Low activated leukocyte cell adhesion molecule expression is associated with advanced tumor stage and early prostate-specific antigen relapse in prostate cancer

Activated leukocyte cell adhesion molecule (CD166) is a member of the immunoglobulin superfamily and is aberrantly expressed in different tumors, including prostate cancer. To learn more on the prevalence and clinical significance of activated leukocyte cell adhesion molecule expression in prostate cancer, a tissue microarray containing 3261 primary prostate cancers treated by radical prostatectomy was used. A total of 2390 different prostate cancers were analyzed by immunohistochemistry in a tissue microarray format. Activated leukocyte cell adhesion molecule immunostaining in cancers was compared with clinical follow-up, which was available for 1746 patients. Membranous activated leukocyte cell adhesion molecule immunostaining was recorded in 1663 (69.6%) of cases. High activated leukocyte cell adhesion molecule expression levels were significantly associated with favorable tumor features (pT: P = .0015; pN: P = .0008; preoperative prostate-specific antigen: P = .0057) and a lower risk of a biochemical recurrence (P = .0067). Cytoplasmatic activated leukocyte cell adhesion molecule staining was usually associated with membranous staining. The small number of cancers with pure cytoplasmatic staining did not reveal any particularities with respect to clinical outcome or tumor phenotype. It is concluded that activated leukocyte cell adhesion molecule protein is almost always expressed in prostate cancer and that decreased levels of activated leukocyte cell adhesion molecule expression may lead to an aggressive behavior of tumor cells. The abundant presence of activated leukocyte cell adhesion molecule and its membranous localization in prostate cancer epithelium make activated leukocyte cell adhesion molecule a potentially attractive structure for targeted therapy.     

Correlation between recent thymic emigrants and CD31+ (PECAM-1) CD4+ T cells in normal individuals during aging and in lymphopenic children

CD31(+)CD45RA(+)RO(-) lymphocytes contain high numbers of T cell receptor circle (TREC)-bearing T cells; however, the correlation between CD31(+)CD4(+) lymphocytes and TREC during aging and under lymphopenic conditions has not yet been sufficiently investigated. We analyzed TREC, telomere length and telomerase activity within sorted CD31(+) and CD31(-) CD4(+) lymphocytes in healthy individuals from birth to old age. Sorted CD31(+)CD45RA(+)RO(-) naive CD4(+) lymphocytes contained high TREC numbers, whereas CD31(+)CD45RA(-)RO(+) cells (comprising < or =5% of CD4(+) cells during aging) did not contain TREC. CD31(+) overall CD4(+) cells remained TREC rich despite an age-related tenfold reduction from neonatal (100 : 1000) to old age (10 : 1000). Besides a high TREC content, CD31(+)CD45RA(+)RO(-)CD4(+) cells exhibited significantly longer telomeres and higher telomerase activity than CD31(-)CD45RA(+)RO(-)CD4(+) cells, suggesting that CD31(+)CD45RA(+)RO(-)CD4(+) cells represent a distinct population of naive T cells with particularly low replicative history. To analyze the value of CD31 in lymphopenic conditions, we investigated six children after allogeneic hematopoietic stem cell transplantation (HSCT). Reemerging overall CD4(+) as well as naive CD45RA(+)RO(-)CD4(+) cells predominantly expressed CD31 and correlated well with the recurrence of TREC 5-12 months after HSCT. Irrespective of limitations in the elderly, CD31 is an appropriate marker to monitor TREC-rich lymphocytes essentially in lymphopenic children after HSCT.     

Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis

There is growing evidence that the great phenotypic variability in patients with cysticfibrosis (CF) not only depends on the genotype, but apart from a combination ofenvironmental and stochastic factors predominantly also on modifier gene effects. It hasbeen proposed that genes interacting with CF transmembrane conductance regulator (CFTR)and epithelial sodium channel (ENaC) are potential modifiers. Therefore, we assessed theimpact of single-nucleotide polymorphisms (SNPs) of several of these interacters on CFdisease outcome. SNPs that potentially alter gene function were genotyped in 95well-characterized p.Phe508del homozygous CF patients. Linear mixed-effect model analysiswas used to assess the relationship between sequence variants and the repeatedmeasurements of lung function parameters. In total, we genotyped 72 SNPs in 10 genes.Twenty-five SNPs were used for statistical analysis, where we found strong associationsfor one SNP in PPP2R4 with the lung clearance index (P≤0.01), thespecific effective airway resistance (P≤0.005) and the forced expiratoryvolume in 1 s (P≤0.005). In addition, we identified one SNP inSNAP23 to be significantly associated with three lung function parameters aswell as one SNP in PPP2R1A and three in KRT19 to show a significantinfluence on one lung function parameter each. Our findings indicate that directinteracters with CFTR, such as SNAP23, PPP2R4 and PPP2R1A, may modify the residualfunction of p.Phe508del-CFTR while variants in KRT19 may modulate the amount ofp.Phe508del-CFTR at the apical membrane and consequently modify CF disease.     

