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Supplementary Table S1. Sanger validated variants. Supplementary Table S2. Mutations in HSTL driver genes. Supplementary Table S3. Other mutations identified by exome sequencing. Supplementary Table S4. Copy number of HSTL patients and cell lines. Supplementary Table S5. Clinical and pathological characteristics of HSTL patients. Supplementary Tables S6, S7. Comparison to HSTL clinical data in the literature. Supplementary Table S8. Mutational frequencies in other lymphomas. Supplementary Table S9. HSTL mutations in other lymphoma driver genes. Supplementary Table S10. Gene set enrichment analysis of DERL2 SETD2 shRNA.

Suppementary Table S1: Gene lists and exon coverage; Supplementary Table S2: Patient Demographics; Supplementary Table S3. Mutational landscape in cfDNA; Supplementary Figure S1: Schema for identification of unique patient cases for analysis; Supplementary Figure S2. Impact of the number of mechanisms of resistance to anti-EGFR therapy on clonality and relative mutant allele frequency; Supplementary Figure S3: Clonal dynamics during anti-EGFR therapy in patient #18.

Supplementary Figure S1. Sanger sequencing chromatograms. Supplementary Figure S2. Cancer cell fraction for driver genes. Supplementary Figure S3. Ideogram with chromosome 7 alterations. Supplementary Figure S4. Examples of Exome Copy Number. Supplementary Figure S5. Exploratory Kaplan-Meier plots for clinical covariates. Supplementary Figure S6. Exploratory Kaplan-Meier plots for molecular covariates. Supplementary Figure S7. Sanger and exome sequencing validation of SETD2 biallelic mutation in one HSTL case. Supplementary Figure S8. SETD2 expression in mutant vs. wildtype cases. Supplementary Figure S9. Mutual exclusivity of STAT5B, PIK3CD, and STAT3 mutations.

Joint and muscle pain, including arthralgia, myalgia, and musculoskeletal pain, are among the common adverse events (AEs) reported for ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). This pooled analysis from nine clinical trials of ibrutinib in CLL and MCL (

PURPOSE Comprehensive genomic profiling to inform targeted therapy selection is a central part of oncology care. However, the volume and complexity of alterations uncovered through genomic profiling make it difficult for oncologists to choose the most appropriate therapy for their patients. Here, we present a solution to this problem, The Molecular Registry of Tumors (MRT) and our Molecular Tumor Board (MTB). PATIENTS AND METHODS MRT is an internally developed system that aggregates and normalizes genomic profiling results from multiple sources. MRT serves as the foundation for our MTB, a team that reviews genomic results for all Duke University Health System cancer patients, provides notifications for targeted therapies, matches patients to biomarker-driven trials, and monitors the molecular landscape of tumors at our institution. RESULTS Among 215 patients reviewed by our MTB over a 6-month period, we identified 176 alterations associated with therapeutic sensitivity, 15 resistance alterations, and 51 alterations with potential germline implications. Of reviewed patients, 17% were subsequently treated with a targeted therapy. For 12 molecular therapies approved during the course of this work, we identified between two and 71 patients who could qualify for treatment based on retrospective MRT data. An analysis of 14 biomarker-driven clinical trials found that MRT successfully identified 42% of patients who ultimately enrolled. Finally, an analysis of 4,130 comprehensive genomic profiles from 3,771 patients revealed that the frequency of clinically significant therapeutic alterations varied from approximately 20% to 70% depending on the tumor type and sequencing test used. CONCLUSION With robust informatics tools, such as MRT, and the right MTB structure, a precision cancer medicine program can be developed, which provides great benefit to providers and patients with cancer.

We recreate a Titan-like climate using an Earth-like global climate model (GCM) by varying a small set of planetary parameters. Understanding the range of possible climate states for Earth-like planets is important for interpreting exoplanet observations and Earth’s own climate history. We find that simply reducing the available water at the surface does not fully reproduce Titan-like conditions. This may indicate that there are many possible “in-between” states an Earth-like planet can have that span the gap between the Earth and Titan climate archetypes. We use three observationally motivated criteria to determine Titan-like conditions: 1) the peak in surface specific humidity is not at the equator, despite it having the warmest annual-mean temperatures (Ádámkovics et al. 2016); 2) the vertical profile of specific humidity in the equatorial column is nearly constant through the lower troposphere (Niemann et al. 2005); and 3) the relative humidity near the surface at the equator is significantly lower than saturation (lower than 60%; Niemann et al. 2005; Tokano et al. 2006). We first limit the available water by placing a continental land strip centered on the equator and varying its width. This mimics Titan’s dry tropics and wet poles, and could be similar to past continental arrangements in Earth’s history. Land strips alone allow some experiments to meet two Titan-like criteria, but none show the near-constant vertical profile of specific humidity. We take three of these land strip widths and vary the rotation period, starting with Earth’s rotation and moving towards Titan’s (16 Earth days). Slowing the rotation results in fewer experiments meeting any of the Titan-like criteria due to increased access to oceanic moisture from the widened Hadley Circulation. For the same three land strip widths and using Earth rotation, we vary the volatility of the condensable via a constant multiplied to the saturation vapor pressure. Titan’s condensable, methane, is more volatile under Titan’s surface conditions than water is on Earth, resulting in high specific humidities. By artificially increasing the saturation vapor pressure, we can approximate this effect without changing the properties of the condensable. Experiments with a volatility constant of 2.5 (the maximum used in this work) meet all three Titan-like criteria, demonstrating that an Earth-like planet can display Titan-like climatology by changing only a few physical parameters.

