Search

The limited success of immune checkpoint inhibitors (ICIs) in the adjuvant setting for glioblastoma highlights the need to explore administering ICIs prior to immunosuppressive radiation. To address the feasibility and safety of this approach, we conducted a phase I study in patients with newly diagnosed Grade 3 and Grade 4 gliomas. Patients received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. Fifteen patients were treated, with four patients on dexamethasone at treatment initiation and five tumors having MGMT promoter methylated. Treatment began a median of 38 days post-surgery. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased (n = 2), anorexia (n = 1), pruritus (n = 1), and rash (n = 3), and one Grade 4 cerebral edema occurred. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months (95% CI, 12.9-NA). Three patients deferred conventional radiochemotherapy for over seven months while ten eventually received it. Progressing tumors tended to exhibit higher LAG-3 levels at baseline compared to shrinking tumors. Analysis of paired pre-treatment and post-progression tissue (n = 5) showed trends of up-regulated TGF-β, ERBB2, ERBB3, and ERBB4 signaling pathways, downregulated PPAR signaling, decreased B cell proportions, and increased monocytes proportions in tumors post-treatment. We show nivolumab plus ipilimumab can be safely administered prior to standard radiotherapy for newly diagnosed gliomas and is operationally feasible. Clinicaltrials.gov NCT03425292 registered February 7, 2018. [ABSTRACT FROM AUTHOR]

A symposium honoring Mark Cane and his role in the advancement of climate science was held at the Lamont-Doherty Earth Observatory of Columbia University in October 2014. Over 150 climate scientists from the United States and abroad participated in the program. First day of the symposium began with a retrospective session on the development of tropical ocean?atmosphere interactions, equatorial wave dynamics, and a theory for ENSO. Steve Zebiak, David Halpern and Ed Sarachik, each provided historical context on the advances during the 1960s to 1980s that led to ENSO prediction. The first session of the second day was devoted to outstanding issues in paleoclimate dynamics. David Battisti. He revisited the question of why the ocean overturning circulation was situated in the Atlantic and not the Pacific, reviewing various hypotheses for why the Atlantic is the saltier ocean. The final session of the symposium highlighted the perspectives of climate dynamics from some key contributors to the field. Tim Palmer discussed nonlinear dynamics and regime shifts as a paradigm for understanding climate changes.

This is the second part of a three-part paper on North American climate in phase 5 of the Coupled Model Intercomparison Project (CMIP5) that evaluates the twentieth-century simulations of intraseasonal to multidecadal variability and teleconnections with North American climate. Overall, the multimodel ensemble does reasonably well at reproducing observed variability in several aspects, but it does less well at capturing observed teleconnections, with implications for future projections examined in part three of this paper. In terms of intraseasonal variability, almost half of the models examined can reproduce observed variability in the eastern Pacific and most models capture the midsummer drought over Central America. The multimodel mean replicates the density of traveling tropical synoptic-scale disturbances but with large spread among the models. On the other hand, the coarse resolution of the models means that tropical cyclone frequencies are underpredicted in the Atlantic and eastern North Pacific. The frequency and mean amplitude of ENSO are generally well reproduced, although teleconnections with North American climate are widely varying among models and only a few models can reproduce the east and central Pacific types of ENSO and connections with U.S. winter temperatures. The models capture the spatial pattern of Pacific decadal oscillation (PDO) variability and its influence on continental temperature and West Coast precipitation but less well for the wintertime precipitation. The spatial representation of the Atlantic multidecadal oscillation (AMO) is reasonable, but the magnitude of SST anomalies and teleconnections are poorly reproduced. Multidecadal trends such as the warming hole over the central-southeastern United States and precipitation increases are not replicated by the models, suggesting that observed changes are linked to natural variability. © 2013 American Meteorological Society.

