Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation

Because information on management and outcome of AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of EBMT. Among 2815 RIC transplants performed for AML in complete remission (CR) between 1999 and 2008, cumulative incidence of relapse was 32% ± 1%. Relapsed patients (263) were included into a detailed analysis of risk factors for overall survival (OS) and building of a prognostic score. CR was reinduced in 32%; remission duration after transplantation was the only prognostic factor for response (P = .003). Estimated 2-year OS from relapse was 14%, thereby resembling results of AML relapse after standard conditioning. Among variables available at the time of relapse, remission after HSCT > 5 months (hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.37-0.67, P < .001), bone marrow blasts less than 27% (HR = 0.53, 95% CI, 0.40-0.72, P < .001), and absence of acute GVHD after HSCT (HR = 0.67, 95% CI, 0.49-0.93, P = .017) were associated with better OS. Based on these factors, 3 prognostic groups could be discriminated, showing OS of 32% ± 7%, 19% ± 4%, and 4% ± 2% at 2 years (P < .0001). Long-term survival was achieved almost exclusively after successful induction of CR by cytoreductive therapy, followed either by donor lymphocyte infusion or second HSCT for consolidation.     

Takotsubo cardiomyopathy has a unique cardiac biomarker profile: NT-proBNP/myoglobin and NT-proBNP/troponin T ratios for the differential diagnosis of acute coronary syndromes and stress induced cardiomyopathy

Background

Takotsubo cardiomyopathy (TC) usually is not recognized until heart catheterization reveals typical wall motion abnormalities in the absence of significant coronary artery disease. It was our aim to identify TC by its unique cardiac biomarker profile at an early stage and, preferably, with non-invasive procedures only.

Methods

Ratios of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and myoglobin, NT-proBNP and troponin T (TnT), NT-proBNP and creatinekinase-MB (CK-MB) were compared in patients with TC (n = 39), patients with ST-elevation myocardial infarction (STEMI, n = 48) and patients with non-ST-elevation myocardial infarction (NSTEMI, n = 34). Biomarkers were recorded serially at admission and at the three consecutive days. Optimal cut-off values to distinguish TC from STEMI and NSTEMI were calculated with receiver operator characteristic (ROC) curves.

Results

At admission a NT-proBNP (ng/l)/myoglobin (μg/l) ratio of 3.8, distinguished TC from STEMI (sensitivity: 89%, specificity: 90%), while a NT-proBNP (ng/l)/myoglobin (μg/l) ratio of 14 separated well between TC and NSTEMI (sensitivity: 65%, specificity: 90%). Best differentiation of TC and ACS was possible with the ratio of peak levels of NT-proBNP (ng/l)/TnT (μg/l). A cut-off value of NT-proBNP (ng/l)/TnT (μg/l) ratio of 2889, distinguished TC from STEMI (sensitivity: 91%, specificity: 95%), while a NT-proBNP (ng/l)/TnT (μg/l) ratio of 5000 separated well between TC and NSTEMI (sensitivity: 83%, specificity: 95%).

Conclusions

TC goes along with a singular cardiac biomarker profile, which might be useful to identify patients with TC among patients presenting with acute coronary syndromes (ACS).     

Lebenslange landwirtschaftliche Schwerarbeit und Arthroseentwicklung an der Hand – Eine kasuistische Untersuchung

Heavy physical work load is a known determinant of osteoarthritis of the hip, which may account for the high risk observed among farmers. On the other hand, the data on influence of heavy manual work in the pathogenesis of hand osteoarthritis are still controversial. We examined 25 retired farm laborers who strenuously worked for more than 50 years. The investigation included a history of professional activity, clinical and radiological examination of the hands, hips and knees, MRI of hand and laboratory evaluation of 4 participants. Interestingly, the farm laborers with osteoarthritis of the hands, hardly complained. In many of the proximal interphalangeal joints, a discrepancy was observed between the clinical hypertrophic changes and the radiological osteoarthritis which was weak or absent. This difference was less pronounced in the distal interphalangeal joints. Furthermore the distribution pattern of the osteoarthritis of the hand was striking with an over-proportional involvement of the metacarpophalangeal joints and less pronounced of the intercarpal joints. Most often both hands have been affected and the typical localization of the metacarphophalangeal joint osteoarthritis was the first, second and third finger. In all but one participant we found at least unilateral osteoarthritis of the hip and compared to the hands, complaints were more severe. Our findings support the hypothesis that the distribution of osteoarthritis in the hand is affected by lifelong farming. As shown by the data on proximal interphalangeal joints, the periarticular tissue can adapt to the mechanical load in the strength grip.     

