia (CML). We analyzed the predictive value of gene expression levels of ESPL1/Separase, PTTG1/Securin and PTTG1IP/Securin interacting protein for MMR achievement within 12 months. Relative expression levels (normalized to GUSB) of ESPL1, PTTG1 and PTTG1IP in white blood cells of patients (responders n = 46, non-responders n = 51) at the time of diagnosis were comparatively analyzed by qRT-PCR. 3D scatter plot analysis combined with a distance analysis performed with respect to a commonly calculated centroid center resulted in a trend to larger distances for non-responders compared to the responder cohort (p = 0.0187). Logistic regression and analysis of maximum likelihood estimates revealed a positive correlation of distance (cut-off) with non-achieving MMR within 12 months (p = 0.0388, odds ratio 1.479, 95%CI: 1.020 to 2.143). Thus, 10% of the tested non-responders (cut-off ≥ 5.9) could have been predicted already at the time of diagnosis. Future scoring of ESPL1, PTTG1 and PTTG1IP transcript levels may be a helpful tool in risk stratification of CML patients before initiation of TKI first = line treatment.

Response and resistance to cladribine in patients with advanced systemic mastocytosis: a registry-based analysis.

We sought to evaluate the efficacy of the purine analogue cladribine in 79 patients with advanced systemic mastocytosis (AdvSM) using data from the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)'. The overall response rate according to modified Valent criteria (46 evaluable patients) for first- (1L) and second-line (2L) cladribine treatment was 41% (12/29) and 35% (6/17, P = 0.690), respectively, and the median overall survival (OS, all patients evaluable) was 1.9 years (n = 48) and 1.2 years (n = 31; P = 0.311). Univariate and multivariable analyses of baseline and on-treatment parameters identified diagnosis of mast cell leukemia (hazard ratio [HR] 3.5, 95% confidence interval [CI, 1.3-9.1], P = 0.012), eosinophilia ≥ 1.5 × 109/L (HR 2.9 [CI 1.4-6.2], P = 0.006) and < 3 cycles of cladribine (HR 0.4 [CI 0.2-0.8], P = 0.008) as independent adverse prognostic parameters for OS. There was no impact of other laboratory (anemia, thrombocytopenia, serum tryptase) or genetic markers (mutations in SRSF2, ASXL1 or RUNX1) on OS. In consequence, none of the recently established prognostic scoring systems (MARS, IPSM, MAPS or GPSM) was predictive for OS. Modified Valent criteria were superior to a single factor-based response assessment (HR 2.9 [CI 1.3-6.6], P = 0.026). In conclusion, cladribine is effective in 1L and 2L treatment of AdvSM. Mast cell leukemia, eosinophilia, application of < 3 cycles and a lack of response are adverse prognostic markers.

Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies.

Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN.

Effects of a Sound Intervention on Physical and Emotional Well-Being in Patients with Cancer: A Prospective Randomized Trial.

AIM: Cancer remains a disease with a significant impact on morbidity and mortality but also on quality of life. This prospective randomized pilot study investigated the effects of a sound intervention on physical and emotional well-being in outpatients with cancer. METHODS: Two self-applied sound interventions were used for this purpose, either active "music playing" with a body monochord or passive sound intervention with headphones to listen to a given music compilation. Interventions were carried out over a period of 4 weeks for at least 15 min in the evening before bedtime. The following self-assessment questionnaires were completed both at baseline and after 4 weeks to evaluate the response: the Pittsburgh Sleep Quality Index (PSQI), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), Visual Analogue Scale (VAS) for pain and fatigue, and the Fear of Progression (FoP) questionnaire. Primary endpoint of this exploratory trial was to describe the rate of patients with improvement in at least one dimension without worsening of any other. RESULTS: 73 patients (29 male, 44 female) were included in the study and randomized to either active (n = 34, 47%) or passive sound intervention (n = 39, 53%). Median age was 52.0 years (range 21-79). Fourteen patients (19%) stated that they were musically active. The sound intervention was carried out on a median of 26 days (range 5-28). A higher percentage of patients in the passive group reached the primary endpoint: n = 15 (39%) versus n = 9 (27%). Response differences in favour of the passive group were seen with the VAS fatigue and with QLQ-30 questionnaires. Overall, an improvement in QLQ-30 questionnaire was seen in 12 patients (31%) in the passive group versus 3 patients (9%). Moreover, sound intervention significantly improved social functioning and shortness of breath in the passive group according to QLQ-C30. Significant improvements were also noticed in the passive group in terms of affective reactions as a domain of the FoP questionnaire. No effects on pain or sleep quality could be observed. CONCLUSION: A 4-week self-administered sound intervention was feasible in outpatients suffering from cancer. Using a panel of 5 questionnaires, passive sound interventions appeared to be more likely to positively influence patient-reported outcomes. In particular, a positive impact was documented in social functioning and fatigue.

