A Compendium of AR Splice Variants in Metastatic Castration-Resistant Prostate Cancer

Treatment-induced AR alterations, including AR alternative splice variants (AR-Vs), have been extensively linked to harboring roles in primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer and therefore have gained momentum. Our aim was to uniformly determine recurrent AR-Vs in metastatic castration-resistant prostate cancer (mCRPC) using whole transcriptome sequencing in order to assess which AR-Vs might hold potential diagnostic or prognostic relevance in future research. This study reports that in addition to the promising AR-V7 as a biomarker, AR45 and AR-V3 were also seen as recurrent AR-Vs and that the presence of any AR-V could be associated with higher AR expression. With future research, these AR-Vs may therefore harbor similar or complementary roles to AR-V7 as predictive and prognostic biomarkers in mCRPC or as proxies for abundant AR expression.</p

Synchronous and metachronous urothelial carcinoma of the upper urinary tract and the bladder: Are they clonally related? A systematic review

Purpose: Following radical nephroureterectomy for upper urinary tract urothelial carcinoma (UTUC), intravesical recurrence (IVR) is found in 22% to 47% of patients. Patients with a primary urothelial carcinoma of the bladder (UCB) have an increased risk of a future UTUC (1%–5%). Paired UTUC and UCB might represent clonally related tumors due to intraluminal seeding of tumor cells or might be separate entities of urothelial carcinoma caused by field cancerization. We systematically reviewed all the relevant literature to address the possible clonal relation of UTUC and paired UCB. Materials and Methods: MEDLINE, EMBASE, and COCHRANE databases were systematically searched for relevant citations published between January 2000 and July 2019. This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Of 5038 citations identified, 86 full papers were screened, and 9 studies met the inclusion criteria. Results: The populations studied and the molecular techniques used to assess clonality of UTUC and paired UCB differed largely over time. Eight studies reported on primary UTUC and meta- or synchronous IVR without a history of UCB. A total of 118 tumors

The value of radiographic markers in the diagnostic work-up of rotator cuff tears, an arthroscopic correlated study

Objective To evaluate the value of radiographs during the diagnostic work-up of rotator cuff tears, using arthroscopy as reference standard. Materials and methods This retrospective study included 236 shoulders of 236 patients. All radiographs were evaluated for inferior cortical acromial sclerosis, lateral acromial spur, superior migration of the humeral head, greater tubercle cysts, and subacromial space calcifications. Predictive value of these radiographic signs in predicting rotator cuff tears was determined with arthroscopy as reference standard. Results According to arthroscopy, 131 shoulders were diagnosed with rotator cuff tears. Seventy-two out of 131 shoulders (55%) had inferior cortical acromial sclerosis, 37 (28%) lateral acromial spur, 21 (16%) superior migration of the humeral head, 7 (5%) greater tubercle cysts and 15 subacromial space calcifications (11%). Inferior cortical acromial sclerosis (P = 0.001), lateral spur (P = 0.001), superior migration (P = 0.002), and cysts (P = 0.03) were significantly and independently associated with rotator cuff tears, whereas subacromial calcifications (p = 0.21) was not. Inferior cortical acromial sclerosis, superior migration, lateral acromial spur, and cysts combined have a positive predictive value of 78%. Conclusions The combination of inferior cortical acromial sclerosis, lateral acromial spur, superior migration of the humeral head, and greater tubercle cysts has a high positive predictive value for the presence of full-thickness rotator cuff tears. In patients with a high suspicion for having a rotator cuff tear based on radiographic findings, MRI can be performed directly without the delay and costs caused by an additional ultrasound exam

What makes an ideal hospital-based medical leader? Three views of healthcare professionals and managers