CD44 expression in benign and malignant colorectal polyps

PURPOSE: This retrospective study was undertaken to evaluate immunohistochemically the expression of CD44 standard protein and CD44v5 and CD44v6 isoforms in colorectal adenomas and early invasive cancers developing within adenomas as possible markers characterizing colorectal polyps with a more aggressive biologic potential. METHODS: Archival tissues of 81 consecutive locally resected colorectal polyps, comprising 57 colorectal adenomas and 24 carcinomas-in-adenomas, were stained immunohistochemically with the use of commercially available mouse monoclonal antibodies: SFF-2 for CD44 standard protein, VFF-8 for CD44v5, and VFF-7 for CD44v6. RESULTS: Sixtythree percent of the colorectal polyps were positive for CD44 standard protein, 59 percent were positive for CD44v5, and 27 percent were positive for CD44v6. Ninetythree percent of the low-grade adenomas were CD44 standard protein-positive, in contrast to 50 percent of the high-grade adenomas and only 42 percent of the carcinomas-in-adenomas (Kendall's Tau =–0.42;P<0.0001). CD44v6 expression was more frequently found in early invasive cancers (54 percent) than in high-grade adenomas (25 percent) and low-grade adenomas (7 percent). This difference also was statistically significant (Kendall's Tau-b =0.39;P=0.00003). Surprisingly, a downregulation of CD44 standard protein expression was observed in the adenoma tissue adjacent to carcinomas (62 percent) and areas with high-grade atypia (71 percent), compared with low-grade adenomas (93 percent; Kendall's Tau-b =–0.28;P=0.004). CONCLUSIONS: Our data suggest that CD44 standard protein and CD44 isoform v6 expression differs considerably in benign and malignant colorectal polyps. Clinical studies with larger patient groups could clarify the prognostic potential of CD44 further     

Differential effects of angiotensin II receptor blockade on pressure-induced left ventricular hypertrophy and fibrosis in rats

The effects of the angiotensin II receptor type 1 (AT1) antagonist losartan on pressure overload-induced left ventricular (LV) hypertrophy were studied in female Sprague-Dawley rats. Starting on the day of surgery, losartan (L, 12 mg/kg/day) was administered as continuous intraperitoneal infusion for 2 weeks by using alzet mini-osmotic-pumps (model 2002). This dose of losartan shifted the in vivo dose-response curve of the angiotensin II-induced elevation of left ventricular systolic pressure (LVSP) to the right. Pressure overload was achieved by placing a band around the aortic arch. This caused an aortic stenosis (AS) with an outer diameter of 1.0 mm. The hemodynamic effects were measured in the intact, anesthetized rats (n = 15). The hearts were excised, and the weights of the left (LV) and right ventricle (RV) were determined. Some of these hearts (n = 7) were perfused with collagenase to obtain isolated cardiac myocytes for the measurement of cell volume. Other hearts (n = 8) were examined for morphological changes. In the animals with AS, LVSP was markedly elevated. Furthermore, LV weight and LV myocyte cell volume were increased in this group, while RV weight and RV myocyte cell volume remained stable in all the groups. L had no significant effect on the AS-induced increase in LVSP and cell size parameters, nor on the weight gain of the LV. Histological analysis revealed that the AS-induced enlargement of the mean myocyte diameter was not affected by L. The interstitial collagen fraction was increased in the AS rats and became normalized by L. These data suggest that the renin-angiotensin system might not be involved in the development of pressure-induced cardiac hypertrophy within the time-frame of these experiments, but that it does play a major role in the genesis of the interstitial fibrosis which is a typical feature of this pathophysiological condition.     

Prognostic relevance of ubiquitin C-terminal hydrolase L1 (UCH-L1) mRNA and protein expression in breast cancer patients

Purpose

The ubiquitin C-terminal hydrolase L1 (UCH-L1) belongs to the family of deubiquitinating enzymes. It is overexpressed in various tumour entities and associated with metastases formation in some solid tumours. However, only limited information about its role in breast cancer is available. The aim of this study was to examine the UCH-L1 expression in primary breast cancer and to determine its relevance as a potential prognostic marker.

Methods

We investigated both UCH-L1 mRNA expression in microarray data from 182 primary mammary carcinomas and UCH-L1 protein expression using a tissue microarray containing samples from 1,622 breast cancer patients.

Results

With both methods, high UCH-L1 expression correlated significantly with negative oestrogen receptor and progesterone receptor status and advanced tumour stage. Moreover by Kaplan–Meier analysis, high UCH-L1 mRNA and protein expression correlated with a significantly shorter overall survival.

Conclusion

The data of our study suggest that high levels of UCH-L1 expression indicate a more aggressive tumour behaviour and might represent a potential target in breast cancer treatment.     

