Astrid Christine Petersen

Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.

Immunoglobulin levels and phagocytes in the cervical mucus plug at term of pregnancy

Background.  To characterize the potential for adaptive immune protection in cervical mucus plugs with respect to immunoglobulin isotypes and effector cells (phagocytes).

Improved overall survival after implementation of targeted therapy for patients with metastatic renal cell carcinoma: Results from the Danish Renal Cancer Group (DARENCA) study-2

AIM To evaluate the implementation of targeted therapy on overall survival (OS) in a complete national cohort of patients with metastatic renal cell carcinoma (mRCC). METHODS All Danish patients with mRCC referred for first line treatment with immunotherapy, TKIs or mTOR-inhibitors between 2006 and 2010 were included. Baseline and outcome data were collected retrospectively. Prognostics factors were identified using log-rank tests and Cox proportional hazard model. Differences in distributions were tested with the Chi-square test. RESULTS 1049 patients were referred; 744 patients received first line treatment. From 2006 to 2010 we observed a significant increase in the number of referred patients; a significant increase in treated patients (64% versus 75%, P=0.0188); a significant increase in first line targeted therapy (22% versus 75%, P<0.0001); a significant increase in second line treatment (20% versus 40%, P=0.0104), a significant increased median OS (11.5 versus 17.2 months, P=0.0435) whereas survival for untreated patients remained unchanged. Multivariate analysis validated known prognostic factors. Moreover, treatment start years 2008 (HR 0.74, 95% CI, 0.55-0.99; P=0.0415), 2009 (HR 0.72, 95% CI, 0.54-0.96; P=0.0277) and 2010 (HR 0.63, 95% CI, 0.47-0.86; P=0.0035) compared to 2006, and more than two treatment lines received for patients with performance status 0-1 (HR 0.76, 95% CI, 0.58-0.99; P=0.0397) and performance status 2-3 (HR 0.19, 95% CI, 0.06-0.60; P=0.0051) were significantly associated with longer OS. CONCLUSION This retrospective study documents that the implementation of targeted therapy has resulted in significantly improved treatment rates and overall survival in a complete national cohort of treated mRCC patients.

The impact of oxygen tension on developmental competence of post-thaw human embryos

The present study compares the culture of human embryos using two different culture systems: a conventional culture incubator with humidified atmospheric air supplemented with 5% CO2 and a closed culture incubator with a humidified 5% O2 and 5% (5.2–5.5) CO2 and 90% N2 partial pressure.

External skeletal fixation as treatment for total puerperal rupture of the pubic symphysis

A caw of total puerperal rupture of the pubic symphysis during non‐operative delivery is rcportcd and the literature reviewed. The patient in our case was successfully treated by external skeletal fixation. In agreement with the literature the authors recommend external skeletal fixation when lesions are unstable, when inadequate reduction is achieved. or when the diastasis is more than 40 mm.

Incidence of fetal akinesia-hypokinesia deformation sequence: a population-based study

2. Paige DG, Bhogal BS, Black MM, Harper JI. Lichen planus pemphigoides in a chilld-immunopathological findings. Clin Exp Dermatol 1993; 18: 552–4. 3. Mora RG, Nesbitt LT Jr., Brantley JB. Lichen planus pemphigoides: clinical and immunofluorescent findings in four cases. J Am Acad Dermatol 1983; 8: 331–6. 4. Hofmann-Wellenhof R, Salmhofer W, Kerl H. Lichen planus pemphigoides in a 9-year-old child: successful treatment with topical corticosteroids. Pediatr Dermatol 1999; 16: 70–1. 5. Zlatkov N, Tsankov N, Pramatarov K, Konstantinov K. Bullous lichen planus and lichen planus pemphigoides. Dermatol Monatsschr 1988; 174: 339–44. 6. Harjai B, Mendiratta V, Kakkar S, Koranne RV. Childhood lichen planus pemphigoides–a rare entity. J Eur Acad Dermatol Venereol 2006; 20: 117–8.

Placental magnetic resonance imaging T2* measurements in normal pregnancies and in those complicated by fetal growth restriction

The magnetic resonance imaging (MRI) variable transverse relaxation time (T2*) depends on multiple factors, one important one being the presence of deoxyhemoglobin. We aimed to describe placental T2* measurements in normal pregnancies and in those with fetal growth restriction (FGR).

