Benefits of aHSCT over alemtuzumab in patients with multiple sclerosis besides disability and relapses: Sustained improvement in cognition and quality of life.

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) exhibits promising results for multiple sclerosis (MS) in the short term. We investigated the long-term outcome differences in disease progression and cognitive impairment after aHSCT and alemtuzumab treatment. METHODS: 20 patients receiving aHSCT and 21 patients treated with alemtuzumab between 2007 and 2020 were included in this monocentric observational cohort study. The primary objective was to compare the outcome of both groups with regards to achieving No Evidence of Disease Activity (NEDA-3), defined by the absence of relapses, EDSS progression, and MRI activity. Secondary endpoints in the study included the assessment of neurocognitive functioning, quality of life (QoL), Multiple Sclerosis Functional Composite (MSFC), and EDSS improvement. RESULTS: Baseline characteristics between both groups were comparable, except for a longer disease duration in the alemtuzumab group of 11.3 years compared to 5.4 years in aHSCT-treated patients (p = 0.002) and a longer mean follow-up time in the aHSCT cohort of 9.0 (range 2.8-15.7) years compared to 5.9 years (range 0.9-9.2) in alemtuzumab patients. NEDA-3 was more frequently observed in the aHSCT group with 75.0 % and 55.0 % at five and 10 years, respectively, than in the alemtuzumab group with only 40.0 % at five years (p = 0.012). Relapse free survival was higher in the aHSCT group (p < 0.001). None of the aHSCT-treated patients showed new T2-lesions six months after therapy initiation until the end of the observational period in contrast to 35.0 % of the alemtuzumab-treated patients showing new T2-lesions (95 %CI 14.2-98.9, p = 0.002). aHSCT-treated patients showed significantly improved cognitive performance in five out of 12 cognitive tests whereas alemtuzumab treated patients deteriorated in four out of 12 tests. Quality of life remained on a constant level for up to 10 years in patients receiving aHSCT with improved scores for the subscale fatigue (p = 0.013). CONCLUSION: aHSCT seems to be superior to alemtuzumab in maintaining long-term NEDA-3 status, improving cognition and stabilizing quality of life for up to 10 years.

Mesocosm experiment reveals scale dependence of movement tendencies in sticklebacks.

Habitat fragmentation can have negative impacts on migratory organisms that rely on the functional connectivity between growing and breeding grounds. Quantifying the population-level phenotypic consequences of such fragmentation requires fine-scaled tracking of individual behaviour and movements across relevant scales. Here we make use of a natural experiment where some populations of 'migrant' three-spined sticklebacks (Gasterosteus aculeatus) became 'residents', following habitat fragmentation five decades ago. To test whether residents have a lower movement tendency than migrants, we developed a novel experimental platform that allows the automated tracking of individual movements via RFID technology in a semi-natural mesocosm where spatio-temporal scales and environmental conditions can be manipulated. We found that residents moved significantly less than migrants at large but not at small spatial scale. This pattern was consistent across time and contexts (water flow and group size). Our study substantiates prior literature on rapid phenotypic divergence in sticklebacks in response to human-induced isolation and highlights the importance of observing behaviour in ecologically relevant set-ups that bridge the gap between laboratory and field studies.

Iron Chelation with Deferasirox Suppresses the Appearance of Labile Plasma Iron During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation.