Purpose Diagnosing primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is challenging because it is a clinicopathologic entity that shares characteristics with other lymphomas and lacks pathognomonic features. We sought to investigate the fidelity between a working diagnosis of PMBCL at our institution and the clinicopathologic criteria established within the 2017 World Health Organization (WHO) classification. Patients and Methods Medical records and archived tissue of patients treated for stage I-II PMBCL from 1998 to 2018 were retrospectively reviewed for clinical and pathologic conformity with current WHO criteria. Disease was characterized as definitely PMBCL if all of the following were present: anterior mediastinal mass with or without lymph node involvement, no extranodal disease, B-cell antigen expression, Epstein-Barr virus negativity, and at least one supportive feature: female gender under age 40, bulky primary tumor, CD30 weakly positive, compartmentalizing alveolar fibrosis, lack of surface immunoglobulin expression, and MUM1 or CD23 positivity. Disease without supportive features or other pathologic findings more suggestive of other entities was characterized as equivocal for PMBCL. Lack of an anterior mediastinal mass, presence of distant lymph node involvement or extranodal disease, lack of B-cell antigen expression, or Epstein-Barr virus positivity were characterized as definitely not PMBCL. Clinical management and outcomes were also assessed. Results Of 63 patients treated for presumed stage I-II PMBCL, 58 (92%) met the criteria for PMBCL. The most common reason for a discordant diagnosis was lack of an anterior mediastinal mass (n = 3). Two additional patients were characterized as having disease equivocal for PMBCL. In retrospect, one patient most likely had a mediastinal gray zone lymphoma due to CD15 positivity and another diffuse large B cell, not otherwise specified, at pathologic review. Five-year progression-free and overall survival were 67% (95% confidence interval, 54-77) and 81% (95% confidence interval, 68-89), respectively, for all patients. Conclusion Despite the complexity of the clinicopathologic criteria of PMBCL, most patients (92%) who were treated for stage I-II PMBCL at our institution appear to have been accurately diagnosed.

Crayfish are an aquatic fauna of conservation concern, yet regional studies are lacking on zoogeography and life history. We compared recent and historical species distribution data and assessed conservation standings of native and nonindigenous crayfish of the Potomac River Basin in West Virginia. From 2007–2011, a total of 1764 crayfish were collected from 159 sites. Data collection included species abundance, morphometrics, and life history parameters. Percentages of the number of individuals of each species of the total catch were 36.3% (Cambarus bartonii), 34.6% (Faxonius obscurus), 23.4% (Faxonius virilis), 3.6% (Procambarus cf. zonangulus) and 2.0% (Cambarus carinirostris). Cambarus bartonii was present throughout the drainage, F. obscurus was collected primarily from the North Branch, South Branch, and Cacapon river watersheds, and C. carinirostris was only collected in the South Branch watershed. Two nonnative species, F. virilis and P. cf. zonangulus, were only present in tributaries downstream of the Cacapon River watershed. Spinycheek crayfish (Faxonius limosus) were not collected during our survey, which suggests its possible extirpation from the West Virginia portion of its range. Our zoogeographic and life history data could serve as a baseline for future conservation-oriented monitoring efforts of the Potomac River watershed.

Introduction It has long been established that high-dose methotrexate is an essential part of therapy for primary central nervous system lymphoma. When regimens utilizing high-dose methotrexate were first studied, a dose of 8 g/m2 was used. More recently, reduced dosing strategies have been studied and adopted in attempts to reduce rates of adverse events. Studies utilizing 3.5 g/m2 of methotrexate have shown promising outcomes and improved rates of adverse events but there have never been any randomized head-to-head studies of differing dose levels of high-dose methotrexate. The purpose of this study was to compare efficacy and safety of different dosing strategies of high-dose methotrexate (HD-MTX) for primary central nervous system lymphoma (PCNSL). Methods This single center retrospective review was conducted between 07/01/2013 to 6/3/2020. The patient population was separated into two arms based upon dose of methotrexate. The high intensity (HiHD) arm was defined as patients who received doses > 3.5 g/m2, while the low intensity (LiHD) arm received ≤ 3.5 g/m2. The primary endpoint was overall response rate (ORR) and secondary endpoints include efficacy via 2-year overall survival (OS), progression to transplant, and utilization of consolidation or salvage therapy. Safety was assessed through monitoring of relevant laboratory studies. Results A total of 92 patients were included in this analysis. Baseline demographics were similar between groups, with the LiHD group trending toward older age. There were 78 patients eligible for assessment for ORR; there was no significant difference between the two groups (42.0% LiHD vs. 44.4% HiHD; p = 1.0). Rates of OS, progression to transplant and progression to consolidation chemotherapy were not different between groups. There were statistically significantly higher rates of renal and/or hepatic dysfunction with the first dose in the HiHD group compared with the LiHD group (11.5% LiHD vs. 64.3% HiHD; p ≤ 0.01). Conclusions In this PCNSL patient cohort, there is no difference in terms of efficacy between HiHD LiHD methotrexate, but patients in the HiHD group had higher rates of renal and hepatic dysfunction. Limitations include small sample size and disparity between group sizes.

Recent advances in next-generation sequencing have allowed for an increase in molecular tumor profiling. We sought to assess the actionability and clinical utilization of molecular tumor profiling results obtained via Foundation Medicine tumor sequencing tests in uterine and ovarian cancers. We performed a single-institution retrospective chart review to obtain demographic and clinical information in patients with uterine and ovarian cancer whose tumors were submitted to Foundation Medicine for molecular tumor profiling over a 7-year period. Alterations identified on testing were stratified according to the OncoKB database actionability algorithm. Descriptive statistics were primarily used to analyze the data. Tumors from 185 women with gynecologic cancer were submitted for molecular tumor profiling between 2013 and 2019. The majority of tests (144/185; 78%) were ordered after a diagnosis of recurrence. In 60 (32%), no actionable molecular alteration was identified. Thirteen (7%) identified an alteration that directed to a US Food and Drug Administration-approved therapy in that tumor type, while 112 (61%) had alterations with investigational or hypothetical treatment implications. In patients with any actionable finding, treatment was initiated in 27 (15%) based on these results. The majority of uterine and ovarian cancers (93%) did not have molecular alterations with corresponding Food and Drug Administration-approved treatments. Even in patients with a potentially actionable alteration, gynecologic oncologists were more likely to choose an alternative therapy. Further investigation is warranted to determine which patients with uterine and ovarian cancer are most likely to benefit from molecular tumor profiling and the ideal timing of testing. The potential to identify effective therapeutic options in a minority of patients needs to be balanced with the current limited clinical applicability of these results in most cases.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Determining the distribution and potential ranges of detrimental invasive species has become an essential task in light of their impacts on the environment. However, this effort has been challenging, especially for global invaders. Our goal was to test whether potential ranges of global invaders can be predicted, and examine the factors that shape them by studying the past, current and potential global distribution of a broad-ranging avian invader. We used the common myna (Acridotheres tristis), one of the most broad-ranging avian invaders whose range is currently expanding globally, as a case study. We collected the first detailed global database of global occurrence (n = 7990) of the common myna over the past 150 years, including records from the native and the introduced ranges. We employed MaxEnt to construct species distribution models (SDM) for the global database using climatic, anthropogenic and environmental factors. We provide evidence that invasive species distributions can be predicted from older records, and that model accuracy requires integrating data from the introduced range. This first comprehensive distribution for an avian invader indicates an extensive expansion in the common myna global distribution, with the potential of large areas worldwide being at risk of common myna invasion, thus threatening local biodiversity globally. Range expansion has been facilitated by proximity to urbanized areas and broad environmental tolerance. Our findings reflect the major role of anthropogenic impact in increasing the global distribution of avian invaders and emphasize the value of using SDMs to inform global management practices.

