Human well-being has been linked to the composition and functional capacity of the intestinal microbiota. As regular exercise is known to improve human health, it is not surprising that exercise was ...previously described to positively modulate the gut microbiota, too. However, most previous studies mainly focused on either elite athletes or animal models. Thus, we conducted a randomised intervention study that focused on the effects of different types of training (endurance and strength) in previously physically inactive, healthy adults in comparison to controls that did not perform regular exercise. Overall study duration was ten weeks including six weeks of intervention period. In addition to 16S rRNA gene amplicon sequencing of longitudinally sampled faecal material of participants (six time points), detailed body composition measurements and analysis of blood samples (at baseline and after the intervention) were performed to obtain overall physiological changes within the intervention period. Activity tracker devices (wrist-band wearables) provided activity status and sleeping patterns of participants as well as exercise intensity and heart measurements. Different biometric responses between endurance and strength activities were identified, such as a significant increase of lymphocytes and decrease of mean corpuscular haemoglobin concentration (MCHC) only within the strength intervention group. In the endurance group, we observed a significant reduction in hip circumference and an increase in physical working capacity (PWC). Though a large variation of microbiota changes were observed between individuals of the same group, we did not find specific collective alterations in the endurance nor the strength groups, arguing for microbiome variations specific to individuals, and therefore, were not captured in our analysis. We could show that different types of exercise have distinct but moderate effects on the overall physiology of humans and very distinct microbial changes in the gut. The observed overall changes during the intervention highlight the importance of physical activity on well-being. Future studies should investigate the effect of exercise on a longer timescale, investigate different training intensities and consider high-resolution shotgun metagenomics technology.
In immunocompromised patients a colonisation with fungi carries the risk to develop serious invasive fungal infection. An early detection is therefore important, but not optimal hitherto. ...Fortunately, molecular genetic methods have increased the sensitivity of fungal detection and limited the time, until results are available. However, their success depends on an efficient extraction of genomic DNA from the fungal cell in the given diagnostic specimen.
To improve the routine DNA preparation method for yeasts and moulds, the impact of bead beating on fungal DNA release was evaluated. PBS, blood and respiratory rinse were spiked with Candida glabrata or Aspergillus fumigatus. DNA was extracted by mechanical bead beating in addition to the different steps of the DNA preparation protocol, which comprised liquid nitrogen treatment, proteinase K digestion and DNA isolation using the EZ1 DNA Tissue Kit and Workstation. In every method variant tested, treatment with liquid nitrogen did not improve the DNA release. Bead beating once followed by proteinase K digestion and EZ1-work-up led to the highest DNA release from fungus, spiked in PBS, and increased the extracted DNA amount of C. glabrata about 100-fold and of A. fumigatus about 10-fold in relation to sole EZ1-work-up. In fungus-spiked respiratory rinse and blood, highest increase in DNA release was measured after triple bead beating with simultaneous proteinase K digestion. Fungal DNA release of C. glabrata increased for >100-fold in respiratory rinse and for >1000-fold in blood and of A. fumigatus for >10-fold in respiratory rinse and about 5- to 10-fold in blood.
The data of this study clearly demonstrate that preparation of fungal DNA from human specimens is optimized by introduction of a bead beating step to the conventional DNA-preparation method without the necessity of a liquid nitrogen step.
Recurrence of cytomegalovirus reactivation remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Monitoring cytomegalovirus-specific cellular ...immunity using a standardized assay might improve the risk stratification of patients. A prospective multicenter study was conducted in 175 intermediate- and high-risk allogeneic hematopoietic stem cell transplant recipients under preemptive antiviral therapy. Cytomegalovirus-specific cellular immunity was measured using a standardized IFN-γ ELISpot assay (T-Track® CMV). Primary aim was to evaluate the suitability of measuring cytomegalovirus-specific immunity after end of treatment for a first cytomegalovirus reactivation to predict recurrent reactivation. 40/101 (39.6%) patients with a first cytomegalovirus reactivation experienced recurrent reactivations, mainly in the high-risk group (cytomegalovirus-seronegative donor/cytomegalovirus-seropositive recipient). The positive predictive value of T-Track® CMV (patients with a negative test after the first reactivation experienced at least one recurrent reactivation) was 84.2% in high-risk patients. Kaplan-Meier analysis revealed a higher probability of recurrent cytomegalovirus reactivation in high-risk patients with a negative test after the first reactivation (hazard ratio 2.73; p=0.007). Interestingly, a post-hoc analysis considering T-Track® CMV measurements at day 100 post-transplantation, a time point highly relevant for outpatient care, showed a positive predictive value of 90.0% in high-risk patients. Our results indicate that standardized cytomegalovirus-specific cellular immunity monitoring may allow improved risk stratification and management of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation. This study was registered at www.clinicaltrials.gov as #NCT02156479.
Objective
Patients with acute myeloid leukemia (AML) carrying FLT3‐ITD mutations (FLT3‐ITD+) who relapse after allogeneic transplantation (allo‐SCT) have a very dismal prognosis with the currently ...available treatment options.