Medical leadership is an increasingly important aspect of hospital management. By engaging physicians in leadership roles, hospitals aim to improve their clinical and financial performances. Research has revealed numerous factors that are regarded as necessary for ‘medical leaders’ to master, however we lack insights into their relative importance. This study investigates the views of healthcare professionals and managers on what they consider the most important factors for medical leadership. Physicians (n = 11), nurses (n = 10), laboratory technicians (n = 4) and managers (n = 14) were interviewed using Q methodology. Participants ranked 34 statements on factors elicited from the scientific literature, including personal features, context-specific features, activities and roles. By-person factor analysis revealed three distinct views of medical leadership. The first view represents a strategic leader who prioritizes the interests of the hospital by participating in hospital strategy and decision making. The second view describes a social leader with strong collaboration and communication skills. The third view reflects an accepted leader among peers that is guided by a clear job description. Despite these differences, all respondents agreed upon the importance of personal skills in collaboration and communication, and having integrity and a clear vision. We find no differences in views related to particular healthcare professionals, managers, or departments as all views were defined by a mixture of departments and participants. The findings contribute to increased calls from both practice and literature to increase conceptual clarity by eliciting the relative importance of medical leadership-related factors. Hospitals that wish to increase the engagement of physicians in improving clinical and financial performances through medical leadership should focus on selecting and developing leaders who are strong strategists, socially skilled and accepted by clinical peers

Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study.</p

Gene length corrected trimmed mean of M-values (GeTMM) processing of RNA-seq data performs similarly in intersample analyses while improving intrasample comparisons

Background: Current normalization methods for RNA-sequencing data allow either for intersample comparison to identify differentially expressed (DE) genes or for intrasample comparison for the discovery and validation of gene signatures. Most studies on optimization of normalization methods typically use simulated data to validate methodologies. We describe a new method, GeTMM, which allows for both inter- and intrasample analyses with the same normalized data set. We used actual (i.e. not simulated) RNA-seq data from 263 colon cancers (no biological replicates) and used the same read count data to compare GeTMM with the most commonly used normalization methods (i.e. TMM (used by edgeR), RLE (used by DESeq2) and TPM) with respect to distributions, effect of RNA quality, subtype-classification, recurrence score, recall of DE genes and correlation to RT-qPCR data. Results: We observed a clear benefit for GeTMM and TPM with regard to intrasample comparison while GeTMM performed similar to TMM and RLE normalized data in intersample comparisons. Regarding DE genes, recall was found comparable among the normalization methods, while GeTMM showed the lowest number of false-positive DE genes. Remarkably, we observed limited detrimental effects in samples with low RNA quality. Conclusions: We show that GeTMM outperforms established methods with regard to intrasample comparison while performing equivalent with regard to intersample normalization using the same normalized data. These combined properties enhance the general usefulness of RNA-seq but also the comparability to the many array-based gene expression data in the public domain

The clonal relation of primary upper urinary tract urothelial carcinoma and paired urothelial carcinoma of the bladder

The risk of developing urothelial carcinoma of the bladder (UCB) in patients treated by radical nephroureterectomy (RNU) for an upper urinary tract urothelial carcinoma (UTUC) is 22% to 47% in the 2 years after surgery. Subject of debate remains whether UTUC and the subsequent UCB are clonally related or represent separate origins. To investigate the clonal relationship between both entities, we performed targeted DNA sequencing of a panel of 41 genes on matched normal and tumor tissue of 15 primary UTUC patients treated by RNU who later developed 19 UCBs. Based on the detected tumor-specific DNA aberrations, the paired UTUC and UCB(s) of 11 patients (73.3%) showed a clonal relation, whereas in four patients the molecular results did not indicate a clear clonal relationship. Our results support the hypothesis that UCBs following a primary surgically resected UTUC are predominantly clonally derived recurrences and not separate entities

Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development

Background Testicular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic germ cell. This study determines intratumour heterogeneity to unravel tumour progression from initiation until metastasis. Methods In total, 42 purified samples of four treatment-resistant nonseminomatous (NS) TGCC were investigated, including the precursor germ cell neoplasia in situ (GCNIS) and metastatic specimens, using whole-genome and targeted sequencing. Their evolution was reconstructed. Results Intratumour molecular heterogeneity did