Summary Background Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ...ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. Methods In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy yes vs no) to receive docetaxel 75 mg/m2 and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov , number NCT01168973. Findings Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1–21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2–18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75–0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3–8·3) for the ramucirumab group compared with 3·0 months (1·4–6·9) for the control group (0·76, 0·68–0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients 49% in the ramucirumab group vs 246 40% in the control group), febrile neutropenia (100 16% vs 62 10%), fatigue (88 14% vs 65 10%), leucopenia (86 14% vs 77 12%), and hypertension (35 6% vs 13 2%). The numbers of deaths from adverse events (31 5% vs 35 6%) and grade 3 or worse pulmonary haemorrhage (eight 1% vs eight 1%) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care. Interpretation Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC. Funding Eli Lilly.
We have developed an efficient strategy that combines immunoglobulin (Ig) gene repertoire analysis and Ig reactivity profiling at the single cell level. Based on surface marker expression individual ...cells at different stages of human B cell development are isolated by fluorescence-activated cell sorting. For each cell Ig heavy and corresponding Ig light chain gene transcripts are amplified by nested RT-PCR and cloned into eukaryotic expression vectors to produce monoclonal human antibodies of the same specificity in vitro. All reactions are performed in 96-well plates and allow cloning of large numbers of Ig genes. The recombinant antibodies are tested for reactivity with diverse self- and non-self antigens and the reactivity profile can be directly linked to the complete Ig heavy and Ig light chain gene sequence information that is obtained as part of the cloning strategy. In summary, our method to clone and express human monoclonal antibodies is unbiased, highly efficient, requires only small cell numbers and the recombinant antibodies allow direct conclusions on the frequency of specific human B cells in a diverse repertoire.
More than half of the nascent B cells in humans initially express autoreactive antibodies. However, most of these autoantibodies are removed from the repertoire at two checkpoints before maturation ...into naive B cells. A third checkpoint excludes remaining autoantibodies from the antigen-experienced IgM+ memory B cell pool. Nevertheless, low-affinity self-reactive antibodies are frequently found in the serum of normal humans. To determine the source of these antibodies, we cloned and expressed antibodies from circulating human IgG+ memory B cells. Surprisingly, we found that self-reactive antibodies including anti-nuclear antibodies were frequently expressed by IgG+ memory B cells in healthy donors. Most of these antibodies were created de novo by somatic hypermutation during the transition between mature naive and IgG+ memory B cells. We conclude that deregulation of self-reactive IgG+ memory B cells may be associated with autoimmunity.
A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but ...subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25-50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5-20% in controls. We conclude that SLE is associated with abnormal early B cell tolerance.
During B lymphocyte development, antibodies are assembled by random gene segment reassortment to produce a vast number of specificities. A potential disadvantage of this process is that some of the ...antibodies produced are self-reactive. We determined the prevalence of self-reactive antibody formation and its regulation in human B cells. A majority (55 to 75%) of all antibodies expressed by early immature B cells displayed self-reactivity, including poly-reactive and anti-nuclear specificities. Most of these autoantibodies were removed from the population at two discrete checkpoints during B cell development. Inefficient checkpoint regulation would lead to substantial increases in circulating autoantibodies.
Long-term humoral immunity is maintained by the formation of high-affinity class-switched memory B cells and long-lived antibody-secreting plasma cells. In healthy humans, a substantial fraction of ...IgG-positive memory B cells express self-reactive and polyreactive IgG antibodies that frequently develop by somatic mutations. Whether self- and polyreactive IgG-secreting B cells are also tolerated in the long-lived plasma cell pool is not known. To address this question, we cloned and expressed the Ig genes from 177 IgG-producing bone marrow plasma cells of four healthy donors. All antibodies were highly mutated but the frequency of self- and polyreactive IgG antibodies was significantly lower than that found in circulating memory B cells. The data suggest that in contrast to the development of memory B cells, entry into the bone marrow plasma cell compartment requires previously unappreciated selective regulation by mechanisms that limit the production of self- and polyreactive serum IgG antibodies.