The amount of data corruption in a wide assortment of flash memories observed during Co-60 total dose tests is shown to have a strong dependence on the direction in which the Co-60 irradiation is performed. The effect is due to dose enhancement from the metal layers above the floating gate. The dose enhancement effect is shown to become greater as technology node scales and is even observed in on a state-of-the-art 3-D NAND flash memory. The radiation hardness assurance implications of this dose enhancement effect are significant and are discussed in detail.

3060 Background: Comprehensive genomic profiling (CGP) is increasingly used to guide management of myeloid and advanced solid malignancies, but its role in non-myeloid hematologic malignancies is less clear. Studies have found a high rate of potentially actionable variants by CGP in this population, but these do not always translate into clinical practice changes. We aimed to determine the rate at which variants found on CGP changed clinical practice. Methods: We retrospectively reviewed a cohort of 101 consecutive patients with non-myeloid hematologic malignancies at Duke, comprising a total of 105 samples that were sent for CGP by FoundationOne Heme (104) or HemeComplete (1) in 2014–2021. We identified variants of clinical significance and classified them by evidence level according to the AMP/ASCO/CAP 2017 guidelines (e.g., for therapies, level A: FDA-approved / in guidelines; B: expert consensus; C: clinical trial / FDA-approved in different tumor type; D: preclinical data). We further identified documented changes in clinical practice that occurred in direct response to CGP results. Results: Commonly cited reasons for CGP included guiding therapy selection (27), identifying resistance mutations (19), refining prognosis (14), and clarifying diagnosis (11). Of the 105 samples sent for sequencing, 92 (88%) yielded at least one pathogenic or likely pathogenic variant. CGP resulted after death in 12 patients and within 1 month of death in another 11 patients. Seventy-three out of 101 patients (72%) had at least one variant with therapy sensitizing, diagnostic, or prognostic significance (levels A–C) or associated with therapy resistance (levels A/D). While 61 patients (60%) had a therapy sensitizing variant, only 6 patients (10%) were offered a biomarker-directed therapy. In contrast, the presence of a resistance mutation led to discontinuation of current therapy or influenced future therapy selection in 9 of 13 patients (69%). The absence of a resistance mutation influenced choice of therapy in another 4 patients. Sequencing results also helped clarify a previously uncertain diagnosis in 4 patients and led to medical genetics referrals in 3 patients. Conclusions: Comprehensive genomic profiling of non-myeloid hematologic malignancies identified variants of clinical significance in 72% of patients and led to changes in practice in 22% of patients. CGP was often sent late in the clinical course. [Table: see text]

Recent advances in next-generation sequencing have allowed for an increase in molecular tumor profiling.We sought to assess the actionability and clinical utilization of molecular tumor profiling results obtained via Foundation Medicine tumor sequencing tests in uterine and ovarian cancers.We performed a single-institution retrospective chart review to obtain demographic and clinical information in patients with uterine and ovarian cancer whose tumors were submitted to Foundation Medicine for molecular tumor profiling over a 7-year period. Alterations identified on testing were stratified according to the OncoKB database actionability algorithm. Descriptive statistics were primarily used to analyze the data.Tumors from 185 women with gynecologic cancer were submitted for molecular tumor profiling between 2013 and 2019. The majority of tests (144/185; 78%) were ordered after a diagnosis of recurrence. In 60 (32%), no actionable molecular alteration was identified. Thirteen (7%) identified an alteration that directed to a US Food and Drug Administration-approved therapy in that tumor type, while 112 (61%) had alterations with investigational or hypothetical treatment implications. In patients with any actionable finding, treatment was initiated in 27 (15%) based on these results.The majority of uterine and ovarian cancers (93%) did not have molecular alterations with corresponding Food and Drug Administration-approved treatments. Even in patients with a potentially actionable alteration, gynecologic oncologists were more likely to choose an alternative therapy. Further investigation is warranted to determine which patients with uterine and ovarian cancer are most likely to benefit from molecular tumor profiling and the ideal timing of testing. The potential to identify effective therapeutic options in a minority of patients needs to be balanced with the current limited clinical applicability of these results in most cases.

There are records of past Earth climates that were ice-free all the way to the poles (Barron 1983), which can be described as “hothouse” climates. These hothouse climates can be contrasted with an ...

There are records of past Earth climates that were ice-free all the way to the poles (Barron 1983), which can be described as “hothouse” climates. These hothouse climates can be contrasted with an “all-tropics” planet, where the tropics are defined by the atmospheric dynamics, i.e. the Hadley Cell extent (Faulk et al. 2017). This classification is thus primarily dependent on a planet’s rotation, rather than its ice-free extent or surface temperatures. We investigate the parameter space between Earth and an all-tropics world using the open-source GCM Isca, developed by Vallis et al (2018). We take an Earth analog and perform a parameter sweep in three dimensions: global reservoir depth (1000m, 100m, 10m, 1m, 1cm); global saturation vapor pressure (1.5x current, 1.4x, 1.3x, 1.2x, 1.1x, 1x); and rotation rate (16 days, 8 days, 1 day). The sweep will allow us to explore the effects of surface liquid coverage, atmospheric moisture content, and large-scale atmospheric circulation on an Earth-like climate. In this presentation we provide a status report and analysis of initial findings.

