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Several studies have demonstrated the prognostic value of circulating tumor DNA (ctDNA); however, the correlation of mean tumor molecules (MTM)/ml of plasma and mean variant allele frequency (mVAF; %) with clinical parameters is yet to be understood. In this study, we analyzed ctDNA data in a pan-cancer cohort of 23 543 patients who had ctDNA testing performed using a personalized, tumor-informed assay (Signatera™, mPCR-NGS assay). For ctDNA-positive patients, the correlation between MTM/ml and mVAF was examined. Two subanalyses were performed: (a) to establish the association of ctDNA with tumor volume and (b) to assess the correlation between ctDNA dynamics and patient outcomes. On a global cohort, a positive correlation between MTM/ml and mVAF was observed. Among 18 426 patients with longitudinal ctDNA measurements, 13.3% had discordant trajectories between MTM/ml and mVAF at subsequent time points. In metastatic patients receiving immunotherapy (N = 51), changes in ctDNA levels expressed both in MTM/ml and mVAF showed a statistically significant association with progression-free survival; however, the correlation with MTM/ml was numerically stronger., (© 2023 Natera, Inc. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non-small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there is significant clinical variability in the duration, dosing, and timing of maintenance therapy after induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes in patients with advanced NSCLC receiving chemoIO., Experimental Design: This retrospective study included 221 patients from a phase III trial of atezolizumab+carboplatin+nab-paclitaxel versus carboplatin+nab-paclitaxel in squamous NSCLC (IMpower131). ctDNA monitoring used the FoundationOne Tracker involving comprehensive genomic profiling of pretreatment tumor tissue, variant selection using an algorithm to exclude nontumor variants, and multiplex PCR of up to 16 variants to detect and quantify ctDNA., Results: ctDNA was detected (ctDNA+) in 96% of pretreatment samples (median, 93 mean tumor molecules/mL), and similar ctDNA dynamics were noted across treatment arms during chemoIO. ctDNA decrease from baseline to C4D1 was associated with improved outcomes across multiple cutoffs for patients treated with chemoIO. When including patients with missing plasma or ctDNA- at baseline, patients with ctDNA- at C4D1 (clearance), had more favorable progression-free survival (median 8.8 vs. 3.5 months; HR, 0.32;0.20-0.52) and OS (median not reached vs. 8.9 months; HR, 0.22; 0.12-0.39) from C4D1 than ctDNA+ patients., Conclusions: ctDNA monitoring during induction chemoIO can inform treatment outcomes in patients with advanced NSCLC. Importantly, monitoring remains feasible and informative for patients missing baseline ctDNA. ctDNA testing during induction chemoIO identifies patients at higher risk for disease progression and may inform patient selection for novel personalized maintenance or second-line treatment strategies., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: Circulating tumor DNA (ctDNA) analyses allow for postoperative risk stratification in patients with curatively treated colon and breast cancers. Use of ctDNA in esophagogastric cancers (EGC) is less characterized and could identify high-risk patients who have been treated with curative intent., Methods: In this retrospective analysis of real-world data, ctDNA levels were analyzed in the preoperative, postoperative, and surveillance settings in patients with EGC using a personalized multiplex polymerase chain reaction-based next-generation sequencing assay. Plasma samples (n = 943) from 295 patients at > 70 institutions were collected before surgery, postoperatively, and/or serially during routine clinical follow-up from September 19, 2019, to February 21, 2022. ctDNA detection was annotated to clinicopathologic features and recurrence-free survival., Results: A total of 295 patients with EGC were analyzed, and 212 patients with stages I-III disease were further explored. Pretreatment ctDNA was detected in 96% (23/24) of patients with preoperative time points. Postoperative ctDNA was detected in 23.5% (16/68) of patients with stage I-III EGC within 16 weeks (molecular residual disease window) after surgery without receiving systemic therapy. ctDNA detection at any time point after surgery (hazard ratio [HR], 23.6; 95% CI, 10.2 to 66.0; P < .0001), within the molecular residual disease window (HR, 10.7; 95% CI, 4.3 to 29.3; P < .0001), and during the surveillance period (HR, 17.7; 95% CI, 7.3 to 50.7; P < .0001) was associated with