503 Phase I radioimmunotherapy (RIT) study of 90Y-CC49 monoclonal antibody (MAb) therapy in patients with advanced non-small cell lung cancer (NSCLC)

503 Phase I radioimmunotherapy (RIT) study of 90Y-CC49 monoclonal antibody (MAb) therapy in patients with advanced non-small cell lung cancer (NSCLC) × Close The Infona portal uses cookies, ie strings of text saved by a browser on the user\u27s device. The portal can access those files and use them to remember the user\u27s data, such as their chosen settings (screen view, interface language, etc.), or their login data. By using the Infona portal the user accepts automatic saving and using this information for portal operation purposes. More information on the subject can be found in the Privacy Policy and Terms of Service. By closing this window the user confirms that they have read the information on cookie usage, and they accept the privacy policy and the way cookies are used by the portal

Is it time to stop being crude? Elderly mortality rates in a refugee camp in Maban County, South Sudan

Background: Mortality is a key indicator in defining and monitoring the scale and severity of a complex humanitarian emergency. While collection of age-disaggregated data is advised in guidelines such as the Sphere handbook, in practice data are rarely disaggregated beyond the under-5s. Despite widespread use of prospective mortality surveillance systems in complex emergencies, there are few guidelines on their implementation and limited evidence of their value. In 2012, 68,000 refugees from Sudan settled in Maban County, South Sudan. MSF introduced a community based surveillance system in Jamam camp to monitor mortality and reported causes of death. Observation of a high proportion of deaths in older refugees led to the adaptation of the surveillance system to collect age-specific mortality data. Here we describe the implementation, outcomes and lessons learnt

Phase I trial of iodine-131-chimeric B72. 3 (human IgG4) in metastatic colorectal cancer

Twelve patients with metastatic colorectal cancer participated in a Phase I trial of 1311-labeled chimeric B72.3 (human IgG4). Consecutive groups of patients received 18 mCi/m 2, 27 mCi/ m 2 and 36 mCi/m a. No acute side effects related to antibody administration were noted. Bone marrow suppression was the only side effect; it was dose-dependent and correlated with whole-body radiation dose estimates. The lowest dose level produced no marrow suppression, whereas 27 mCi/m 2 resulted in Grade 1 and 2 marrow suppression in two of three patients. The maximum tolerated close was 36 mCi/m 2 with all six patients at this dose level having at least Grade 1 and two patients with Grade 3 and 4 marrow suppression. Eight of 12 patients had radioimmune imaging of tumor sites at 5- 22 days. Seven patients had an antibody response to initial infusion. On retreatment, whole-body kinetics and imaging were altered for patients with a high anti-ch-B72.3 response. Thus, chimeric B72.3 (IgG4) has limited utility as a means of delivering multiple therapeutic doses of 1311 in the majority of patients; alternative strategies including second generation anti-TAG-72 monoclonal antibodies, other radioisotopes and other chimeric human isotypes will need to be pursued

Pharmacokinetics, immune response, and biodistribution of iodine-131-labeled chimeric mouse/human IgG1, k 17-1A monoclonal antibody

Pharmacokinetics,immunogenicity,and biodistributionof a 131I-Iabeledmouse/human chimenc monoclonal antibody (C17-1A) was studiedin six metastaticcoloncancerpatients. Pharmacokinetics obtalned from serum radioactivity or chi mera concentration were identical after 5 mCi of 131I(\u3e17-1A withmeanalphahalf-livesof 17.6±2.3 and19.7±2.9 and meanbeta half-livesof 100.9±16.1 and 106.4±14.1 hr, respectively. HPLC analysis documented the monomeric chi rneiic17-lA withoutevidenceof immunecomplexesorfree 1311 None of the patients developed antibody after ‘31I-chi merle17-1A exposure.Radiolocalizationoccurredin known areas of disease \u3e4 cm in all patients. The half-life of total body radioactivity was 58 ±7 hr by whole-body counts and 64 ±13 hr by urine measurements. Whole-body and bone marrow dose estimates ranged from 0.75-1 .03 and 0.76- 1.05rad/mCi,respectively.Thesestudiesconfirmthe pro longedcirculationand reducedimmunogenicityof chimeric 171Aversusmunne17-1A.Marrowradiationexposureusing antibodies with prolonged circulation is a critical factor in planningforradioimmunotherapeutic application

Latent Classes of Childhood Poly-victimization and Associations with Suicidal Behavior among Adult Trauma Victims: Moderating Role of Anger