ECEL1 mutation causes fetal arthrogryposis multiplex congenita

Arthrogryposis multiplex congenita (AMC) is a descriptor for the clinical finding of congenital fixation of multiple joints. We present a consanguineous healthy couple with two pregnancies described with AMC due to characteristic findings on ultrasonography of fixated knee extension and reduced fetal movement at the gestational age of 13 weeks + 2 days and 12 weeks + 4 days. Both pregnancies were terminated and postmortem examinations were performed. The postmortem examinations confirmed AMC and suggested a diagnosis of centronuclear myopathy (CNM) due to characteristic histological findings in muscle biopsies. Whole exome sequencing (WES) was performed on all four individuals and the outcome was filtered by application of multiple filtration parameters satisfying a recessive inheritance pattern. Only one gene, ECEL1, was predicted damaging and had previously been associated with neuromuscular disease or AMC. The variant found ECEL1 is a missense mutation in a highly conserved residue and was predicted pathogenic by prediction software. The finding expands the molecular basis of congenital contractures and the phenotypic spectrum of ECEL1 mutations. The histological pattern suggestive of CNM in the fetuses can expand the spectrum of genes causing CNM, as we propose that mutations in ECEL1 can cause CNM or a condition similar to this. Further investigation of this is needed and we advocate that future patients with similar clinical presentation or proven ECEL1 mutations are examined with muscle biopsy. Secondly, this study illustrates the great potential of the clinical application of WES in couples with recurrent abortions or stillborn neonates.

Prognostic Impact of a 12-gene Progression Score in Non–muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study

BACKGROUND Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed. OBJECTIVE To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study. DESIGN, SETTING, AND PARTICIPANTS We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions. RESULTS AND LIMITATIONS The progression score was significantly (p<0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guérin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p<0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p<0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R2=0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients). CONCLUSIONS The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens. PATIENT SUMMARY Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens.

A five-factor biomarker profile obtained week 4-12 of treatment for improved prognostication in metastatic renal cell carcinoma: Results from DARENCA study 2

Abstract Background: Several biomarkers of treatment efficacy have been associated with a better prognosis in patients with metastatic renal cell carcinoma (mRCC). The prognostic significance of biomarkers in the early treatment phase is unclear. Material and methods: In a complete national cohort of mRCC patients receiving first-line tyrosine kinase inhibitors (TKI) or interleukin-2 based immunotherapy (IT) from 2006 to 2010, overall survival (OS) was analysed for baseline International mRCC Database Consortium (IMDC) classification factors and on-treatment time-dependent biomarkers obtained day 1 each cycle week 4–12 after treatment initiation with multivariate analysis and bootstrap validation. Results: A total of 735 patients received first-line TKI (59%) or IT (41%). Median OS was overall 14.0 months and 33.4, 18.5, and 5.8 months for baseline IMDC favourable, intermediate, and poor risk groups, respectively (p < 0.0001). Systolic blood pressure ≥140 mmHg, neutrophils < lower level of normal (LLN), platelets < LLN, sodium ≥ LLN, and LDH ≤1.5 times upper level of normal after treatment initiation were significantly associated with favourable OS independent of baseline IMDC risk group in multivariate analyses stratified for TKI and IT (p ≤ 0.04). Concordance (C)-index for IMDC classification alone was 0.625 (95% CI 0.59–0.66) and combined with the five-factor biomarker profile 0.683 (95% CI 0.64–0.72). For patients with good (3–5 factors) and poor (0–2 factors) biomarker profile median OS were 23.5 and 9.6 months, respectively (p < 0.0001). Adding the five-factor biomarker profile significantly improved prognostication in IMDC intermediate (25.7 vs. 12.0 months, p < 0.0001) and poor (12.8 vs. 6.4 months, p < 0.0001) risk groups. A trend was seen in IMDC favourable risk group (38.9 vs. 28.7 months, p = 0.112). Conclusion: On-treatment hypertension, neutropenia, thrombocytopenia, LDH below 1.5 times upper level of normal, and normal sodium, obtained week 4–12 of treatment, are independent biomarkers of favourable outcome in mRCC, independent of treatment type.