Mette Østergaard Poulsen

Does the Finnish intervention prevent obstetric anal sphincter injuries?: a systematic review of the literature

Objectives A rise in obstetric anal sphincter injuries (OASIS) has been observed and a preventive approach, originating in Finland, has been introduced in several European hospitals. The aim of this paper was to systematically evaluate the evidence behind the ‘Finnish intervention’. Design A systematic review of the literature conducted according to the Preferred Reporting for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Outcome measures The primary outcome was OASIS. Secondary outcomes were (perinatal): Apgar scores, pH and standard base excess in the umbilical cord, and (maternal): episiotomy, intact perineum, first and second-degree perineal lacerations, duration of second stage, birth position and womens perceptions/birth experiences. Methods Multiple databases (Cochrane, Embase, Pubmed and SveMed) were systematically searched for studies published up to December 2014. Both randomised controlled trials and observational studies were eligible for inclusion. Studies were excluded if a full-text article was not available. Studies were evaluated by use of international reporting guidelines (eg, STROBE). Results Overall, 1042 articles were screened and 65 retrieved for full-text evaluation. Seven studies, all observational and with a level of evidence at 2c or lower, were included and consistently reported a significant reduction in OASIS. All evaluated episiotomy and found a significant increase. Three studies evaluated perinatal outcomes and reported conflicting results. No study reported on other perineal outcomes, duration of the second stage, birth positions or womens perceptions. Conclusions A reduction in OASIS has been contributed to the Finnish intervention in seven observational studies, all with a low level of evidence. Knowledge about the potential perinatal and maternal side effects and womens perceptions of the intervention is extremely limited and the biological mechanisms underlying the Finnish intervention are not well documented. Studies with a high level of evidence are needed to assess the effects of the intervention before implementation in clinical settings can be recommended.

Uterine, but not ovarian, female reproductive organ involvement at presentation by diffuse large B-cell lymphoma is associated with poor outcomes and a high frequency of secondary CNS involvement

Involvement of the internal female reproductive organs by diffuse large B‐cell lymphoma (DLBCL) is uncommon, and there are sparse data describing the outcomes of such cases. In total, 678 female patients with DLBCL staged with positron emission tomography/computed tomography and treated with rituximab‐containing chemotherapy were identified from databases in Denmark, Great Britain, Australia, and Canada. Overall, 27/678 (4%) had internal reproductive organ involvement: uterus (n = 14), ovaries (n = 10) or both (n = 3). In multivariate analysis, women with uterine DLBCL experienced inferior progression‐free survival and overall survival compared to those without reproductive organ involvement, whereas ovarian DLBCL was not predictive of outcome. Secondary central nervous system (CNS) involvement (SCNS) occurred in 7/17 (41%) women with uterine DLBCL (two patients with concomitant ovarian DLBCL) and 0/10 women with ovarian DLBCL without concomitant uterine involvement. In multivariate analysis adjusted for other risk factors for SCNS, uterine involvement by DLBCL remained strongly associated with SCNS (Hazard ratio 14·13, 95% confidence interval 5·09–39·25, P < 0·001). Because involvement of the uterus by DLBCL appears to be associated with a high risk of SCNS, those patients should be considered for CNS staging and prophylaxis. However, more studies are needed to determine whether the increased risk of secondary CNS involvement also applies to women with localized reproductive organ DLBCL.

Validation of the German high-grade non-hodkin lymphoma study group (DSHNHL) prognostic model for CNS replapse in a large cohort of PET/CT staged patients

009 Table 1.

Do we know enough? A quality assessment of the Finnish intervention to prevent obstetric anal sphincter injuries.

Abstract Objective: Especially in the Nordic countries, increases in obstetric anal sphincter injuries (OASIS) have prompted standard use of the Finnish intervention for their prevention. We performed a quality assessment of the introduction of the intervention in a Danish hospital setting. Methods: All vaginal deliveries by primiparous women the year before (N = 343) and after (N = 334) the introduction were compared in a retrospective, observational design. Fisher’s exact test, Student’s t-test, and multiple logistic regression analysis were performed. Results: No significant difference in OASIS (OR: 0.5; 95% CI: 0.3–1.1) was found. The post-implementation group saw a significant increase in episiotomy (OR: 1.8; 95% CI: 1.1–2.9) and the length of second stage labor (p < 0.05) while intact perineum (OR: 0.5; 95% CI: 0.3–0.9), use of upright positions for birth (OR: 3.2; 95% CI: 1.8–5.5), and neonatal blood gas levels were significantly reduced (p < 0.05). Conclusions: Introduction of the Finnish intervention was not followed by a significant reduction of OASIS, but a downward trend was seen. The study results raise questions about potential side effects of the Finnish intervention on neonatal outcomes, intact perineum, and women’s free choice of birth positions. More knowledge on effect and side effects from high-evidence studies are needed.

