Abstract
Background. We hypothesized that circulating tumor DNA (ctDNA) can be used as a prognostic biomarker, improve the assessment of response and enhance detection of minimal residual disease in ...patients with locally advanced rectal cancer (LARC) treated with neoadjuvant therapy (NAT).
Methods. We analyzed data from 31 LARC patients treated at Memorial Sloan Kettering as part of the Organ Preservation in Rectal Adenocarcinoma (OPRA) phase II clinical trial. Patients had stage II or III rectal adenocarcinoma and received NAT including chemoradiation and chemotherapy. Patients without a clinical complete response (cCR) underwent surgical resection, while patients with a cCR were enrolled in a watch-and-wait protocol for organ preservation. Complete response (CR) after NAT was defined as either pathological complete response or a cCR sustained for ≥2 years. Disease-free survival (DFS) was measured from the start of NAT. Median follow-up was 5.41 years range 2.96-8.38. ctDNA analyses were performed using the C2i Genomics platform. A patient-specific molecular profile was created by performing whole-genome sequencing (WGS) of their tumor and matched normal DNA (40x coverage). WGS (20x coverage) was performed on plasma samples collected at baseline (before NAT), interval evaluation (halfway through NAT), re-staging evaluation (8 weeks after NAT) and follow-up (3-6 months after NAT).
Results. Tumor was detected in plasma samples from 24/25 patients at baseline (96% sensitivity). The tumor fraction (TF) levels detected at baseline separated responders from non-responders (median TF 6.2e-4 vs 1.4e-3; p=0.055). Tumor detection at interval was associated with a lower rate of CR (25% vs. 75%, p=0.0095) and shorter time to recurrence (58.3% vs. 94.1% 3-year DFS, p=0.02). Tumor detection at follow-up was associated with a higher rate of recurrence (p=0.037) and tumor was detected at follow-up for all 5/5 patients who developed recurrence. Overall TF dynamics showed clearance of ctDNA down to the non-detection level throughout treatment in patients with a CR, while non-responders exhibited non-decreasing and often increasing estimates of ctDNA burden. Analysis of tissue WGS data identified multiple patients with colibactin associated mutational signatures, which provides additional insights into their cancer etiology.
Conclusions. The WGS-based approach for ctDNA analysis exhibited very high sensitivity for detection at baseline. TF across multiple time points separated responders from non-responders, suggesting potential value as a prognostic marker. Detection of ctDNA at follow-up for all patients who recurred is indicative of potential clinical utility for treatment de-escalation in the context of organ preservation strategies.
Citation Format: Francisco Sanchez-Vega, Chin-Tung Chen, Danielle Afterman, Dana Omer, Madison Darmofal, Ino de Bruijn, Walid K. Chatila, Matthew Drescher, Grittney Tam, Tomer Lauterman, Maja Kuzman, Santiago Gonzalez, Dunja Glavas, James Samdbeck, Dillon Maloney, Jurica Levatic, Sunil Deochand, Michael Yahalom, Ryan Ptashkin, Iman Tavassoly, Zohar Donenhirsh, Eric White, Ravi Kandasamy, Ury Alon, Michael F. Berger, Brian Loomis, Paz Polak, Boris Oklander, Asaf Zviran, Julio Garcia-Aguilar. Ultra-sensitive detection of circulating tumor DNA by whole-genome sequencing of blood samples from locally advanced rectal cancer patients receiving neoadjuvant therapy and enrolled in watch-and-wait strategies for organ preservation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2305.
The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data release (DR9) of the SDSS project includes ...535,995 new galaxy spectra (median z ~ 0.52), 102,100 new quasar spectra (median z ~ 2.32), and 90,897 new stellar spectra, along with the data presented in previous data releases. These spectra were obtained with the new BOSS spectrograph and were taken between 2009 December and 2011 July. In addition, the stellar parameters pipeline, which determines radial velocities, surface temperatures, surface gravities, and metallicities of stars, has been updated and refined with improvements in temperature estimates for stars with T eff < 5000 K and in metallicity estimates for stars with Fe/H > -0.5. DR9 includes new stellar parameters for all stars presented in DR8, including stars from SDSS-I and II, as well as those observed as part of the SEGUE-2. The astrometry error introduced in the DR8 imaging catalogs has been corrected in the DR9 data products. The next data release for SDSS-III will be in Summer 2013, which will present the first data from the APOGEE along with another year of data from BOSS, followed by the final SDSS-III data release in 2014 December.
This paper demonstrates a time-series production technique to quantify the deer harvest and deer hunting benefits of controlled burns or prescribed fire. The time series regression model showed a ...statistically significant and positive effect of prescribed fire on deer harvest. The net economic value of the resulting additional deer hunting benefit was estimated using the Contingent Valuation Method at $ 98 per additional deer harvested. The initial deer hunting benefits of an additional 1,000 acres of prescribed burning are between $ 2,674 and $ 3,128 or $ 2-3 per acre. The costs of prescribed burning greatly exceed these benefits, suggesting that deer hunting benefits represent only a small part of the multiple use benefits of prescribed fire.
Phenothiazines are known to inhibit the activity of protein kinase C. To identify structural features that determine inhibitory
activity against the enzyme, we utilized a semiautomated assay Anal. ...Biochem. 187:84-88 (1990) to compare the potency of
greater than 50 phenothiazines and related compounds. Potency was decreased by trifluoro substitution at position 2 on the
phenothiazine nucleus and increased by quinoid structures on the nucleus. An alkyl bridge of at least three carbons connecting
the terminal amine to the nucleus was required for activity. Primary amines and unsubstituted piperazines were the most potent
amino side chains. We selected 7,8-dihydroxychlorpromazine (DHCP) (IC50 = 8.3 microM) and 2-chloro-9-(3-1-piperazinylpropylidene)thioxanthene
(N751) (IC50 = 14 microM) for further study because of their potency and distinct structural features. Under standard (vesicle)
assay conditions, DHCP was noncompetitive with respect to phosphatidylserine and a mixed-type inhibitor with respect to ATP.
N751 was competitive with respect to phosphatidylserine and noncompetitive with respect to ATP. Using the mixed micelle assay,
DHCP was a competitive inhibitor with respect to both phosphatidylserine and ATP. DHCP was selective for protein kinase C
compared with cAMP-dependent protein kinase, calmodulin-dependent protein kinase type II, and casein kinase. N751 was more
potent against protein kinase C compared with cAMP-dependent protein kinase and casein kinase but less potent against protein
kinase C compared with calmodulin-dependent protein kinase type II. DHCP was analyzed for its ability to inhibit different
isoenzymes of protein kinase C, and no significant isozyme selectivity was detected. These data provide important information
for the rational design of more potent and selective inhibitors of protein kinase C.
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