Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.

Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.

Pulse article: opioid prescription for pain after spinal cord damage (SCD), differences from recommended guidelines, and a proposed algorithm for the use of opioids for pain after SCD.

Study design: Online questionnaire of spinal cord injury (SCI) physicians. Objectives: The objective of this study is to characterize the approach to opioid prescription for persons with spinal cord damage (SCD). Setting: An international online questionnaire. Methods: A survey was posted online and circulated among international societies within the field of SCI medicine from August to November 2018. Results: One hundred and twenty-three physicians responded to the survey. Of these, 107 (92%) managed pain for persons with SCD. Most (82%) felt that opioid prescription was appropriate for uncontrolled acute pain, but fewer (67%) felt it was appropriate for chronic pain. Of those who felt opioids had a role in the treatment of neuropathic pain, 46% did not think there should be a specific upper limit of opioid dose. The majority (85%) would continue prescribing high doses (250 morphine milligram equivalent (MME) doses/day) if that dose were effective. Tramadol was the most common opioid prescribed first line. Conclusion: Most physicians who responded to this survey prescribe opioids for intractable pain after SCD. A significant proportion of respondents believed that there should not be a specific upper limit of opioid dose prescribed if the drug is tolerated; this does not align with current recommendations. Most physicians do not feel influenced in their prescribing habits by regulatory bodies. If physicians decide to taper an opioid that is being tolerated well, it is most commonly related to a fear of the patient developing an opioid-use disorder. The authors propose an algorithm that may help align practice patterns with current recommended practice guidelines.