shorter recurrence-free survival. In multivariable analysis, ctDNA status and clinical stage of disease were independently associated with outcomes., Conclusion: Using real-world data, we demonstrate that postoperative tumor-informed ctDNA detection in EGC is feasible and allows for enhanced patient risk stratification and prognostication during curative-intent therapy., Competing Interests: Brandon M. HuffmanStock and Other Ownership Interests: Doximity Vasily N. AushevEmployment: NateraStock and Other Ownership Interests: NateraTravel, Accommodations, Expenses: Natera Griffin L. BuddeEmployment: NateraStock and Other Ownership Interests: NateraTravel, Accommodations, Expenses: Natera Joseph ChaoConsulting or Advisory Role: Lilly, Merck, AstraZeneca, Foundation Medicine, Daiichi Sankyo, Amgen, Bristol Myers Squibb, Astellas Pharma, Turning Point Therapeutics, Roche, Silverback Therapeutics, Novartis, Coherus Biosciences, Geneos, Guardant HealthSpeakers' Bureau: Merck, Bristol Myers SquibbResearch Funding: Merck (Inst), Novonco Therapeutics (Inst), Brooklyn Immunotherapeutics (Inst)Travel, Accommodations, Expenses: Merck, Macrogenics, Foundation Medicine, AmgenOther Relationship: Yiviva Farshid DayyaniEmployment: RocheConsulting or Advisory Role: Genentech/Roche, Array BioPharma, Exelixis, Eisai, QED Therapeutics, SignateraSpeakers' Bureau: Genentech/Roche, Amgen, Eisai, ipsen, Exelixis, Sirtex Medical, Deciphera, Natera, ServierResearch Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Merck (Inst), Genentech (Inst), Taiho Pharmaceutical (Inst), Exelixis (Inst), Ipsen (Inst) Diana HannaConsulting or Advisory Role: Boehringer Ingelheim, AstraZeneca Gregory P. BottaHonoraria: NateraConsulting or Advisory Role: NateraSpeakers' Bureau: Natera Daniel V.T. CatenacciHonoraria: Genentech/Roche, Lilly, Amgen, Foundation Medicine, Taiho Pharmaceutical, Guardant Health, Merck, Bristol Myers Squibb, Gritstone Bio, Five Prime Therapeutics, Astellas Pharma, Seattle Genetics, Tempus, Pieris Pharmaceuticals, Daiichi Sankyo/UCB Japan, Zymeworks, QED Therapeutics, Natera, Archer, NovartisConsulting or Advisory Role: Genentech/Roche, Amgen, Merck, Lilly, Taiho Pharmaceutical, Bristol Myers Squibb, Astellas Pharma, Seattle Genetics, Daiichi Sankyo/UCB Japan, Zymeworks, Guardant HealthSpeakers' Bureau: Guardant Health, Genentech, Lilly, Merck, Tempus, Daiichi Sankyo/Astra Zeneca Steven B. MaronStock and Other Ownership Interests: Calithera BiosciencesHonoraria: Vindico Medical Education, Clarion Healthcare, Physicans' Education ResourceConsulting or Advisory Role: Natera, Basilea, Daichi Sankyo, Bicara Therapeutics, Novartis, AmgenResearch Funding: Guardant Health (Inst), Epic Sciences Shifra KrinshpunEmployment: NateraStock and Other Ownership Interests: NateraTravel, Accommodations, Expenses: Natera Shruti SharmaEmployment: NateraStock and Other Ownership Interests: Natera Giby V. GeorgeEmployment: NateraStock and Other Ownership Interests: Natera Meenakshi MalhotraEmployment: NateraStock and Other Ownership Interests: Natera Adham JurdiEmployment: NateraStock and Other Ownership Interests: Natera, Cardiff OncologySpeakers' Bureau: NateraTravel, Accommodations, Expenses: Natera Solomon MoshkevichEmployment: Natera, Mahana TherapeuticsStock and Other Ownership Interests: NateraPatents, Royalties, Other Intellectual Property: Named as inventor on a patent filed by Natera, incTravel, Accommodations, Expenses: Natera Alexey AleshinEmployment: Natera, NateraLeadership: NateraStock and Other Ownership Interests: NateraConsulting or Advisory Role: Mission BioTravel, Accommodations, Expenses: Natera Pashtoon M. KasiConsulting or Advisory Role: Taiho Pharmaceutical (Inst), Ipsen (Inst), Natera, Foundation Medicine, MSD Oncology, Tempus, Bayer, Lilly, Delcath Systems, Inflecton Point Biomedical Advisors, QED Therapeutics, Boston Healthcare Associates, SERVIER, Taiho Oncology, Exact Sciences, Daiichi Sankyo/Astra Zeneca, Eisai, Seattle GeneticsResearch Funding: Advanced Accelerator Applications (Inst), Tersera (Inst), Boston Scientific (Inst)Travel, Accommodations, Expenses: AstraZeneca Samuel J. KlempnerThis author is a member of the JCO Precision Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Stock and Other Ownership Interests: TP Therapeutics, Nuvalent, IncHonoraria: NateraConsulting or Advisory Role: Lilly, Astellas Pharma, Bristol Myers Squibb, Pieris Pharmaceuticals, Merck, Daiichi Sankyo/UCB Japan, Sanofi/Aventis, Mersana, Exact Sciences, NovartisResearch Funding: Leap Therapeutics (Inst), BeiGene (Inst), Silverback Therapeutics (Inst)Other Relationship: NCCNNo other potential conflicts of interest were reported.

