Disease-specific outcomes of Radical Prostatectomies in Northern Norway; A case for the impact of perineural infiltration and postoperative PSA-doubling time

Background Prostate cancer is the most common male malignancy and a mayor cause of mortality in the western world. The impact of clinicopathological variables on disease related outcomes have mainly been reported from a few large US series, most of them not reporting on perineural infiltration. We therefore wanted to investigate relevant cancer outcomes in patients undergoing radical prostatectomy in two Norwegian health regions with an emphasis on the impact of perineural infiltration (PNI) and prostate specific antigen- doubling time (PSA-DT). Methods We conducted a retrospective analysis of 535 prostatectomy patients at three hospitals between 1995 and 2005 estimating biochemical failure- (BFFS), clinical failure- (CFFS) and prostate cancer death-free survival (PCDFS) with the Kaplan-Meier method. We investigated clinicopathological factors influencing risk of events using cox proportional hazard regression. Results After a median follow-up of 89 months, 170 patients (32%) experienced biochemical failure (BF), 36 (7%) experienced clinical failure and 15 (3%) had died of prostate cancer. pT-Stage (p = 0.001), preoperative PSA (p = 0.047), Gleason Score (p = 0.032), non-apical positive surgical margins (PSM) (p = 0.003) and apical PSM (p = 0.031) were all independently associated to BFFS. Gleason score (p = 0.019), PNI (p = 0.012) and non-apical PSM (p = 0.002) were all independently associated to CFFS while only PNI (P = 0.047) and subgroups of Gleason score were independently associated to PCDFS. After BF, patients with a shorter PSA-DT had independent and significant worse event-free survivals than patients with PSA-DT > 15 months (PSA-DT = 3-9 months, CFFS HR = 6.44, p < 0.001, PCDFS HR = 13.7, p = 0.020; PSA-DT < 3 months, CFFS HR = 11.2, p < 0.001, PCDFS HR = 27.5, p = 0.006). Conclusions After prostatectomy, CFFS and PCDFS are variable, but both are strongly associated to Gleason score and PNI. In patients with BF, PSA-DT was most strongly associated to CF and PCD. Our study adds weight to the importance of PSA-DT and re-launches PNI as a strong prognosticator for clinically relevant endpoints

Assessing PDL-1 and PD-1 in NoneSmall Cell Lung Cancer: A Novel Immunoscore Approach

Published version. Source at http://dx.doi.org/10.1016/j.cllc.2016.09.009 Novel immune biomarkers could complement the TNM classification for nonesmall cell cancer (NSCLC), improving the prognostic accuracy. The present study evaluated the prognostic significance of the immune checkpoint molecules programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1) in 536 patients with stage I to IIIA NSCLC using an Immunoscore approach. Independently, and in combination, the infiltration of immune cells expressing PD-L1 and PD-1 predicted patient survival, supplementing the TNM classification in each stage. Introduction: Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand, PD-L1, have gained momentum in the treatment of nonesmall cell lung cancer (NSCLC). However, their prognostic significance remains controversial. The present study evaluated the expression of PD-L1 and PD-1 and their potential role in an Immunoscore, supplementing the TNM classification of NSCLC. Materials and Methods: Tissue microarrays constructed from tumor tissue samples from 2 cohorts of a total of 536 patients (University Hospital of North Norway, n ¼ 285; Nordland Hospital, n ¼ 251) with primary resected stage I to IIIA NSCLC. PD-L1 and PD-1 were evaluated by immunohistochemistry in the primary tumor and metastatic lymph node tissue. Results: In univariate analysis, a high density of PD-L1þ immune cells in the stromal compartment (S-PD-L1) and PD-1þ intraepithelial tumor infiltrating lymphocytes (T-PD-1) was associated with favorable disease-specific survival (DSS; S-PD-L1, P ¼ .004; T-PD-1, P ¼ .012), both limited to the squamous cell carcinoma histologic subgroup (S-PD-L1, P ¼ .002; T-PD-1, P ¼ .034). A combined low S-PD-L1 and T-PD-1 was associated with poor survival in all patients (DSS: hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.37-2.40; P < .001) at both centers and for all pathologic stages. In multivariate analysis, S-PD-L1 and T-PD-1 were independent positive prognostic factors, and combined low scores remained an independent prognosticator for poor survival (DSS: HR, 1.72; 95% CI, 1.29-2.28; P < .001; disease-free survival, P ¼ .001; overall survival, P ¼ .005). Conclusion: Our study identified S-PD-L1 and T-PD-1 as independent positive prognostic factors for NSCLC patients. Their combination added significant prognostic impact within each pathologic stage and hence are feasible to include in a TNM Immunoscore

Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer

Source at https://doi.org/10.1038/s41598-018-23417-z. Licensed CC BY-NC-ND 4.0.Lung cancer is the leading cause of cancer deaths. Novel predictive biomarkers are needed to improve treatment selection and more accurate prognostication. PAX6 is a transcription factor with a proposed tumour suppressor function. Immunohistochemical staining was performed on tissue microarrays from 335 non-small cell lung cancer (NSCLC) patients for PAX6. Multivariate analyses of clinico-pathological variables and disease-specific survival (DSS) was carried out, and phenotypic changes of two NSCLC cell lines with knockdown of PAX6 were characterized. While PAX6 expression was only associated with a trend of better disease-specific survival (DSS) (p = 0.10), the pN+ subgroup (N = 103) showed significant correlation between high PAX6 expression and longer DSS (p = 0.022). Median survival for pN + patients with high PAX6 expression was 127.4 months, versus 22.9 months for patients with low PAX6 expression. In NCI-H661 cells, knockdown of PAX6 strongly activated serum-stimulated migration. In NCI-H460 cells, PAX6 knockdown activated anchorage-independent growth. We did not observe any significant effect of PAX6 on proliferation in either of cell lines. Our findings strongly support the proposition of PAX6 as a valid and positive prognostic marker in NSCLC in node-positive patients. There is a need for further studies, which should provide mechanistical explanation for the role of PAX6 in NSCLC

High expression of miR-17-5p in tumor epithelium is a predictor for poor prognosis for prostate cancer patients

MicroRNAs (miRs) are small non-coding RNA molecules, which are involved in the development of various malignancies, including prostate cancer (PCa). miR-17-5p is considered the most prominent member of the miR-17-92 cluster, with an essential regulatory function of fundamental cellular processes. In many malignancies, up-regulation of miR-17-5p is associated with worse outcome. In PCa, miR-17-5p has been reported to increase cell proliferation and the risk of metastasis. In this study, prostatectomy specimens from 535 patients were collected. Tissue microarrays were constructed and in situ hybridization was performed, followed by scoring of miR-17-5p expression on different tumor compartments. High expression of miR-17-5p in tumor epithelium was associated with biochemical failure (BF, p p = 0.019). In multivariate analyses, high miR-17-5p expression in tumor epithelial cells was an independent negative prognostic factor for BF (HR 1.87, 95% CI 1.32–2.67, p < 0.001). In vitro analyses confirmed association between overexpression of miR-17-5p and proliferation, migration and invasion in prostate cancer cell lines (PC3 and DU145). In conclusion, our study suggests that a high cancer cell expression of miR-17-5p was an independent negative prognostic factor in PCa

Mutasjonstesting ved ikke-småcellet lungekreft

Bakgrunn. Epidermal vekstfaktorreseptor (EGFR) tyrosinkinasehemmere (EGFR-TKI) er en relativt ny klasse legemidler til behandling av ikke-småcellet lungekreft. Den nasjonale faggruppen for lungekreft, Norsk Lunge Cancer Gruppe, anbefaler at pasienter med ikke-småcellet lungekreft testes for mutasjoner i EGFRgenet. Vi rapporterer her erfaringene som er gjort etter at slik testing ble innført i Norge i 2010. Materiale og metode. Opplysninger om hvor mange som er testet, kjønnsfordeling, histopatologiske data og analyseresultater er samlet inn fra de molekylærpatologiske laboratorier ved universitetssykehusene i Tromsø, Trondheim, Bergen og Oslo for perioden mai 2010 til mai 2011. Resultater. 1 058 pasienter med lungekreft ble testet for mutasjoner i EGFRgenet i denne perioden, hvilket svarer til ca. halvdelen av alle som fikk diagnosen ikke-småcellet lungekreft. Mutasjon ble påvist hos 123 pasienter (11,6 %). Det var en høyere andel mutasjonspositive kvinner enn menn (17,6 % mot 6,3 %, p < 0,001), og lavere andel ved plateepitelkarsinom enn ved andre histopatologiske undertyper (3,0 % mot 12,9 %, p = 0,001). Av 80 cytologiske prøver var ni (11,3 %) positive. Fortolkning. På bakgrunn av den relativt høye mutasjonsfrekvensen og et ikke ubetydelig antall positive i plateepitelkarsinomgruppen, anbefaler vi videreføring av mutasjonstesting av alle pasienter med ikke-småcellet lungekreft

