Differential expression of prolyl hydroxylase 1 in patients with ulcerative colitis versus patients with Crohn's disease/infectious colitis and healthy controls

Background: Inhibition of prolyl hydroxylases (PHDs) leads to the induction of a transcriptional program that, in the gut, promotes intestinal epithelial cell survival. PHD inhibitors have recently been suggested as a promising alternative treatment for inflammatory bowel disease (IBD). In this study, we explored the colonic mucosal expression of the different PHD-isoforms (PHD1, 2 and 3) in order to identify the key isoform(s) involved in the pathogenesis of IBD. Methods: The mRNA expression of inflammatory cytokines (IL-8 and TNF-alpha), an apoptosis marker (caspase 3) and PHD1, 2 and 3 was analysed in biopsies of IBD patients (UC and CD), patients with infectious colitis and healthy controls using qRT-PCR. PHD protein levels were evaluated using western blot. Cellular localization of PHD 1, 2 and 3 was determined by immunohistochemistry. Results: PHD1 was significantly up-regulated in IBD patients, both at the mRNA (UC: p < 0.0001 and CD: p < 0.05) and at the protein level (UC: p < 0.05 and CD: p < 0.05), and showed a very good correlation with the expression of the inflammatory cytokines IL-8 and TNF-alpha and the apoptosis marker caspase 3. Colonic mucosal PHD2 mRNA and protein expressions were not altered in IBD. PHD3 expression was increased in inflamed biopsies from UC patients (p < 0.0001), but only at the mRNA level. PHD1 and PHD2 expression was found both in the colonic lamina propria and the epithelium while PHD3 was mainly located in the endothelium of blood vessels. Conclusions: In this exploratory expression analysis, PHD1 comes forward as the primary therapeutic target for UC and, to a lesser extent, for (colonic) CD

EGFR mutation positive stage IV non small-cell lung cancer: treatment beyond progression

Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer for both men en women. Chemotherapy is the mainstay of treatment in advanced disease, but is only marginally effective. In about 30% of patients with advanced NSCLC in East Asia and in 10-15% in Western countries, EGFR mutations are found. In this population, first-line treatment with the tyrosine kinase inhibitors (TKI) erlotinib, gefitinib or afatinib is recommended. The treatment beyond progression is less well-defined. In this paper we present 3 patients, EGFR mutation positive, with local progression after an initial treatment with TKI. These patients were treated with local radiotherapy. TKI was temporarily stopped and restarted after radiotherapy. We give an overview of the literature and discuss the different treatment options in case of progression after TKI: TKI continuation with or without chemotherapy, TKI continuation with local therapy, alternative dosing or switch to next-generation TKI or combination therapy. There are different options for treatment beyond progression in EGFR mutation positive metastatic NSCLC, but the optimal strategy is still to be defined. Further research on this topic is ongoing

Multifocal cytokeratin expression in a dedifferentiated solitary fibrous tumor with heterologous rhabdomyosarcomatous differentiation : a challenging diagnosis!

We report the case of a dedifferentiated solitary fibrous tumor with heterologous rhabdomyosarcomatous differentiation in a 74-year-old male presenting with a rapidly growing, large soft tissue tumoral mass in the gluteal muscles of the right hip. Dedifferentiation in solitary fibrous tumor had not been recognized until very recently and is an extremely rare phenomenon in this tumor type. In the present case, the diagnosis of dedifferentiated solitary fibrous tumor was difficult because of the absence of areas of conventional solitary fibrous tumor with a predominantly poorly differentiated, anaplastic tumor component in the incision biopsy composed of heterogeneous areas with small blue round cell (Ewing sarcoma-like), rhabdoid, epithelioid, and pleomorphic morphology. Moreover, the unforeseen strong patchy to multifocal positivity for cytokeratin AE1/AE3 and desmin made the diagnosis of a dedifferentiated solitary fibrous tumor even more challenging in this case. The morphology (presence of branching thin-walled, hemangiopericytoma-like blood vessels) and the immunohistochemical profile (including STAT6 and GRIA2 positivity) were very useful to differentiate this very challenging case of a cytokeratin-positive dedifferentiated solitary fibrous tumor with heterologous rhabdomyosarcomatous differentiation from a broad list of differential diagnoses

