Nova genera plantarum...

pt.3, 5 1783-8

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Swedish-Norwegian co-operation in the treatment of three hypothermia victims: a case report

Abstract Background Accidental hypothermia with cardiac arrest represents a challenge for pre-hospital rescuers as well as in-hospital staff. For pre-hospital personnel, the main focus is to get the patient to the correct destination without unnecessary delay. For in-hospital personnel early information is vital to assess the possibility for resuscitation with extracorporeal re-warming. The challenge is augmented when rescuers must cross national borders to reach and/or deliver the patients. We present a case where three adolescent boys suffered severe hypothermia after a canoeing accident in Sweden. Case presentation Three 14-year-old boys were canoeing a mountain lake close to the Norwegian border when their boat capsized and they all fell into the cold water. The rescue operation was hampered by rough weather conditions, and immersion times spanned from 63 to 125 min. Flight times from the scene of accident to the nearest ECMO center in Norway (Trondheim) and Sweden (Umeå) were about 30 and 90 min respectively. Two of the victims showed no vital signs after retrieval from the water and had extremely low body temperatures. They were brought to Trondheim University Hospital where they were resuscitated successfully with extracorporeal re-warming. Unable to be weaned from ECMO in the initial phase, both patients were retrieved by mobile ECMO teams to Karolinska University Hospital, from where they were discharged to their homes with good outcomes, although with some sequelae. A third victim with moderate to severe hypothermia without cardiac arrest was treated at a local hospital, from where he after a short stay was discharged without physical sequelae. Conclusion These cases are a reminder of the traditional mantra that «no one is dead until warm and dead». Good communication between pre- and in-hospital staff can be vital for optimizing patient treatment when handling victims of severe hypothermia, and especially when there is multiple victims. Communication between neighboring countries, but even neighboring regions within the same country, can be challenging. We encourage regions similar to ours to review protocols regarding hypothermia management, making them more robust before incidents like this take place

Fiskebiologiske undersøkelser i Auravassdraget. Rapport for perioden 2008-2010

Jensen, A.J., Berg, M., Bremset, G., Eide, O., Finstad, B., Hvidsten, N.A., Jensås, J.G., Johnsen, B.O. & Lund, E. 2011. Fiskebiologiske undersøkelser i Auravassdraget. Rapport for perioden 2008-2010. - NINA Rapport 659. 77 s. Formålet med denne undersøkelsen er å overvåke utviklingen av bestandene av laks og sjøørret i Auravassdraget. Resultatene danner grunnlag for å evaluere tiltak som gjennomføres som kompensasjon for negative effekter av kraftutbygginger som berører vassdragets nedslagsfelt. Denne rapporten gir primært resultater fra de siste tre års undersøkelser (2008-2010), men inkluderer også resultater fra tidligere år der det har vært hensiktsmessig. Vassdraget har vært gjenstand for tre store kraftutbygginger. Utbyggingene ble fullført i 1953 (Aura), 1962 (Takrenna) og 1975 (Grytten). Vann ble ført bort fra vassdraget i alle tre tilfellene. Dette har medført en samlet reduksjon i middelvannføringen i Eira ved utløpet av Eikesdals-vatnet på 58 prosent. Reguleringene førte til at fisket etter laks og sjøørret gikk kraftig tilbake. For å kompensere for dette, har regulanten pålegg om årlig å sette ut 50000 laksesmolt og 2500 sjøørretsmolt i vassdraget. Av dette blir 6000 laksesmolt og 2000 sjøørretsmolt merket med nummererte Carlin-merker. Undersøkelsene i 2008-2010 bestod av følgende hovedelementer: 1) Kontroll av kvalitet på utsatt smolt og optimalisering av utsettingsrutiner, 2) Oppfølging av forsøk med Carlin-merking av anleggsprodusert smolt, samt rapportering av gjenfangster av tidligere merket fisk, 3) Inn-samling og analyse av skjellprøver av voksen laks og sjøørret i vassdraget, 4) Fangst av ut-vandrende smolt i felle, og beregning av villsmoltproduksjonen i Eira, 5) Kvantitativt elfiske etter ungfisk på 15 utvalgte lokaliteter i vassdraget, 6) Registrering av gytefisk i Eira og Aura, og 7) Telling av gytegroper i Eira. Ut fra sjøvannstoleransetestene har laksesmolten hatt en god sjøvannstoleranse hvert år siden produksjonsregimene for smolt ble endret våren 1995. For 2010 viste igjen laksen en god sjøvannstoleranse. Sjøørreten har i alle år hatt en dårligere sjøvannstoleranse enn laksen, og også for 2010 gjenspeilet dette seg i resultatene fra testingene. Utsettingsforsøkene viste et høyere stressnivå hos fisk prøvetatt i hvilemerd, men sammenlignet med en direkte utsetting var stressnivåene lavere enn tidligere observert. Siden 1992 er det bare fire utsettinger (2001, 2002, 2006 og 2008) som har gitt høyere gjenfangster av Carlin-merket laks enn 0,2 %. Best overlevelse ble registrert etter utsettingene i 2002, med 0,8 %. Forøvrig er det registrert 0,4 % gjenfangst fra utsettingene i 2001 og 2008, og 0,5 % i 2006. Dette er betydelig lavere enn på 1960- og 1970-tallet, da gjenfangsten de fles-te år var 1-2 %, og enkeltforsøk ga opptil 8,9 % gjenfangst. Merkeforsøk med sjøørret startet i 1995, men de fleste årene har det vært få gjenfangster. Det beste resultatet er fra utsettingene i 2007, med 3,8 %. Øvrige gjenfangster har ligget på 0,6 % eller lavere. Dette stemmer overens med resultatene fra saltvannstestene, som viste best kvalitet på ørretsmolten fra 2007. Av de 40 000 laksungene som ble satt ut i Eikesdalsvatnet i årene 2004-2007 har vi estimert at 1,2 - 3,5 % vandret ut i sjøen. De tre siste årene har smolten fra anlegget i økende grad blitt sluppet gjennom fella uten berøring, og få fisk ble derfor kontrollert for kjevebeinsklipping. Merkemetoden for å evaluere tilslaget for laksungene som settes ut i Eikesdalsvatnet er derfor fra høsten 2010 endret fra klipping til PIT-merking. Det vil bli montert ei antenne i smoltfella våren 2011 som kan registrere merket fisk automatisk uten å berøre fisken