A prospective trial of colchicine and methotrexate in the treatment of primary biliary cirrhosis.

BACKGROUND & AIMS: The aim of this study was to determine if colchicine or methotrexate improves blood test results, symptoms, and/or liver histology in patients with primary biliary cirrhosis. METHODS: Patients with histologically confirmed primary biliary cirrhosis whose serum alkaline phosphatase (ALP) levels were at least 2 times above normal and who were not yet candidates for liver transplantation received colchicine or methotrexate and were followed up for 2 years. RESULTS: In patients receiving colchicine (n = 43), mean pruritus score decreased from 1.63 to 1.12 (P = 0.04), ALP level from 494 to 355 U/L (P < 0.0001), and alanine aminotransferase (ALT) level from 79 to 61 U/L (P < 0.0001). In patients receiving methotrexate (n = 42), pruritus score decreased from 1.25 to 0.44 (P = 0.0001), ALP from 478 to 235 U/L (P < 0.0001), and ALT from 96 to 61 U/L (P = 0.0001). Methotrexate but not colchicine significantly improved liver histology (P = 0.005) and serum immunoglobulin G levels (P = 0.0002). Methotrexate improved most blood test results more than colchicine. Serum bilirubin levels increased slightly with each drug, and albumin levels decreased slightly. CONCLUSIONS: Both colchicine and methotrexate improved biochemical test results and symptoms in primary biliary cirrhosis, but the response to methotrexate was greater.     

Identification of circulating microRNAs in HNF1A-MODY carriers

Aims/hypothesis

HNF1A-MODY is a monogenic form of diabetes caused by mutations in the HNF1A gene. Here we identify, for the first time, HNF1A-MODY-associated microRNAs (miRNAs) that can be detected in the serum of HNF1A-MODY carriers.

Methods

An miRNA array was carried out in rat INS-1 insulinoma cells inducibly expressing the common human Pro291fsinsC-HNF1A frame shift mutation. Differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of miRNAs in the serum of HNF1A-MODY carriers (n?=?31), MODY-negative family members (n?=?10) and individuals with type 2 diabetes mellitus (n?=?17) was quantified by absolute real-time PCR analysis.

Results

Inducible expression of Pro291fsinsC-HNF1A in INS-1 cells caused a significant upregulation of three miRNAs (miR-103, miR-224, miR-292-3p). The differential expression of two miRNAs (miR-103 and miR-224) was validated in vitro. Strongly elevated levels of miR-103 and miR-224 could be detected in the serum of HNF1A-MODY carriers compared with MODY-negative family controls. Serum levels of miR-103 distinguished HNF1A-MODY carriers from HbA_1c-matched individuals with type 2 diabetes mellitus.

Conclusions/interpretation

Our study demonstrates that the pathophysiology of HNF1A-MODY is associated with the overexpression of miR-103 and miR-224. Furthermore, our study demonstrates that these miRNAs can be readily detected in the serum of HNF1A-MODY carriers.     

Influence of Partial Pressure of Oxygen in Blood Samples on Measurement Performance in Glucose-Oxidase-Based Systems for Self-Monitoring of Blood Glucose

Background

Partial pressure of oxygen (pO₂) in blood samples can affect blood glucose (BG) measurements, particularly in systems that employ the glucose oxidase (GOx) enzyme reaction on test strips. In this study, we assessed the impact of different pO₂ values on the performance of five GOx systems and one glucose dehydrogenase (GDH) system. Two of the GOx systems are labeled by the manufacturers to be sensitive to increased blood oxygen content, while the other three GOx systems are not.

Methods

Aliquots of 20 venous samples were adjusted to the following pO₂ values: <45, ~70, and ≥150 mmHg. For each system, five consecutive measurements on each sample aliquot were performed using the same test strip lot. Relative differences between the mean BG results at pO₂ ~70 mmHg, which is considered to be similar to pO₂ in capillary blood samples, and the mean BG result at pO₂ <45 and ≥150 mmHg were calculated.

Results

For all tested GOx systems, mean relative differences in the BG measurement results were between 6.1% and 22.6% at pO₂ <45 mmHg and between -7.9% and -14.9% at pO₂ ≥150 mmHg. For both pO₂ levels, relative differences of all tested GOx systems were significant (p < .0001). The GDH system showed mean relative differences of -1.0% and -0.4% at pO₂ values <45 and ≥150 mmHg, respectively, which were not significant.

Conclusions

These data suggest that capillary blood pO₂ variations lead to clinically relevant BG measurement deviations in GOx systems, even in GOx systems that are not labeled as being oxygen sensitive.