During conditioning chemotherapy prior to allogeneic haematopoietic stem cell transplantation (HSCT), non-transferrin-bound iron and its chelatable form, labile plasma iron (LPI), regularly appear in the blood of patients at high levels of transferrin saturation (TfS). As these free iron species potentially favor infection and mediate transplantation-associated toxicities, chelation therapy could be an approach to improve outcome after transplantation. However, data addressing iron chelation in the immediate peritransplantation period are sparse. In this study, we investigated the influence of iron chelation with deferasirox during conditioning chemotherapy on the appearance of LPI, the incidence of infection and toxicities, and the tolerability of this treatment in the peritransplantation period. We conducted this single-center prospective observational study in 25 adults with iron overload (serum ferritin >1000 µg/L) undergoing allogeneic HSCT after myeloablative busulfan-based conditioning chemotherapy. Patients received iron chelation with deferasirox (14 mg/kg) from the start of conditioning until day 3 post-transplantation. Iron parameters, including LPI, were obtained at the chelator's trough level daily until day 0 and then on days 4, 7, and 14. Data on infection (bacteremia or invasive fungal disease) and toxicity, as well as the tolerability of deferasirox, were collected until the end of the follow-up period on day 28. Data were analyzed descriptively. TfS levels exceeded 70% in median on 6 days (range, 4 to 10 days) and in 63.6% (range, 36.4% to 90.9%) of the samples per patient, although in 19 of 25 patients (76%), no elevated LPI values were detected during the intake of deferasirox despite high TfS levels. Only 6 patients (24%) showed mildly increased LPI values (≤0.5 units) during the intake of deferasirox, 3 of whom had presented with elevated LPI values before the start of conditioning. Deferasirox was well tolerated, and no aggravation of toxicities was observed. Infection occurred in 5 patients (20%), including 3 of the 6 patients with elevated LPI values despite chelation therapy. In the present study, we demonstrate that iron chelation with deferasirox safely suppresses the appearance of LPI and might decrease the incidence of infection, whereas the impact on transplantation-associated toxicities remains to be elucidated.

Additional cytogenetic features determine outcome in patients allografted for TP53 mutant acute myeloid leukemia.

BACKGROUND: The presence of TP53 mutations is associated with an unfavorable outcome in patients allografted for acute myeloid leukemia (AML), leading some to question the benefit of an allogeneic stem cell transplantation (allo-SCT) for this patient group, although this has not been studied in a large cohort. METHODS: A total of 780 patients with AML in first complete remission, with either intermediate- or adverse-risk cytogenetics, whose TP53 mutation status was reported, were included in this study from the European Society for Blood and Marrow Transplantation. RESULTS: Two-year overall survival (OS) was impaired in patients (n = 179) with evidence of a TP53 mutation at diagnosis (35.1%; 95% confidence interval [CI], 26.7-43.7) as compared to the cohort without (n = 601) (64%; 95% CI, 59.1-68.4; P = .001). In patients with mutant TP53 AML with no evidence of either chromosome 17p loss (17p-) and/or complex karyotype (CK) (n = 53, 29.6%), 2-year OS was 65.2% (95% CI, 48.4-77.6). This was not significantly different to patients without TP53 mutations. In patients with mutant TP53 AML with either 17p- and/or CK (n = 126, 70.4%), the OS was lower (24.6%; 95% CI, 16.2-34; P = .001). CONCLUSIONS: In summary, the adverse prognostic effect of TP53 mutations in AML following an allo-SCT is not evident in patients with neither co-occurring 17p- and/or CK, and these data inform decisions regarding allo-SCT in patients with TP53 mutant AML.

Iron Chelation With Deferasirox Increases Busulfan AUC During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation.

The negative effects of iron overload caused by repetitive blood transfusions and iron release during cytotoxic chemotherapy might be ameliorated by early treatment with an iron chelator. However, in the setting of allogeneic hematopoietic stem cell transplantation (HSCT), chelation therapy is often postponed until the late post-transplantation period because of potential drug interactions. Therefore we systematically investigated the influence of iron chelation with deferasirox on the pharmacokinetics of intravenous busulfan in adult patients in the context of routine therapeutic drug monitoring (TDM) before HSCT. We conducted a single-center, prospective, observational study in 25 adult patients with planned allogeneic HSCT after myeloablative, busulfan-based, TDM-guided conditioning chemotherapy. Busulfan was administered intravenously over 3 hours with an initial dose of 3.2 mg/kg once daily (based on adjusted ideal body weight [AIBW] in overweight patients). Four consecutive dosages were planned to achieve a cumulative area under the curve (AUC) of 80 mg · h/L. Patients received deferasirox for transfusional iron overload as per approval from the start of conditioning until day 3 after transplantation. Model-based calculation of the busulfan AUC was carried out by means of Bayesian prediction based on a population pharmacokinetic model after the first or second dose of busulfan, and dose adjustments were performed accordingly. Calculated median cumulative AUC before dose adjustment was 93.7 mg · h/L (65.1-151.4 mg · h/L), which was considerably above the target AUC of 80 mg · h/L ± 10%. Median dose adjustment was -17.1% (-50.0% to 18.2%), and patients ultimately received busulfan with a median cumulative dose of 10.60 mg/kg (6.38 - 15.62) mg/kg. A busulfan dose reduction was necessary in 19 patients (76%) whereas a dose increase was only needed in 1 patient. After dose adjustment the median AUC was 79.7 mg/L · h (62.5 - 84.2 mg/L · h). Median busulfan clearance was 0.134 L/h/kg (0.084 - 0.203 L/h/kg), which is significantly lower than the average clearance of 0.2 L/h/kg reported in the literature, whereas volume of distribution was not altered. We were able to demonstrate, that TDM is the key point to facilitate a safe co-administration of both medications, because the intake of deferasirox leads to a considerable increase in the busulfan AUC of about 35% to 40%. The reason for the increase in busulfan AUC is a reduction in busulfan clearance by about one third; therefore a lower initial dose of busulfan followed by TDM could be considered in patients with comedication with deferasirox.