This article explores the emergence of formal and informal bridging organizations to facilitate solutions to water conflict at the scale of the water resource. This new approach to governance is of particular importance on rivers within or shared by countries in which water management is fragmented among national and sub-national levels of government as well as among governmental sectors. This article focuses on the Columbia River Basin, in the United States and Canada. Review of the Columbia River Treaty governing shared management of the river has opened a public dialogue on river governance. Treaty review coincides with change in both the biophysical setting and the values and capacity of basin residents. Climate change is altering the timing of flow relied on by the management of developed river infrastructure and the annual runs of the basins’ salmonid species. River development increased economic development in the basin, but at the cost of ecosystem function. Assertion of legal rights by indigenous communities has brought an alternative world view to the review—one that seeks to maintain the benefits of river development while reconciling that development with ecosystem function. This article identifies the governance mechanisms needed to achieve reconciliation and describes their emergence in the Columbia River Basin through an analytical framework focused on local capacity building and network formation across jurisdictions, sectors, and scales of governance. Both countries fragment water management authority among jurisdictions and sectors, but bridging organizations have emerged to link interests and government at the watershed and basin scale. Emergence of new governance is facilitated by increases in local, regional, and indigenous governance capacity. This networked governance emerging at the biophysical scale while embedded in and linked to a hierarchy of formal international, national, state, and local government is characterized as the ecology of governance.

INTRODUCTION Diffuse large B-cell lymphoma (DLBCL) represents several distinct clinical pathologic entities recently identified by molecular profiling. Treatment with anti-CD19 chimeric antigen receptor (CAR) T-cell therapies is now standard for many patients with relapsed/refractory (R/R) disease. Although antigen loss of CD19 represents a known cause of late relapses, the majority of CAR-T cell treatment failure occurs very soon after treatment at which time the impact of molecular subtype and other somatic mutations of DLBCL is undefined. We sought to determine impact of molecular features of DLBCL tumors on clinical outcomes in a cohort of patients with R/R disease who were treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in order to provide insight into the mechanism of response or resistance to CAR-T cell therapy. METHODS We collected clinical data and formalin-fixed, paraffin embedded (FFPE) biopsy specimens from 121 DLBCL patients at the time of R/R disease after prior treatment with standard chemoimmunotherapy across 12 US academic medical centers who subsequently received commercial CAR-T cell treatment. Whole exome and transcriptome sequencing was performed on all cases to measure gene expression and gene copy number alterations. Genetic analysis was done on 96 patients with pre-treatment biopsies that passed sequencing quality filters, and expression analysis on 93 patients. Progression-free and overall survival (PFS, OS) measured from the day of CAR-T cell infusion were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS Baseline demographics and treatment details of the patient population are shown in the Table (Panel A). Best overall response was CR in 43% of patients and PR in 10% patients. PFS and OS were significantly different based on best response to treatment (P CONCLUSIONS DLBCL patients whose tumors have molecular features that are predictive of inferior response to standard frontline treatment including the high-risk subgroups (C2/A53) and (C5/MCD) have favorable treatment outcomes with CAR-T cell therapy. In contrast, individual driver mutations including MYC and BCL2, CDKN2A, and KLHL6 are associated with inferior PFS with CAR-T cell therapy, while mutations in BTG2, MYD88, and CD79B are associated with a favorable PFS. In addition, gene expression analysis implicates a potential role for the microenvironment in modulating responses to CAR-T therapy. These findings suggest that predictive biomarkers for response to traditional chemoimmunotherapy and cellular immunotherapy are distinct. Our results provide insight into potentially targetable pathways for the development of rational treatment strategies that may augment response CAR-T cell therapy. Figure 1 Figure 1. Disclosures Hill: Celgene (BMS): Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. McKinney: Novartis: Research Funding; Nordic Nanovector: Research Funding; Molecular Templates: Consultancy, Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Incyte: Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy; Celgene: Consultancy, Research Funding; BTG: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Verastem: Consultancy. Neff: Spring Discovery: Consultancy, Ended employment in the past 24 months; EUSA Pharma: Speakers Bureau; Enzyvant: Consultancy. Reshef: BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy; ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Bayer: Consultancy; Gilead and Novartis: Honoraria. Oluwole: Janssen: Consultancy; Pfizer: Consultancy; Curio Science: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Ghosh: Incyte: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Genentech: Research Funding. Chen: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium. Hernandez-Ilizaliturri: AbbVie: Other: Advisory Boards; Incyte: Other: Advisory Boards; Celgene: Other: Advisory Boards; BMS: Other: Advisory Boards; Pharmacyclics: Other: Advisory Boards; Amgen: Other: Advisory Boards; Kite: Other: Advisory Boards; Gilead: Other: Advisory Boards; Epyzime: Other: Advisory Boards. Shah: Lily: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Epizyme: Consultancy; Legend: Consultancy; Incyte: Consultancy; Umoja: Consultancy. Stephens: Epizyme: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; JUNO: Research Funding; Novartis: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy; Celgene: Consultancy; Mingsight: Research Funding; Arqule: Research Funding. Patel: Janssen: Consultancy; Kite Pharma: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Speakers Bureau; MEI Pharma: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy; Morphosys: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Lilly: Consultancy. Pagel: Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; Incyte/MorphoSys: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/AbbVie: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy; MEI Pharma: Consultancy. Hsi: AbbVie Inc, Eli Lilly: Research Funding. Goy: Genentech/Hoffman la Roche: Research Funding; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Medscape: Consultancy; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Xcenda: Consultancy, Honoraria; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; LLC(Targeted Oncology): Consultancy; Hoffman la Roche: Consultancy; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; Infinity/Verastem: Research Funding; MorphoSys: Honoraria, Other; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Xcenda: Consultancy; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; OncLive Peer Exchange: Honoraria; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Incyte: Honoraria; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Novartis: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Karyopharm: Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Phamacyclics: Research Funding; Constellation: Research Funding; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Ohgami: Stemline Therapeutics: Research Funding. Andreadis: CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Epizyme: Honoraria; Incyte: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; Karyopharm: Honoraria; Atara: Consultancy, Honoraria; BMS: Research Funding; Merck: Research Funding. Thacker: Data Driven Bioscience: Current Employment. Rozzi: Data Driven Bioscience: Current Employment. Parker: Data Driven Bioscience: Current Employment. Happ: Data Driven Bioscience: Current Employment. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

