Abstract: Practices in early-stage FL are variable and include radiation alone, systemic therapy, CMT, or observation. Each practice resulted in similar excellent outcomes; randomized trials are required to determine the optimal treatment.

Abstract: The best parts of Robert Y. Turner's article “Dramatic Conventions in All's Well That Ends Well ( PMLA, lxxv, Dec. 1960) concern the denouement of that play. He acutely points out that it is Bertram, with his agonies and perplexities, not Diana, who ”holds the center of the stage“ during her long series of paradoxes; he shows how Shakespeare has added details to his source which prolong and intensify Bertram's distress; and he relates this distress to that of other similar heroes as well as to that of earlier comic butts. I should like, however, to question a number of other points in this article and thereby to challenge as unproved what I take to be its main thesis: that in All's Well Shakespeare ”produced a comedy more of an age than for all time“ because he chose there to follow a contemporary vogue for ”prodigal son comedies“ whose conventions ”have lost their savor.“

Abstract: Background Stage I/II or early-stage follicular lymphoma (ESFL) is considered potentially curable with radiotherapy (XRT). While XRT does achieve local disease control in 〉 90% of cases, more than half the patients (pts) relapse by 10 years (yr), generally outside of the radiation field. A recent randomized controlled trial (TROG 99.03) demonstrated that combined modality therapy (CMT), with sequential XRT and systemic therapy, significantly improved PFS but not overall survival (OS) compared to XRT alone in ESFL. However, only half the pts were staged with 18F‐FDG positron emission tomography and computed tomography (PET) and 58% of CMT pts did not receive rituximab.Compared with CT staging, 20-60% of cases are upstaged by PET. Consequentially, there are limitations in applying this trial to modern populations. Despite the support of current guidelines, only one third of pts in clinical practice are treated with XRT. This suggests a need to better understand the role of other treatments, including watchful waiting (WW), in the PETera. Our aim was to compare outcomes with real-world treatment approaches in rigorously staged ESFL patients. Methods We conducted an international, multicenterretrospective study of stage I and II FL pts rigorously staged with bone marrow biopsy and PET. Eligible pts were 〉 18yr with newly-diagnosed grade 1-3A FL and ≥3 months follow up. Primary outcome measures were overall response rate (ORR), progression free survival (PFS), OS and risk of transformation. Survival curves were estimated with the Kaplan-Meier method and uni- and multi-variate analysis was performed using Cox regression model. Results A total of 387 pts treated at 13 Australian and 3 Canadian centres between 2005-2017 were studied. Median follow-up was 45 months (range 3.1 - 164.0).5-yrPFS and OS rates were 73.5% (95% CI 66.0-78.5) and 94.4% (95% CI 89.4-93.6) respectively. 22 patients had stage IE duodenal FL with 5-yr PFS and OS rates of 100% and 100% respectively. Considering the unique biology and favorable prognosis of duodenal FL, these cases were excluded from subsequent analyses. Treatment approaches 365 pts included WW (defined as absence of treatment within 6 months from diagnosis) (23.2%), XRT (46.8%), immunochemotherapy (17.2%) and CMT (12.6%). Treatment regimens were: R-CHOP (48.1%), R-CVP (24.4%), BR (9.9%), other (17.6%). First-line therapies for actively treated pts yielded comparable ORRs of 95.6%, 96.7% and 95.9% for XRT, immunochemotherapy and CMT, respectively (P=0.94). Overall, 18.2% of pts relapsed at distant sites, 88.2% of all relapses. Treatment cohorts differed in baseline clinical characteristics. WW pts were significantly older (P=0.007) but otherwise comparable to those treated actively. Compared to chemotherapy or CMT pts, those treated with XRT had more favorable features including fewer B symptoms (4.2% vs 11.2% p=0.029), bulk (≥7cm) (6.8% vs 25.3%, p 〈 0.001), nodal sites (≥3) (1.9% vs 9.5% p=0.005) and a higher frequency of stage I FL (73.1% vs 42.1% p 〈 0.001). Outcomes differed among treatment approaches. Active treatment was associated with superior PFS compared with WW pts (HR 0.54 p=0.004) however, 49.4% of WW pts remained untreated at 5-yrs (Fig 1a). Considering actively treated pts, systemic therapy (immunochemotherapy or CMT) was associated with superior PFS compared to XRT by univariate analysis (HR 0.49, p=0.009) (Fig 1b). This association remained after multivariate adjustment for bulk, B symptoms, nodal sites and stage (HR 0.41 p=0.002). Treatment with immunochemotherapy and CMT demonstrated a comparable PFS (p=0.2). Maintenance rituximab (n=45) was associated with superior PFS compared with observation after systemic therapy (HR 0.24, p=0.017). There were no differences in OS among treatment approaches (P=0.734). There was a higher incidence of transformation in XRT pts compared to systemic therapy pts (6.4% vs 1.6% p=0.046). Conclusion In the largest assessment of rigorously-staged ESFL pts in the PETera, pts treated with systemic therapy (chemotherapy or CMT) had a superior PFS and a lower rate of transformation compared to pts treated with XRT, although treatments were not randomized. These findings are similar to the TROG 99.03 trial and challenge the paradigm that ESFL should be uniformly treated with XRT alone. Half the pts observed from diagnosis remained treatment-free at 5-yrs, suggesting that WW may be appropriate in selected pts. Disclosures Tobin: Celgene: Research Funding; Amgen: Other: Educational Travel. Tam:Roche: Honoraria; Roche: Honoraria; Pharmacyclics: Honoraria, Travel funding; Pharmacyclics: Honoraria; Beigene: Honoraria, Other: Travel funding; Beigene: Honoraria, Other: Travel funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Gilead: Honoraria; AbbVie: Honoraria, Research Funding. Abro:Amgen: Other: education support congress attendance; Celgene: Other: education support congress attendance; Bristol-Myers Squibb: Speakers Bureau; Janssen: Other: education support congress attendance; Novartis: Consultancy. Hawkes:Bristol Myers Squibb: Other: Speaker fee, Research Funding; Takeda: Other: Speaker fee; Astra Zeneca: Research Funding; Merck Sharpe Dohme: Research Funding; Merck KGA: Research Funding; Celgene: Other: Advisory board, Research Funding; Merck: Other: Advisory board; Roche: Other: Speaker fee; advisory board. Talaulikar:Amgen: Consultancy, Honoraria; Roche: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Research Funding; Novartis: Honoraria, Speakers Bureau. Gandhi:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: In T-cell lymphoma, malignant T cells arising from a founding clone share an identical T cell receptor (TCR) and can be identified by the over-representation of this TCR relative to TCRs from the patient’s repertoire of normal T cells. Here, we demonstrate that TCR information extracted from RNA-seq data can provide a higher resolution view of peripheral T cell lymphomas (PTCLs) than that provided by conventional methods. Results For 60 subjects with PTCL, flow cytometry/FACS was used to identify and sort aberrant T cell populations from diagnostic lymph node cell suspensions. For samples that did not appear to contain aberrant T cell populations, T helper (TH), T follicular helper (TFH) and cytotoxic T lymphocyte (CTL) subsets were sorted. RNA-seq was performed on sorted T cell populations, and TCR alpha and beta chain sequences were extracted and quantified directly from the RNA-seq data. 96% of the immunophenotypically aberrant samples had a dominant T cell clone readily identifiable by RNA-seq. Of the samples where no aberrant population was found by flow cytometry, 80% had a dominant clone by RNA-seq. This demonstrates the increased sensitivity and diagnostic ability of RNA-seq over flow cytometry and shows that the presence of a normal immunophenotype does not exclude clonality. Availability and Implementation R scripts used in the processing of the data are available online at https://www.github.com/scottdbrown/RNAseq-TcellClonality Supplementary information Supplementary data are available at Bioinformatics online.

