Key role for myeloid cells: phase II results of anti-G(D2) antibody 3F8 plus granulocyte-macrophage colony-stimulating factor for chemoresistant osteomedullary neuroblastoma.

Anti-G(D2) murine antibody 3F8 plus subcutaneously (sc) administered granulocyte-macrophage colony-stimulating factor (GM-CSF) was used against primary refractory neuroblastoma in metastatic osteomedullary sites. Large study size and long follow-up allowed assessment of prognostic factors in a multivariate analysis not reported with other anti-G(D2) antibodies. In a phase II trial, 79 patients without prior progressive disease were treated for persistent osteomedullary neuroblastoma documented by histology and/or metaiodobenzyl-guanidine (MIBG) scan. In the absence of human antimouse antibody, 3F8 + scGM-CSF cycles were repeated up to 24 months. Minimal residual disease (MRD) in bone marrow was measured by quantitative reverse transcription-polymerase chain reaction pre-enrollment and post-cycle #2, before initiation of 13-cis-retinoic acid. Study endpoints were: (i) progression-free survival (PFS) compared with the predecessor trial of 3F8 plus intravenously administered (iv) GM-CSF (26 patients) and (ii) impact of MRD on PFS. Using all 105 patients from the two consecutive 3F8 + GM-CSF trials, prognostic factors were analyzed by multivariate Cox regression model. Complete response rates to 3F8 + scGM-CSF were 87% by histology and 38% by MIBG. Five-year PFS was 24 ± 6%, which was significantly superior to 11 ± 7% with 3F8 + ivGM-CSF (p = 0.002). In the multivariate analysis, significantly better PFS was associated with R/R or H/R FCGR2A polymorphism, sc route of GM-CSF and early MRD response. MYCN amplification was not prognostic. Complement consumption was similar with either route of GM-CSF. Toxicities were manageable, allowing outpatient treatment. 3F8 + scGM-CSF is highly active against chemoresistant osteomedullary neuroblastoma. MRD response may be an indicator of tumor sensitivity to anti-G(D2) immunotherapy. Correlative studies highlight the antineoplastic potency of myeloid effectors.

Cascading hazards of a major Bengal basin earthquake and abrupt avulsion of the Ganges River.

Earthquakes present severe hazards for people and economies and can be primary drivers of landscape change yet their impact to river-channel networks remains poorly known. Here we show evidence for an abrupt earthquake-triggered avulsion of the Ganges River at ~2.5 ka leading to relocation of the mainstem channel belt in the Bengal delta. This is recorded in freshly discovered sedimentary archives of an immense relict channel and a paleo-earthquake of sufficient magnitude to cause major liquefaction and generate large, decimeter-scale sand dikes >180 km from the nearest seismogenic source region. Precise luminescence ages of channel sand, channel fill, and breached and partially liquefied floodplain deposits support coeval timing of the avulsion and earthquake. Evidence for reorganization of the river-channel network in the world's largest delta broadens the risk posed by seismic events in the region and their recognition as geomorphic agents in this and other tectonically active lowlands. The recurrence of comparable earthquake-triggered ground liquefaction and a channel avulsion would be catastrophic for any of the heavily populated, large river basins and deltas along the Himalayan arc (e.g., Indus, Ganges, Brahmaputra, Ayeyarwady). The compounding effects of climate change and human impacts heighten and extend the vulnerability of many lowlands worldwide to such cascading hazards.

Sediment delivery to sustain the Ganges-Brahmaputra delta under climate change and anthropogenic impacts.

The principal nature-based solution for offsetting relative sea-level rise in the Ganges-Brahmaputra delta is the unabated delivery, dispersal, and deposition of the rivers' ~1 billion-tonne annual sediment load. Recent hydrological transport modeling suggests that strengthening monsoon precipitation in the 21st century could increase this sediment delivery 34-60%; yet other studies demonstrate that sediment could decline 15-80% if planned dams and river diversions are fully implemented. We validate these modeled ranges by developing a comprehensive field-based sediment budget that quantifies the supply of Ganges-Brahmaputra river sediment under varying Holocene climate conditions. Our data reveal natural responses in sediment supply comparable to previously modeled results and suggest that increased sediment delivery may be capable of offsetting accelerated sea-level rise. This prospect for a naturally sustained Ganges-Brahmaputra delta presents possibilities beyond the dystopian future often posed for this system, but the implementation of currently proposed dams and diversions would preclude such opportunities.

Disclosure of symptoms of postnatal depression, the perspectives of health professionals and women: a qualitative study.

