Hairy Cell Leukemia Patients Have a Normal Life Expectancy—A 35-Year Single-Center Experience and Comparison with the General Population

Classic hairy cell leukemia (HCL) is an uncommon hematologic malignancy characterized by an excellent prognosis since purine analogues (PA), such as cladribine (2-CdA), have been introduced in the 1990s. However, most data on long-term outcomes is gathered from patients treated with PA first-line or include limited information on previous treatment outcomes, i.e., Interferon-α (IFN-α). Survival curves from previous series did not reach a plateau, indicating that nearly all patients ultimately relapse. Yet, overall survival (OS) data were rarely corrected for life expectancy of the general population. We here report 83 consecutive HCL patients treated between 1983 and 2017 at the University Center in Innsbruck, Austria. Median follow-up was 170 months (1–498). IFN-α, the first-line treatment of choice before 1990, was administered to 24 patients, achieving an overall response rate (ORR) of 86% and an unconfirmed complete remission (CRu) in 23%. All these patients relapsed after a median progression-free survival (PFS) of 30 months (3–80), but either remained drug-sensitive upon re-exposure to IFN-α or were successfully salvaged with PA. All 42 patients exposed to first-line 2-CdA responded (ORR of 100%). Sixteen patients received two to four successive courses of PA with a continuous decrease in the response quality (CRu rate 85.7% 1st-line vs. 41.5% 3rd-line treatment). Median PFS was not reached in both treatment-naïve patients and those retreated at first relapse. Although pretreatment with IFN-α was associated with a shortened median PFS of 81 months (43–118) after PA therapy, this tendency of inferior PFS did not result in inferior OS. OS of all 83 patients was excellent and equivalent to that of age-, sex-, and diagnostic period-matched controls from the Tyrolean general population (standardized mortality ratio 0.8), regardless of their age at diagnosis or whether they were diagnosed until or after the year 2000. These results confirm that HCL patients may look forward to a normal lifespan when treated with PA irrespective of their pretreatment history

The Austrian rock glacier inventory RGI_1 and the related rock glacier catchment inventory RGCI_1 in ArcGis (shapefile) format

Abstract: A first consistent and homogenized polygon-based inventory of rock glaciers of the Austrian Alps is presented. Compiling previous inventories and updating them by using digital elevation models (1 m grid resolution) derived from airborne laser scanning yield a dataset of 5769 rock glaciers in a ca. 48400 km² large area. A consistent methodological approach for assigning attributes, stored in a detailed attribute table, was developed and applied here to improve comparability and reproducibility. The majority (60 %) of the studied landforms is considered to be relict (no permafrost); the remaining 40 % may still contain permafrost ice and are thus classified as intact. Rock glaciers range in elevation from 476 to 3312 m a.s.l. and cover a total area of 303 km². The distribution of rock glaciers is mainly related to the topography of the Austrian Alps and related effects such as past glaciation history. In addition, a comprehensive analysis of the hydrological catchment areas of all individual rock glaciers was carried out. A hydrological catchment analysis in rock glacier areas is of great interest for sustainable water management issues in alpine catchments as these landforms represent shallow aquifer systems with a relatively high storage and thus buffer capability, especially in crystalline bedrock areas. A total area of almost 1280 km² is drained through rock glaciers. The presented rock glacier and rock glacier catchment inventories provide an important basis for further research, particularly for a better understanding of the hydrogeology and geomorphology of alpine catchments and their potential alteration in the light of climate change, but also in terms of paleoglaciation and deglaciation in the Alpine Lateglacial to Holocene period. As such, the inventories are seen as an important base to stimulate further research

Population Characteristics and Clinical Outcomes from the Renal Transplant Outcome Prediction Validation Study (TOPVAS)