Determining Good Environmental Status under the Marine Strategy Framework Directive: Case study for descriptor 8 (chemical contaminants).

The European Union Marine Strategy Framework Directive (MSFD) requires individual member states to develop a robust set of tools for defining eleven qualitative descriptors of Good Environmental Status (GES), such as demonstrating that "Concentrations of contaminants are at levels not giving rise to pollution effects" (GES descriptor 8). Adopting the recommendations of the ICES/OSPAR Study Group for the Integrated Monitoring of Contaminants and Biological Effects (SGIMC), we present a case study demonstrating how the proposed approach, using chemical contaminant (metals and polycyclic aromatic hydrocarbons and polychlorinated biphenyls) and biological effects (EROD, bile metabolites and pathology) data in different matrices (sediment and biota), could be used to contribute to the determination of GES in a region of the North Sea region off the east coast of the UK.

The correlation between coloration and exploration behaviour varies across hierarchical levels in a wild passerine bird.

In vertebrates, darker individuals are often found to be more active and willing to take risks (representing characteristics of a 'proactive' coping style), whereas lighter individuals are instead more cautious and less active (representing characteristics of a 'reactive' coping style). It is thus generally expected that melanin-based coloration and proactivity form a suite of positively integrated traits at the among-individual level. Here, we use a multigenerational pedigree of free-living great tits (Parus major) to partition variation in, and the correlation between, melanin-based breast stripe ('tie') size and exploration behaviour (a proxy for coping style) into its among- and within-individual components. We show that both traits harbour heritable variation. Against predictions, tie size and speed of exploration were negatively correlated at the among-individual level due to the combined influences of permanent environmental and additive genetic effects. By contrast, the two traits were weakly positively correlated within individuals (i.e. individuals increasing in tie size after moult tended to become more explorative). The patterns of among-individual covariance were not caused by correlational selection as we found additive and opposite selection pressures acting on the two traits. These findings imply that testing hypotheses regarding the existence of a 'syndrome' at the among-individual level strictly requires variance partitioning to avoid inappropriate interpretations as the negative 'unpartitioned' phenotypic correlation between exploration and tie size resulted from counteracting effects of within- and among-individual correlations. Identifying sources and levels of (co)variation in phenotypic traits is thus critical to our understanding of biological patterns and evolutionary processes.

Reduced-Intensity Allografting as First Transplantation Approach in Relapsed/Refractory Grades One and Two Follicular Lymphoma Provides Improved Outcomes in Long-Term Survivors.