Variability of Mexican hydroclimate, with special attention to persistent drought, is examined using observations, model simulations forced by historical sea surface temperature (SST), tree ring reconstructions of past climate and model simulations and projections of naturally and anthropogenically forced climate change. During the winter half year, hydroclimate across Mexico is influenced by the state of the tropical Pacific Ocean with the Atlantic playing little role. Mexican winters tend to be wetter during El Nino conditions. In the summer half year northern Mexico is also wetter when El Nino conditions prevail, but southern Mexico is drier. A warm tropical North Atlantic Ocean makes northern Mexico dry and southern Mexico wet. These relationships are reasonably well reproduced in ensembles of atmosphere model simulations forced by historical SST for the period from 1856 to 2002. Large ensembles of 100 day long integrations are used to examine the day to day evolution of the atmospheric circulation and precipitation in response to a sudden imposition of a El Nino SST anomaly in the summer half year. Kelvin waves propagate east and immediately cause increased column-integrated moisture divergence and reduced precipitation over the tropical Americas and Intra-America Seas. Within a few days a low level high pressure anomaly develops over the Gulf of Mexico. A forced nonlinear model is used to demonstrate that this low is forced by the reduced atmospheric heating over the tropical Atlantic-Intra-America Seas area. Tree ring reconstructions that extend back before the period of instrumental precipitation data coverage are used to verify long model simulations forced by historical SST. The early to mid 1950s drought in northern Mexico appears to have been the most severe since the mid nineteenth century and likely arose as a response to both a multiyear La Nina and a warm tropical North Atlantic. A drought in the 1890s was also severe and appears driven by a multiyear La Nina alone. The drought that began in the 1990s does not exceed these droughts in either duration or severity. Tree ring records extending back to the fourteenth century suggest that the late sixteenth century megadrought may have been the longest drought to have ever affected Mexico. While the last decade or so in north and central Mexico has been drier than preceding decades, the associated continental pattern of hydroclimate change does not fit that which models project to occur as a consequence of rising greenhouse gases and global warming. However, models robustly predict that Mexico will dry as a consequence of global warming and that this drying should already be underway. At least for now, in nature, this is likely obscured by strong natural atmosphere-ocean variability.

Heidi Chwan Ko,1,* RJ Seager,2,* Sarabjot Pabla,2 Maria-Fernanda Senosain,2 Erik Van Roey,2 Shuang Gao,2 Kyle C Strickland,1,3 Rebecca Ann Previs,1,4 Michelle F Green,1 Maureen Cooper,1 Mary K Nesline,1 Stephanie B Hastings,1 Kobina Agyaful Amoah,1 Shengle Zhang,2 Jeffrey M Conroy,2 Taylor J Jensen,1 Marcia Eisenberg,5 Brian Caveney,5 Eric A Severson,1 Shakti Ramkissoon,1,6 Shipra Gandhi7 1Labcorp Oncology, Durham, NC, USA; 2Labcorp Oncology, Buffalo, NY, USA; 3Department of Pathology, Duke University Medical Center, Duke Cancer Institute, Durham, NC, USA; 4Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC, USA; 5Labcorp, Burlington, NC, USA; 6Department of Pathology, Wake Forest Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA; 7Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA*These authors contributed equally to this workCorrespondence: Heidi Chwan Ko, Email Heidi.ko@labcorp.comBackground: The understanding of molecular characteristics of HER2-low breast cancer is evolving since the establishment of trastuzumab deruxtecan. Here, we explore the differences in expression patterns of immune-related genes in the tumor immune microenvironment (TME) and survival between HER2-low and HER2-zero breast cancers.Methods: Comprehensive genomic and immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on FFPE samples from 129 patients with advanced HER2-negative (immunohistochemistry (IHC) 0, 1+ or 2+ with negative ERBB2 amplification by in-situ hybridization) breast cancer. Both estrogen receptor (ER) and HER2 statuses were obtained from available pathology reports. mRNA expressions of immune biomarkers, except for PD-L1 IHC and TMB, were derived from RNA-seq. Statistical comparisons were performed using the Kruskal–Wallis or Wilcoxon Rank-Sum test or the two-sample test for equality of proportions with continuity correction (p≤ 0.05 for significance). Survival differences were calculated using Kaplan-Meier analysis (p≤ 0.05 for significance).Results: There were no significant differences in mRNA expressions of immune-related genes between HER2-low and HER2-zero breast cancers. However, HER2-low breast cancers were associated with a higher proportion of ER-positivity. When ER was analyzed along with HER2, we observed a significantly higher tumor immunogenic signature (TIGS) expression in HER2-zero/ER-negative tumors than in HER2-low/ER-positive tumors (p=0.0088). Similarly, lower expression of PD-L1 and T cell immunoglobulin and ITIM domain (TIGIT) mRNA was observed in HER2-low/ER-positive tumors when compared to HER2-zero/ER-negative tumors (p=0.014 and 0.012, respectively). Patients with HER2-low tumors had a longer median OS than those with HER2-zero tumors (94 months vs 42 months, p=0.0044).Conclusion: Patients with HER2-low breast cancer have longer survivals yet display no differences in immune-related gene expression when compared to those with HER2-zero cancers. The differences in survival can be attributed to the higher rate of ER-positivity seen in HER2-low breast cancers, compared to HER2-zero tumors.Keywords: HER2-low breast cancer, estrogen receptor, tumor immune microenvironment, immune checkpoint biomarkers, gene expression profiling, immune profiling