Kidney transplantation is the preferred method for selected patients with kidney failure. Despite major improvements over the last decades, a significant proportion of organs are still lost every year. Causes of graft loss and impaired graft function are incompletely understood and prognostic tools are lacking. Here, we describe baseline characteristics and outcomes of the non-interventional Transplant Outcome Prediction Validation Study (TOPVAS). A total of 241 patients receiving a non-living kidney transplant were recruited in three Austrian transplantation centres and treated according to local practices. Clinical information as well as blood and urine samples were obtained at baseline and consecutive follow-ups up to 24 months. Out of the overall 16 graft losses, 11 occurred in the first year. The patient survival rate was 96.7% (95% CI: 94.3–99.1%) in the first year and 94.3% (95% CI: 91.1–97.7%) in the second year. Estimated glomerular filtration rate (eGFR) improved from 37.1 ± 14.0 mL/min/1.73 m2 at hospital discharge to 45.0 ± 14.5 mL/min/1.73 m2 at 24 months. The TOPVAS study provides information on current kidney graft and patient survival, eGFR trajectories, and rejection rates, as well as infectious and surgical complication rates under different immunosuppressive drug regimens. More importantly, it provides an extensive and well-characterized biobank for the future discovery and validation of prognostic methods

Empagliflozin Inhibits IL-1β-Mediated Inflammatory Response in Human Proximal Tubular Cells

SGLT2 inhibitor-related nephroprotection is—at least partially—mediated by anti-inflammatory drug effects, as previously demonstrated in diabetic animal and human studies, as well as hyperglycemic cell culture models. We recently presented first evidence for anti-inflammatory potential of empagliflozin (Empa) under normoglycemic conditions in human proximal tubular cells (HPTC) by demonstrating Empa-mediated inhibition of IL-1β-induced MCP-1/CCL2 and ET-1 expression on the mRNA and protein level. We now add corroborating evidence on a genome-wide level by demonstrating that Empa attenuates the expression of several inflammatory response genes in IL-1β-induced (10 ng/mL) normoglycemic HPTCs. Using microarray-hybridization analysis, 19 inflammatory response genes out of >30.000 human genes presented a consistent expression pattern, that is, inhibition of IL-1β (10 ng/mL)-stimulated gene expression by Empa (500 nM), in both HK-2 and RPTEC/TERT1 cells. Pathway enrichment analysis demonstrated statistically significant clustering of annotated pathways (enrichment score 3.64). Our transcriptomic approach reveals novel genes such as CXCL8/IL8, LOX, NOV, PTX3, and SGK1 that might be causally involved in glycemia-independent nephroprotection by SGLT2i

Empagliflozin Inhibits Basal and IL-1β-Mediated MCP-1/CCL2 and Endothelin-1 Expression in Human Proximal Tubular Cells

SGLT2 inhibitors (SGLT2i) slow the progression of chronic kidney disease; however, evidence for the underlying molecular mechanisms is scarce. We investigated SGLT2i-mediated effects on differential gene expression in two independent human proximal tubular cell (HPTC) lines (HK-2 and RPTEC/TERT1) at the mRNA and protein levels under normoglycemic conditions, utilizing IL-1β as a pro-inflammatory mediator. Microarray hybridization identified 259 genes that were uniformly upregulated by IL-1β (10 mg/mL) and downregulated by empagliflozin (Empa) (500 nM) after 24 h of stimulation in two independent HPTC lines (n = 2, each). The functional annotation of these genes identified eight pathway clusters. Among 12 genes annotated to the highest ranked cluster (enrichment score, 3.51), monocyte chemoattractant protein-1/CC-chemokine ligand 2 (MCP-1/CCL2) and endothelin-1 (ET-1) were selected for verification at mRNA and protein levels based on their established involvement in the early pathogenesis of chronic kidney disease: IL-1β upregulated basal MCP-1/CCL2 (15- and 19-fold) and ET-1 (3- and 8-fold) mRNA expression, while Empa downregulated basal MCP-1/CCL2 (0.6- and 0.5-fold) and ET-1 (0.3- and 0.2-fold) mRNA expression as early as 1 h after stimulation and for at least 24 h in HK-2 and RPTEC/TERT1 cells, respectively. The co-administration of Empa inhibited IL-1β-mediated MCP-1/CCL2 (0.2-fold, each) and ET-1 (0.2-fold, each) mRNA expression as early as 1 h after ligand stimulation and for at least 24 h in both HPTC lines, respectively. This inhibitory effect of Empa on basal and IL-1β-mediated MCP-1/CCL2 and ET-1 mRNA expression was corroborated at the protein level. Our study presents novel evidence for the interference of SGLT2 inhibition with tubular inflammatory response mechanisms under normoglycemic conditions that might account for SGLT2i-mediated nephroprotection