Ein Lebensbild, aus ihren Aufzeichnungen und Briefen zusammengestellt für ihre Enkel und Urenkel

EIN LEBENSBILD, AUS IHREN AUFZEICHNUNGEN UND BRIEFEN ZUSAMMENGESTELLT FÜR IHRE ENKEL UND URENKEL Ein Lebensbild, aus ihren Aufzeichnungen und Briefen zusammengestellt für ihre Enkel und Urenkel / Trendelenburg, Ferdinande (Public Domain) ( - ) Abbildung: Ferdinande Trendelenburg geb. Becker / Hanfstaengl, Franz ( - ) Title page ( - ) Dedication ( - ) Contents ( - ) Überliefertes und Erlebtes von Ferdinande Trendelenburg ([1]) Adolf Trendelenburgs Jugend im Elternhause ([46]) Aus Ferdinandens Briefen an ihren Bruder Ferdinand 1831-1834 und die Verlobung ([51]) Brautstand und Hochzeit. Oktober 1835 bis April 1836 ([82]) Aus den Jahren 1836-1848 ([120]) Das Jahr 1848-49 ([162]) 1850 bis zur silbernen Hochzeit 1861 ([181]) 1861-1870 ([231]) 1870 bis zu Adolf Trendelenburgs Tod. 24. Januar 1872 ([266]) 1872-1883 ([315]) Das letzte Jahrzehnt ([351]) Gesammeltes aus Briefen der Großmutter Ferdinande ([389]) Anhang ([425]) I. Adolf Trendelenburg an Marianne Lentz ([427]) II. Aus Ferdinand Beckers Aufzeichnungen für eine Freundin. Schottland 1824-1825 ([433]) III. Dr. K. F. Becker an seine Tochter Minna in London ([436]) IV. Aus Ferdinande Beckers Briefen in ihr Elternhaus. England 1829 und 1830 ([438]) V. Die Familie Becker ([443]) Berichtigungen ( - ) Imprint ( - ) ColorChart ( -

Immuno-oncological biomarkers for squamous cell cancer of the head and neck : current state of the art and future perspectives

Simple Summary Squamous cell cancer of the head and neck is a common malignancy with poor prognosis. Despite the success of PD-L1 expression, the landscape of diagnostic, prognostic, and predictive biomarkers has delivered limited contributions to the clinic in the last decade. The dissection of the immunological landscape through investigation of the immune infiltrate, blood-based biomarkers, and genetic profiling has shown substantial scientific potential but all are yet to be validated. Further exploration is warranted though implementation of biomarkers. This should ideally be performed through prospective studies using standardized methods with harmonization of technical requirements. This review serves as a comprehensive overview for state-of-the-art knowledge and biomarkers in squamous cell cancer of the head and neck (SCCHN) that may prove their worth in future clinical practice. The era of immune checkpoint inhibitors has altered the therapeutic landscape in squamous cell cancer of the head and neck (SCCHN). Our knowledge about the tumor microenvironment has fueled the research in SCCHN, leading to several well-known and less-known prognostic and predictive biomarkers. The clinical staging, p16/HPV status, and PD-L1 expression are currently the main tools for assessing the patients' diagnosis and prognosis. However, several novel biomarkers have been thoroughly investigated, some reaching actual significant clinical contributions. The untangling of the immune infiltrate with the subtyping of tissue-associated tumor infiltrating lymphocytes, tumor-associated macrophages, and circulating blood-based biomarkers are an interesting avenue to be further explored and prospectively assessed. Although PD-L1 expression remains the most important response predictor for immune checkpoint inhibitors, several flaws impede proper assessment such as technical issues, different scoring protocol, and intra-, inter-, and temporal heterogeneity. In addition, the construction of an immune-related gene panel has been proposed as a prognostic and predictive stratification but lacks consensus. Recently, the role of microbioma have also been explored regarding its systemic and antitumor immunity. This review gives a comprehensive overview of the aforementioned topics in SCCHN. To this end, the integration of these clinically advantageous biomarkers via construction of an immunogram or nomogram could be an invaluable tool for SCCHN in future prospects