The aims of the present study were first to identify discrete patterns of childhood victimization experiences including crime, child maltreatment, peer/sibling victimization, sexual violence, and witnessing violence among adult trauma victims using latent class analysis; second, to examine the association between class-membership and suicidal behavior, and third to investigate the differential role of dispositional anger on the association between class-membership and suicidal behavior. We hypothesized that those classes with accumulating exposure to different types of childhood victimization (e.g., poly-victimization) would endorse higher suicidal behavior, than the other less severe classes, and those in the most severe class with higher anger trait would have stronger association with suicidal behavior. Respondents were 346 adults (N = 346; Mage = 35.0 years; 55.9% female) who had experienced a lifetime traumatic event. Sixty four percent had experienced poly-victimization (four or more victimization experiences) and 38.8% met the cut-off score for suicidal behavior. Three distinct classes emerged namely, the Least victimization (Class 1), the Predominantly crime and sibling/peer victimization (Class 2), and the Poly-victimization (Class 3) classes. Regression analysis controlling for age and gender indicated that only the main effect of anger was significantly associated with suicidal behavior. The interaction term suggested that those in the Poly-victimization class were higher on suicidal behavior as a result of a stronger association between anger and suicidal behavior in contrast to the association found in Class 2. Clinical implications of findings entail imparting anger management skills to facilitate wellbeing among adult with childhood poly-victimization experiences

ATRX loss in pediatric glioma results in epigenetic dysregulation of G2/M checkpoint maintenance and sensitivity to ATM inhibition

ATRX is a histone chaperone protein recurrently mutated in pediatric glioma. The mechanism which mediates the proliferative advantage of ATRX loss in pediatric glioma remains unexplained. Recent data revealed a distinct pattern of DNA binding sites of the ATRX protein using ChIP-seq in mouse neuronal precursor cells (mNPCs). Using the ATRX peaks identified in p53-/- mNPCs, we confirmed that ATRX binding sites were significantly enriched in gene promoters (p \u3c 0.0001) and CpG islands (p \u3c 0.0001) compared with random regions. Gene set enrichment (GSE) analysis identified that cell cycle and regulation of cell cycle were among the most significantly enriched gene sets (p=2.52e-16 and 1.61e-9, respectively). We found that ATRX loss resulted in dysfunction of G2/M checkpoint maintenance: (1) ATRX-deficient pediatric glioblastoma (GBM) cells exhibited a seven-fold increase in mitotic index at 16 hours after sub-lethal radiation, and (2) murine GBM cells with ATRX knockdown demonstrated impaired pChk1 signaling on western blot at multiple time points after radiation compared to controls (p=0.0187). Notably, the ATM signaling (pChk2) remained intact in those cells, suggesting a potential therapeutic target. ATRX-deficient mouse cells were uniquely sensitive to ATM inhibitors at 1 uM alongside 8 Gy radiation compared to controls with intact ATRX (AZD0156: p=0.0027 and AZD01390: p=0.0436). Mice intra-cranially implanted with ATRX-deficient GBM cells showed improved survival (n=10, p=0.0018) when treated with AZD0156 combined with radiation. Our findings suggest that ATRX loss in glioma results in unique sensitivity to ATM inhibition via epigenetic dysregulation of G2/M checkpoint maintenance

Pexidartinib and standard neoadjuvant therapy in the adaptively randomized I-SPY2 trial for early breast cancer.

PURPOSE: We investigated the small-molecule receptor tyrosine kinase-inhibitor of colony-stimulating factor-1 receptor pexidartinib in the stage II/III breast cancer in the I-SPY2 platform trial. METHODS: I-SPY2 is an adaptive platform trial that features multiple arms of experimental agents administered on a background of standard neoadjuvant therapy with paclitaxel and adriamycin/cyclophosphamide, followed by definitive surgery. The adaptive randomization engine preferentially assigns patients based upon cumulative performance of each agent in a given breast cancer subtype based on hormone receptor and HER2 receptor status. The study endpoint is pathologic complete response. RESULTS: A total of 9 participants were randomized to receive pexidartinib with neoadjuvant paclitaxel before enrollment was halted due to a serious adverse event of vanishing bile duct syndrome. No participants received a full course of the study drug. CONCLUSION: Although there remains interest in agents targeting CSF-1, hepatic toxicity appears to be a limiting factor for their use in early breast cancer. TRIAL REGISTRATION: NCT01042379 ( www. CLINICALTRIALS: gov/ct2/show/NCT01042379 )

Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy graduates if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted

Synergistic HNO3_{3}–H2_{2}SO4_{4}–NH3_{3} upper tropospheric particle formation

New particle formation in the upper free troposphere is a major global source of cloud condensation nuclei (CCN)$^{1,2,3,4}$. However, the precursor vapours that drive the process are not well understood. With experiments performed under upper tropospheric conditions in the CERN CLOUD chamber, we show that nitric acid, sulfuric acid and ammonia form particles synergistically, at rates that are orders of magnitude faster than those from any two of the three components. The importance of this mechanism depends on the availability of ammonia, which was previously thought to be efficiently scavenged by cloud droplets during convection. However, surprisingly high concentrations of ammonia and ammonium nitrate have recently been observed in the upper troposphere over the Asian monsoon region5,6. Once particles have formed, co-condensation of ammonia and abundant nitric acid alone is sufficient to drive rapid growth to CCN sizes with only trace sulfate. Moreover, our measurements show that these CCN are also highly efficient ice nucleating particles—comparable to desert dust. Our model simulations confirm that ammonia is efficiently convected aloft during the Asian monsoon, driving rapid, multi-acid HNO$_{3}$–H$_{2}$SO$_{4}$–NH$_{3}$ nucleation in the upper troposphere and producing ice nucleating particles that spread across the mid-latitude Northern Hemisphere