Abstract: Gonadotropin-releasing hormone (GnRH) is a decapeptide that regulates reproductive function via binding to the GnRH receptor, which is a G-protein-coupled receptor (GPCR). For several members of this family, the C-terminal domain of intracellular loop III is important in ligand-mediated coupling to G-proteins; mutations in that region can lead to constitutive activity. A specific alanine residue is involved in certain GPCRs, the equivalent of which is Ala-261 in the GnRH receptor. Mutation of this residue to Leu, Ile, Lys, Glu or Phe in the human GnRH receptor did not result in constitutive activity and instead led to complete uncoupling of the receptor (failure to support GnRH-stimulated inositol phosphate production). When this residue was mutated to Gly, Pro, Ser or Val, inositol phosphate production was still supported. All the mutants retained the ability to bind ligand, and the affinity for ligand, where measured, was unchanged. These results show that Ala-261 cannot be involved in ligand binding but is critical for coupling of the receptor to its cognate G-protein. Coupling is also dependent on the size of the residue in position 261. When the amino acid side chain has a molecular mass of less than 40 Da efficient coupling is still possible, but when its molecular mass exceeds 50 Da the receptor is uncoupled. Internalization studies on the Ala261 → Lys mutant showed a marked decrease in receptor internalization compared with the wild type, indicating that coupling is necessary for effective receptor internalization in the GnRH receptor system. Activation of protein kinase C (with PMA), but not protein kinase A (with forskolin) markedly increased the internalization of the mutant receptor while having a small effect on the wild-type receptor.

Abstract: Over the last 10–20 years there has been an ever-increasing international awareness of risks to modern society from adverse and potentially harmful – and in extreme cases even disastrous – space weather events. Many individual countries and even international organisations like the United Nations (UN) have begun to increase their activities in preparing for and mitigating effects of adverse space weather. As in the rest of the world there is also in Europe an urgent need for coordination of Space Weather efforts in individual countries as well as in and among European organisations such as the European Space Agency (ESA) and the European Union (EU). This coordination should not only improve our ability to meet space weather risks, but also enable Europe to contribute to on-going global space weather efforts. While space weather is a global threat, which needs a global response, it also requires tailored regional and trans-regional responses that require coordination at all levels. Commissioned by the European Space Science Committee (ESSC) of the European Science Foundation, the authors – together with ex-officio advice from ESA and the EU – have over two years assessed European activities in the realm of space weather and formulated a set of recommendations to ESA, the EU and their respective member states, about how to prepare Europe for the increasing impact of adverse space weather effects on man-made infrastructure and our society as a whole. We have also analysed parallel international activities worldwide, and we give advice how Europe could incorporate its future activities into a global scheme.