Collision tumors revealed by prospectively assessing subtype-defining molecular alterations in 904 individual prostate cancer foci.

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063)

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.Radiolog

Kvalitetsforbedringsprosjekt: Hvordan øke andelen slagpasienter som behandles på slagenhet på Ullevål sykehus?

Tema/problemstilling: Ca. 15 000 personer rammes av hjerneslag hvert år. Hjerneslag er den tredje hyppigste årsaken til død i Norge, og en dominerende årsak til alvorlig funksjonshemning. Det foreligger klare retningslinjer for slag og slagbehandling der det presiseres at alle slagpasienter bør behandles ved slagenhet. Ved Ullevål sykehus har det blitt observert at pasienter med mistenkt slag ikke legges direkte inn på seksjon for hjerneslag, men heller på andre avdelinger. Ifølge tall fra Norsk hjerneslagregister er andelen slagpasienter ved Ullevål som legges direkte inn på seksjon for hjerneslag 73,1 %. Hensikten med prosjektet er å øke andelen slagpasienter som legges direkte inn på seksjon for hjerneslag på Ullevål sykehus. Kunnskapsgrunnlag: Vi utformet et PICO-spørsmål og utførte et pyramidesøk i McMaster PLUS med søkeordene «acute stroke care.» Vi fant retningslinjer fra UpToDate, BMJ i tillegg til nasjonale retningslinjer for behandling og rehabilitering ved hjerneslag fra 2010, som er basert på en Cochrane review «Organised inpatient (stroke unit) care for stroke.» I sistnevnte har behandling i slagenhet vs. annen avdeling vist å ha effekt både på dødelighet og alvorlige funksjonshemninger med en absolutt risikoreduksjon (ARR) for død og død eller alvorlig funksjonshemning på hhv. 4 % og 4,7 %. Disse kildene er i tråd med hverandre og anbefaler behandling i slagenhet heller enn andre avdelinger. Tiltak/kvalitetsindikator: Vårt tiltak dreier seg om at alle pasienter med mistenkt slag skal undersøkes av nevrolog i akuttmottaket og dermed heve terskelen for innleggelse på seksjon for hjerneslag. Dette er allerede beskrevet i prosedyre «Hjerneslag – diagnostikk og behandling» fra 2015, og er utarbeidet av dr. Sigurd Vatne. I tillegg skal LIS i nevrologi avgjøre hvilke pasienter som skal flyttes til denne sengeposten. Som kvalitetsindikator har vi valgt en prosessindikator. Denne måler andelen slagpasienter som legges direkte inn på seksjon for hjerneslag. Ledelse/organisering: Prosjektet er planlagt å foregå over tolv måneder med vurderinger etter tre og seks måneder. Forbedringsprosjektet vil bli ledet av en prosjektgruppe, som har overordnet ansvar for prosess, organisering, evaluering og målsetting. Den vil bestå av representanter fra klinikkledelsen, seksjon for hjerneslag (enhetsleder, fagansvarlig lege, fysioterapeut og sykepleier) samt akuttmottaket (koordinator, indremedisiner og nevrolog). Det vil også være en implementeringsgruppe som vil ha ansvaret for implementering av prosjektet. Denne gruppen vil bestå av representanter som er involvert i pasientflyten: akuttmottaket (koordinator, indremedisiner og nevrolog) og seksjon for hjerneslag (lege, sykepleier og enhetsleder). Det overordnete målet er at 90 % av akutte slagpasienter innlegges direkte på seksjon for hjerneslag med delmål. Delmålene er at etter tre måneder skal 80 % av akutte slagpasienter innlegges direkte på seksjon for hjerneslag, og etter seks måneder skal andelen være 90 %. For å evaluere om delmål og overordnet mål er nådd, skal implementeringsgruppen hver fjerde uke innhente informasjon fra DIPS om både antall pasienter som legges inn med slag som hoveddiagnose, og hvor disse primært legges inn etter akuttmottaket. Implementeringsgruppen vil presentere resultater etter tre, seks og tolv måneder for prosjektgruppen. Det vil også gis personlig tilbakemelding til legen ansvarlig for innleggelse i akuttmottaket når det har skjedd et avvik (slagpasient ikke lagt inn på seksjon for hjerneslag). Gjennom hele prosjektet vil det være mulig for tilbakemeldinger fra involverte aktører. Etter hver evaluering vil prosjektgruppen ta stilling til om det er nødvendig å justere tiltaket, behov for nytt tiltak eller behov for mer tid for å se effekt. Diskusjon/konklusjon: Det er klar evidens for mindre dødelighet og alvorlig funksjonshemning ved behandling i slagenhet vs. andre avdelinger. Primærtiltaket vi har valgt retter seg mot tidlig diagnostikk og avklaring av pasienter som legges inn på seksjon for hjerneslag. Ved hjelp av dette tiltaket håper vi å heve kvaliteten på slagbehandling på Ullevål sykehus. Vi mener prosjektet er gjennomførbart. Det er konkret og lite ressurskrevende. Gjennomførbarheten er avhengig av en rekke faktorer som inkl. tilstrekkelig endringsvilje og synliggjøring av viktigheten av prosjektet. Det kan forventes at motstand oppleves ved at det blir en økt arbeidsbelastning på nevrologer, gå ut over andre pasientgrupper og sengekapasitet på andre avdelinger. Det er derfor viktig at alle berørte parter er involvert

