The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia

Although central nervous system (CNS) leukemic relapse is frequent in adult acute lymphocytic leukemia (ALL), the need for prophylaxis in different risk groups for CNS relapse, the value of high-dose systemic and intrathecal (IT) chemotherapy, and the timing of prophylaxis are not well defined. This analysis was conducted to investigate these questions and to assess the value of a risk-oriented CNS prophylaxis approach. We analyzed the incidence of CNS leukemia after initiation of therapy in patients treated on 4 consecutive trials for adult ALL including different CNS prophylactic modalities. The treatment groups included (1) the program preceeding the vincristine-Adriamycin- dexamethasone (VAD) regimen, with no CNS prophylaxis; (2) the VAD regimen with prophylaxis using high-dose systemic chemotherapy; (3) the modified VAD program with high-dose systemic chemotherapy to all patients and IT chemotherapy for high-risk patients after achieving complete remission; and (4) the hyperCVAD program with early high-dose systemic and IT chemotherapy starting during induction to all patients, with more IT injections (16IT) administered to the high-risk group for CNS relapse compared with the low-risk group (4IT). A total of 391 patients were included, 73 of whom were treated with preVAD, 112 with VAD, 114 with modified VAD, and 92 with hyperCVAD. The overall CNS relapse rates were 31%, 18%, 17%, and 3%, respectively for the 4 groups (P < .001). For the high-risk group for CNS relapse, they were 42%, 26%, 20%, and 2%, respectively (P < .001). The differences in CNS relapse rates in the low-risk group were not statistically significant. At 3 years, the overall CNS leukemia event-free rates were 48%, 76%, and 98%, respectively (P < .001). In the high-risk group, the CNS event- free rates were 38%, 66%, 75%, and 98%, respectively (P < .001); however, there was no difference in the low-risk group. We conclude that (1) high-dose systemic chemotherapy is a useful prophylactic measure; (2) early IT chemotherapy is necessary to reduce the incidence of CNS leukemia overall and in the high-risk group; and (3) a risk- oriented approach is appropriate to tailor the intensity of CNS prophylaxis.     

Counting every stillbirth and neonatal death through mortality audit to improve quality of care for every pregnant woman and her baby

Background

While there is widespread acknowledgment of the need for improved quality and quantity of information on births and deaths, there has been less movement towards systematically capturing and reviewing the causes and avoidable factors linked to deaths, in order to affect change. This is particularly true for stillbirths and neonatal deaths which can fall between different health care providers and departments. Maternal and perinatal mortality audit applies to two of the five objectives in the Every Newborn Action Plan but data on successful approaches to overcome bottlenecks to scaling up audit are lacking.

Methods

We reviewed the current evidence for facility-based perinatal mortality audit with a focus on low- and middle-income countries and assessed the status of mortality audit policy and implementation. Based on challenges identified in the literature, key challenges to completing the audit cycle and affecting change were identified across the WHO health system building blocks, along with solutions, in order to inform the process of scaling up this strategy with attention to quality.

Results

Maternal death surveillance and review is moving rapidly with many countries enacting and implementing policies and with accountability beyond the single facility conducting the audits. While 51 priority countries report having a policy on maternal death notification in 2014, only 17 countries have a policy for reporting and reviewing stillbirths and neonatal deaths. The existing evidence demonstrates the potential for audit to improve birth outcomes, only if the audit cycle is completed. The primary challenges within the health system building blocks are in the area of leadership and health information. Examples of successful implementation exist from high income countries and select low- and middle-income countries provide valuable learning, especially on the need for leadership for effective audit systems and on the development and the use of clear guidelines and protocols in order to ensure that the audit cycle is completed.

Conclusions

Health workers have the power to change health care routines in daily practice, but this must be accompanied by concrete inputs at every level of the health system. The system requires data systems including consistent cause of death classification and use of best practice guidelines to monitor performance, as well as leaders to champion the process, especially to ensure a no-blame environment, and to access change agents at other levels to address larger, systemic challenges.