BACKGROUND: In the UK, 8-15% of women suffer from postnatal depression with long term consequences for maternal mood and child development. Current guidelines state that health visitors and GPs should continue to have a major role in the detection and management of postnatal depression. Previous literature suggests that women are reluctant to disclose symptoms of postnatal depression. This study aimed to explore general practitioners' (GPs), health visitors' and women's views on the disclosure of symptoms which may indicate postnatal depression in primary care. METHODS: In-depth interviews with GPs, health visitors and women who were participating in a randomised controlled trial of anti-depressants versus health visitor delivered non-directive counselling for the treatment of postnatal depression. Interviews were audio-taped and fully transcribed. Thematic analysis with an iterative approach was used, allowing the views of practitioners and patients to be explored and then compared. RESULTS: Nineteen GPs, 14 health visitors and 28 women were interviewed. A number of common themes were identified across all three data sets: understanding and negotiating the diagnosis of postnatal depression, hindering and facilitating disclosure, and the system of care. Both women and health professionals described postnatal depression in psychosocial terms: an adjustment reaction to change in life circumstances and the reality of motherhood not meeting personal expectations. Women described making a conscious decision about whether or not to disclose their feelings to their GP or health visitor. Health professionals described strategies used to hinder disclosure and described a reluctance to make a diagnosis of postnatal depression, as they had few personal resources to manage women with postnatal depression themselves, and no services to which to refer women for further treatment. CONCLUSION: To improve disclosure of symptoms in primary care, there should be a move away from questioning why health professionals do not make the diagnosis of depression and in response suggesting that education and training will improve skills and thus improve detection of depression. Improving the detection and management of postnatal depression in primary care requires recognition of the context in which women consult, and system changes that ensure health professionals work in an environment that can facilitate disclosure and that the necessary resources for management are available. TRIAL REGISTRATION: ISRCTN 16479417.

GPs' and health visitors' views on the diagnosis and management of postnatal depression: a qualitative study.

BACKGROUND: In the UK, 8-15% of women suffer from postnatal depression, with long-term consequences for maternal mood and child development. Previous literature suggests that health visitors struggle with their conflicting roles with respect to mother and infant. Current policy is redirecting the emphasis and organisation of health visitor work, but guidelines state that health visitors and GPs should continue to have a major role in the detection and management of postnatal depression. AIM: To explore the views of GPs and health visitors on the diagnosis and management of postnatal depression. DESIGN OF STUDY: A qualitative study nested within a multicentre randomised controlled trial. SETTING: Nine primary care trusts in Bristol, Manchester, and London. METHOD: In-depth interviews with GPs and health visitors from primary care trusts participating in a randomised controlled trial of antidepressants versus health visitor-delivered non-directive counselling. Interviews were audiotaped and fully transcribed. Thematic analysis with an iterative approach was used to develop conceptual categories from the transcripts. RESULTS: Nineteen GPs and 14 health visitors were interviewed. GPs and health visitors described their work in making and negotiating the diagnosis of postnatal depression, the value of a long-term relationship with the woman, and how labelling affects management of women with postnatal depression. Responders described how they viewed others' roles in the management of postnatal depression, and how national policy and local organisational changes had an impact on patient care, so that no one health professional was assuming overall responsibility for the care of women with postnatal depression. CONCLUSION: Ongoing organisational changes within primary care, such as the implementation of corporate working by health visitors, affect care provided to women after birth, which in turn has an impact on the diagnosis and management of postnatal depression.

Anatomy of Mississippi Delta growth and its implications for coastal restoration.

The decline of several of the world's largest deltas has spurred interest in expensive coastal restoration projects to make these economically and ecologically vital regions more sustainable. The success of these projects depends, in part, on our understanding of how delta plains evolve over time scales longer than the instrumental record. Building on a new set of optically stimulated luminescence ages, we demonstrate that a large portion (~10,000 km2) of the late Holocene river-dominated Mississippi Delta grew in a radially symmetric fashion for almost a millennium before abandonment. Sediment was dispersed by deltaic distributaries that formed by means of bifurcations at the coeval shoreline and remained active throughout the life span of this landform. Progradation rates (100 to 150 m/year) were surprisingly constant, producing 6 to 8 km2 of new land per year. This shows that robust rates of land building were sustained under preindustrial conditions. However, these rates are several times lower than rates of land loss over the past century, indicating that only a small portion of the Mississippi Delta may be sustainable in a future world with accelerated sea-level rise.

KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma.