Female patients with DLBCL and involvement of the reproductive organs have poor outcomes and markedly increased risk of CNS relapse with R-chop(-like) therapy

151 Table CD3 P ≥ 50 CD4 P ≥ 50 CD8 P ≥ 50 CD3/B-cell P ≥ 50 CD4/CD8 P ≥ 50 CD4 TFH/CD4 + P ≥ 75 Age (%) <60 years 39 34 29 21 55 21 ≥60 years 59 56 57 43 43 39 Histological grade (%) 1–2 45 43 35 27 58 29 3 89 67 89 67 0 11 Bulky disease (%) No 57 53 46 60 46 23 Yes 22 17 33 11 56 29 Extranodal (%) ≤1 58 52 51 58 47 23 >1 21 21 21 26 53 29 Leukemic phase (%) No 56 50 48 32 60 22 Yes 10 10 10 0 46 25 182 Poster Presentations resistance. Immune cells in the lymphoma tumour microenvironment have been implicated in disease progression (Dave et al., NEJM 2004) and may play a role in transformation. We recently discovered that expression of the inhibitory receptor PD-1 was associated with suppressed cytokine signalling in FL tumour-infiltrating T cells (Myklebust et al., Blood 2013). Furthermore, it has been suggested that PD-1 int cells are the truly exhausted T cells and that PD-1 high cells are normal T follicular helper cells (TFH) (Yong et al., Blood Cancer J 2015). Antibody immunotherapy targeting PD-1 has shown significant promise in aggressive malignancies (Topalian et al., NEJM 2012), suggesting that exhausted T cells can regain functionality, including anti-tumour effects. Methods: Three mass cytometry (CyTOF) panels were designed to detect 30 markers per cell and used to characterize FL tumour biopsies (n = 9) and human tonsils. In the first panel, inhibitory and co-stimulatory receptors were quantified across 5 major T-cell subsets and maturation stages (Nicholas and Greenplate et al., manuscript in preparation). In the second panel, key surface markers were combined with antibodies to detect 12 phosphoproteins to correlate signalling responses with inhibitory receptor profiles. The last panel was designed to characterize healthy and malignant B cells. The dimensionality-reduction tool viSNE was used to analyse the high-dimensional mass cytometry data. Fluorescent flow panels were used in parallel to measure 9 inhibitory receptors in selected T-cell subsets. Results: viSNE analysis of 23 surface markers revealed a high degree of phenotypic similarity between T cells infiltrating FL and T cells in tonsils. In contrast, viSNE characterized the significant phenotypic differences between malignant B cells and healthy B cells within the same tumour. PD1 + T cells from FL samples displayed reduced cytokine signalling compared to PD1 cells, confirming previous results. TFH cells were identified as CXCR5 hi ICOS + CD4 memory T cells. Among the ICOS + cells in tonsils, a distinct CXCR5 population was identified with intermediate PD1 expression, suggesting an exhausted phenotype. These cells expressed less TIGIT, BTLA and LAIR1 than TFH but contained a subpopulation of TIM3 + cells that was not seen within the TFH population. Conclusions: Striking similarities in phenotype and signalling response of the T cells infiltrating FL tumours and T cells from healthy tonsil observed by mass cytometry suggest active immune responses in these tissues. These results provide further support for characterizing relationships between receptor signalling and T cell function and for researching into combination immunotherapies for FL focused on modulating adaptive immune responses. 151 T-CELL SUBPOPULATIONS QUANTIFIED BY FLOW CYTOMETRY IN LYMPH NODE CELL SUSPENSIONS IDENTIFY A GROUP OF PATIENTS WITH FOLLICULAR LYMPHOMA WITH FAVORABLE OUTCOME L. Magnano 1 , J. Carreras 2 , A. Martinez 2 , A. Martinez-Trillos 1 , J. Rovira 1 , I. Dlouhy 1 , E. Gine 1 , T. Bauman 1 , O. Balague 2 , E. Campo 2 , N. Villamor 3 , A. López-Guillermo 1 . 1 Hematología, Hospital Clinic de Barcelona, Barcelona, Spain, 2 Pathology Department, Hospital Clinic de Barcelona, Barcelona, Spain, 3 Hematopathology Unit, Hospital Clinic de Barcelona, Barcelona, Spain. Introduction: Tumour microenvironment plays an important role in the behaviour of follicular lymphoma (FL). By gene expression and immunohistochemistry, an increase in macrophages has been associated with poor outcome, while an increase in T cells is associated with good prognosis. The aim of the study was to explore the prognostic impact of subpopulations of T cells using flow cytometry and to identify different groups of risk in FL patients. Methods: Seventy-five patients (36 men/39 women, median age 60 years) diagnosed of FL (grades 1–2, 87%; grade 3, 13%) between 1984 and 2009 (median follow-up of 6.5 years) with sample at diagnosis were included in the present study. In 41 cases, T-cell staining were semiquantitatively analysed by immunohistochemical (IHC), including their distribution (intra, inter or perifollicular). T-cell populations from lymph node were quantified by multiparametric flow cytometry in cell suspensions in all cases. The percentage of B-cells, CD3 + , CD4 + , CD8 + , CD57 + , CD4TFH cells (double staining CD4 + CD57 + ), as well as the ratio T/B-cells, CD3 + /CD4 + , CD3 + /CD8 + , CD4 + /CD8 + and CD4TFH/CD4 + were analysed and correlated with initial features and outcome. Copyright