This study was conducted to compare long-term outcomes in patients with refractory/relapsed grades 1 and 2 follicular lymphoma (FL) after allogeneic (allo) versus autologous (auto) hematopoietic cell transplantation (HCT) in the rituximab era. Adult patients with relapsed/refractory grades 1 and 2 FL undergoing first reduced-intensity allo-HCT or first autograft during 2000 to 2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger and more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto-HCT versus allo-HCT groups for nonrelapse mortality (NRM) were 5% versus 26% (P < .0001); relapse/progression: 54% versus 20% (P < .0001); progression-free survival (PFS): 41% versus 58% (P < .001), and overall survival (OS): 74% versus 66% (P = .05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months after HCT (relative risk [RR], 4.4; P < .0001) and worse PFS (RR, 2.9; P < .0001) beyond 11 months after HCT. In the first 24 months after HCT, auto-HCT was associated with improved OS (RR, .41; P < .0001), but beyond 24 months, it was associated with inferior OS (RR, 2.2; P = .006). A landmark analysis of patients alive and progression-free at 2 years after HCT confirmed these observations, showing no difference in further NRM between both groups, but there was significantly higher risk of relapse/progression (RR, 7.3; P < .0001) and inferior PFS (RR, 3.2; P < .0001) and OS (RR, 2.1; P = .04) after auto-HCT. The 10-year cumulative incidences of second hematological malignancies after allo-HCT and auto-HCT were 0% and 7%, respectively. Auto-HCT and reduced-intensity-conditioned allo-HCT as first transplantation approach can provide durable disease control in grades 1 and 2 FL patients. Continued disease relapse risk after auto-HCT translates into improved PFS and OS after allo-HCT in long-term survivors.

Janus kinase inhibitors and allogeneic stem cell transplantation for myelofibrosis.

Myelofibrosis (MF) is a manifestation of several disorders of hematopoiesis, collectively referred to as myeloproliferative neoplasms. Allogeneic hematopoietic stem cell transplantation (ASCT) is the only therapy with proven curative potential. However, most patients with MF are in their 6th or 7th decade of life, and only some of these patients have been considered suitable transplantation candidates. The development of reduced-intensity conditioning regimens with limited toxicity has allowed clinicians to offer ASCT to a growing number of older patients. The availability of Janus Kinase (JAK) 1/2 inhibitors allows clinicians to provide symptom relief and improved quality of life for MF patients. These drugs may also affect the decision regarding, in particular, the timing of ASCT. Future studies need to address the role of JAK1/2 inhibitors in patients who are transplantation candidates and determine their role before and, possibly, after transplantation. The identification of indications for the use of JAK1/2 inhibitors in the context of transplantation may lead to new therapeutic strategies for patients with MF.

Micafungin as antifungal prophylaxis in recipients of allogeneic hematopoietic stem cell transplantation: results of different dosage levels in clinical practice.

Micafungin has been approved for the prophylaxis of Candida infections in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report a single-center experience of three different dose levels regarding efficacy, toxicity, and colonization with Candida ssp. in clinical practice. In total, 150 consecutive adult patients who underwent allo-HSCT received micafungin at a dosage of 50, 100, or 150 mg once daily for primary antifungal prophylaxis. Of those patients receiving more than six d of micafungin prophylaxis, 12/46 (26%), 6/44 (14%), and 9/46 (20%) were switched to empiric antifungal treatment. The frequency of invasive fungal infections (IFIs) according to EORTC criteria did not differ significantly (7/46; 15% vs. 5/44; 11% vs. 5/46; 11%) across the different dosage groups. In the 50-mg group, there was one case of candidemia with C. parapsilosis after 12 d of micafungin prophylaxis. In all three groups, micafungin prophylaxis was well tolerated without any case of toxicity-related treatment discontinuation. Renal function was not significantly altered, while increase of bilirubin was mainly due to concomitant ATG application. The incidence of IFIs is similar irrespective of the micafungin dosage while there was a trend toward more frequent change to empiric antifungal treatment as well as oropharyngeal colonization with candida in the lowest dosage group.

Exploring patterns of variation in clutch size-density reaction norms in a wild passerine bird.

Negative density dependence of clutch size is a ubiquitous characteristic of avian populations and is partly due to within-individual phenotypic plasticity. Yet, very little is known about the extent to which individuals differ in their degree of phenotypic plasticity, whether such variation has a genetic basis and whether level of plasticity can thus evolve in response to selection. Using 18 years of data of a Dutch great tit population (Parus major), we show that females reduced clutch size with increasing population density (slopes of the reaction norms), differed strongly in their average clutch size (elevations of the reaction norms) at the population-mean density and that the latter variation was partly heritable. In contrast, we could not detect individual variation in phenotypic plasticity ('I × E'). Level of plasticity is thus not likely to evolve in response to selection in this population. Observed clutch sizes deviated more from the estimated individual reaction norms in certain years and densities, implying that the within-individual between-year variance (so-called residual variance) of clutch size was heterogeneous with respect to these factors. Given the observational nature of this study, experimental manipulation of density is now warranted to confirm the causality of the observed density effects. Our analyses demonstrate that failure to acknowledge this heterogeneity would have inflated the estimate of 'I × E' and led to misinterpretation of the data. This paper thereby emphasizes the fact that heterogeneity in residuals can provide biologically insightful information about the ecological processes underlying the data.

