Real-world outcomes in elderly ALL patients with and without allogeneic hematopoietic stem cell transplantation: a single-center evaluation over 10 years

Elderly patients (EP) of 60 years and above with acute lymphoblastic leukemia (ALL) have a dismal prognosis, but pediatric-inspired chemotherapy and allogeneic stem cell transplantation (allo HCT) are used reluctantly due to limited data and historical reports of high treatment-related mortality in EP. We analyzed 130 adult ALL patients treated at our center between 2009 and 2019, of which 26 were EP (range 60-76 years). Induction with pediatric-inspired protocols was feasible in 65.2% of EP and resulted in complete remission in 86.7% compared to 88.0% in younger patients (YP) of less than 60 years. Early death occurred in 6.7% of EP. Three-year overall survival (OS) for Ph - B-ALL was significantly worse for EP (n = 16) than YP (n = 64) with 30.0% vs 78.1% (p ≤ 0.001). Forty-nine patients received allo HCT including 8 EP, for which improved 3-year OS of 87.5% was observed, whereas EP without allo HCT died after a median of 9.5 months. In Ph + B-ALL, 3-year OS did not differ between EP (60.0%, n = 7) and YP (70.8%, n = 19). Non-relapse mortality and infection rate were low in EP (14.3% and 12.5%, respectively). Our data indicate that selected EP can be treated effectively and safely with pediatric regimens and might benefit from intensified therapy including allo HCT. Keywords: Acute lymphoblastic leukemia; Allogeneic hematopoietic stem cell transplantation; Elderly; Treatmen

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Hypertension après transplantation rénale [Hypertension after kidney transplantation]

Kidney transplantation is the treatment of choice for end-stage renal disease. While graft survival has considerably improved with current immunosuppressive strategies, long-term prognosis is dependent on cardiovascular complications. There is a high prevalence of arterial hypertension after kidney transplantation. Hypertension can be associated with traditional risk factors or directly linked with the anatomy and the function of the kidney allograft, as well as with the immunosuppressive treatment. Current blood pressure targets are <130/80 mmHg, but there is a lack of evidence regarding the impact on cardiovascular and graft outcomes. In this review, we discuss the epidemiology, the causes as well as the management of hypertension after kidney transplantation

The Rational Use of Complement Inhibitors in Kidney Diseases.

The development of complement inhibitors represented one of the major breakthroughs in clinical nephrology in the last decade. Complement inhibition has dramatically transformed the outcome of one of the most severe kidney diseases, the atypical hemolytic uremic syndrome (aHUS), a prototypic complement-mediated disorder. The availability of complement inhibitors has also opened new promising perspectives for the management of several other kidney diseases in which complement activation is involved to a variable extent. With the rapidly growing number of complement inhibitors tested in a rapidly increasing number of indications, a rational use of this innovative and expensive new therapeutic class has become crucial. The present review aims to summarize what we know, and what we still ignore, regarding complement activation and therapeutic inhibition in kidney diseases. It also provides some clues and elements of thoughts for a rational approach of complement modulation in kidney diseases

Targeting the Complement Pathway in Kidney Transplantation.

The complement system is paramount in the clearance of pathogens and cell debris, yet is increasingly recognized as a key component in several pathways leading to allograft injury. There is thus a growing interest in new biomarkers to assess complement activation and guide tailored therapies after kidney transplantation. C5 blockade has revolutionized post-transplant management of atypical hemolytic uremic syndrome, a paradigm of complement-driven disease. Similarly, new drugs targeting the complement amplification loop hold much promise in the treatment and prevention of recurrence of C3 glomerulopathy. Although unduly activation of the complement pathway has been described following brain death and ischemia-reperfusion, any clinical attempts to mitigate the ensuing renal insults have so far provided mixed results. However, the intervention timing, strategy, and type of complement blocker need to be optimized in these settings. Furthermore, the fast-moving field of ex-vivo organ perfusion technology opens new avenues to deliver complement-targeted drugs to kidney allografts with limited iatrogenic risks. Complement plays also a key role in the pathogenesis of donor-specific ABO- and HLA-targeted alloantibodies. However, C5 blockade failed overall to improve outcomes in highly-sensitized patients and prevent the progression to chronic antibody-mediated rejection. Similarly, well-conducted studies with C1-inhibitor in sensitized recipients yielded disappointing results so far, in part due to subtherapeutic dosage used in clinical studies. The emergence of new complement blockers raises hope to significantly reduce the negative impact of ischemia-reperfusion, antibody-mediated rejection, and nephropathy recurrence on outcomes after kidney transplantation

Toxicity of cerium dioxide nanoparticles - effects from a 90-day inhalation study

Frequent use of cerium dioxide nanoparticles e.g. as diesel fuel additive requires assessment of possible health effects. Although exposure via the respiratory tract is likely, little is known about impacts after inhalation. To address this issue, a 90-day nose-only inhalation study was initiated. Early indicators of genotoxic and carcinogenic effects were determined. Results will be compared to a combined chronic inhalation toxicity and carcinogenicity study with similar test items and conditions (BASF, Ludwigshafen, Germany). Rats were exposed to 0, 0.1, 0.3, 1 and 3 mg/m3 CeO2 nanoparticles (6 h/day, 5 days/week, 13 weeks). Exposure to a high concentration of nanoscaled barium sulfate (50 mg/m3) was included as well. Investigations were performed after one and 28 exposure days, as well as after one, 28 and 90 days post-exposure. Obligatory endpoints (OECD guideline 413) were extended by gene expression analysis in pneumocytes type II and immunohistochemistry to identify biomarkers for effects including genotoxicity, oxidative stress and apoptosis. Histopathological findings indicated the presence of inflammatory cells in lung tissue after treatment to 3 mg/m3 CeO2. Severity of effects was increasing over time and remained persistent during post-exposure. Bronchoalveolar lavage fluid analysis displayed a similar trend. Expression of over 30 genes was significantly influenced by nanoparticle exposure. The present findings suggest that CeO2 nanoparticles affect the rats’ respiratory system. Importance of those observations, especially regarding long term effects will be assessed including all upcoming investigations of this study. This project is funded by the German Federal Ministry of Education and Research (BMBF) – 03X0149A