In Silico Pan-Cancer Analysis Reveals Prognostic Role of the Erythroferrone (ERFE) Gene in Human Malignancies.

The erythroferrone gene (ERFE), also termed CTRP15, belongs to the C1q tumor necrosis factor-related protein (CTRP) family. Despite multiple reports about the involvement of CTRPs in cancer, the role of ERFE in cancer progression is largely unknown. We previously found that ERFE was upregulated in erythroid progenitors in myelodysplastic syndromes and strongly predicted overall survival. To understand the potential molecular interactions and identify cues for further functional investigation and the prognostic impact of ERFE in other malignancies, we performed a pan-cancer in silico analysis utilizing the Cancer Genome Atlas datasets. Our analysis shows that the ERFE mRNA is significantly overexpressed in 22 tumors and affects the prognosis in 11 cancer types. In certain tumors such as breast cancer and adrenocortical carcinoma, ERFE overexpression has been associated with the presence of oncogenic mutations and a higher tumor mutational burden. The expression of ERFE is co-regulated with the factors and pathways involved in cancer progression and metastasis, including activated pathways of the cell cycle, extracellular matrix/tumor microenvironment, G protein-coupled receptor, NOTCH, WNT, and PI3 kinase-AKT. Moreover, ERFE expression influences intratumoral immune cell infiltration. Conclusively, ERFE is aberrantly expressed in pan-cancer and can potentially function as a prognostic biomarker based on its putative functions during tumorigenesis and tumor development.

Therapy resistance mechanisms in hematological malignancies.

Hematologic malignancies are model diseases for understanding neoplastic transformation and serve as prototypes for developing effective therapies. Indeed, the concept of systemic cancer therapy originated in hematologic malignancies and has guided the development of chemotherapy, cellular therapies, immunotherapy and modern precision oncology. Despite significant advances in the treatment of leukemias, lymphomas and multiple myelomas, treatment resistance associated with molecular and clinical relapse remains very common. Therapy of relapsed and refractory disease remains extremely difficult, and failure of disease control at this stage remains the leading cause of mortality in patients with hematologic malignancies. In recent years, many efforts have been made to identify the genetic and epigenetic mechanisms that drive the development of hematologic malignancies to the stage of full-blown disease requiring clinical intervention. In contrast, the mechanisms responsible for treatment resistance in hematologic malignancies remain poorly understood. For example, the molecular characteristics of therapy-resistant persisting cells in minimal residual disease (MRD) remain rather elusive. In this mini-review we want to discuss that cellular heterogeneity and plasticity, together with adaptive genetic and epigenetic processes, lead to reduced sensitivity to various treatment regimens such as chemotherapy and pathway inhibitors such as tyrosine kinase inhibitors. However, resistance mechanisms may be conserved across biologically distinct cancer entities. Recent technological advances have made it possible to explore the underlying mechanisms of therapy resistance with unprecedented resolution and depth. These include novel multi-omics technologies with single cell resolution combined with advanced biocomputational approaches, along with artificial intelligence (AI) and sophisticated disease models for functional validation.

A new aberrantly spliced BCR-ABL1 transcript variant (e13a1) identified in routine monitoring using different quantitative reverse transcription polymerase chain reaction techniques in a patient with chronic myeloid leukemia.

Quantitative reverse transcription polymerase chain reaction (qRT-PCR) of BCR-ABL1 transcript level is an essential part of routine disease monitoring in patients with chronic myeloid leukemia. One patient sample (e13a2 transcript detected by nested PCR) attracted attention by revealing an aberrantly spliced BCR-ABL1 transcript variant e13a1. The last 38 base pairs (bp) of BCR exon 13 were replaced by a 37 bp insertion of the ABL1 intron 1-2/exon 1 sequence. The rare aberrant BCR-ABL1 fusion transcript can cause discrepancies in molecular diagnostics. This scenario highlights the importance of an individual characterization of the BCR-ABL1 fusion sequence in case of unclear qRT-PCR results.