BK Virus Associated Haemorrhagic Cystitis. A systematic review of current prevention and treatment strategies.

BACKGROUND: BK virus is a major cause of late onset haemorrhagic cystitis in patients undergoing Haematopoietic Cell Transplantation (HCT). The evidence for the management of BK Virus Associated Haemorrhagic Cystitis (BKV-HC) is limited. Much of the published data consists of non-randomised case series and case reports. To our knowledge this is the first systematic review for the management of BKV-HC in both paediatric and adult populations. Our primary outcome was to examine the evidence for strategies of 1) prevention and 2) cessation of haematuria associated with BKV. Secondary outcomes were to assess the toxicity of treatment strategies and devise management recommendations for clinicians. MATERIALS AND METHODS: We performed a systematic review of the PubMed and Central databases to evaluate the current evidence. A search protocol was prepared and registered with the PROSPERO database (CRD42017082442). The review was conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement and AMSTAR (Assessing the methodological quality of systematic reviews) guidelines. Results were classified by treatment type. Qualitative analysis of included articles was performed, and grades of recommendations were devised for each treatment. RESULTS: Of 896 titles screened, 44 articles were included for qualitative analysis. The overall quality of evidence was low. There is insufficient evidence to recommend prophylactic quinolones. 40 studies evaluated treatments for established BKV-HC. There are no high-quality comparative studies. Cidofovir is the most studied treatment but quality of evidence is low, and grade of recommendation is weak. Hyperbaric oxygen therapy, Fibrin glue, Leflunomide, Sodium Pentosan Polysulfate, Intravesical Alum and Radiological embolisation have all been described but the effectiveness of these treatments is unclear. CONCLUSION: There remains no clear specific treatment for BKV-HC. An effective multi-disciplinary approach leading to early recognition and initiation of treatment is encouraged. The development of novel therapies followed by well-designed clinical studies are urgently needed.

Analysis of hematopoietic recovery after autologous transplantation as method of quality control for long-term progenitor cell cryopreservation.

Hematopoietic precursor cells (HPC) are able to restore hematopoiesis after high-dose chemotherapy and their cryopreservation is routinely employed prior to the autologous hematopoietic cell transplantation (AHCT). Although previous studies showed feasibility of long-term HPC storage, concerns remain about possible negative effects on their potency. To study the effects of long-term cryopreservation, we compared time to neutrophil and platelet recovery in 50 patients receiving two AHCT for multiple myeloma at least 2 years apart between 2006 and 2016, using HPC obtained from one mobilization and collection attempt before the first transplant. This product was divided into equivalent fractions allowing a minimum of 2 × 106 CD34+ cells/kg recipient's weight. One fraction was used for the first transplant after median storage of 60 days (range, 17-165) and another fraction was used after median storage of 1448 days (range, 849-3510) at the second AHCT. Neutrophil recovery occurred at 14 days (median; range, 11-21) after the first and 13 days (10-20) after the second AHCT. Platelets recovered at a median of 16 days after both procedures. Considering other factors, such as disease status, conditioning and HPC dose, this single institution data demonstrated no reduction in the potency of HPC after long-term storage.

The Ti-Mn system revisited: experimental investigation and thermodynamic modelling.

