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Miguel A Checa,1,2 Mario Brassesco,2 Margalida Sastre,1 Manuel Gómez,2 Julio Herrero,3 Laura Marque,3 Arturo Brassesco,2 Juan José Espinós3 1Department of Obstetrics and Gynecology, Parc de Salut Mar, Universitat Autònoma de Barcelona, 2Centro de Infertilidad y Reproducción Humana (CIRH), 3Centro de Reproducción Asistida Sagrada Familia, Clínica Sagrada Familia, Barcelona, Spain Abstract: The aim of this study is to evaluate the feasibility and safety of random-start controlled ovarian hyperstimulation (COH) for emergency fertility preservation, regardless of the phase of the menstrual cycle. A self-controlled pilot clinical trial (NCT01385332) was performed in an acute-care teaching hospital and in two private reproductive centers in Barcelona, Spain. Eleven egg donors participated in the study. Two random-start gonadotropin-releasing hormone (GnRH) antagonist protocols were assessed in which ganirelix was initiated on either day 10 (protocol B) or on day 20 (protocol C) of the menstrual cycle and was continued until estradiol levels were below 60 pg/dL. These protocols were compared with a standard protocol (protocol A). The main outcome of interest was the number of metaphase 2 oocytes retrieved. Results from this study show that the number of mature oocytes retrieved was comparable across the different protocols (14.3±4.6 in the standard protocol versus 13.0±9.1 and 13.2±5.2 in protocols B and C, respectively; values expressed as mean ± standard deviation). The mean number of days needed for a GnRH antagonist to lower estradiol levels, as well as the ongoing pregnancy rates, were also similar when protocols B (stimulation in follicular phase) and C (stimulation on luteal phase) were compared with protocol A (standard stimulation). GnRH antagonists can be effectively used for random-start controlled ovarian hyperstimulation with an ovarian response similar to that of standard protocols, and the antagonists appear suitable for emergency fertility preservation in cancer patients. Keywords: controlled ovarian hyperstimulation, GnRH antagonists, emergency fertility preservation, cancer patients

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer.

Phylogenetic inference is generally performed on the basis of multiple sequence alignments (MSA). Because errors in an alignment can lead to errors in tree estimation, there is a strong interest in identifying and removing unreliable parts of the alignment. In recent years several automated filtering approaches have been proposed, but despite their popularity, a systematic and comprehensive comparison of different alignment filtering methods on real data has been lacking. Here, we extend and apply recently introduced phylogenetic tests of alignment accuracy on a large number of gene families and contrast the performance of unfiltered versus filtered alignments in the context of single-gene phylogeny reconstruction. Based on multiple genome-wide empirical and simulated data sets, we show that the trees obtained from filtered MSAs are on average worse than those obtained from unfiltered MSAs. Furthermore, alignment filtering often leads to an increase in the proportion of well-supported branches that are actually wrong. We confirm that our findings hold for a wide range of parameters and methods. Although our results suggest that light filtering (up to 20% of alignment positions) has little impact on tree accuracy and may save some computation time, contrary to widespread practice, we do not generally recommend the use of current alignment filtering methods for phylogenetic inference. By providing a way to rigorously and systematically measure the impact of filtering on alignments, the methodology set forth here will guide the development of better filtering algorithms., Systematic Biology, 64 (5), ISSN:1063-5157, ISSN:1076-836X

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.

This article summarises the information to be offered to women about mammography. After a delineation of the aim of early diagnosis of breast cancer, the difference between screening mammography and diagnostic mammography is explained. The need to bring images and reports from the previous mammogram (and from other recent breast imaging examinations) is highlighted. Mammography technique and procedure are described with particular attention to discomfort and pain experienced by a small number of women who undergo the test. Information is given on the recall during a screening programme and on the request for further work-up after a diagnostic mammography. The logic of the mammography report and of classification systems such as R1-R5 and BI-RADS is illustrated, and brief but clear information is given about the diagnostic performance of the test, with particular reference to interval cancers, i.e., those cancers that are missed at screening mammography. Moreover, the breast cancer risk due to radiation exposure from mammography is compared to the reduction in mortality obtained with the test, and the concept of overdiagnosis is presented with a reliable estimation of its extent. Information about new mammographic technologies (tomosynthesis and contrast-enhanced spectral mammography) is also given. Finally, frequently asked questions are answered. Key Points: • Direct digital mammography should be preferred to film-screen or phosphor plates. • Screening (in asymptomatic women) should be distinguished from diagnosis (in symptomatic women). • A breast symptom has to be considered even after a negative mammogram. • Digital breast tomosynthesis increases cancer detection and decreases the recall rate. • Contrast-enhanced spectral mammography can help in cancer detection and lesion characterisation. © 2016, The Author(s).