Introduction: Colorectal cancer (CRC) is a highly prevalent disease, wherein, ~30%-40% of patients with CRC relapse postresection. In some patients with CRC, adjuvant chemotherapy can help delay recurrence or be curative. However, current biomarkers show limited clinical utility in determining if/when chemotherapy should be administered, to provide benefit. Circulating tumour DNA (ctDNA) can measure molecular residual disease (MRD) and relapse with high specificity and sensitivity. This study protocol investigates the clinical utility of ctDNA for optimal use of adjuvant chemotherapy in patients with surgically resected CRC and to detect early disease progression in the surveillance setting., Methods and Analysis: This is a multicentre prospective, observational cohort study. A total of 2000 stage I-IV patients will be enrolled in up to 200 US sites, and patients will be followed for up to 2 years with serial ctDNA analysis, timed with the standard-of-care visits. The primary endpoints are to observe the impact of bespoke ctDNA testing on adjuvant treatment decisions and to measure CRC recurrence rates while asymptomatic and without imaging correlate. The secondary endpoints are MRD clearance rate (MRD+ to MRD-) during or after adjuvant chemotherapy, percentage of patients that undergo surgery for oligometastatic recurrence, survival of MRD-negative patients treated with adjuvant chemotherapy versus no adjuvant chemotherapy (active surveillance), overall survival, examine the number of stage I CRC that have recurrent disease detected postsurgery, and patient-reported outcomes., Ethics and Dissemination: This study has received ethical approval from the Advarra Institutional Review Board (IRB) protocol: Natera-20-041-NCP/3766.01, BESPOKE Study of ctDNA Guided Therapy in Colorectal Cancer (BESPOKE CRC) (Pro00041473) on 10 June 2021. Data protection and privacy regulations will be strictly observed in the capturing, forwarding, processing and storing of patients' data. Publication of any study results will be approved by Natera in accordance with the site-specific contract., Trial Registration Number: NCT04264702., Competing Interests: Competing interests: PMK: consultancy/advisory board: Taiho Oncology, Ipsen, Natera, Foundation Medicine; Research/Trial Support (to institution): BMS, Celgene, AstraZeneca, BTG, Advanced Accelerator Applications, Array Biopharma. AG: Research funding from Array BioPharma, Bayer, Boston Biomedical, Daiichi Sankyo, Eisai, Genentech/Roche, Lilly, Pfizer. SKo: research funding from Amgen, Array BioPharma, Biocartis, EMD Serono, Genentech/Roche, Guardant Health, Lilly, MedImmune, Novartis, Sanofi. All other authors are employees of Natera, Inc. with stock/options to own stock on the company. This study is being sponsored by Natera, Inc., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: More than 50% of patients with stage IV colorectal cancer (metastatic colorectal cancer [mCRC]) relapse postresection. The efficacy of postoperative systemic treatment is limited in this setting. Thus, these patients would greatly benefit from the use of a reliable prognostic biomarker, such as circulating tumor DNA (ctDNA) to identify minimal or molecular residual disease (MRD)., Patients and Methods: We analyzed a cohort of 112 patients with mCRC who had undergone metastatic resection with curative intent as part of the PREDATOR clinical trial. The study evaluated the prognostic value of ctDNA, correlating MRD status postsurgery with clinical outcomes by using a personalized and tumor-informed ctDNA assay (bespoke multiple PCR, next-generation sequencing assay). Postresection, systemic therapy was given to 39.2% of the patients at the discretion of the treating physician., Results: Postsurgical, MRD positivity was observed in 54.4% (61 of 112) of patients, of which 96.7% (59 of 61) progressed at the time of data cutoff (hazard ratio [HR]: 5.8; 95% CI, 3.5 to 9.7; P < .001). MRD-positive status was also associated with an inferior overall survival: HR: 16.0; 95% CI, 3.9 to 68.0; P < .001. At the time of analyses, 96% (49 of 51) of patients were alive