Methods
We treated eight patients with FLT3‐ITD+ AML who had relapsed in median 91 d (range, 28–249) following allo‐SCT with a combination of the multikinase inhibitor sorafenib and the DNA methyltransferase inhibitor azacitidine (Aza).
Results
Patients received a median of five cycles of Aza (range, 2–9) and sorafenib with a median daily dosage of 750 mg (range 400–800) for 129 d (range, 61–221). Six of eight patients received donor lymphocyte infusions (DLI) with a median number of two DLI per patient (range, 1–4). Following this treatment, four patients (50%) achieved a complete remission and three of them a complete molecular remission. Median duration of CR was 182 d (range, 158–406), and two patients remain in ongoing remission for 406 and 168 d. Median overall survival was 322 d (range, 108–574 d) with three patients being currently alive.
Conclusion
Taken together, the combination of sorafenib, Aza, and DLI shows promising efficacy and deserves further evaluation in larger patient groups.
Allogeneic hematopoietic stem cell transplantation (aHSCT) cures a considerable number of patients with myeloid malignancies, but relapse is the most frequent cause of death. We retrospectively ...studied relapse rate, kinetics, treatment, and outcome after first aHSCT in 446 patients during a 13-year period. Relapse occurred in 167 patients after a median of 4.6 months (116 hematologic (HR), 38 molecular (MR), and 13 extramedullary relapses (XR)). Median survival after relapse was 8.4 months and 2-year overall survival was 25%. Regarding survival after relapse, type (MR/HR/XR) and timepoint of relapse (</> 12 months), age (</> 50), diagnosis (MDS/AML and sAML), and remission status at transplant (CR and untreated MDS vs. refractory disease) were relevant in univariate analyses, in multivariate analyses timepoint, and type of relapse, age, and diagnosis. One hundred fifty-six patients were treated, most frequently with hypomethylating agents (HMA,
n
= 109) or intensive chemotherapy (
n
= 12). Donor lymphocyte infusion (DLI) was administered to 99 patients. Second aHSCT was performed in three patients as first and in 21 as higher salvage treatment. A complete remission (CR) was achieved in 46 patients (30%). Among CR patients, 65% had received HMA and DLI. Median survival of patients achieving CR was 105 months and 2-year overall survival was 80%. We conclude that with HMA and DLI or second aHSCT, a substantial number of patients, who relapse after aHSCT, can re-achieve remission and long-term survival. Techniques to further improve the detection of minimal residual disease are urgently needed because early treatment of MR results in significantly better survival.
We sought to refine the clinical picture of primary adrenal lymphoma (PAL), a rare lymphoid malignancy with predominant adrenal manifestation and risk of adrenal insufficiency.
Ninety-seven patients ...from 14 centers in Europe, Canada and the United States were included in this retrospective analysis between 1994 and 2017.
Of the 81 patients with imaging data, 19 (23%) had isolated adrenal involvement (iPAL), while 62 (77%) had additional extra-adrenal involvement (PAL+). Among patients who had both CT and PET scans, 18FDG-PET revealed extra-adrenal involvement not detected by CT scan in 9/18 cases (50%). The most common clinical manifestations were B symptoms (55%), fatigue (45%), and abdominal pain (35%). Endocrinological assessment was often inadequate. With a median follow-up of 41.6 months, 3-year progression-free (PFS) and overall (OS) survival rates in the entire cohort were 35.5% and 39.4%, respectively. The hazard ratios of iPAL for PFS and OS were 40.1 (95% CI: 2.63-613.7, P = 0.008) and 2.69 (95% CI: 0.61-11.89, P = 0.191), respectively. PFS was much shorter in iPAL vs PAL+ (median 4 months vs not reached, P = 0.006), and OS also appeared to be shorter (median 16 months vs not reached), but the difference did not reach statistical significance (P = 0.16). Isolated PAL was more frequent in females (OR = 3.81; P = 0.01) and less frequently associated with B symptoms (OR = 0.159; P = 0.004).
We found unexpected heterogeneity in the clinical spectrum of PAL. Further studies are needed to clarify whether clinical distinction between iPAL and PAL+ is corroborated by differences in molecular biology.
•Secondary hemophagocytic lymphohistiocytosis (sHLH) is rare but life-threatening.•sHLH can also be triggered by falciparum malaria.•The optimal strategy for the diagnosis and treatment of sHLH in ...adults is not yet well defined.•This article reports the successful treatment of sHLH after falciparum malaria with ruxolitinib.•Ruxolitinib might be a promising, rapidly acting treatment option for severe sHLH.
JAK/STAT signaling plays a major role in the pathogenesis of secondary hemophagocytic lymphohistiocytosis. This case report on a critically ill patient with secondary hemophagocytic lymphohistiocytosis due to falciparum malaria treated successfully with ruxolitinib, demonstrates that JAK1/2 inhibition might be a promising treatment option for severe cases.