Successful delivery after vaginal occlusion in addition to cerclage in a trachelectomy patient with recurrent second trimester pregnancy loss: a case report

Pregnancy outcome after trachelectomy has high risk of complications such as second trimester pregnancy loss and preterm birth. We report beneficial effect of a simple procedure of vaginal occlusion in addition to cerclage in a patient with trachelectomy and two prior second trimester pregnancy losses.

Validation of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) prognostic model for CNS relapse in a large cohort of PET/CT staged patients

009 Table 1.

R-CHOP(-like) treatment of diffuse large B-cell lymphoma significantly reduces CT-assessed vertebral bone density: a single center study of 111 patients

Abstract Treatment of diffuse large B-cell lymphoma (DLBCL) with R-CHOP(-like) regimens include large cumulative doses of prednisolone. In this retrospective study, we evaluated changes in vertebral bone density (VD) in DLBCL patients by measuring CT-ascertained Hounsfield units (HU) at the L3 level. In total, 111 patients diagnosed from 2007 to 2012 and response assessed following first line treatment were included. Post-treatment VD was significantly reduced to 86% of pretreatment VD on average (p < .001). Neither female sex nor high age (>70 years) were significantly associated with greater post-treatment VD reduction. Two years after completing R-CHOP treatment, VD remained significantly lower than baseline VD (p < .001). Vertebral compression fractures visualized by CT were found in 16/111 patients (14%) during follow-up. In conclusion, bone mineral density is significantly reduced following R-CHOP(-like) treatment and vertebral compression fractures are common. Glucocorticoid-induced osteoporosis may therefore have impact on survivorship for the large fraction of DLBCL patients with durable remissions.

Female patients with DLBCL and involvement of the reproductive organs have poor outcomes and markedly increased risk of central nervous system relapse with R-CHOP(-like) therapy