New tie-points for the geomagnetic polarity time scale during the Middle Miocene from the Mogán Group on Gran Canaria and Ocean Drilling Program Leg 157 site 953

A thick sequence of volcaniclastic sediments drilled at site 953 during Ocean Drilling Program (ODP) Leg 157 northeast of Gran Canaria (Canary Islands) contains an almost complete magneto-stratigraphy back to the shield stage of the island 14.8 Ma ago. Onshore, a sequence of reversals has been identified and dated in 19 dominantly peralkaline rhyolitic ignimbrites, one rhyolitic, and one basaltic lava flow of the Mogán Group (13.35–13.95 Ma), which overlie basalt flows of the island's shield stage (>14 Ma). The magneto-stratigraphy of the ignimbrites onshore has been correlated with the marine magneto-stratigraphy at site 953, determined in syn-ignimbritic volcaniclastic turbidites, which were deposited practically synchronously immediately following the entry of the parent pyroclastic flows into the sea around the circumference of the island. The four polarity intervals recorded in the sequence of the Mogán Group ignimbrites correspond to C5ACr, C5ACn, C5ADr and C5ADn. Single crystal 40Ar/39Ar-age determinations of the ignimbrites bracketing the polarity changes gave the following ages and uncertainties for the reversals C5AD (t) (13.95±0.07 Ma), C5AC(o) (13.89±0.08 Ma), and C5AC(t) (13.47±0.09 Ma). The newly dated polarity changes fit and refine the Miocene age model proposed in the global polarity time scale

Magnetostratigraphy of ODP Hole 157-953C (Table 1)

A thick sequence of volcaniclastic sediments drilled at site 953 during Ocean Drilling Program (ODP) Leg 157 northeast of Gran Canaria (Canary Islands) contains an almost complete magneto-stratigraphy back to the shield stage of the island 14.8 Ma ago. Onshore, a sequence of reversals has been identified and dated in 19 dominantly peralkaline rhyolitic ignimbrites, one rhyolitic, and one basaltic lava flow of the Mogán Group (13.35-13.95 Ma), which overlie basalt flows of the island's shield stage (>14 Ma). The magneto-stratigraphy of the ignimbrites onshore has been correlated with the marine magneto-stratigraphy at site 953, determined in syn-ignimbritic volcaniclastic turbidites, which were deposited practically synchronously immediately following the entry of the parent pyroclastic flows into the sea around the circumference of the island. The four polarity intervals recorded in the sequence of the Mogán Group ignimbrites correspond to C5ACr, C5ACn, C5ADr and C5ADn. Single crystal 40Ar/39Ar-age determinations of the ignimbrites bracketing the polarity changes gave the following ages and uncertainties for the reversals C5AD(t) (13.95±0.07 Ma), C5AC(o) (13.89±0.08 Ma), and C5AC(t) (13.47±0.09 Ma). The newly dated polarity changes fit and refine the Miocene age model proposed in the global polarity time scale