Degeneration of the Cerebellum in Huntington's Disease (HD): Possible Relevance for the Clinical Picture and Potential Gateway to Pathological Mechanisms of the Disease Process

Huntington's disease (HD) is a polyglutamine disease and characterized neuropathologically by degeneration of the striatum and select layers of the neo‐ and allocortex. In the present study, we performed a systematic investigation of the cerebellum in eight clinically diagnosed and genetically confirmed HD patients. The cerebellum of all HD patients showed a considerable atrophy, as well as a consistent loss of Purkinje cells and nerve cells of the fastigial, globose, emboliform and dentate nuclei. This pathology was obvious already in HD brains assigned Vonsattel grade 2 striatal atrophy and did not correlate with the extent and distribution of striatal atrophy. Therefore, our findings suggest (i) that the cerebellum degenerates early during HD and independently from the striatal atrophy and (ii) that the onset of the pathological process of HD is multifocal. Degeneration of the cerebellum might contribute significantly to poorly understood symptoms occurring in HD such as impaired rapid alternating movements and fine motor skills, dysarthria, ataxia and postural instability, gait and stance imbalance, broad‐based gait and stance, while the morphological alterations (ie ballooned neurons, torpedo‐like axonal inclusions) observed in the majority of surviving nerve cells may represent a gateway to the unknown mechanisms of the pathological process of HD.     

ATP/IL‐33‐triggered hyperactivation of mast cells results in an amplified production of pro‐inflammatory cytokines and eicosanoids

IL‐33 and ATP are alarmins, which are released upon damage of cellular barriers or are actively secreted upon cell stress. Due to high‐density expression of the IL‐33 receptor T1/ST2 (IL‐33R), and the ATP receptor P2X7, mast cells (MCs) are one of the first highly sensitive sentinels recognizing released IL‐33 or ATP in damaged peripheral tissues. Whereas IL‐33 induces the MyD88‐dependent activation of the TAK1‐IKK2‐NF‐κB signalling, ATP induces the Ca²⁺‐dependent activation of NFAT. Thereby, each signal alone only induces a moderate production of pro‐inflammatory cytokines and lipid mediators (LMs). However, MCs, which simultaneously sense (co‐sensing) IL‐33 and ATP, display an enhanced and prolonged activation of the TAK1‐IKK2‐NF‐κB signalling pathway. This resulted in a massive production of pro‐inflammatory cytokines such as IL‐2, IL‐4, IL‐6 and GM‐CSF as well as of arachidonic acid‐derived cyclooxygenase (COX)‐mediated pro‐inflammatory prostaglandins (PGs) and thromboxanes (TXs), hallmarks of strong MC activation. Collectively, these data show that co‐sensing of ATP and IL‐33 results in hyperactivation of MCs, which resembles to MC activation induced by IgE‐mediated crosslinking of the FcεRI. Therefore, the IL‐33/IL‐33R and/or the ATP/P2X7 signalling axis are attractive targets for therapeutical intervention of diseases associated with the loss of integrity of cellular barriers such as allergic and infectious respiratory reactions.     