[Salvage prostatectomy. Principles of diagnostics and operative therapy]. / Salvage-Prostatektomie. Grundlagen der Diagnostik und operativen Therapie.

Organ-confined prostate cancer can be treated with curative intent by different types of radiotherapy or by radical surgery. Regardless of improvements in radiotherapy about 60% of patients with prostate cancer develop biochemical recurrence (BCR) which is defined by the progressive increase in serum prostate-specific antigen (PSA) and necessitates further diagnostic procedures. If non-organ-confined cancer and metastasis are categorically excluded by cross-sectional imaging using computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography CT (PET-CT) and bone scintigraphy, a prostate biopsy should be performed. Biopsy proven detection of recurrent or persisting prostate cancer after irradiation is essential prior to a salvage prostatectomy. The function of the lower urinary tract should be evaluated prior to surgery. Preoperative PSA measurement is the best prognostic indicator prior to surgery. Salvage prostatectomy in irradiated patients is more challenging and requires extensive skill. The most common complications are incontinence, rectal injury and anastomotic strictures. Both functional and oncologic outcome have improved due to better irradiation techniques and surgical skills. Provided post-radiotherapy recurrence of prostate cancer is diagnosed early enough, curing is possible by salvage prostatectomy.

[Progressive dyspnoea in two patients with carcinoid syndrome]. / Progrediente Dyspnoe bei Karzinoidsyndrom.

In patients with carcinoid syndrome, there has always to be considered cardiac impairment. We report about two patients with hepatic and bone metastases of a neuroendocrine tumor of the midgut, who suffered from progressive dyspnea. This was caused in both cases by a right-to-left atrial shunt, in case 1 based on a patent foramen ovale (PFO), in case 2 based on a secundum atrial septal defect. Symptoms were significantly reduced by percutaneous closure of PFO and ASD, respectively. Right-to-left atrial shunt was facilitated by right-sided carcinoid induced endocardial fibrosis with the consequence of severe tricuspid regurgitation, leading to an increase of right atrial pressure.

[Performance and interpretation of esophageal manometry: recommendations of the German Societies for Neurogastroenterology and Motility (DGNM), for Digestive and Metabolic Diseases (DGVS) and for General and Visceral Surgery (DGAV)]. / Durchführung und Interpretation der Osophagusmanometrie: Empfehlungen der Deutschen Gesellschaften für Neurogastroenterologie und Motilität (DGNM), für Verdauungs- und Stoffwechselerkrankungen (DGVS) und für Allgemein- und Viszeralchirurgie (DGAV).

Esophageal manometry examines the pressure profiles of the tubular esophagus and of the esophageal sphincters during resting conditions and in response to swallowing. It is regarded as the reference method for detection of esophageal motility disturbances but, up to date, performance of the procedure is not standardized among centers. This review depicts the recommendations of the German Societies for Neurogastroenterology and Motility, for Digestive and Metabolic Disturbances and for General and Visceral Surgery on indications, performance and analysis of conventional esophageal manometry. In addition to concise recommendations we give detailed background information so that the article can serve as a practical guideline for inexperienced investigators as well as an exensive review for the experienced one. Moreover, recommendations on the use of newer and/or supplementary diagnostic techniques, that is long-term and high resolution manometry as well as esophageal impedance measurements are also given.

GLP-1 regulates gastroduodenal motility involving cholinergic pathways.