Humoral Immune Response to a Timely Booster mRNA Vaccination in Non-Responders to a Standard Vaccination Schedule against COVID-19 in Kidney Transplant Recipients

Kidney transplant recipients who are at increased risk for COVID-19 infection and associated morbidity and mortality have been shown to be prone to an impaired humoral immune response to a standard vaccination schedule against COVID-19 with two doses of SARS-CoV-2 mRNA vaccines. In this study, response rate of 94 kidney transplant recipients without detectable seroconversion after two doses of a mRNA vaccine who were offered a timely third mRNA vaccine after completion of the standard vaccination schedule was retrospectively analyzed. After a median of 28 days, antibody titers against the S1 spike protein showed a non-response rate of 53%. No significant risk factors for non-response could be identified. The responders showed a high variation in antibody titers (median 73.9 BAU/mL, IQR 221.5). In conclusion, a third booster mRNA vaccine in non-responding kidney transplant recipients leads to a detectable humoral immune response in approximately half of the patients. In the seroconversion group, antibody titers were highly variable, indicating that even non-responders to the standard vaccination schedule might develop a significant humoral immune response after a timely booster vaccine

Application of a combination of dating techniques to reconstruct the Lateglacial and early Holocene landscape history of the Albula region (eastern Switzerland)

Landforms in Val Mulix and the Albula region in eastern Switzerland offer a detailed insight into the period between the Oldest Dryas until the early Holocene. To better understand Lateglacial and Holocene climate change in the central Alps, glacial (moraines, polished bedrock) and periglacial (rock glacier) landforms were dated using a combined approach of numerical (cosmogenic 10Be) and relative (Schmidt-hammer, weathering rind thickness) dating techniques. At high-elevation sites near the Last Glacial Maximum (LGM) trimline, 10Be exposure ages of glacially modified bedrock are between 11.2 ka and 13.5 ka. This suggests the persistence of long-lasting small local ice caps after the breakdown of the LGM ice domes or, alternatively, a reformation of ice perhaps during the Younger Dryas. In Val Mulix we obtained one of the first ages for the Daun-stadial (> 14.7 ka) moraines (14.9 ± 1.8 ka), supporting a pre-Bølling chronological position. The age is in excellent agreement with the age of a boulder from an Egesen I moraine located up-valley which we postulate may be a Daun moraine that was re-occupied during the Egesen stadial. A boulder from an Egesen II moraine gave an age of 10.7 ka, which is similar to ages of Egesen II moraines at other sites in the Alps. 10Be ages from boulders found on a relict rock glacier in Val Mulix indicate that the main active phase lasted from the Lateglacial until the early Holocene. The derived mean annual flow rate is of the order of decimetres, which is in accordance with values stated in the literature based on measuring active rock glaciers in the Alps. Exposure ages from a glacially polished rock barrier showed that this area was ice-free at the end of the Younger Dryas (9.0 ± 0.7 ka and 11.9 ± 0.9 ka). The polished bedrocks are located a few hundred meters down-valley from the Little Ice Age (LIA) moraines. This gives direct evidence of a fast ice retreat towards the end of the Younger Dryas, with glacier length variations that did not exceed the 1850 AD extension (Little Ice Age maximum). Surface exposure dating is, however, limited by several methodological constraints. The choice of suitable snow depths plays a crucial role in the calculation of the 10Be ages. Shielding of surfaces from cosmic rays by snow can significantly influence the exposure age, and variations in the estimated annual snowfall in the Albula region since the LGM is therefore a potential source of considerable uncertainty in our measurements. While the measurement of weathering rind thicknesses turned out to be an appropriate tool to support the reconstruction of Lateglacial landscape evolution, Schmidt-hammer R-values were less helpful. The R-values enabled a temporal distinction of landforms within the Holocene (LIA moraine, active rock glaciers) but not within the Lateglacial. From a methodological point of view, the different dating methods enabled a cross-checking, an extended interpretation of the data and a more accurate estimate of the possible sources of error