The article presents general positions and features of a water quality assessment according to the norms of the European Union (EU), shows their difference from the national (Ukrainian) standards. It ...is proposed to improve the Ukrainian standards for assessing a water quality in accordance with the EU standards. On the example of the Danube and the Dniester rivers, a chronological variability of the water quality indicators is considered, the time trends of the indicators are approximated and the parameters of their distribution laws are determined. The following dependences are established: when approximating the distribution of the indicators it is better to use the lognormal law; an indicators time trend is reflected more accurately by the exponential dependence; a lognormal distribution of a trend-normalized indicator can be formally considered as one-parameter (one of the parameters - an average value of the logarithms of the normalized series - is zero). It is shown that for the previous period of time and in the future when normalizing the discharges of pollutants together with wastewater, a water quality assessment in the control points of the water bodies will meet the requirements of the EU standards on a frequency of exceeding the maximum permissible concentrations with the security which is equal to 5 or 10% depending on the purpose of the water body (5% - for fishery facilities, 10% - for drinking and recreational water use facilities).
Autoantibodies are removed from the repertoire at two checkpoints during B cell development in the bone marrow and the periphery. Despite these checkpoints, up to 20% of the antibodies expressed by ...mature naive B cells in healthy humans show low levels of self-reactivity. To determine whether self-reactive antibodies are also part of the antigen-experienced memory B cell compartment, we analyzed recombinant antibodies cloned from single circulating human IgM+ memory B cells. Cells expressing antibodies specific for individual bacterial polysaccharides were expanded in the IgM+ memory compartment. In contrast, B cells expressing self-reactive and broadly bacterially reactive antibodies were removed from the repertoire in the transition from naive to IgM+ memory B cell. Selection against self-reactive antibodies was implemented before the onset of somatic hypermutation. We conclude that a third checkpoint selects against self-reactivity during IgM+ memory B cell development in humans.
A majority of the antibodies expressed by nascent B cells in healthy humans are self-reactive, but most of these antibodies are removed from the repertoire during B cell development. In contrast, ...untreated systemic lupus erythematosus (SLE) patients fail to remove many of the self-reactive and polyreactive antibodies from the naive repertoire. Here, we report that SLE patients in clinical remission continue to produce elevated numbers of self-reactive and polyreactive antibodies in the mature naive B cell compartment, but the number of B cells expressing these antibodies is lower than in patients with active disease. Our finding that abnormal levels of self-reactive mature naive B cells persist in the majority of patients in clinical remission suggests that early checkpoint abnormalities are an integral feature of SLE.
Background
Outcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical ...trials.
Methods
In this multi‐center retrospective study, data were ed from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first‐line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression‐free survival (PFS) were evaluated using the Kaplan‐Meier method and Cox regression.
Results
At start of first‐line systemic anticancer therapy, 92.4% of patients with SS and 91.1% of patients with MRCL had metastatic lesions. However, 74.7% of patients with SS and 72.3% of patients with MRCL had ≥2 lines of systemic therapy. Median OS and median PFS from first‐line therapy for SS was 24.7 months (95% CI, 20.9‐29.4) and 7.5 months, respectively (95% CI, 6.4‐8.4). Median OS and median PFS from start of first‐line therapy for MRCL was 29.9 months (95% CI, 27‐44.6) and 8.9 months (95% CI 4.5‐12.0).
Conclusions
To the best of our knowledge, this is the largest retrospective study of patients with SS and MRCL. It provides an analysis of real‐world clinical outcomes among patients treated at major sarcoma cancer centers and could inform treatment decisions and design of clinical trials. In general, the survival outcomes for this selected population appear more favorable than in published literature.
This comprehensive analysis of real‐world outcomes in patients with advanced synovial sarcoma and myxoid round cell liposarcoma provides greater insight into clinical outcomes than previously published research. These data have the potential to inform prognosis and treatment decisions, as well as provide guidance in the development of future clinical trials.
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