The gut-born incretin hormone glucagon-like peptide-1 (GLP-1) delays gastric emptying. To elucidate the mechanisms by which GLP-1 affects gastroduodenal motility and glycaemia, we studied the effects of exendin(9-39), a potent GLP-1 receptor antagonist, on gastroduodenal motility and pancreatic hormones. In this randomized, double-blind, placebo-controlled, four-arm, cross-over trial, 10 healthy volunteers were studied during the interdigestive period followed by duodenal perfusion of a mixed liquid meal (250 kcal). On four separate days, exendin(9-39), atropine, exendin(9-39) + atropine or saline were infused intravenously. Antro-pyloro-duodenal and fundic motility were assessed. The compliance of the proximal stomach was determined by isobaric distensions. During fasting, exendin(9-39) did not influence proximal gastric volume, pyloric tone, and duodenal contractility. Exendin(9-39) significantly increased antral waves only in the absence of atropine. During duodenal meal perfusion, exendin(9-39) significantly reduced proximal gastric volume accommodation, abbreviated postprandial antral inhibition, reduced the postprandial increase in pyloric tone, and reduced gastric compliance. Atropine abolished the effects of exendin(9-39) on gastric volume accommodation but did not affect its effects on postprandial antroduodenal motility and on gastric compliance. Exendin(9-39) increased fasting and postprandial glycaemia and plasma glucagon but not insulin concentrations. Atropine did not affect GLP-1 secretion. Cholinergic mechanisms mediate the effects of GLP-1 on postprandial gastric accommodation but not on antro-pyloro-duodenal motility. GLP-1 reduces fasting and postprandial glycaemia, in part by reducing glucagon secretion.

[An unusual breast tumor]. / Ein ungewöhnlicher Mammatumor.

The presented case shows how difficult it can be to diagnose rare diseases if they present with masses in atypical locations. In an extensive further diagnostic workup other characteristic findings then point to the correct diagnosis.

Importance of changes in gastric emptying for postprandial plasma glucose fluxes in healthy humans.

OBJECTIVE: Regulation of postprandial (pp) plasma glucose excursions is complex. Insulin and glucagon are thought to play the predominant role. Nevertheless, only 50% of the variation in pp plasma glucose excursions is explained by variations by the latter. Theoretically, gastric emptying (GE) should be another important factor. However, its impact on pp glucose homeostasis is unknown. RESEARCH DESIGN AND METHODS: We examined the consequences of pramlintide-induced delay in GE on pp glycemia and glucose fluxes, determined isotopically. GE was recorded by scintigraphy. Fourteen healthy subjects (8 men, 6 women; age 40 +/- 3 yr, body mass index 27.8 +/- 1.1 kg/m2) ate a mixed meal, and 30 microg of pramlintide (PRAM) or placebo (PBO) were injected subcutaneously. RESULTS: At 60 min, greater proportions of the initial gastric contents remained in the stomach (PBO vs. PRAM). Thereafter, GE slopes paralleled until 240 min. Fifty percent retention times were lower when PBO was given (P < 0.001). GE was greater from 240 min to the end of the PRAM experiments, so that only slightly greater proportions of the meal remained in the stomach at 330 min. Reductions of GE lowered pp glucose (7.5 +/- 0.3 vs. 6.0 +/- 0.2 mmol/l, P < 0.001), even though plasma insulin was lower with PRAM (164 +/- 13 vs. 138 +/- 13 pmol/ml, both P < 0.01). Reduction in total glucose appearance (P < 0.001) was due to reduced meal-derived glucose appearance (10.2 +/- 0.5 vs. 7.0 +/- 0.4 micromol.kg(-1).min(-1), P < 0.001). Endogenous glucose appearance was greater with PRAM (P < 0.001). Splanchnic glucose uptake was greater with PRAM (26.5 +/- 1.6 vs. 32.5 +/- 2.1%, P = 0.014). CONCLUSIONS: These data support the concept that GE is an important physiological regulator of pp glucose homeostasis in humans.

[Reflux disease: standards, news and trends]. / Strategien für Standardfälle und Problempatienten. Zeigen Sie dem Reflux die rote Karte!

Proton pump inhibitors (PPI) are currently the standard treatment for reflux disease. A symptom correlated diagnosis with the help of 24-h-pH-metry and/or multiple intraluminal impedance (MII) allows the objective and differentiated classification of endoscopy-negative patients despite PPI symptoms.