in the MRD-negative arm compared with 52.4% (32 of 61) in the MRD-positive arm. Patients who did not receive systemic therapy and were MRD-negative in the combined ctDNA analysis at two time points had an overall survival of 100%. In the multivariate analysis, ctDNA-based MRD status was the most significant prognostic factor associated with disease-free survival (HR: 5.78; 95% CI, 3.34 to 10.0; P < .001)., Conclusion: This study confirms that in mCRC undergoing resection of metastases, postoperative MRD analysis is a strong prognostic biomarker. It holds promises for being implemented in clinical decision making, informing clinical trial design, and further translational research., Competing Interests: Fotios Loupakis Consulting or Advisory Role: Amgen, Sanofi, Bayer, Amal Therapeutics Speakers' Bureau: Roche, Sanofi, Bayer, Amgen Research Funding: Roche, Merck Serono, Amgen, Bayer Travel, Accommodations, Expenses: Roche, Amgen, Merck Serono Shruti Sharma Employment: Natera Stock and Other Ownership Interests: Natera Madiha Derouazi Employment: AMAL Therapeutics Leadership: AMAL Therapeutics Travel, Accommodations, Expenses: AMAL Therapeutics Derrick Renner Employment: Natera Stock and Other Ownership Interests: Natera Travel, Accommodations, Expenses: Natera Svetlana Shchegrova Employment: Natera Stock and Other Ownership Interests: Natera Allyson Koyen Malashevich Employment: Natera Stock and Other Ownership Interests: Natera Meenakshi Malhotra Employment: Natera Stock and Other Ownership Interests: Natera Himanshu Sethi Employment: Natera Stock and Other Ownership Interests: Natera Research Funding: Natera Patents, Royalties, Other Intellectual Property: Patents Travel, Accommodations, Expenses: Natera Bernhard G. Zimmermann Employment: Natera Stock and Other Ownership Interests: Natera Honoraria: Natera Patents, Royalties, Other Intellectual Property: Multiple patents and patent applications Alexey Aleshin Employment: Natera Leadership: Natera Stock and Other Ownership Interests: Natera Consulting or Advisory Role: Mission Bio Travel, Accommodations, Expenses: Natera Solomon Moshkevich Employment: Natera, Evidation Health Stock and Other Ownership Interests: Natera Patents, Royalties, Other Intellectual Property: Named as inventor on a patent filed by Natera Inc Travel, Accommodations, Expenses: Natera Paul R. Billings Employment: Natera Leadership: Biological Dynamics, OmniSeq, Alveo Technologies, Mission Bio Stock and Other Ownership Interests: Natera, Trovagene, Biological Dynamics, OmniSeq, Alveo Technologies Consulting or Advisory Role: Bethesda Group, Guidepoint Global Jonathon D. Sedgwick Employment: Boehringer Ingelheim Travel, Accommodations, Expenses: Boehringer Ingelheim Umberto Cillo Consulting or Advisory Role: Springer Health Care, Novartis, Johnson & Johnson, Astellas, Sandoz Speakers' Bureau: Eisai Angelo Paolo Dei Tos Consulting or Advisory Role: Bayer, Roche Vittorina Zagonel Consulting or Advisory Roles: Bristol Myers Squibb, MSD, Eisai, Italfarmaco Speakers' Bureau: Roche, Bristol Myers Squibb, Astellas Pharma, Servier, AstraZeneca, MSD, Jansen, Ipsen Research Funding: Bayer, Roche, Lilly, Astra Zeneca, BMS, Ipsen, Astellas Pharma Travel, Accommodations, Expenses: Bayer, Roche, Servier Sara Lonardi Consulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb Speakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen Research Funding: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb Matteo Fassan Consulting or Advisory Role: Astellas Pharma, Tesaro, GlaxoSmithKline, Diaceutics, Diaceutics, Roche Research Funding: Astellas Pharma, QED Therapeutics, Macrophage Pharma No other potential conflicts of interest were reported.Fotios Loupakis Consulting or Advisory Role: Amgen, Sanofi, Bayer, Amal Therapeutics Speakers' Bureau: Roche, Sanofi, Bayer, Amgen Research Funding: Roche, Merck Serono, Amgen, Bayer Travel, Accommodations, Expenses: Roche, Amgen, Merck Serono Shruti Sharma Employment: Natera Stock and Other Ownership Interests: Natera Madiha Derouazi Employment: AMAL Therapeutics Leadership: AMAL Therapeutics Travel, Accommodations, Expenses: AMAL Therapeutics Derrick Renner Employment: Natera Stock and Other Ownership Interests: Natera Travel, Accommodations, Expenses: Natera Svetlana Shchegrova Employment: Natera Stock and Other Ownership Interests: Natera Allyson Koyen Malashevich Employment: Natera Stock and Other Ownership Interests: Natera Meenakshi Malhotra Employment: Natera Stock and Other Ownership Interests: Natera Himanshu Sethi Employment: Natera Stock and Other Ownership Interests: Natera Research Funding: Natera Patents, Royalties, Other Intellectual Property: Patents Travel, Accommodations, Expenses: Natera Bernhard G. Zimmermann Employment: Natera Stock and Other Ownership Interests: Natera Honoraria: Natera Patents, Royalties, Other Intellectual Property: Multiple patents and patent applications Alexey Aleshin Employment: Natera Leadership: Natera Stock and Other Ownership Interests: Natera Consulting or Advisory Role: Mission Bio Travel, Accommodations, Expenses: Natera Solomon Moshkevich Employment: Natera, Evidation Health Stock and Other Ownership Interests: Natera Patents, Royalties, Other Intellectual Property: Named as inventor on a patent filed by Natera Inc Travel, Accommodations, Expenses: Natera Paul R. Billings Employment: Natera Leadership: Biological Dynamics, OmniSeq, Alveo Technologies, Mission Bio Stock and Other Ownership Interests: Natera, Trovagene, Biological Dynamics, OmniSeq, Alveo Technologies Consulting or Advisory Role: Bethesda Group, Guidepoint Global Jonathon D. Sedgwick Employment: Boehringer Ingelheim Travel, Accommodations, Expenses: Boehringer Ingelheim Umberto Cillo Consulting or Advisory Role: Springer Health Care, Novartis, Johnson & Johnson, Astellas, Sandoz Speakers' Bureau: Eisai Angelo Paolo Dei Tos Consulting or Advisory Role: Bayer, Roche Vittorina Zagonel Consulting or Advisory Roles: Bristol Myers Squibb, MSD, Eisai, Italfarmaco Speakers' Bureau: Roche, Bristol Myers Squibb, Astellas Pharma, Servier, AstraZeneca, MSD, Jansen, Ipsen Research Funding: Bayer, Roche, Lilly, Astra Zeneca, BMS, Ipsen, Astellas Pharma Travel, Accommodations, Expenses: Bayer, Roche, Servier Sara Lonardi Consulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb Speakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen Research Funding: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb Matteo Fassan Consulting or Advisory Role: Astellas Pharma, Tesaro, GlaxoSmithKline, Diaceutics, Diaceutics, Roche Research Funding: Astellas Pharma, QED Therapeutics, Macrophage Pharma No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Five-year kidney graft loss currently stands at about 30%. We evaluate the clinical utility of a blood test measuring donor-derived cell-free DNA that detects rejection earlier and, potentially, improves diagnostic and therapeutic accuracy., Methods: In a randomized controlled experiment, we measured the clinical practice of 175 practicing nephrologists, both with and without the use of dd-cfDNA testing. Providers cared for six simulated post-renal transplant patient cases whose ages ranged from 30 to 75 years and were 3-24 months post-transplant with typical presentations., Results: 154 nephrologists completed two rounds of simulated cases. At baseline, the study arms performed similarly, demonstrating no significant differences either in primary diagnosis (p = 0.853), decisions to biopsy or refer to transplant center (p = 1.000), or therapeutic management (p = 0.488). After introduction of the dd-cfDNA test, intervention nephrologists were more likely to arrive at the diagnosis of rejection (OR 4.00, 95% CI 1.93-8.30), make a correct decision on biopsy/transplant center referral (OR 11.07, 95% CI 4.87-25.16), and properly adjust therapeutic management (OR 2.37, 95% CI 1.07-5.24)., Conclusion: A sample of nationally representative, practicing nephrologists given dd-cfDNA to evaluate post-transplant patients were more likely to correctly diagnose early and subclinical allograft rejection, to send for biopsy or refer to transplant center, and to appropriately change treatment than those nephrologists without dd-cfDNA access.