Introduction Blood cancers are collectively common and strikingly heterogeneous diseases both clinically and molecularly. According to the WHO taxonomy, there are over 100 distinct myeloid and lymphoid neoplasms. Genomic profiling of blood cancers has been applied in a somewhat ad hoc fashion using diverse sequencing approaches including the use of targeted panels, whole exome sequencing, whole genome sequencing, RNA sequencing, etc. The lack of data uniformity has made it difficult to comprehensively understand the clinical and molecular spectrum within and across diseases. Systematic genomic approaches can address the central challenges in the diagnosis and treatment of blood cancers. For the diagnosis of blood cancers, the incorporation of genomics could greatly enhance the accuracy and speed of clinical diagnostics. Genomics could also inform their pathology classification. However, these applications must be preceded by a clear understanding of the particular genetic aberrations and expression profiles that unite and distinguish different leukemias and lymphomas. Therapeutic development can also be aided by genomic approaches through identification of new targets and establishing the relevance of existing targets and treatments. Targeted therapies including those directed at specific surface markers (e.g. CD19, CD30 and CD123) or molecular targets (e.g. BCR-ABL fusions, IDH1 mutations and EZH2 mutations) are rarely restricted to a single disease, with most occurring in multiple blood cancers. A systematic understanding of the presence or overlap of these targets within or across blood cancers would significantly expand the therapeutic possibilities and better enable the use of existing therapies in both common and rare cancers. However, such therapeutic possibilities need to be established through a rigorous, data-driven approach. We initiated the Atlas of Blood Cancers Genomes (ABCG) project to systematically elucidate the molecular basis of all leukemias and lymphomas by building upon advances in genomic technologies, our capabilities for data analysis and economies of scale. Using a uniform approach to systematically profile all blood cancers through DNA and RNA sequencing at the whole exome/whole transcriptome level, we aim to link genomic events with clinical outcomes, disease categories and subcategories, thereby providing a complete molecular blueprint of blood cancers. Methods/Results The ABCG project consists of collaborators from 25 institutions around the world who have collectively contributed samples from 10,481 patients comprising every type of blood cancer in the current WHO classification. The samples include thousands of myeloid leukemias and mature B cell lymphomas, hundreds of Hodgkin lymphoma and plasma cell myeloma, as well as every rare type of hematologic malignancy (along with case-matched normal tissue). All cases were de-identified and their associated pathology and detailed clinical information entered into a purpose-built web-based system that included disease-specific data templates. All cases were subjected to centralized pathology review and clinical data review by experienced hematopathologists and oncologists. All 10,481cases are being sequenced at the DNA and RNA level, and are being profiled to define the genetic alterations and expression changes that are characteristic of each disease. Analysis will include translocations, copy number alterations, and viral status. These molecular features will be examined in conjunction with genetic events, pathologic factors, and the clinical features. We have already generated results for ALK-negative anaplastic large B cell lymphoma and primary mediastinal B cell lymphomas (N=210). These data demonstrate novel subgroup and molecular discoveries that are enabled by integrative DNA and RNA sequencing analysis and the examination of molecular features across different diseases as well as within individual entities. In addition, other disease entities and the collective data will be presented in the meeting. Conclusion The ABCG project will comprehensively study the genetic and clinicopathological features of all blood cancers using systematic genomic approaches. We anticipate our data, approaches and results will serve as a lasting resource for the molecular classification and therapeutic development for leukemias and lymphomas. Disclosures McKinney: Novartis: Research Funding; Nordic Nanovector: Research Funding; Molecular Templates: Consultancy, Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Incyte: Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy; Celgene: Consultancy, Research Funding; BTG: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Verastem: Consultancy. Behdad: Lilly: Speakers Bureau; Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau.

Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rare non-Hodgkin lymphoma subtype that occurs predominantly in young adults, with an overall favorable prognosis. The cell of origin is presumed to be thymic medullary B-cells and the gene expression profile of PMBL is similar to classic Hodgkin lymphoma. Recent studies have begun unravelling the genomic alterations underlying PMBL. Frequent, recurrent mutations (e.g. B2M, TNFAIP3, SOCS1, STAT6, GNA13) have been reported, but most of the studies have analyzed a small number of cases. To gain further insights into disease biology, we recruited 63 cases of PMBL as part of the Atlas of Blood Cancer Genomes (ABC-G) initiative, a consortium consisting of 25 institutions. Methods: Formalin-fixed paraffin-embedded (FFPE) biopsies and clinical data were collected. All cases were subjected to centralized review by an experienced panel of hematopathologists to ensure accurate diagnosis. Whole-exome DNA and RNA sequencing was performed using the Illumina platform and the DNA and RNA reads aligned to the GRCh38 genome and transcriptome respectively. Exonic variants were filtered using a set of paired normal samples and population-based databases to identify putative driver mutations, which were then aggregated at the gene level. Mutational analysis was performed on 56 samples that passed quality filtering and expression analysis on 45 samples. RNAseq data was normalized using DESeq2. Results: The cohort included samples from 16 males and 24 females, with a median age of 33 years (range 16 - 72) at the time of diagnosis. The majority of patients were treated with R-CHOP (47%) or R-EPOCH (43%), with 93% of patients surviving through the end of follow-up (median follow-up: 60.1 months). Besides the known recurrent mutations involving the JAK-STAT (STAT6 -21%, SOCS1 - 26%), NFKB (TNFAIP3 - 27%, NFKB1A - 7%), immune escape (B2M - 20%, LTB - 11%, IRF8 - 9%, IRF4 -9%), and chromatin modification (ZNF217 - 16%, CREBBP - 11%, KMT2D -11%) pathways , we discovered recurrent somatic variants in novel candidate driver genes in this disease, including NOTCH4 (7%), DICER1 (11%), MCL1 (7%), amongst others. EZH2, EP300, and XPO1 mutations were not detected. CIITA mutations and fusions were observed in 14% and 11% of cases, respectively, with novel partner genes (IGHA2, IGHG1, CDC6) detected in 67% of the fusion positive cases. Copy number alterations included gains at 2p16.1 (REL - 20%) and 9p24.2 (JAK2/PDL1/PDL2 - 24%), as well as loci not previously implicated in PMBL, 8q24.3 and 9q34.3 (each in 20%). Of note, CIITA alterations and 9p24 gains were virtually mutually exclusive, highlighting diverse mechanisms of immune escape in this entity. The transcriptomes of cases harboring CIITA alterations demonstrated differential enrichment of genes involved in protein glycosylation. The PMBLs in our series showed significant enrichment of the reported PMBL genetic classifier score, compared to nodal diffuse large B cell lymphoma (DLBCL) (p=0.0003). Finally, the gene expression profile of thymic B cells was more similar to that of PMBL than nodal DLBCL (p=0.0144). Conclusions: Our study, representing one of the largest comprehensive genomic and transcriptomic analyses of PMBL, expands the mutational landscape of PMBL, provides evidence for biologically distinct disease subsets and suggests an origin of PMBLs from thymic B-cells. Disclosures Hsi: AbbVie: Research Funding; Eli Lilly: Research Funding; Cytomx: Honoraria; Seattle Genetics: Honoraria. McKinney: BTG: Consultancy; Celgene: Consultancy, Research Funding; Epizyme: Consultancy; Genetech: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Molecular Templates: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Novartis: Research Funding; Pharmacyclics: Consultancy; Verastem: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau. Jaye: Stemline Therapeutics: Honoraria. Cohen: Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding; Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy. Behdad: Lilly: Speakers Bureau; Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