High expression of SCHLAP1 in primary prostate cancer is an independent predictor of biochemical recurrence, despite substantial heterogeneity

In primary prostate cancer, the common multifocality and heterogeneity are major obstacles in finding robust prognostic tissue biomarkers. The long noncoding RNA SCHLAP1 has been suggested, but its prognostic value has not been investigated in the context of tumor heterogeneity. In the present study, expression of SCHLAP1 was investigated using real-time RT-PCR in a multisampled series of 778 tissue samples from radical prostatectomies of 164 prostate cancer patients (median follow-up time 7.4 y). The prognostic value of SCHLAP1 was evaluated with biochemical recurrence as endpoint.In total, 29% of patients were classified as having high expression of SCHLAP1 in at least one malignant sample. Among these, inter- and intrafocal heterogeneity was detected in 72% and 56%, respectively. High expression of SCHLAP1 was shown to be a predictor of biochemical recurrence in both uni- and multivariable cox regression analyses (P < 0.001 and P = 0.02). High expression of SCHLAP1 was also significantly associated with adverse clinicopathological characteristics, including grade group, high pT stage, invasive cribriform growth/intraductal carcinoma of the prostate, and reactive stroma. In conclusion, high expression of SCHLAP1 in at least one malignant sample is a robust prognostic biomarker in primary prostate cancer. For the first time, high SCHLAP1 expression has been associated with the aggressive histopathologic feature reactive stroma. The expression of SCHLAP1 is highly heterogeneous, and analysis of multiple samples is therefore crucial in determination of the SCHLAP1 status of a patient

In situ expression of ERG protein in the context of tumor heterogeneity identifies prostate cancer patients with inferior prognosis

Prognostic biomarkers for prostate cancer are needed to improve prediction of disease course and guide treatment decisions. However, biomarker development is complicated by the common multifocality and heterogeneity of the disease. We aimed to determine the prognostic value of candidate biomarkers transcriptional regulator ERG and related ETS family genes, while considering tumor heterogeneity. In a multisampled, prospective, and treatment-naïve radical prostatectomy cohort from one tertiary center (2010–2012, median follow-up 8.1 years), we analyzed ERG protein (480 patients; 2047 tissue cores), and RNA of several ETS genes in a subcohort (165 patients; 778 fresh-frozen tissue samples). Intra- and interfocal heterogeneity was identified in 29% and 33% (ERG protein) and 39% and 27% (ETS RNA) of patients, respectively. ERG protein and ETS RNA was identified exclusively in a nonindex tumor in 31% and 32% of patients, respectively. ERG protein demonstrated independent prognostic value in predicting biochemical (P = 0.04) and clinical recurrence (P = 0.004) and appeared to have greatest prognostic value for patients with Grade Groups 4–5. In conclusion, when heterogeneity is considered, ERG protein is a robust prognostic biomarker for prostate cancer

Comparative evaluation of circular truncated-cone and paraboloid shapes for thermal energy storage tanks based on thermal stratification performance

In solar water heating systems, geometrical configurations of thermal energy storage (TES) play a crucial role in the enhancement of system performances. Upon conducting a thorough study on the influence of different shapes and aspect ratios of TES tanks, the present study focuses on the choice of suitable TES tank geometry based on the key performance parameters, viz. Richardson number, stratification number, storage efficiency and the initial thermocline thickness. Thermal stratification characteristics are investigated and analyzed in detail for three chosen shapes of TES, namely truncated-cone, paraboloid, and cylinder, using a two-dimensional unsteady numerical model. Results of the numerical model on cylindrical TES is found to have good agreement with the findings of the in-house experiments. With increasing aspect ratio (AR) of the paraboloid and truncated cone TES tanks, initial thermocline thickness and the energy losses increase, whereas, Richardson number and average stratification number decrease, indicating better stratification performance in storage tanks with lower AR. However, there is a limit on reducing the AR. At every AR investigated for the two shapes of TES, Richardson number for the paraboloid TES is greater than that of the truncated-cone TES, qualitatively suggesting a better temperature stratification in the paraboloid TES. The effect of flow rate on the thermal stratification characteristics is also studied, which suggests that increasing the flow rate enhances mixing and deteriorates stratification. The findings can be used as guidelines for designing TES with improved thermal performance