Background: The clinical utility of early detection and treatment of allograft rejection is well-established. Despite frequent testing called for by standard of care protocols, the five-year kidney allograft survival rate is estimated to be as low as 71%. Herein, we report on posttransplant care provided to kidney allograft recipients by board-certified nephrologists in the United States., Methods: We measured clinical practice in a representative sample of 175 practicing nephrologists. All providers cared for simulated patients' status after renal transplant ranging from 30-75 years in age and 3-24 months after transplant. Our sample of nephrologists cared for a total of 525 allograft cases. Provider responses to the cases were reviewed by trained clinicians, and care was compared to evidence-based care standards and accepted standard of care protocols., Results: Among nephrologists, practicing in settings ranging from transplant centers to community practice, we found that the clinical workup of kidney injury in posttransplant patients is highly variable and frequently deviates from evidence-based care. In cases with pathologic evidence of rejection, only 29.1% (102/350) received an appropriate, evidence-based biopsy, whereas, in cases with no pathological evidence of rejection, 41.3% (45/109) received low-value, unnecessary biopsies., Conclusion: Clinical care in the posttransplant setting is highly variable. Biopsies are often ordered in cases where their results do not alter treatment. Additionally, we found that misdiagnosis was common as were opportunities for earlier biopsy and detection of rejection. This evidence suggests that better diagnostic tools may be helpful to determine which transplant patients should be biopsied and which should not. This study suggests that nephrologists and transplant patients need better tests than creatinine and proteinuria and less invasive approaches than routine biopsies to determine when transplant patients should be investigated for rejection and additional treatment.

Standard noninvasive methods for detecting renal allograft rejection and injury have poor sensitivity and specificity. Plasma donor-derived cell-free DNA (dd-cfDNA) has been reported to accurately detect allograft rejection and injury in transplant recipients and shown to discriminate rejection from stable organ function in kidney transplant recipients. This study used a novel single nucleotide polymorphism (SNP)-based massively multiplexed PCR (mmPCR) methodology to measure dd-cfDNA in various types of renal transplant recipients for the detection of allograft rejection/injury without prior knowledge of donor genotypes. A total of 300 plasma samples (217 biopsy-matched: 38 with active rejection (AR), 72 borderline rejection (BL), 82 with stable allografts (STA), and 25 with other injury (OI)) were collected from 193 unique renal transplant patients; dd- cfDNA was processed by mmPCR targeting 13,392 SNPs. Median dd-cfDNA was significantly higher in samples with biopsy-proven AR (2.3%) versus BL (0.6%), OI (0.7%), and STA (0.4%) ( p < 0.0001 all comparisons). The SNP-based dd-cfDNA assay discriminated active from non-rejection status with an area under the curve (AUC) of 0.87, 88.7% sensitivity (95% CI, 77.7⁻99.8%) and 72.6% specificity (95% CI, 65.4⁻79.8%) at a prespecified cutoff (>1% dd-cfDNA). Of 13 patients with AR findings at a routine protocol biopsy six-months post transplantation, 12 (92%) were detected positive by dd-cfDNA. This SNP-based dd-cfDNA assay detected allograft rejection with superior performance compared with the current standard of care. These data support the feasibility of using this assay to detect disease prior to renal failure and optimize patient management in the case of allograft injury.