Nature in cities is concentrated in urban green spaces, which are key areas for urban biodiversity and also important areas to connect people with nature. To conserve urban biodiversity within these natural refugia, habitat restoration such as weed control and revegetation is often implemented. These actions are expected to benefit biodiversity, although species known to be affected by urbanization may not be interacting with restoration in the ways we anticipate. In this study, we use a case study to explore how urban restoration activities impact different bird species. Birds were grouped into urban sensitivity categories and species abundance, and richness was then calculated using a hierarchical species community model for individual species responses, with “urban class” used as the hierarchical parameter. We highlight variable responses of birds to revegetation and weed control based on their level of urban sensitivity. Revegetation of open grassy areas delivers significant bird conservation outcomes, but the effects of weed control are neutral or in some cases negative. Specifically, the species most reliant on remnant vegetation in cities seem to remain stable or decline in abundance in areas with weed control, which we suspect is the result of a simplification of the understorey. The literature reports mixed benefits of weed control between taxa and between locations. We recommend, in our case study site, that weed control be implemented in concert with replanting of native vegetation to provide the understory structure preferred by urban sensitive birds. Understanding the impacts of revegetation and weed control on different bird species is important information for practitioners to make restoration decisions about the allocation of funds for conservation action. This new knowledge can be used both for threatened species and invasive species management.

Background: Allogeneic hematopoietic transplantation (HCT) is frequently considered for patients (pts) with relapsed T-cell lymphoma (TCL) and less often as consolidation of initial therapy. Outcomes from prior registry data show that only 31% of pts remain disease free 3 years after HCT (Smith et al. JCO 2013). However, several single institution studies have superior outcomes. We previously presented an analysis of allogeneic transplant in T-cell lymphoma but have expanded this effort to 12 academic centers with longer follow up (Mehta-Shah ASH 2017). Methods: We analyzed the patient characteristics at time of diagnosis and transplant, treatment history, overall (OS) and progression-free survival (PFS) in consecutive TCL pts who had an HCT from 1/1/2000-12/31/2019 at 12 academic institutions. Results: Patient characteristics are shown in Table 1. 508 pts were identified with median age 51 years (16 - 72). 452 (86.5%) had known remission status at the time of HCT: 245 (54.4%) complete remission (CR), 168 (37.2%) partial remission (PR), 23 (5.0%) stable disease (SD), 16 (3.2%) progressive disease (PD). Seventy-eight (15.5%) had a prior autologous HCT. Thirty-six (7%) pts underwent HCT in CR1, 352 (69%) for relapsed/refractory TCL, and was not specified in 120 pts (24%). The median HCT comorbidity index (HCT-CI) score was 1 (0-11). Conditioning regimens were myeloablative (n=180), reduced intensity/non-myeloablative (n=323), unknown (n=3). Donor type was known for 471 pts: 192 matched related (MRD), 183 matched unrelated (MUD), 53 mismatched (MMD), 18 haploidentical donors, 25 umbilical cord blood. In this series, the 2 year OS and PFS rate following HCT were 59.1% (95%CI: 54.6-63.3%) and 45.8% (95%CI: 41.3-50.2%) respectively. 5 year OS and PFS rate were 50.8% (95%CI: 46.1-55.3%) and 39.4% (95%CI: 34.9-43.9%) (Fig 1) For disease specific 2-year and 5-year PFS, see Table 1. At a median follow-up of 29.7 mo (0.1-263 mo), 163 pts had relapsed and 261 pts had died. The median time from relapse post HCT to death was 10.2 mo (0-158.4 mo). Of 261 deaths: 81 were due to transplant related mortality (TRM), 69 were confirmed to be from TCL, and 111 were from non-relapse mortality/unknown. There was not a significant difference in PFS for pts with AITL, PTCL-NOS, ALK positive ALCL or ALK negative ALCL, with median PFS of 23.2 mo (95%CI:15.3-64.2). However, when AITL was compared specifically to PTCL-NOS or ALCL, those with AITL had a trend towards improved median PFS (51.4 mo vs. 18.4 mo, p=0.14) and improved median OS (not reached vs. 73.1 mo, p=0.26). At 5 years, PFS was worse for CTCL (18.6%, 95% CI: 9.7%-30.0%) compared to PTCL subtypes (43.8%; 95% CI: 37.3%-50.0%)(p Disease status at the time of HCT was associated with PFS (p Conclusions: We present the largest series of HCT in TCL. In this dataset, HCT provided durable disease control for a significant portion of pts with relapsed or refractory or otherwise high risk TCL. Depth of response to therapy immediate prior to HCT was associated with PFS. Patients with AITL appeared to have a trend towards improved outcome with HCT compared to other common PTCL histologies. Patients with CTCL had a higher rate of relapse compared to PTCL subtypes, but OS was similar. MRD HCTs were associated with lower TRM. This data supports the curative potential of HCT in a patient group with otherwise poor survival and limited treatment options. Disclosures Mehta-Shah: Corvus: Research Funding; Genetech/Roche: Research Funding; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Bristol Myers-Squibb: Research Funding; Celgene: Research Funding; C4 Therapeutics: Consultancy; Kyowa Hakko Kirin: Consultancy; Innate Pharmaceuticals: Research Funding. Dahi:Kite: Consultancy. Sauter:Sanofi-Genzyme: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Spectrum Pharamaceuticals: Consultancy; Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding. Moskowitz:Merck: Research Funding; Imbrium Therapeutics, L.P.: Consultancy; Bristol-Myers Squibb: Research Funding; Miragen Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Incyte: Research Funding; Seattle Genetics: Research Funding. Jacobsen:Novartis: Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding; F. Hoffmann-LaRoche: Research Funding; Astra-Zeneca: Consultancy; Acerta: Consultancy; Merck: Consultancy. William:Celgene: Consultancy, Honoraria; Guidepoint Global: Consultancy; Seattle Genetics: Research Funding; Dova: Research Funding; Incyte: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria. Barta:Monsanto: Consultancy; Pfizer: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Atara: Honoraria. Allen:Clinical Care Options: Speakers Bureau; Curio Sciences: Honoraria; Research to Practice: Speakers Bureau; Imbrium: Consultancy, Other; Bayer: Consultancy, Other. Song:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene,Takeda: Consultancy, Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding; Otsuka: Honoraria. Ruan:Celgene: Consultancy, Research Funding; Seattle Genetics: Research Funding; Kite Pharma: Consultancy; Juno: Consultancy; BMS: Consultancy, Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Consultancy, Research Funding. McKinney:Kite/Gilead: Honoraria, Speakers Bureau; Kite/Gilead, Seattle Genetics, Molecular Templates, BTG, Pharmacyclics, Verastem, Genentech, Inc., Celgene: Consultancy; UNUM, Molecular Templates, Incyte, Beigene, Denovo Biopharma, Pharmacyclics, Nordic Nanovector, BMS, Genentech, Inc., Celgene: Research Funding. Beaven:Tessa Therapeutics: Research Funding; Roche: Research Funding; Seattle Genetics: Research Funding; MorphoSysAb: Research Funding; LoxoOncology: Research Funding; Celgene: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Alpdogan:Seattle Genetics: Consultancy; Kiowa Kirin: Consultancy. Porcu:Kiowa Kirin: Research Funding; Kura Oncology: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Daiichi: Consultancy, Honoraria; Celgene: Research Funding; Cell Medica: Research Funding; Miragen: Research Funding; Verastem: Consultancy; Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Horwitz:Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; ASTEX: Consultancy.