     

Redox regulation of NF‐κB p50 and M1 polarization in microglia

Redox‐signaling is implicated in deleterious microglial activation underlying CNS disease, but how ROS program aberrant microglial function is unknown. Here, the oxidation of NF‐κB p50 to a free radical intermediate is identified as a marker of dysfunctional M1 (pro‐inflammatory) polarization in microglia. Microglia exposed to steady fluxes of H₂O₂ showed altered NF‐κB p50 protein–protein interactions, decreased NF‐κB p50 DNA binding, and augmented late‐stage TNFα expression, indicating that H₂O₂ impairs NF‐κB p50 function and prolongs amplified M1 activation. NF‐κB p50^?/? mice and cultures exhibited a disrupted M2 (alternative) response and impaired resolution of the M1 response. Persistent neuroinflammation continued 1 week after LPS (1 mg/kg, IP) administration in the NF‐κB p50^?/? mice. However, peripheral inflammation had already resolved in both strains of mice. Treatment with the spin‐trap DMPO mildly reduced LPS‐induced 22 h TNFα in the brain in NF‐κB p50^+/+ mice. Interestingly, DMPO failed to reduce and strongly augmented brain TNFα production in NF‐κB p50^?/? mice, implicating a fundamental role for NF‐κB p50 in the regulation of chronic neuroinflammation by free radicals. These data identify NF‐κB p50 as a key redox‐signaling mechanism regulating the M1/M2 balance in microglia, where loss of function leads to a CNS‐specific vulnerability to chronic inflammation. GLIA 2015;63:423–440     

Therapeutic effectiveness of frozen platelet concentrates for transfusion

Six patients received platelet concentrate transfusions from their HLA- identical siblings. Platelet concentrates were administered either fresh, or after being frozen in 10% dimethylsulfoxide, at a slow controlled rate (1 degree C/min) or rapidly (approximately 8 degrees C/min) in the vapor-phase of a liquid nitrogen refrigerator. The median freeze-thaw loss was 13.5%. The mean 1-hr and 20-hr corrected increments in platelet count were calculated for fresh platelet concentrates transfused before and after transfusion with controlled- rate frozen and vapor-phase frozen platelet concentrates. There was no significant difference among the first and second transfusion of fresh platelet concentrates, nor was the difference observed between fresh and controlled-rate frozen platelet concentrates significant. The difference between fresh and vapor-phase frozen platelet concentrates, and between controlled-rate frozen and vapor-phase frozen platelet concentrates were highly significant (p < 0.01). In vitro tests of aggregation using ristocetin and platelet ultrastructural studies paralleled the transfusion experience. Our results indicate that HLA- identical platelet concentrates can be successfully frozen and thawed for transfusion if a slow, controlled rate of freezing is employed. The use of HLA-identical frozen platelet concentrates may be important in emergency situations for the refractory patient and potentially for the establishment of a platelet concentrate bank.     

Extra-relational sex among Hispanic women and their condom-related behaviours and attitudes

Limited data are available concerning sexual behaviour of Hispanic women. A total of 318 Hispanic women were surveyed concerning extra-relational sex and their condom-related attitudes. Fifteen per cent of the sample had a secondary sex partner (apart from the first partner) during the three months preceding the survey. Of these women, 77 and 53% used condoms with their secondary and primary partners, respectively. Among women in monogamous relationships, condom use was low (17%), and nearly two-thirds (61%) of those with a high-risk partner did not use condoms. The most common concerns about condom use among these Hispanic women were a reduction in pleasurable sensations and embarrassment associated with buying condoms. Women with concurrent partners as compared to those with a single partner felt more at risk for HIV and STDs, were less likely to believe condoms have side effects or are unacceptable to their male partners and were more able to use condoms in long-term relations. In conclusion, extra-relational sex among Hispanic women may be higher than previously reported, although more favourable attitudes to condom use are seen among women with concurrent than those with a single partner. HIV/STD programmes in the Hispanic community should tailor to the sexual behaviour of their participants.     

