Citations

Background:Crohn’s disease (CD) exhibits variability in colorectal cancer (CRC) incidence and prognostic factors due to diverse clinical and behavioral characteristics, presenting inconsistencies between Western and Eastern patients.Objectives:This study compared clinical characteristics between CD patients with CRC from the US and Korean tertiary referral centers and defined the prognostic factors related to mortality.Design:Retrospective study.Methods:We reviewed the electronic medical records of 236 adult CD patients with colorectal adenocarcinoma evaluated at Mayo Clinic Rochester, Florida, or Arizona ( N = 200) and Asan Medical Center in Korea ( N = 36) between January 1989 and August 2022.Results:Asan patients had a younger age, shorter CD duration, more colonic involvement (L2 plus L3), penetrating behavior, perianal fistula, and shorter biological treatment duration before CRC diagnosis than Mayo patients. Furthermore, despite significant differences in body mass index, smoking status, primary sclerosing cholangitis, immunomodulators, CRC diagnosis period, clinical presentation, CRC location, surgery, and some histopathological details between the two groups, overall survival was not statistically different ( p value, 0.29, log-rank test). Advanced age (adjusted hazard ratio (aHR), 1.03 per year; 95% confidence interval (CI), 1.01–1.04; p value, <0.01), unresectable CRC (aHR, 5.02; 95% CI, 2.49–10.12; p value, <0.01), and advanced CRC stage (aHR, 1.45 per stage; 95% CI, 1.07–1.97; p value, 0.02) were significantly associated with increased risk of death. CD remission at CRC diagnosis (aHR, 0.26; 95% CI, 0.08–0.91; p value, 0.04), CRC diagnosis period of 2011–2022 (aHR relative to 1989–2000, 0.46; 95% CI, 0.25–0.87; p value, 0.02), and CRC diagnosis by surveillance (aHR, 0.56; 95% CI, 0.32–0.98; p value, 0.04) were significantly associated with decreased risk of death.Conclusion:Notably, some clinical features of CD with CRC differed between Asan and Mayo patients; however, overall survival was not different. CD remission, CRC surveillance, and more recent diagnosis of CRC were associated with a reduced risk of death.

Abstract Background: Stage III triple negative(TN) inflammatory breast cancer(IBC) is associated with a poor prognosis evidenced by a 15 month(mo) median disease free survival(DFS) and overall survival(OS) of 34 mo. The substantial incidence of developing distant metastasis may be due to the prevalence of cancer cells with stem cell-like features (e.g. CD44+/CD24-) in TNIBC. The transcriptional pathway JAK2/STAT3 is associated with the survival of CD44+/CD24- cells, and preclinical data demonstrates overexpression of activated STAT3(pSTAT3) in &gt; 95% of TNIBC. Preclinical studies have shown that ruxolitinib (Incyte®Corporation), an approved JAK1/JAK2 inhibitor, suppresses pSTAT3 in IBC patient derived xenograft models, and when combined with paclitaxel, results in a synergistic reduction in tumor weight. Given the lack of a known therapeutic target in TNIBC, this preoperative proof of principle study exploits the survival mechanism of CD44+/CD24- stem cells prevalent in this disease, by combining ruxolitinib(Rux) with paclitaxel(T) followed by doxorubicin/cyclophosphamide(AC). Methods: Up to 64 pts with newly diagnosed stage III TNIBC (cT4d, any N, M0) are eligible if they have adequate organ function and are willing to undergo 2 research biopsies(rbx) of the affected breast. Following baseline rbx, pts are randomized to a 7 day(d) run-in phase of Rux vs Rux(15 mg bid) + T(80mg/m2/wkx1). A 2nd rbx is obtained after the run-in phase. Pts randomized to RuxT continue to receive a total of Tx12 wks+Rux. Pts randomized to Rux alone, are re-randomized to receive Tx12 wks+Rux vs Tx12wks alone. Following T, all pts receive AC (A-60mg/m2,C-600mg/m2) every 14d x 4. Pts proceed to modified radical mastectomy (MRM) followed by chest wall/regional lymph nodes radiation therapy. Correlatives: To assess the effect of JAK inhibition with Rux on pSTAT3 and STAT3 related gene expression, molecular and genomic markers (e.g. RNA-seq, ChIPseq, FISH) will be determined in each rbx and residual tumor at MRM. The relative frequency and topology of CD44+/CD24- cell population and pSTAT3 expression by IHC will also be assessed in these tumor specimens. IL-6 and CRP plasma concentrations will be measured at baseline, prior to T and AC and prior to MRM. Statistics: The primary endpoint is change in markers of JAK/STAT inhibition. If the proportion of rbx exhibit a biologic response to Rux alone (i.e. change from pSTAT3 expression to pSTAT3 negative) is &lt;10%, then Rux alone is minimally effective on JAK inhibition vs alternative hypothesis that Rux inhibits JAK if the proportion of biologic response is ≥33%. If ≥5/25 rbx treated with Rux alone have a biologic response then the hypothesis that biologic response is ≤10% is rejected with an error rate of 0.098 (target 0.10). If ≤4/25 rbx have a biologic response then the hypothesis that biologic response is ≥33% is rejected with an error rate of 0.05 (target 0.10). Biologic response of rbx with Rux alone will also be compared with the proportion of biologic response to RuxT (33% vs. 66% based upon presumed synergy with RuxT). Secondary endpoints are clinical: pathologic complete response in breast/lymph nodes, Residual Cancer Burden, DFS and OS. Clinical Trial Information: NCT02876302. Citation Format: Overmoyer B, Regan M, Polyak K, Brock J, Van Poznak C, King T, Haddad T, Stearns V, Hwang S, Winer E. TBCRC 039: Phase II study of combination ruxolitinib (INCB018424) with preoperative chemotherapy for triple negative inflammatory breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-01.

Acetyl‐CoA carboxylase 2 (ACC2) is an isoform of ACC functioning as a negative regulator of fatty acid β‐oxidation. Spot14, a thyroid hormone responsive protein, and Mig12, a Spot14 paralog, have recently been identified as regulators of fatty acid synthesis targeting ACC1, a distinctive subtype of ACC. Here, we examined whether Spot14/Mig12 modulates ACC2. Nanoscale protein topography mapped putative protein–protein interactions between purified human Spot14/Mig12 and ACC2, validated by functional assays. Human ACC2 displayed consistent enzymatic activity, and homogeneous particle distribution was probed by atomic force microscopy. Citrate‐induced polymerization and enzymatic activity of ACC2 were restrained by the addition of the recombinant Spot14/Mig12 heterocomplex but only partially by the oligo‐heterocomplex, demonstrating that the heterocomplex is a designated metabolic inhibitor of human ACC2. Moreover, Spot14/Mig12 demonstrated a sequestering role preventing an initial ACC2 nucleation step during filamentous polymer formation. Thus, the Spot14/Mig12 heterocomplex controls human ACC2 polymerization and catalytic function, emerging as a previously unrecognized molecular regulator in catalytic lipid metabolism. © 2013 The Authors. Journal of Molecular Recognition published by John Wiley & Sons, Ltd.