A probabilistic method to estimate the burden of maternal morbidity in resource-poor settings: preliminary development and evaluation

Background

Maternal morbidity is more common than maternal death, and population-based estimates of the burden of maternal morbidity could provide important indicators for monitoring trends, priority setting and evaluating the health impact of interventions. Methods based on lay reporting of obstetric events have been shown to lack specificity and there is a need for new approaches to measure the population burden of maternal morbidity. A computer-based probabilistic tool was developed to estimate the likelihood of maternal morbidity and its causes based on self-reported symptoms and pregnancy/delivery experiences. Development involved the use of training datasets of signs, symptoms and causes of morbidity from 1734 facility-based deliveries in Benin and Burkina Faso, as well as expert review. Preliminary evaluation of the method compared the burden of maternal morbidity and specific causes from the probabilistic tool with clinical classifications of 489 recently-delivered women from Benin, Bangladesh and India.

Results

Using training datasets, it was possible to create a probabilistic tool that handled uncertainty of women’s self reports of pregnancy and delivery experiences in a unique way to estimate population-level burdens of maternal morbidity and specific causes that compared well with clinical classifications of the same data. When applied to test datasets, the method overestimated the burden of morbidity compared with clinical review, although possible conceptual and methodological reasons for this were identified.

Conclusion

The probabilistic method shows promise and may offer opportunities for standardised measurement of maternal morbidity that allows for the uncertainty of women’s self-reported symptoms in retrospective interviews. However, important discrepancies with clinical classifications were observed and the method requires further development, refinement and evaluation in a range of settings.

     

Efficient migration of dendritic cells toward lymph node chemokines and induction of T(H)1 responses require maturation stimulus and apoptotic cell interaction

Dendritic cells (DCs) have the unique ability to initiate primary immune responses, and they can be conditioned for vaccinal purposes to present antigens after the engulfment of apoptotic cells. To recruit the rare antigen-specific naive T cells, DCs require a maturation step and subsequent transport toward lymph node (LN). To date, prostaglandin E2 (PGE2) is the best-characterized compound inducing this LN-directed migration in vitro, but PGE2 may skew the immune responses in a T(H)2 direction. We demonstrate here that on incubation with apoptotic tumor cells and tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS), human monocyte-derived DCs become fully mature and acquire high migratory capacities toward LN-directing chemokines. The migration of TNF-alpha-treated DCs occurs only after cotreatment with apoptotic cells but not with necrotic cells. DC migration requires CD36 expression and incubation with apoptotic cells in the presence of heat-labile serum components. Moreover, on treatment with apoptotic cells and LPS, the migrating DCs are able to recruit naive T cells to generate T(H)1 immune responses. Our results show that the cotreatment of DCs with apoptotic tumor cells and inflammatory signals is promising for the design of an antitumoral DC-based vaccine.     

Graft-Versus-Host Disease and Graft-Versus-Leukemia Effect in Mice Grafted With Peripheral Newborn Blood

We previously used peripheral newborn blood (NBB) as a possible invivo experimental model for cord blood (CB) transplantation and showedthat B10.D2 NBB cells successfully reconstituted adult (DBA/2 × B10.D2)F1 mice without causing graft-versus-host disease (GVHD),probably because of their phenotypic and functional immaturity. Here weinvestigated the influence of T-cell maturation occurring in NBB cellsduring the early postbirth period on the degree of engraftment, theincidence of GVHD, and the graft-versus-leukemia (GVL) potential. Theseparameters were compared in recipients grafted with bone marrow (BM)cells. We observed an increased percentage of CD4⁺ matureT cells accompanied by the acquisition of proliferative responses tophytohemagglutinin (PHA) and to allogeneic cells of day-5 NBB cells.The capacity of day-2 NBB to engraft was moderately reduced andrecipients developing GVHD were occasionally observed after the graftof day-5 NBB cells. No GVL effect was evidenced regardless of the timeof postbirth blood collection. However, the GVL effect can be obtainedby the delayed infusion of donor mature T cells to recipients graftedwith day-0 NBB, without causing GVHD. In contrast, the same protocolapplied to mice grafted with BM cells induced GVHD mortality of allrecipients. Interleukin (IL)-10 but not IL-2 messenger RNA wasexpressed in NBB cells as opposed to BM cells. These findings suggestthat, in terms of GVHD incidence, delayed infusion of mature T cells aspost-transplant tumor immunotherapy would be more effective whenapplied after CB than after BM transplantation.     