As the Ti-Mn phase diagram is part of numerous ternary and higher order systems of technological importance, the present paper defines phase relations which have been experimentally established throughout this work from 800 °C to the melting range based on Differential Thermal Analyses (DTA), X-ray powder diffraction, metallography and Electron Probe Micro Analysis (EPMA) techniques on ∼50 alloys, which were prepared by arc melting or high frequency melting under high purity argon starting from freshly cleaned metal ingots. Novel compounds were identified and reaction isotherms were redefined accordingly. In the Ti-rich region a novel compound TiMn was detected, sandwiched between the known phases: TiMn1-x (∼45 at% Mn) and TiMn1+x (∼55 at% Mn). In the Mn-rich region the hitherto unknown crystal structure of TiMn∼3 was solved from X-ray single crystal diffraction data and found to be of a unique structure type Ti6(Ti1-xMnx)6Mn25 (x = 0.462; space group Pbam (#55); a = 0.79081(3) nm, b = 2.58557(9) nm, c = 0.47931(2) nm), which consists of two consecutive layers of the hexagonal MgZn2-type Laves phase (TiMn2) and a combined layer of alternate structure blocks of MgZn2 type and Zr4Al3 type. Whereas TiMn can be considered as a line compound (solubility range <∼1 at%), the homogeneity regions of the Ti-Mn compounds are significant (determined by EPMA): TiMn1-x (44.0 to 46.6 at% Mn), TiMn1+x (54.6 to 56.3 at% Mn), Ti1+xMn2-x (MgZn2-type, 59 to 69 at% Mn at 1000 °C: -0.08 < x < 0.23), TiMn∼3 (unique type; 74 to 76.5 at% Mn) and TiMn∼4 (R-phase: Ti8(TixMn1-x)6Mn39, 80 to 84 at% Ti). Supported by ab initio calculations of the ground state energy for the Laves phase, the new experimental results enabled thermodynamic modelling of the entire Ti-Mn phase diagram providing a complete and novel set of thermodynamic data thus providing a sound basis for future thermodynamic predictions of higher order Ti-Mn-X-Y systems.

Syndromic surveillance of surgical site infections--a case study in coronary artery bypass graft patients.

OBJECTIVE: There is a wealth of data routinely collected and stored by healthcare facilities, which are not consistently exploited for surveillance of healthcare associated infections (HCAI). Syndromic surveillance has not yet been widely applied to HCAI. This study aimed to create syndromic surveillance for surgical site infections (SSI) following coronary artery bypass graft (CABG) procedures. METHODS: A cohort of CABG patients from Imperial College Healthcare NHS Trust was investigated. Data from the local Patient Administration System, Laboratory Information Management System, radiology department, cardiac registry and Health Protection Agency SSI surveillance were linked. This data was explored for biological markers and proxies of infection, which were used to develop syndromic surveillance algorithms; sensitivity analysis was used to determine the best algorithms. RESULTS: 303 patients were included, with a SSI incidence of 6.6%. Wound culture requests, raised platelet and fibrinogen levels were all found to be good indicators of SSI. Two algorithms were generated, one to detect all SSI (sensitivity: 90%; specificity: 93.8%) and one to detect organ space infections specifically (sensitivity: 100%; specificity: 98.5%). CONCLUSION: Data which is routinely collected and stored in healthcare facilities can be used for syndromic surveillance of SSI, allowing for an efficient surveillance system without the need for resource intensive data collection.

Escalating-dose HLA-mismatched DLI is safe for the treatment of leukaemia relapse following alemtuzumab-based myeloablative allo-SCT.

Although the feasibility of using HLA-mismatched unrelated donors as an alternate graft source for haematopoietic SCT (HSCT) has been shown, little is known about the safety of HLA-mismatched DLI for the treatment of relapse. We examined the outcome of 58 consecutive leukaemia patients who received escalating-dose DLI for treatment of relapse after alemtuzumab-conditioned myeloablative unrelated donor HSCT at our institution. High-resolution HLA typing on stored DNA samples revealed mismatches in 28/58 patients who were considered HLA-matched at the time of transplantation. Following DLI from HLA-matched (10/10) (n=30) or -mismatched (7-9/10) (n=28) unrelated donors, we found no significant difference in the incidence of acute GVHD (17.2% versus 23.1%, P=0.59), probability of remission at 3 years (62.1% versus 63.9%, P=0.89) or 5-year OS (89.8% versus 77.7%, P=0.22). We conclude that escalating-dose DLI can be safely given to HLA-mismatched recipients following T-depleted myeloablative HSCT.