Hepatosplenic T-cell lymphoma (HSTL) is a rare, mature peripheral T-cell lymphoma with predilection for affecting young men, and cases often have an aggressive, morbid, or fatal clinical course. Here we review the molecular/biologic basis as well as salient clinical features, diagnostic criteria, and current treatment pathways in this disease. Lastly, we describe potential ways forward for improving the outcome in this dreaded disease based upon ongoing basic and translational research in HSTL and extrapolation from experience with other T-cell lymphoma subtypes.

The federal public lands, a defining characteristic of the American West, are embroiled in change and controversy. This is nothing new as these lands have long ignited passions linked to debates over resource development versus protection and federal-state relations. During the past fifty years, however, changes engulfing the region have helped enflame these historic debates, driven by unparalleled population growth, major economic and social shifts, water conflicts, energy development demands, climate change impacts, emergent recreational and environmental values, new scientific knowledge, extensive litigation, reduced agency budgets, new community-based collaborative initiatives, and the like. These remarkable changes are testing the legal and institutional framework governing the public lands, which has changed little during the past fifty years despite recurrent criticism directed toward its shortcomings. In fact, the last comprehensive review of federal public land and resource law occurred during the 1960s, when the Public Land Law Review Commission convened and issued a groundbreaking report that helped prompt much-needed legal reforms, such as the Federal Land Policy and Management Act, National Forest Management Act, Payment in Lieu of Taxes Act, and Public Rangelands Improvement Act. Given the level of controversy prevailing on the public lands today, this Article addresses the question whether the time has come for another comprehensive review of the relevant laws governing these publicly owned lands and their resources. The Article identifies the changes that are inexorably reshaping public land policies, reviews past efforts through federal commissions to examine and reform the laws governing these lands, and assesses the prospects for another comprehensive review. Noting the extreme level of controversy and distrust that persists today, it concludes by proposing a more limited review effort, one focused on accelerating recreational uses and conflicts that may present an opportunity to achieve consensus for the sake of the landscape that everyone is sharing and values.

10586 Background: Clonal hematopoiesis (CH) is the presence of expanded somatic clones in hematopoietic cells and is associated with higher overall mortality (OM). Studies suggest atherosclerotic cardiovascular disease may drive mortality, but the detailed mechanisms remain unclear. CH mutations can be detected in solid tumor sequencing, often confounding genomic tumor analysis. We evaluated the association of CH in solid tumor next-generation sequencing (NGS) with echocardiographic findings and OM. Methods: Sequential adult patients treated at the Duke Cancer Institute with solid tumor NGS analysis by FoundationOne were captured retrospectively. CH mutations present at a variant allele fraction ≥2% across 57 genes previously associated with hematologic malignancies were included. Patients with echocardiograms between 2 years before NGS testing and up to 5 years afterward were analyzed. Association between CH mutations with cardiomyopathy (CM, left ventricular ejection fraction < 45%) and global longitudinal strain (GLS) was determined using logistic and linear regression, respectively. In a subset of patients with detailed cancer diagnosis date and clinical follow-up, Cox proportional hazard models were used to associate CH mutations with OM, with or without TP53/ KRAS (included in most CH analyses but highly prevalent in solid tumors). Analyses were adjusted for age, gender and race. Results: Of 3029 patients with NGS testing, 2212 (73.0%) carried at least one CH related mutation, the majority of which were in TP53/ KRAS. When excluding TP53/ KRAS, CH mutations were observed in 806 of 3029 (26.6%) patients. CH mutations were associated with age (est 2.1, 95% CI 1.1-3.2, p < 0.001). Excluding TP53/ KRAS strengthened the association between CH and age (est 2.8, 95% CI 1.8-3.9, p < 0.001). Echocardiogram data were available in 828 patients, of whom 48 (5.8%) had CM. CH mutations were not associated with CM (OR 1.3, 95% CI 0.6-2.6, p = 0.5), however when excluding TP53 and KRAS, CH mutations were associated with lower odds of (OR 0.4, 95% CI 0.1-0.9, p = 0.03). GLS was available in 423 patients and was not associated with CH mutations (p = 0.8 with TP53/ KRAS; p = 0.4 without TP53/ KRAS as CH). In 222 patients with clinical information, OM did not differ between the CH vs no CH cohorts (HR 0.8, 95% CI 0.6 = 1.2, p = 0.3 inclusive of TP53/KRAS). When excluding TP53/ KRAS mutations, in this population of patients with cancer, non- TP53/ KRAS CH was associated with less OM (HR 0.6, 95% CI 0.4-0.9, p = 0.01). Conclusions: In this patient population with cancer, CH mutations did not associate with higher CM. In contrast to prior studies, CH detected in solid tumor does not associate with OM in this population. CH mutations confound tumor sequencing and these findings support the value of paired tumor-blood sequencing to determine true CH. Consensus around CH variants should be undertaken in future studies.