Focus on 16p13.3 Locus in colon cancer

Background : With one million new cases of colorectal cancer (CRC) diagnosed annually in the world, CRC is the third most commonly diagnosed cancer in the Western world. Patients with stage I-III CRC can be cured with surgery but are at risk for recurrence. Colorectal cancer is characterized by the presence of chromosomal deletions and gains. Large genomic profiling studies have however not been conducted in this disease. The number of a specific genetic aberration in a tumour sample could correlate with recurrence-free survival or overall survival, possibly leading to its use as biomarker for therapeutic decisions. At this point there are not sufficient markers for prediction of disease recurrence in colorectal cancer, which can be used in the clinic to discriminate between stage II patients who will benefit from adjuvant chemotherapy. For instance, the benefit of adjuvant chemotherapy has been most clearly demonstrated in stage III disease with an approximately 30 percent relative reduction in the risk of disease recurrence. The benefits of adjuvant chemotherapy in stage II disease are less certain, the risk for relapse is much smaller in the overall group and the specific patients at risk are hard to identify. Materials and Methods : In this study, array-comparative genomic hybridization analysis (array-CGH) was applied to study high-resolution DNA copy number alterations in 93 colon carcinoma samples. These genomic data were combined with parameters like KRAS mutation status, microsatellite status and clinicopathological characteristics. Results : Both large and small chromosomal losses and gains were identified in our sample cohort. Recurrent gains were found for chromosome 1q, 7, 8q, 13 and 20 and losses were mostly found for 1p, 4, 8p, 14, 15, 17p, 18, 21 and 22. Data analysis demonstrated that loss of chromosome 4 is linked to a worse prognosis in our patients series. Besides these alterations, two interesting small regions of overlap were identified, which could be associated with disease recurrence. Gain of the 16p13.3 locus (including the RNA binding protein, fox-1 homolog gene, RBFOX1) was linked with a worse recurrence-free survival in our patient cohort. On the other hand, loss of RBFOX1 was only found in patients without disease recurrence. Most interestingly, above mentioned characteristics were also found in stage II patients, for whom there is a high medical need for the identification of new prognostic biomarkers. Conclusions : In conclusion, copy number variation of the 16p13.3 locus seems to be an important parameter for prediction of disease recurrence in colon cancer

Adherence to guidelines for the management of donors after brain death

Purpose: Guideline adherence for the management of a donor after brain death (DBD) is largely unknown. This study aimed to perform an importance-performance analysis of prioritized key interventions (KIs) by linking guideline adherence rates to expert consensus ratings for the management of a DBD. Materials and methods: This observational, cross-sectional multicenter study was performed in 21 Belgian ICUs. A retrospective review of patient records of adult utilized DBDs between 2013 and 2016 used 67 KIs to describe adherence to guidelines. Results: A total of 296 patients were included. Thirty-five of 67 KIs had a high level of adherence congruent to a high expert panel rating of importance. Nineteen of 67 KIs had a low level of adherence in spite of a high level of importance according to expert consensus. However, inadequate documentation proved an important issue, hampering true guideline adherence assessment. Adherence ranged between 3 and 100% for single KI items and on average, patients received 72% of the integrated expert panel recommended care set. Conclusions: Guideline adherence to an expert panel predefined care set in DBD donor management proved moderate leaving substantial room for improvement. An importance-performance analysis can be used to improve implementation and documentation of guidelines