External beam radiation therapy improves survival in elderly metastatic prostate cancer patients with low PSA

BackgroundIt is unknown, whether metastatic prostate cancer (CaP) patients with intermediate life expectancy (5–10 years) should be considered for external beam radiation therapy (EBRT) to the prostate. We addressed this void.MethodsWithin the Surveillance, Epidemiology, and End Results database (2004–2016), we identified 835 M1a or M1b CaP substaged patients with prostate-specific antigen (PSA) < 20 ng/ml and with intermediate life expectancy (LE) 5 to 10 years, treated with EBRT or no EBRT. Inverse probability of treatment-weighting (IPTW), Kaplan-Meier plots and Cox-regression models (CRMs) were used.ResultsOverall, 179 (21.4%) patients received EBRT and 656 (78.6%) did not. EBRT rates increased from 13.9 to 23.8% (2004–2016; P= 0.04). After IPTW-adjustment, median OS was 45 vs. 35 months, in EBRT vs. no EBRT patients (P < 0.001). In IPTW-adjusted Cox-regression models, EBRT independently predicted lower overall mortality (hazard ratio [HR]: 0.7, CI 0.61–0.89; P= 0.001). After stratification according to M1 substages, EBRT was associated with lower overall mortality in M1a (HR: 0.2, CI 0.05–0.91; P= 0.03) and M1b (HR: 0.7, CI 0.55–0.88; P = 0.003) substages.ConclusionEBRT was associated with lower mortality in metastatic CaP patients with low PSA and intermediate LE (5–10 years). In consequence, greater consideration for EBRT should be given in those patients. However, it is important to consider study limitations until clinical trials confirm the proposed benefit.     

Outcome of the frozen elephant trunk procedure as a redo operation

 Open in a separate windowOBJECTIVESThe goal of this study was to determine the outcome of patients undergoing an elective frozen elephant trunk (FET) procedure as a redo operation following previous cardiac surgery.METHODSOne hundred and eighteen consecutive patients underwent FET procedures between October 2010 and October 2019 at our centre. Patients were registered in a dedicated database and analysed retrospectively. Clinical and follow-up characteristics were compared between patients undergoing a FET operation as a primary (primary group) or a redo procedure (redo group) using logistic regression and Cox regression analysis. Emergency procedures (n = 33) were excluded from the analysis.RESULTSA total of 36.5% (n = 31) of the FET procedures were redo operations (redo group) and 63.5% (n = 54) of the patients underwent primary surgery (primary group). There was no significant difference in the 30-day mortality [primary group: 7.4%; redo group: 3.2%; 95% confidence interval (CI) (0.19–35.29); P = 0.63] and the 3-year mortality [primary group: 22.2%; redo group: 16.7%; 95% CI (0.23–3.23); P = 0.72] between redo and primary cases. Furthermore, the adjusted statistical analysis did not reveal significant differences between the groups in the occurrence of transient or permanent neurological deficit, paraplegia, acute renal failure and resternotomy. The redo group showed a higher rate of recurrent nerve palsy, which did not reach statistical significance [primary group: 3.7% (n = 2); redo group: 19.4% (n = 6); P = 0.091].CONCLUSIONSElective FET procedures as redo operations performed by a dedicated aortic team following previous cardiac surgery demonstrate an adequate safety profile.     

Association between vaginal bulge and anatomical pelvic organ prolapse during pregnancy and postpartum: an observational study

Introduction and hypothesis

Pelvic organ prolapse (POP) is defined as the coexistence of anatomical POP and relevant symptoms. Vaginal bulge is the symptom most closely associated with the anatomical condition in nonpregnant women. Even if childbearing is a major risk factor for the development of POP, there is scant knowledge on the prevalence of specific POP symptoms, and how these symptoms relate to anatomical POP during pregnancy and postpartum. The aim of this study was to explore whether vaginal bulge symptoms were associated with anatomical POP in pregnancy and postpartum, and to present the prevalence of vaginal bulge symptoms throughout this period.

Methods

A prospective observational study was carried out following 300 nulliparous pregnant women with repeat assessments from mid-pregnancy until 1 year postpartum. Symptoms of vaginal bulge defined as the sensation of a vaginal bulge inside and/or outside the vagina were assessed by electronic questionnaires. Anatomical POP defined as pelvic organ prolapse quantification system (POP-Q) stage ≥2 has been presented in a previous publication and showed a range of 1–9%. The association between the symptom vaginal bulge and anatomical POP at the various visits was analyzed using Fisher’s exact test.

Results

Prevalence of vaginal bulge ranged between 16 and 23%. At 6 weeks postpartum the symptom was associated with anatomical POP; otherwise, these two features were unrelated.

Conclusions

The symptom vaginal bulge was barely associated with anatomical POP, and cannot identify anatomical POP in pregnancy or postpartum.