The most important land and water issues facing North America and the world – including land-use patterns, water management, biodiversity protection, and climate adaptation – require innovative governance arrangements. Most of these issues need to be addressed at several scales simultaneously, ranging from local to global. They require action at the scale of large landscapes given that the geographic scope of the issues often transcends the legal and geographic reach of existing jurisdictions and institutions. No single entity has the authority to address these types of cross-boundary issues, resulting in gaps in governance and a corresponding need to create formal and informal ways work more effectively across administrative boundaries, land ownerships, and political jurisdictions. In response to this challenge, numerous models of “network governance” are emerging. These approaches vary in terms of purpose, spatial scale, composition, organization, and complexity. This article explains what network governance is, why it is emerging, how it compares to other models of natural resource governance, and the different ways in which it develops and evolves.

Crayfishes are keystone species and ecosystem engineers in freshwater systems and are considered the third most imperiled taxa on the planet. In 1906, Arnold Ortmann published one of the most complete historic crayfish surveys ever conducted, which has allowed Pennsylvania to assess changes to crayfish fauna over the past century. More recently, waterways have been impacted by anthropogenic stressors such as urbanization and extractive industry. Our primary goal is to determine changes in species distributions and relative abundances of crayfishes in western Pennsylvania by visiting historical and new sites. Surveys in 2015-16 focused on collecting primary burrowers by trapping and burrow excavation. In 2017, efforts shifted to epigean species in the Upper Ohio River drainage, using standardized sampling of 10 seine hauls/site to assess 265 sites. Populations of primary burrowing crayfishes were found at 20% of 61 historical sites and 72% of 57 new collection sites. Of epigean crayfishes, 79% were found at 102 historical sites and 97% of 163 new sites. These collections represent approximately 60% of the survey, with remaining collections to occur in 2018. Important findings were three nonnative species: Faxonius rusticus (Rusty Crayfish), Procambarus clarkii (Red Swamp Crayfish), and Procambarus acutus (White River Crayfish). Preliminary data suggests that crayfish fauna in western Pennsylvania has remained moderately stable over the last century, though the presence of nonnative crayfishes indicates the need for continued monitoring. Efforts in Pennsylvania must focus on prevention and management of the spread of nonnative species to preserve the native crayfish populations that remain.

Crayfish are the third most threatened taxa worldwide. In 2016, two Appalachian endemic species were federally listed by the United States Fish & Wildlife Service: Cambarus callainus (Big Sandy Crayfish) and Cambarus veteranus (Guyandotte River Crayfish), which are listed as threatened and endangered respectively. Both species were listed due to limited and declining ranges caused by various anthropogenic activities, especially those causing stream sedimentation. Captive propagation can be used as a tool for crayfish conservation by helping to restore the native range of a species or improving their fecundity within their current range. Over a ten week period 120 young-of-the-year (YOY) Cambarus chasmodactylus (New River Crayfish), a surrogate species for C. callainus and C. veteranus, were raised in individual cells to compare (1) growth and (2) survival on two different diets. They were fed every other day, with half (60) raised on trout diet pellets (TD) and the other half raised on blood worms (BW). Results showed that the YOY grew more on BW (17.3% growth) than TD (13.6% growth), and there was increased survival with BW (84.5% survival) versus TD (70.5% survival). These findings may be due in part to the fact that blood worms are easier for the crayfish to eat and may have increased nutritional value over TD. This study suggest a BW diet is more effective in captive rearing of crayfishes than TD, and future studies should explore additional dietary needs.

Cambarus veteranus Faxon, 1914 (Guyandotte River Crayfish), is an endangered, narrow endemic, residing in just two streams in the southern coalfields of West Virginia. A life history study was initiated for C. veteranus in Clear Fork of the Guyandotte River, Wyoming County, West Virginia to gather basic life history information needed for future conservation efforts. Monthly collections began June 2017 and will continue through June 2018. Two 400-meter stream reaches were designated as life history study sites with two different 100-meter sub-reaches sampled each month. Specimens, regardless of species, were collected, sexed, and molt stage determined. Preliminary results suggest an importance of water temperature on crayfish capture with December yielding considerably higher capture rates of C. veteranus relative to other species collected. Form I males are ever present and reach their highest density in early winter. Pre-glaired females reached their highest densities in October and December with glaired females present nearly every month. Thus far, a single ovigerous female has been found, bearing just two stage 4 juveniles. A molting event occurred between September and October with pre-molting individuals present in September and freshly molted individuals present in October. Providing life history information for C. veteranus will assist in conservation efforts and possible repatriation of C. veteranus in the future. Additionally, life history information for C. veteranus can be compared to closely related species that are often used as surrogates for C. veteranus in captive rearing studies.

“Liquid biopsy” approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in EGFR, mediating resistance by blocking binding of anti-EGFR antibodies. Patients with EGFR ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1–13; median, 4). These results suggest that cfDNA profiling can effectively define the genomic landscape of cancer and yield important biological insights. Significance: This study provides one of the first examples of how large-scale genomic profiling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identified novel EGFR ectodomain mutations. Cancer Discov; 8(2); 164–73. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 127

The American West is defined first and foremost by aridity, scarcity, and variability of water resources. In response to this geographic imperative, the region has evolved a robust menu of legal, institutional, and community-based approaches to managing water and conflicts at local, state, and national levels. While far from perfect, this framework may offer lessons to other regions throughout the world that are increasingly faced with water conflicts due to scarcity and variability of water resources. The resulting menu of approaches reflects an adaptive, collaborative, and nested system of governing water resources.

Enteropathy-associated T cell lymphoma (EATL) is the most common oncologic complication of celiac disease. Moffitt and colleagues identify novel EATL-defining mutations in SETD2, as well as clinically relevant mutations in the JAK-STAT pathway., Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1. We also identified mutations in KRAS, TP53, and TERT. Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell–specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369–79. ©2017 AACR. See related commentary by Yoshida and Weinstock, p. 352. This article is highlighted in the In This Issue feature, p. 339