Molecular analysis of angiogenic markers as prognostic factors for non-small cell lung cancer (NSCLC)

Nydannelse av blodkar er avgjørende for at en kreftsvulst skal etablere seg og vokse og et viktig angrepspunkt for ny kreftbehandling. Arbeidet undersøker molekyler som er viktig for reguleringen av blodkardannelse i kreftsvulster og hvordan disse påvirker overlevelsesprognosen for lungekreftpasienter. Avhandlingens tittel er ”Molecular analysis of angiogenic markers as prognostic factors for non-small cell lung cancer (NSCLC)”, den ble forsvart for graden PhD 20.03.09. På verdensbasis er lungekreft den vanligste kreftsykdommen og den kreftformen som forårsaker flest dødsfall. I Norge dør rundt 2000 mennesker av lungekreft hvert år. Angiogenese (nydannelse av blodkar) er en forutsetning for at en svulst skal bli større en 1-2mm og mange nye medikamenter designes for å hindre slik karnydannelse. Foreløpig har resultatene vært relativt beskjedne innen lungekreftbehandling, men biologisk bør potensialet være stort. Ved å optimalisere kombinasjonen av angrepspunkt og plukke ut de pasientene man forventer å ha effekt, kan anti-angiogenese behandling bli et viktig bidrag i kampen mot lungekreft. Avhandlingen er basert på et arbeid utgått fra en translasjonsforsknings-gruppe innen lungekreft. Dette er et samarbeid mellom Kreftavdelingen og Patologisk avdeling ved Universitetssykehuset Nord-Norge / Universitetet i Tromsø og Patologisk avdeling ved Nordlandssykehuset, Bodø. Materialet består av vevsprøver av ikke-småcellet lungekreft (NSCLC) fra 335 pasienter operert i Tromsø og Bodø i tidsperioden 1990-2004. På bakgrunn av vevsmatriser fra samtlige svulster og med innhentede kliniske og demografiske data har man undersøkt tre sentrale familier av angiogenese (nydannelse av blodkar) molekyler. I kreftcellene har flere ulike angiogenese molekyler betydning for om pasienten overlever sykdommen. I tillegg er ulike molekyler også i bindevevet rundt kreftcellene viktig for lungekreftpasientenes overlevelse. Videre har vi også observert at kombinasjoner av angiogenesemolekyler fra forskjellige familier har meget sterk prognostisk verdi for grupper av lungekreftpasienter. Hos disse kan det være spesielt interessant å gjøre nye undersøkelser for å se hvilken effekt de kan ha av kombinert anti-angiogenese behandling

Dying at “home” - a qualitative study of end-of-life care in rural Northern Norway from the perspective of health care professionals

Abstract Background ‘Most patients want to die at home’ is a familiar statement in palliative care. The rate of home deaths is therefore often used as a success criterion. However, providing palliative care and enabling patients to die at home in rural and remote areas may be challenging due to limited health care resources and geographical factors. In this study we explored health care professionals’ experiences and reflections on providing palliative care to patients at the end of life in rural Northern Norway. Methods This is a qualitative focus group and interview study in rural Northern Norway including 52 health care professionals. Five uni-professional focus group discussions were followed by five interprofessional focus group discussions and six individual interviews. Transcripts were analysed thematically. Results Health care professionals did their utmost to fulfil patients’ wishes to die at home. They described pros and cons of providing palliative care in rural communities, especially their dual roles as health care professionals and neighbours, friends or even relatives of patients. Continuity and carers’ important contributions were underlined. When home death was considered difficult or impossible, nurses expressed a pragmatic attitude, and the concept of home was extended to include ‘home place’ in the form of local health care facilities. Conclusions Providing palliative care in patients’ homes is professionally and ethically challenging, and health care professionals’ dual roles in rural areas may lead to additional pressure. These factors need to be considered and addressed in discussions of the organization of care. Nurses’ pragmatic attitude when transfer to a local health care facility was necessary underlines the importance of building on local knowledge and collaboration. Systematic use of advance care planning may be one way of facilitating discussions between patients, family carers and health care professionals with the aim of achieving mutual understanding of what is feasible in a rural context

Evaluating a centralised cancer support centre in the remote region of Northern Norway