Impact of TCR status and genotype on outcome in adult T-cell acute lymphoblastic leukemia: a LALA-94 study

Patients with T-cell acute lymphoblastic leukemias (T-ALLs) within the Leucemies Aigues Lymphoblastiques de l'Adulte-94 (LALA-94) prospective trial were treated with a 4-drug per 4-week induction, with intermediate-dose cytarabine and mitoxantrone salvage treatment for patients not achieving complete remission (CR) in 1 course. Only the latter received allografts, if possible, thus providing an informative setting for assessing early response. Representative patients with T-ALL (91 patients) were classified into surface T-cell receptor (TCR)-expressing T-ALL patients (TCRalphabeta+ or TCRgammadelta+), pre-alphabeta T-ALL patients (cTCRbeta+, TCR-), and immature (IM) cTCRbeta-, TCR- T-ALL patients; 81 patients underwent genotyping for SIL-TAL1, CALM-AF10, HOX11, and HOX11L2. Overall, CR was obtained in 81 (89%) patients; relapse rate was 62% at 4 years and overall survival (OS) rate was 38%. CR rate was significantly lower in IM T-ALL patients after 1 course (45% vs 87%; P < .001) and after salvage (74% vs 97%; P = .002), with the latter inducing a higher rate of CR (9 [64%] of 14) than initial induction. Once CR was obtained, cumulative relapse rates were similar for IM, pre-alphabeta, and TCR+ T-ALL patients (P = .51), but were higher in HOX11L2 (83%) and SIL-TAL1 (82%) T-ALL patients compared with other genetic subgroups (48%; P = .05). This was associated with an inferior OS for HOX11L2 T-ALLs (13% vs 47% in HOX11L2-T-ALLs; P = .009). The majority of patients with HOX11 T-ALL underwent allografting, predominantly in second CR, but were not associated with a superior OS. Both TCR and genotypic stratification can therefore contribute to risk-adapted management of adult T-ALLs.     

Activating mutations in human acute megakaryoblastic leukemia

Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. To gain insight into the oncogenic process leading to acute megakaryoblastic leukemia (AMKL), we performed sequence analyses of a subset of oncogenes known to be activated in human myeloid and myeloproliferative disorders. In a series of human AMKL samples from both Down syndrome and non-Down syndrome patients, mutations were identified within KIT, FLT3, JAK2, JAK3, and MPL genes, with a higher frequency in DS than in non-DS patients. The novel mutations were analyzed using BaF3 cells, showing that JAK3 mutations were activating mutations. Finally, we report a novel constitutively active MPL mutant, MPLT487A, observed in a non-Down syndrome childhood AMKL that induces a myeloproliferative disease in mouse bone marrow transplantation assay.     

A comparison of two modalities of stereotactic body radiation therapy for peripheral early-stage non-small cell lung cancer: results of a prospective French study

Objectives:This prospective, observational, non-randomized multicentric study was conducted to compare efficiency and toxicity using different modalities of stereotactic body radiation therapy (SBRT) in early-stage peripheral non-small cell lung cancer (NSCLC).Methods:From 9 April to 11 December, 106 patients were treated according to the local equipment availability for peripheral NSCLC with SBRT: 68 by linear accelerator equipped for SBRT and 38 by Cyberknife^®. Multivariate analysis and propensity score analysis using Inverse Probability Treatment Weighting (IPTW) were undertaken in an effort to adjust for potential bias due to non-randomization.Results:2-year local control rates were 97.0% (95% CI: [90.6%; 99.4%]) with SBRT by Linac vs 100% (95% CI: ([100%; 100%]) with Cyberknife^® (p = 0.2839). 2-year PFS and 2-year OS rates were 52.7% (95% CI [39.9%;64.0%]) versus 54.1% (95% CI [36.8; 68.6%]) (p = 0.8582) and 65.1% (95% CI: [51.9%; 75.5%] versus 83.9% (95% CI: [67.5%; 92.4%] (p = 0.0831) using Linac and Cyberknife^® respectively. Multivariate regression analysis indicates no significant effect of SBRT treatment type on PFS or OS. Local relapse could not be modeled due to the small number of events (n = 2). Acute and late toxicity rates were not significantly different. After IPTW adjustment, results were unchanged.Conclusions:No difference in efficiency or toxicity was shown after SBRT of peripheral NSCLC treatment using Linac or Cyberknife^®.Advances in knowledge:This is the first large prospective non-randomized study focusing on peripheral localized NSCLC comparing SBRT using an appropriately equipped linac with Cyberknife^®. No significant difference in efficiency or toxicity was shown in this situation.     

C3 nephritic factor associated with C3 glomerulopathy in children

Background

C3 glomerulopathy (C3G) is characterized by predominant C3 deposits in glomeruli and dysregulation of the alternative pathway of complement. Half of C3G patients have a C3 nephritic factor (C3NeF). C3G incorporated entities with a range of features on microscopy including dense deposit diseases (DDD) and C3 glomerulonephritis (C3GN). The aim of this work was to study children cases of C3G associated with C3NeF.

Methods

We reviewed 18 cases of C3G with a childhood onset associated with C3NeF without identified mutations in CFH, CFI, and MCP genes.

Results

Clinical histories started with recurrent hematuria for seven patients, nephrotic syndrome for four, acute post-infectious glomerulonephritis for three and acute renal failure for four. Twelve patients had a low C3 at first investigation. Kidney biopsy showed ten C3GN and eight DDD. Twenty-three percent of the patients tested presented elevated sC5b9. Seven patients relapsed 3 to 6 years after the onset. At the end of follow-up, two patients were under dialysis, 11 had a persistent proteinuria, five had none; four patients did not follow any treatment. Steroids were first used in 80 % of cases.

Conclusions

C3NeF associated C3G has a heterogeneous presentation and outcome. Anti-proteinuric agents may control the disease during follow-up, even after nephrotic syndrome at the onset. The efficiency of immunosuppressive therapy remains questionable.