Overexpression of the transcriptional coregulators C-terminal binding proteins 1 and 2 (CtBP) occurs in many human solid tumors and is associated with poor prognosis. CtBP modulates oncogenic gene expression programs and is an emerging drug target, but its oncogenic role is unclear. Consistent with oncogenic potential, exogenous CtBP2 transformed primary mouse and human cells to anchorage independence similarly to mutant H-Ras. To investigate CtBP’s contribution to in vivo tumorigenesis, Apcmin/+ mice, which succumb to massive intestinal polyposis, were bred to Ctbp2+/− mice. CtBP interacts with Adenomatous Polyposis Coli (APC) protein, and is stabilized in both APC-mutated human colon cancers and Apcmin/+ intestinal polyps. Ctbp2 heterozygosity increased the median survival of Apcmin/+ mice from 21 to 48 weeks, and reduced polyp formation by 90%, with Ctbp2+/− polyps exhibiting reduced levels of β-catenin and its oncogenic transcriptional target, cyclin D1. Ctbp’s potential as a therapeutic target was studied by treating Apcmin/+ mice with the CtBP small molecule inhibitors 4-methlythio-2-oxobutyric acid and 2-hydroxy-imino phenylpyruvic acid, both of which reduced polyposis by more than half compared with vehicle treatment. Phenocopying Ctbp2 deletion, both Ctbp inhibitors caused substantial decreases in the protein level of Ctbp2, as well its oncogenic partner β-catenin, and the effects of the inhibitors on CtBP and β-catenin levels could be modeled in an APC mutated human colon cancer cell line. CtBP2 is thus a druggable transforming oncoprotein critical for the evolution of neoplasia driven by Apc mutation.

Background: Despite good evidence that supports significant improvements in pain and physical function following a total ankle replacement (TAR) for end-stage ankle arthritis, there is a subset of patients who do not significantly benefit from surgery. The purpose of this study was to perform a preliminary analysis to determine if preoperative Patient-Reported Outcome Measurement Information System (PROMIS) scores could be used to predict which patients were at risk of not meaningfully improving following a TAR. Methods: Prospectively collected preoperative and ≥2-year postoperative PROMIS physical function, pain interference, pain intensity, and depression scores for 111 feet in 105 patients were included in the study. Significant postoperative improvement was defined using minimal clinically important differences (MCIDs). Logistic regression models and area under the curve (AUC) analyses were used to determine whether preoperative PROMIS scores were predictive of postoperative outcomes. Results: Receiver operating characteristic curves found statistically significant AUCs for the PROMIS physical function (AUC = 0.728, P = .004), pain intensity (AUC = 0.720, P = .018), and depression (AUC = 0.761, P < .001) domains. The preoperative PROMIS pain interference domain did not achieve a statistically significant AUC. Conclusion: Preoperative PROMIS physical function and pain intensity t scores may be used to predict postoperative improvement in patients following a fixed-bearing TAR; however, preoperative PROMIS pain interference scores were not good predictors. The results of this study may be used to guide research regarding patient-reported outcomes following TAR. Level of Evidence: Level III, retrospective comparative series.

Ctbp2 is a uniquely targetable oncogenic transcriptional coregulator, exhibiting overexpression in most common solid tumors, and critical to the tumor-initiating cell (TIC) transcriptional program. In the “CKP” mouse pancreatic ductal adenocarcinoma (PDAC) model driven by mutant K-Ras, Ctbp2 haploinsufficiency prolonged survival, abrogated peritoneal metastasis, and caused dramatic downregulation of c-Myc, a known critical dependency for TIC activity and tumor progression in PDAC. A small-molecule inhibitor of CtBP2, 4-chloro-hydroxyimino phenylpyruvate (4-Cl-HIPP) phenocopied Ctbp2 deletion, decreasing tumor burden similarly to gemcitabine, and the combination of 4-Cl-HIPP and gemcitabine further synergistically suppressed tumor growth. Pharmacodynamic monitoring revealed that the 4-Cl-HIPP/gemcitabine combination induced robust and synergistic tumor apoptosis and marked downregulation of the TIC marker CD133 in CKP PDAC tumors. Collectively, our data demonstrate that targeting CtBP represents a fruitful avenue for development of highly active agents in PDAC that cooperate with standard therapy to limit both primary and metastatic tumor burden.

Introduction: Mental health diagnoses involving depression or anxiety are common and can have a dramatic effect on patients with musculoskeletal pathologies. In orthopaedics, depression/anxiety (D/A) is associated with worse postoperative patient-reported outcomes. However, few studies have assessed the effect of D/A on expectations and satisfaction in foot and ankle patients. Methods: Adult patients undergoing elective foot and ankle surgery were prospectively enrolled. Preoperatively, patients completed the eight-item Patient Health Questionnaire Depression Scale, Generalized Anxiety Disorder Screener-7, Foot and Ankle Outcome Score (FAOS), and Expectations Survey. At 2 years postoperatively, surveys including satisfaction, improvement, and fulfillment of expectations were administered. Fulfillment of expectations (fulfillment proportion) and FAOS scores were compared between patients with D/A and non-D/A patients. Results: Of 340 patients initially surveyed, 271 (80%) completed 2-year postoperative expectations surveys. One in five patients had D/A symptoms. Preoperatively, D/A patients had greater expectations of surgery (P = 0.015). After adjusting for measured confounders, the average 2-year postoperative fulfillment proportion was not significantly lower among D/A compared with non-D/A (0.86 versus 0.78, P = 0.2284). Although FAOS scores improved postoperatively for both groups, D/A patients had significantly lower preoperative and postoperative FAOS scores for domains of symptoms, activity, and quality of life (P < 0.05 for all). D/A patients reported less improvement (P = 0.036) and less satisfaction (P = 0.005) and were less likely willing to recommend surgery to others (P = 0.011). Discussion: Patients with D/A symptoms had higher preoperative expectations of surgery. Although D/A patients had statistically similar rates of fulfillment of expectations compared with non-D/A patients, they had markedly lower FAOS scores for domains of symptoms, activity, and quality of life. D/A patients also perceived less improvement and were more often dissatisfied with their outcomes. These findings should not dissuade providers from treating these patients surgically but rather emphasize the importance of careful patient selection and preoperative expectation management. Level of Evidence: Level III; retrospective review of prospective cohort study