Background: The 22q11.2 deletion syndrome is a variably expressed disorder that can include cardiac, palate, and other physical abnormalities, immunodeficiency, and hypocalcemia. Because of the extreme variability in phenotype, there has been no available estimate of the total medical expenditure associated with the average case., Methods: We have developed a model to estimate the cost from the time of diagnosis to age 20. Costs were based on patients seen at a specialty center but also considered those components of care expected to have been provided by external healthcare facilities. Expense was based on billed medical charges extracted from the electronic medical billing system for all patients with a diagnosis of DiGeorge or velocardiofacial syndrome from 1993-2015. Expenditures included maternal prenatal care directly related to an affected pregnancy, molecular/cytogenetic diagnosis, consultations, surgery, and/or other treatment and management. Most mental health services (except inpatient), therapy related to cognitive, behavioral, speech, pharmacy, and nonmedical costs (special education, vocational, respite, lost earnings) were not included., Results: Data were available for 642 patients with 50.7% diagnosed prenatally or in the first year of life. The average cost for a patient was $727,178. Costs were highest for patients ascertained prenatally ($2,599,955) or in the first year of life ($1,043,096), those with cardiac abnormalities or referred for cardiac evaluation ($751,535), and patients with low T-cell counts ($1,382,222)., Conclusion: This study demonstrates that there are significant medical costs associated with 22q11.2 deletion syndrome., (© 2017 Natera. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: The choice of antiplatelet therapy after acute coronary syndrome (ACS) is complicated: Ticagrelor and prasugrel are novel alternatives to clopidogrel, patients with some genotypes may not respond to clopidogrel, and low-cost generic formulations of clopidogrel are available., Objective: To determine the most cost-effective strategy for dual antiplatelet therapy after percutaneous coronary intervention for ACS., Design: Decision-analytic model., Data Sources: Published literature, Medicare claims, and life tables., Target Population: Patients having percutaneous coronary intervention for ACS., Time Horizon: Lifetime., Perspective: Societal., Intervention: Five strategies were examined: generic clopidogrel, prasugrel, ticagrelor, and genotyping for polymorphisms of CYP2C19 with carriers of loss-of-function alleles receiving either ticagrelor (genotyping with ticagrelor) or prasugrel (genotyping with prasugrel) and noncarriers receiving clopidogrel., Outcome Measures: Direct medical costs, quality-adjusted life years(QALYs), and incremental cost-effectiveness ratios (ICERs)., Results of Base-Case Analysis: The clopidogrel strategy produced$179 301 in costs and 9.428 QALYs. Genotyping with prasugrel was superior to prasugrel alone, with an ICER of $35 800 per QALY relative to clopidogrel. Genotyping with ticagrelor was more effective than genotyping with prasugrel ($30 200 per QALY relative to clopidogrel). Ticagrelor was the most effective strategy($52 600 per QALY relative to genotyping with ticagrelor)., Results of Sensitivity Analysis: Stronger associations between genotype and thrombotic outcomes rendered ticagrelor substantially less cost-effective ($104 800 per QALY). Genotyping with prasugrel was the preferred therapy among patients who could not tolerate ticagrelor., Limitation: No randomized trials have directly compared genotyping strategies or prasugrel with ticagrelor., Conclusion: Genotype-guided personalization may improve the cost-effectiveness of prasugrel and ticagrelor after percutaneous coronary intervention for ACS, but ticagrelor for all patients may bean economically reasonable alternative in some settings.

In vitro destruction of carboxymethylcephades (CMC) polymer, its based polymer isoniazid produced, and the in vivo remedial and long effect of the latter on a tuberculous process were studied. It was found that a polymer isoniazid in blood plasma gradually degraded by 80% within 5-6 days. The experiments on animals demonstrated a minimum reactive action of CMC capable of gradually biodegrading in the tissues. A possible treatment of tuberculosis with a polymer isoniazid administered once every week is shown.

The article presents the results of an UV-spectroscopic experimental study of monomer release from basic stomatological compounds into the distilled water and the media which simulated the biological ones. The releasing was accelerated and the monomer levels increased in acid and base media as related to neutral ones. The prosthetic stomatites were shown to be related with the presence of a residual monomer.