151 Table CD3 P ≥ 50 CD4 P ≥ 50 CD8 P ≥ 50 CD3/B-cell P ≥ 50 CD4/CD8 P ≥ 50 CD4 TFH/CD4 + P ≥ 75 Age (%) <60 years 39 34 29 21 55 21 ≥60 years 59 56 57 43 43 39 Histological grade (%) 1–2 45 43 35 27 58 29 3 89 67 89 67 0 11 Bulky disease (%) No 57 53 46 60 46 23 Yes 22 17 33 11 56 29 Extranodal (%) ≤1 58 52 51 58 47 23 >1 21 21 21 26 53 29 Leukemic phase (%) No 56 50 48 32 60 22 Yes 10 10 10 0 46 25 182 Poster Presentations resistance. Immune cells in the lymphoma tumour microenvironment have been implicated in disease progression (Dave et al., NEJM 2004) and may play a role in transformation. We recently discovered that expression of the inhibitory receptor PD-1 was associated with suppressed cytokine signalling in FL tumour-infiltrating T cells (Myklebust et al., Blood 2013). Furthermore, it has been suggested that PD-1 int cells are the truly exhausted T cells and that PD-1 high cells are normal T follicular helper cells (TFH) (Yong et al., Blood Cancer J 2015). Antibody immunotherapy targeting PD-1 has shown significant promise in aggressive malignancies (Topalian et al., NEJM 2012), suggesting that exhausted T cells can regain functionality, including anti-tumour effects. Methods: Three mass cytometry (CyTOF) panels were designed to detect 30 markers per cell and used to characterize FL tumour biopsies (n = 9) and human tonsils. In the first panel, inhibitory and co-stimulatory receptors were quantified across 5 major T-cell subsets and maturation stages (Nicholas and Greenplate et al., manuscript in preparation). In the second panel, key surface markers were combined with antibodies to detect 12 phosphoproteins to correlate signalling responses with inhibitory receptor profiles. The last panel was designed to characterize healthy and malignant B cells. The dimensionality-reduction tool viSNE was used to analyse the high-dimensional mass cytometry data. Fluorescent flow panels were used in parallel to measure 9 inhibitory receptors in selected T-cell subsets. Results: viSNE analysis of 23 surface markers revealed a high degree of phenotypic similarity between T cells infiltrating FL and T cells in tonsils. In contrast, viSNE characterized the significant phenotypic differences between malignant B cells and healthy B cells within the same tumour. PD1 + T cells from FL samples displayed reduced cytokine signalling compared to PD1 cells, confirming previous results. TFH cells were identified as CXCR5 hi ICOS + CD4 memory T cells. Among the ICOS + cells in tonsils, a distinct CXCR5 population was identified with intermediate PD1 expression, suggesting an exhausted phenotype. These cells expressed less TIGIT, BTLA and LAIR1 than TFH but contained a subpopulation of TIM3 + cells that was not seen within the TFH population. Conclusions: Striking similarities in phenotype and signalling response of the T cells infiltrating FL tumours and T cells from healthy tonsil observed by mass cytometry suggest active immune responses in these tissues. These results provide further support for characterizing relationships between receptor signalling and T cell function and for researching into combination immunotherapies for FL focused on modulating adaptive immune responses. 151 T-CELL SUBPOPULATIONS QUANTIFIED BY FLOW CYTOMETRY IN LYMPH NODE CELL SUSPENSIONS IDENTIFY A GROUP OF PATIENTS WITH FOLLICULAR LYMPHOMA WITH FAVORABLE OUTCOME L. Magnano 1 , J. Carreras 2 , A. Martinez 2 , A. Martinez-Trillos 1 , J. Rovira 1 , I. Dlouhy 1 , E. Gine 1 , T. Bauman 1 , O. Balague 2 , E. Campo 2 , N. Villamor 3 , A. López-Guillermo 1 . 1 Hematología, Hospital Clinic de Barcelona, Barcelona, Spain, 2 Pathology Department, Hospital Clinic de Barcelona, Barcelona, Spain, 3 Hematopathology Unit, Hospital Clinic de Barcelona, Barcelona, Spain. Introduction: Tumour microenvironment plays an important role in the behaviour of follicular lymphoma (FL). By gene expression and immunohistochemistry, an increase in macrophages has been associated with poor outcome, while an increase in T cells is associated with good prognosis. The aim of the study was to explore the prognostic impact of subpopulations of T cells using flow cytometry and to identify different groups of risk in FL patients. Methods: Seventy-five patients (36 men/39 women, median age 60 years) diagnosed of FL (grades 1–2, 87%; grade 3, 13%) between 1984 and 2009 (median follow-up of 6.5 years) with sample at diagnosis were included in the present study. In 41 cases, T-cell staining were semiquantitatively analysed by immunohistochemical (IHC), including their distribution (intra, inter or perifollicular). T-cell populations from lymph node were quantified by multiparametric flow cytometry in cell suspensions in all cases. The percentage of B-cells, CD3 + , CD4 + , CD8 + , CD57 + , CD4TFH cells (double staining CD4 + CD57 + ), as well as the ratio T/B-cells, CD3 + /CD4 + , CD3 + /CD8 + , CD4 + /CD8 + and CD4TFH/CD4 + were analysed and correlated with initial features and outcome. Copyright