Gene transfer into human bone marrow hematopoietic cells mediated by adenovirus vectors [see comments]

Human bone marrow mononuclear cells (BMMNCs) and enriched CD34 positive (CD34+) cells were transduced with adenovirus vectors encoding Escherichia coli beta-galactosidase gene. Tranductions were carried out by 24-hour coincubation with adenovirus vectors at different multiplicities of infections (moi). Efficacy of gene transfer into BM cells and expression of the gene product (ie, beta-galactosidase) were studied using X-Gal histochemical staining and flow cytometric analysis. X-Gal staining demonstrated that the percentage of positive cells at mois of 5 to 500 was 3.4% to 34.5% for BMMNCs and 6.0% to 20.0% for enriched CD34+ cells. Similar results (1.5% to 35.7% for BMMNCs and 5.4% to 24.2% for enriched CD34+ cells) were obtained with flow cytometric analysis using fluorescein di-beta-D-galactopyranoside (FDG). Multicolor flow cytometry analysis, which included FDG, demonstrated that BM progenitors (CD34+ or CD34+CD38-), T cells (CD2+), B cells (CD19+), natural killer cells (CD56+), granulocytes, and monocytes all expressed the adenovirus transgene. To ascertain the effects of adenovirus vectors on normal BM progenitors, the numbers of colony forming unit-granulocyte/macrophage (CFU-GM), burst-forming unit- erythrocyte (BFU-E), and high-proliferative potential-colony-forming cells (HPP-CFC) after 24-hour coincubation with adenovirus vectors were determined. When BMMNCs or enriched CD34+ cells were incubated with adenovirus vectors at mois of 5 and 50, no significant differences in the numbers of CFU-GM, BFU-E, and HPP-CFC were observed compared with the uninfected control cells. However, the numbers of CFU-GM were significantly (P < .01) decreased when BMMNCs or enriched CD34+ cells were incubated with adenovirus vectors at a moi of 500, compared with the uninfected control cells. The adenovirus infected cells, purified by cell sorting for FDG expression, were capable of growing in culture and gave rise to various colonies (ie, CFU-GM, BFU-E, and HPP-CFC). These data indicate that recombinant adenovirus vectors can be used to transfer genes to human BM hematopoietic cells with expression of the exogenous gene at a high transduction efficiency.     

Synovium in haemophilic arthropathy

Summary. Synovium is an essential component of the joint and plays a critical role in maintaining a balance between physiological processes and pathological changes in the joint. Recurrent intra-articular bleeding as occur in haemophilia induce pathological synovial changes in the joint. From a certain point on, synovitis inevitably plays a major role in joint destruction, although in the early phase of haemophilic arthropathy its role may be secondary to cartilage damage as a result of the direct effects of blood on cartilage. The changed haemosiderotic, synovial tissue produces catabolic cytokines and enzymes harmful for cartilage.     

Does food intolerance play a role in juvenile chronic arthritis?

Sixty children with juvenile chronic arthritis (JCA) have been examined at the paediatric rheumatology out-patient clinic in Maastricht, of whom three ultimately appeared to have a food intolerance. In one of these three patients, there appeared to be a relationship with joint complaints. In the course of the elimination/challenge tests which were conducted, severe painful swelling of the knee occurred rapidly after each challenge. Three challenges were carried out with the same result each time. Since the symptoms did not disappear entirely following elimination of milk, it was concluded that milk intolerance in this case was an aggravating factor in a seronegative monoarticular JCA. In the second and third patients, a strict diet had no positive effect on the joint problems. In conclusion, the existence of such a connection between food and chronic joint complaints has been made clear, it only plays a role in incidental cases.