High rate of stem cell mobilization failure after thalidomide and oral cyclophosphamide induction therapy for multiple myeloma.

Novel agents are increasingly used during induction therapy for multiple myeloma (MM), but there is concern about their potential impact on stem cell mobilization. Regimens containing either thalidomide or cyclophosphamide have little or no impact on stem cell collection. In this retrospective review of 136 patients with newly diagnosed MM, we show that the combination of thalidomide and oral CY with dexamethasone (CTD) during induction therapy impaired stem cell mobilization substantially. Compared with VAD (vincristine, doxorubicin, dexamethasone) and a VAD-like induction regimen, the stem cell collection yield after CTD was decreased by 49% (median 5.0 vs 9.8 × 10(6) CD34+cells/kg, P<0.001). Following CTD, more patients failed to mobilize enough stem cells for one (25.4 vs 5.8%, P=0.002) or two (39.4 vs 15.9%, P=0.002) transplants. These results demonstrate that the combination of thalidomide and oral CY impairs stem cell mobilization and indicate that drugs with no previously reported relevant effect on stem cell mobilization can have a substantial impact when given in combination.

[Paroxysmal nocturnal hemoglobinuria and its association with aplastic anemia]. / Paroxyzmální nocní hemoglobinurie a její souvislost s aplastickou anémií.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of haematopoiesis. Clinically it is characterized by intravascular haemolysis, venous thrombosis and often by bone marrow hypoplasia. Haemolysis and thrombosis develop as a consequence of deficiency of several proteins on the cell membrane of the affected clone of blood elements. This is caused by somatic mutations in the PIG-A gene, which encodes an enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI) anchor. Spectrum of mutations in the PIG-A gene is different to that observed in other genes. The mutations are mainly small deletions and insertions causing frameshift; large deletions are rare. Recently, however, a 88 base pairs direct tandem repeat insertion has been reported in a patient with PNH developed on the background of aplastic anaemia (AA). The peculiar pattern of the PIG-A gene mutations and the finding that more than one mutated clone is commonly present in patients with PNH might suggest that some form of hypermutability, caused by decreased DNA stability, deficient repair or increased generation of mutagens, might underline PNH. As most mutations cause cell death, it would explain the hypoplastic nature of the disorder and its association with AA. Other models of pathogenesis of PNH are also discussed.

Paroxysmal nocturnal haemoglobinuria due to an 88 bp direct tandem repeat insertion in the PIG-A gene.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired stem cell abnormality which frequently develops in patients with aplastic anaemia. The disease is due to somatic mutations in the PIG-A gene, and a variety of mutations have been reported. The majority are point mutations, or small insertions and deletions resulting in a frameshift. Previous insertions reported have all been within the range of 1-10 bp. We describe here a patient with PNH due to a large insertion of 88 bp; DNA sequencing showed this to be a tandem repeat of PIG-A sequences. The same mutation could be found in granulocytes and lymphocytes, indicating a pluripotent stem cell origin.

Selenium, cadmium, lead, and mercury concentrations in human breast milk, in placenta, maternal blood, and the blood of the newborn.

The concentrations of the trace elements Cd, Hg, Pb, and Se during the perinatal period in human placenta and in the blood of the mother and the newborn (cord blood) were determined. Breast milk (colostrum and mature milk) was also included to permit correlations between the different compartments. For Cd, a placental barrier exists, in accord with previous observations. For Pb, a strong correlation between the concentrations in the blood of the mother and of the newborn was found. The concentration of Hg was in most cases below the detection limit. Its concentration in colostrum was higher than in the mature milk. The results for Se reflect the knowledge about an essential trace element. Strong positive correlations were noted between maternal blood and cord blood and maternal milk. Anodic stripping voltammetry (DPASV) was used for the determination of Cd and Pb, cold vapor AAS (CVAAS) for the determination of Hg, and instrumental neutron activation analysis (INAA) for the determination of Se.