Stem cell dynamics and cellular heterogeneity across lineage subtypes of castrate-resistant prostate cancer.

To resist lineage-dependent therapies such as androgen receptor inhibition, prostate luminal epithelial adenocarcinoma cells often adopt a stem-like state resulting in lineage plasticity and phenotypic heterogeneity. Castrate-resistant prostate adenocarcinoma can transition to neuroendocrine (NE) and occasionally to amphicrine, co-expressed luminal and NE, phenotypes. We developed castrate-resistant prostate cancer (CRPC) patient-derived organoid models that preserve heterogeneity of the originating tumor, including an amphicrine model displaying a range of luminal and NE phenotypes. To gain biological insight and to identify potential treatment targets within heterogeneous tumor cell populations, we assessed the lineage hierarchy and molecular characteristics of various CRPC tumor subpopulations. Transcriptionally similar stem/progenitor (St/Pr) cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent St/Pr cells that produced mainly quiescent differentiated amphicrine progeny. By contrast, adenocarcinoma CRPC progeny originated from St/Pr cells and self-renewing differentiated luminal cells. Neuroendocrine prostate cancer (NEPC) was composed almost exclusively of self-renewing St/Pr cells. Amphicrine subpopulations were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures that characterize clinical progression. Finally, the amphicrine St/Pr subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. These data illuminate distinct stem cell (SC) characteristics for subtype-specific CRPC in addition to demonstrating a context for targeting differentiation-competent prostate SCs.

Effects of an opioid stewardship program on opioid consumption and related outcomes after multilevel lumbar spine fusion: a pre- and postimplementation analysis of 268 patients.

OBJECTIVE: Opioid stewardship programs combine clinical, regulatory, and educational interventions to minimize inappropriate opioid use and prescribing for orthopedic and spine surgery. Most evaluations of stewardship programs quantify effects on prescriber behavior, whereas patient-relevant outcomes have been relatively neglected. The authors evaluated the impact of an opioid stewardship program on perioperative opioid consumption, prescribing, and related clinical outcomes after multilevel lumbar fusion. METHODS: The study was based on a retrospective, quasi-experimental, pretest-posttest design in 268 adult patients who underwent multilevel lumbar fusion in 2016 (preimplementation, n = 141) or 2019 (postimplementation, n = 127). The primary outcome was in-hospital opioid consumption (morphine equivalent dose [MED], mg). Secondary outcomes included numeric rating scale pain scores (0-10), length of stay (LOS), incidence of opioid-induced side effects (gastrointestinal, nausea/vomiting, respiratory, sedation, cognitive), and preoperative and discharge prescribing. Outcomes were measured continuously during the hospital admission. Differences in outcomes between the epochs were assessed in bivariable (Wilcoxon signed-rank or Fisher's exact tests) and multivariable (Wald's chi-square test) analyses. RESULTS: In bivariable analyses, there were significant decreases in preoperative opioid use (46% vs 28% of patients, p = 0.002), preoperative opioid prescribing (MED 30 mg [IQR 20-60 mg] vs 20 mg [IQR 11-39 mg], p = 0.003), in-hospital opioid consumption (MED 329 mg [IQR 188-575 mg] vs 199 mg [100-372 mg], p < 0.001), the incidence of any opioid-related side effect (62% vs 50%, p = 0.03), and discharge opioid prescribing (MED 90 mg [IQR 60-135 mg] vs 60 mg [IQR 45-80 mg], p < 0.0001) between 2016 and 2019. There were no significant differences in postanesthesia care unit pain scores (4 [IQR 3-6] vs 5 [IQR 3-6], p = 0.33), nursing floor pain scores (4 [IQR 3-5] vs 4 [IQR 3-5], p = 0.93), or total LOS (118 hours [IQR 81-173 hours] vs 103 hours [IQR 81-132 hours], p = 0.21). On multivariable analysis, the opioid stewardship program was significantly associated with decreased discharge prescribing (Wald's chi square = 9.45, effect size -52.4, 95% confidence interval [CI] -86 to -19.0, p = 0.002). The number of lumbar levels fused had the strongest effect on total opioid consumption during the hospital stay (Wald's chi square = 16.53, effect size = 539, 95% CI 279.1 to 799, p < 0.001), followed by preoperative opioid use (Wald's chi square = 44.04, effect size = 5, 95% CI 4 to 7, p < 0.001). CONCLUSIONS: A significant decrease in perioperative opioid prescribing, consumption, and opioid-related side effects was found after implementation of an opioid stewardship program. These gains were achieved without adverse effects on pain scores or LOS. These results suggest the major impact of opioid stewardship programs for spine surgery may be on changing prescriber behavior.

Transoral endoscopic vestibular approach Sistrunk procedure: First reported case series.

BACKGROUND: Standard of care for management of thyroglossal duct cysts (TGDCs) is a Sistrunk procedure performed through a transcervical incision. We describe the first series of Sistrunk procedures performed through a transoral endoscopic vestibular approach, eliminating a visible external scar. METHODS: The transoral endoscopic vestibular approach to the Sistrunk (TEVAS) was performed in patients with TGDCs meeting inclusion criteria who desired a scarless approach. RESULTS: Six patients (five females and one male) underwent TEVAS, with a mean age of 38 years (range 16-56 years) and a mean TGDC size of 1.8 cm (range 1.1-2.4 cm). Mean operative time was approximately 5 h (range 2-8 h). There were no surgical complications or recurrences. CONCLUSIONS: For appropriately selected patients, the TEVAS is an alternative to open neck surgery that provides improved cosmesis while maintaining successful resection outcomes. More data on outcomes including complications and recurrences are needed as additional case information is collected.