While
F-FDG PET/CT yields valuable prognostic information for patients in first-line therapy of multiple myeloma (MM), its prognostic relevance in relapse is not established. Available studies of ...relapsed MM describe prognostic thresholds for frequently used PET/CT parameters that are significantly higher than those identified in the first-line setting. The purpose of this study was to evaluate the prognostic role of PET/CT in relapsed MM, based on parameters used in the first-line setting.
Our retrospective study included 36 patients with MM who had received autologous or allogeneic stem cell transplantation, suffered at least one relapse, and underwent FDG-PET/CT at relapse. Number of focal bone lesions (FL), maximal standardised uptake value (SUVmax), and presence of PET-positive extramedullary lesions (EMD) were analysed.
For the number of FLs, the prognostic value was demonstrated with a cut-off of > 3 (median OS 3.8 months vs. not reached, p = 0.003). Median OS of patients with SUVmax ≤ 4 was not reached, while it was 3.9 months in patients with SUVmax > 4 (p = 0.014). Presence of EMD was a significant prognostic parameter too, with median OS of 3.6 months versus not reached (p = 0.004). The above-mentioned parameters showed prognostic significance for PFS as well. Combination of higher ISS stage and PET/CT parameters identified patients with particularly short OS (3.7 months vs. not reached, p < 0.001) and PFS (3.6 vs. 11.7 months p < 0.001).
The PET/CT parameters SUVmax > 4, nFL > 3, and presence of EMD identify patients with poor prognosis not only in the first-line setting but also in relapsed MM.
Serious clinical complications (SCC; CTCAE grade ≥ 3) occur frequently in patients treated for hematological malignancies. Early diagnosis and treatment of SCC are essential to improve outcomes. Here ...we report a deep learning model-derived SCC-Score to detect and predict SCC from time-series data recorded continuously by a medical wearable. In this single-arm, single-center, observational cohort study, vital signs and physical activity were recorded with a wearable for 31,234 h in 79 patients (54 Inpatient Cohort (IC)/25 Outpatient Cohort (OC)). Hours with normal physical functioning without evidence of SCC (regular hours) were presented to a deep neural network that was trained by a self-supervised contrastive learning objective to extract features from the time series that are typical in regular periods. The model was used to calculate a SCC-Score that measures the dissimilarity to regular features. Detection and prediction performance of the SCC-Score was compared to clinical documentation of SCC (AUROC ± SD). In total 124 clinically documented SCC occurred in the IC, 16 in the OC. Detection of SCC was achieved in the IC with a sensitivity of 79.7% and specificity of 87.9%, with AUROC of 0.91 ± 0.01 (OC sensitivity 77.4%, specificity 81.8%, AUROC 0.87 ± 0.02). Prediction of infectious SCC was possible up to 2 days before clinical diagnosis (AUROC 0.90 at -24 h and 0.88 at -48 h). We provide proof of principle for the detection and prediction of SCC in patients treated for hematological malignancies using wearable data and a deep learning model. As a consequence, remote patient monitoring may enable pre-emptive complication management.
•WT1 mRNA expression level is applicable as MRD marker in most patients with AML and MDS.•WT1 mRNA expression level is measurable by a standardized assay providing a validated cutoff level.•WT1 mRNA ...expression level is measurable in peripheral blood and therefore coherent with high patient comfort.•WT1 mRNA expression level predicts relapse after allo-HSCT with a sensitivity of 85% and specificity of 97%.•In 62% of cases, overexpression of WT1 led to earlier BM biopsy and diagnosis of relapse.
Overexpression of the Wilms' tumor 1 (WT1) gene is informative in many patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) and is measurable in peripheral blood (PB). Despite these advantages, WT1 has not broadly been established as a marker for minimal residual disease (MRD) monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to limited patient numbers, differing sample sources, and nonstandardized in-house methods. To estimate the value of WT1 as an MRD marker, we serially quantified PB WT1 expression using a standardized European LeukemiaNet-certified assay in 59 patients with AML and MDS after allo-HSCT. We compared its performance with routine methods such as chimerism, XY-fluorescence in situ hybridization (FISH), disease-specific cytogenetic, and molecular analyses, which were accessible in 100%, 34%, 68%, and 37%, respectively. Twenty-four patients (41%) relapsed within a median of 126 days after allo-HSCT, and 20 of them showed at least 1 elevated WT1 value above the validated cutoff. The other 35 patients (59%) remained in complete remission, and only 1 patient had a transient increase in WT1 expression. This reflects a sensitivity of 83% and a specificity of 97% for WT1 and appears to be favorable compared with the sensitivities and specificities observed for chimerism (33% and 91%), XY-FISH (67% and 73%), cytogenetic (33% and 77%), and molecular (78% and 85%) analyses. Further supporting its predictive impact, elevated WT1 expression prompted an earlier BM biopsy and consecutively the diagnosis of relapse in 62% of patients. The results of this real-life experience imply that PB WT1 expression is measurable by a standardized assay and predicts imminent relapse after allo-HSCT with high sensitivity and specificity in most patients with AML and MDS.
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