PURPOSE: In patients with neuroblastoma (NB), treatment with anti-GD2 monoclonal antibody (mAb) directs natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, tumor cytotoxicity is attenuated by ligation of inhibitory killer immunoglobulin-like receptors (KIRs) by HLA class I molecules. KIR3DL1 polymorphism influences its ability to engage HLA-Bw4 ligands. We tested the hypothesis that poorly interacting combinations of KIR3DL1 and HLA ligands are more permissive of mAb-mediated antitumor effect. METHODS: KIR3DL1 and HLA-B subtyping were performed with a multiplex intermediate-resolution polymerase chain reaction assay for a cohort of 245 patients who were treated with antibody 3F8 for high-risk NB. Patient outcomes were analyzed according to expected degree of interaction between KIR3DL1 and HLA-B subtypes and grouped as strong, weak, or noninteractors. A comparison of NK response to 3F8 mAb opsonized NB cells between strong- and noninteracting donors was performed by flow cytometry. RESULTS: KIR3DL1 and HLA-B subtype combinations associated with noninteraction as a result of lack of receptor expression [KIR3DL1(-)], failure of interaction with inhibitory ligands [KIR3DS1(+)], or absence of KIR ligands resulted in significantly improved overall and progression-free survival. Patients with KIR3DL1 and HLA-B subtype combinations that were predictive of weak interaction had superior outcomes compared with those that were predictive of strong interaction; however, both groups were inferior to those with noninteracting subtype combinations. In vitro analysis of 3F8-mediated ADCC showed that KIR3DL1(-) and 3DS1(+) NK cells were insensitive to inhibition by HLA-Bw4-expressing NB targets. CONCLUSION: We conclude that KIR3LD1 and HLA-B allele combinations can have a prognostic impact on patient survival after treatment with anti-GD2 mAb that relies on NK-ADCC. The survival advantage seen in noninteracting combinations supports the therapeutic disinhibition of individuals with strongly interacting KIR and ligand pairs.

Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission.

PURPOSE: Anti-GD2 monoclonal antibody (MoAb) combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown efficacy against neuroblastoma (NB). Prognostic variables that could influence clinical outcome were explored. PATIENTS AND METHODS: One hundred sixty-nine children diagnosed with stage 4 NB (1988 to 2008) were enrolled onto consecutive anti-GD2 murine MoAb 3F8 ± GM-CSF ± 13-cis-retinoic acid (CRA) protocols after achieving first remission (complete remission/very good partial remission). Patients enrolled in regimen A (n = 43 high-risk [HR] patients) received 3F8 alone; regimen B (n = 41 HR patients), 3F8 + intravenous GM-CSF + CRA, after stem-cell transplantation (SCT); and regimen C (n = 85), 3F8 + subcutaneous GM-CSF + CRA, 46 of 85 after SCT, whereas 28 of 85 required additional induction therapy and were deemed ultra high risk (UHR). Marrow minimal residual disease (MRD) was measured by quantitative reverse transcription polymerase chain reaction. Survival probability was calculated by the Kaplan-Meier method, and prognostic variables were analyzed by multivariate Cox regression model. RESULTS: At 5 years from the start of immunotherapy, progression-free survival (PFS) improved from 44% for HR patients receiving regimen A to 56% and 62% for those receiving regimens B and C, respectively. Overall survival (OS) was 49%, 61%, and 81%, respectively. PFS and OS of UHR patients were 36% and 75%, respectively. Relapse was mostly at isolated sites. Independent adverse prognostic factors included UHR (PFS) and post-cycle two MRD (PFS and OS), whereas the prognostic factors for improved outcome were missing killer immunoglobulin-like receptor ligand (PFS and OS), human antimouse antibody response (OS), and regimen C (OS). CONCLUSION: Retrospective analysis of consecutive trials from a single center demonstrated that MoAb 3F8 + GM-CSF + CRA is effective against chemotherapy-resistant marrow MRD. Its positive impact on long-term survival can only be confirmed definitively by randomized studies.

Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment.

Survival outcomes for patients with high-risk neuroblastoma (NB) have significantly improved with anti-disialoganglioside GD2 mAb therapy, which promotes NK cell activation through antibody-dependent cell-mediated cytotoxicity. NK cell activation requires an interaction between inhibitory killer cell immunoglobulin-like receptors (KIRs) and HLA class I ligands. NK cells lacking KIRs that are specific for self HLA are therefore "unlicensed" and hyporesponsive. mAb-treated NB patients lacking HLA class I ligands for their inhibitory KIRs have significantly higher survival rates, suggesting that NK cells expressing KIRs for non-self HLA are mediating tumor control in these individuals. We found that, in the presence of mAb, both licensed and unlicensed NK cells are highly activated in vitro. However, HLA class I expression on NB cell lines selectively inhibited licensed NK cell activity, permitting primarily unlicensed NK cells to mediate antibody-dependent cell-mediated cytotoxicity. These results indicate that unlicensed NK cells play a key antitumor role in patients undergoing mAb therapy via antibody-dependent cell-mediated cytotoxicity, thus explaining the potent "missing KIR ligand" benefit in patients with NB.