Introduction: Being diagnosed with cancer and undergoing treatment is a life-changing experience, and many cancer patients find the physical, emotional and social effects of the disease to be stressful. This study explores the experiences of cancer patients and their relatives from all parts of Northern Norway visiting the centralised cancer support centre. Methods: In a comprehensive prospective survey, 286 visitors were invited to participate and 181 of these accepted. The characteristics of the participants, their expectations for visiting the centre, whether they wanted to meet peers or volunteers rather than clinicians and how they viewed the centre in the context of cancer care were evaluated. Results: Most satisfied were visitors aged less than 50 years, women and those reporting a ‘strong social network’. The majority of the visitors wanted to have better access to peers (with a similar cancer diagnosis) (89%), cancer nurses (75%) or oncologists (71%). About a third of the participants (29.8%) lived in communities with fewer than 5000 inhabitants and 59.4% in municipalities with fewer than 15 inhabitants/km2. There were no significant differences in the characteristics of the participants, or in their evaluation of the support centre, when stratified by number of inhabitants or population density in their home community. Conclusion: The cancer support centre was highly valued by patients and their relatives for meeting peers. The centre was most frequently visited by and most popular among women and those self-reporting strong social networks. Access to oncology doctors and nurses in this setting could be valuable. Participants living in remote areas had similar characteristics and evaluated the support centre similarly to those living in more urban areas

Prognostic Impact of Fibroblast Growth Factor 2 in NSCLC : Co-Expression with VEGFR-3 and PDGF-B Predicts Poor Survival

Purpose: Fibroblast growth factor 2 (FGF2; basic fibroblast growth factor, b-FGF) and its main receptor FGFR-1 are important in both hemangiogenesis and lymphangiogenesis. Murine studies have indicated a close interplay between both FGF2 and platelet-derived growth factor –B (PDGF-B) as well as FGF2 and vascular endothelial growth factor -3 (VEGFR-3). This study investigates the prognostic impact of FGF2 and FGFR-1 in tumor cells and tumor stroma of resected non-small cell lung carcinomas (NSCLC) and explores the importance of their co-expression with VEGFR-3 or PDGF-B. Methods: Tumor tissue samples from 335 resected patients with stage I to IIIA NSCLC were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and tumor-related stroma from each specimen. Immunohistochemistry was used to evaluate the expression of the molecular markers FGF2, FGFR-1, VEGFR-3 and PDGF-B. Results: In univariate analyses, high tumor cell FGF2 expression (P = 0.015) was a negative prognostic indicator for disease-specific survival (DSS). In tumor stroma, high FGF2 (P = 0.024) expression correlated with good prognosis. In multivariate analyses, high expression of FGF2 in tumor cells (P = 0.038) was an independent negative prognostic factor whereas increased FGF2 in stroma (P = 0.015) was a positive prognosticator. Tumor cell coexpressions of FGF2/VEGFR-3 (P < 0.001) and GFR-1/PDGF-B (P = 0.002) were significant indicators of poor prognosis. Conclusions: Expression of FGF2 in tumor cells is an independent negative prognostic factor, and the co-expressions of FGF2/VEGFR-3 and FGFR-1/PDGF-B are strongly associated with poor survival in NSCLC patients

Digitally quantified CD8+ cells: the best candidate marker for an immune cell score in non-small cell lung cancer?

The TNM classification is well established as a state-of-the-art prognostic and treatment-decision-making tool for non-small cell lung cancer (NSCLC) patients. However, incorporation of biological data may hone the TNM system. This article focuses on choosing and incorporating subsets of tissue-infiltrating lymphocyte (TIL), detected by specific immunohistochemistry and automatically quantified by open source software, into a TNM-Immune cell score (TNM-I) for NSCLC. We use common markers (CD3, CD4, CD8, CD20 and CD45RO) of TILs to identify TIL subsets in tissue micro-arrays comprising tumor tissue from 553 patients resected for primary NSCLC. The number of TILs is automatically quantified using open source software (QuPath). Their prognostic efficacy, alone and within a TNM-I model, is evaluated in all patients and histological subgroups. Compared with previous manual semi-quantitative scoring of TILs in the same cohort, the present digital quantification proved superior. As a proof-of-concept, we construct a TNM-I, using TNM categories and the CD8+ TIL density. The TNM-I is an independent prognosticator of favorable diagnosis in both the overall cohort and in the main histological subgroups. In conclusion, CD8+ TIL density is the most promising candidate marker for a TNM-I in NSCLC. The prognostic efficacy of the CD8+ TIL density is strongest in lung squamous cell carcinomas, whereas both CD8+ TILs and CD20+ TILs, or a combination of these, may be candidates for a TNM-I in lung adenocarcinoma. Furthermore, based on the presented results, digital quantification is the preferred method for scoring TILs in the future