Circulating cell-free DNA as predictor of pathological complete response in locally advanced rectal cancer patients undergoing preoperative chemoradiotherapy.

Background: The watch and wait (W&W) strategy is proposed for patients with locally advanced rectal cancer (LARC) achieving clinical complete response (cCR) after neoadjuvant radiotherapy. cCR is only in partial concordance with pathological complete response (pCR) due to persisting viable tumour cells. The aim was to investigate circulating-free-deoxyribonucleic-acid (cfDNA) as a biomarker for prediction of pCR. Materials and methods: Patients treated with neoadjuvant radiotherapy for LARC, were included in a prospective biomarker study in Aarhus, Denmark from 2017 to 2020. Plasma cfDNA levels were analysed by a direct fluorescent assay (DFA). Surgical specimens were reviewed by pathologists to categorize response to cytotoxic therapy. Results: In total, 76 patients were included with plasma available at baseline (n = 70), mid therapy (n = 50), and end of therapy (n = 54). Higher cfDNA levels were observed in LARC patients compared with healthy subjects (p < 0.01). By ROC analysis (AUC: 0.87 (95% CI, 0.81-0.92)) the optimal cut-off was 0.71 ng/µL for differentiation between healthy subjects and LARC patients. Thirteen patients obtained pCR with a median cfDNA level of 0.57 ng/µL at end of therapy. Patients with cfDNA levels at end of therapy below the cut-off (p < 0.02) and 'cfDNA responders' with descending levels greater than the 75th percentile during therapy had a significantly higher chance of pCR (p < 0.01). Conclusion: This hypothesis generating study indicates that low cfDNA levels at end of treatment or ´cfDNA responders might be associated with pCR. Quantification of cfDNA by the rapid and feasible DFA analysis could potentially facilitate personalized follow-up as a complementary tool to identify candidates for a W&W strategy.

Nonplatinum-based therapy with Paclitaxel and Capecitabine for advanced squamous cell carcinomas of the anal canal: A population-based Danish anal cancer group study.

BACKGROUND: First-line platinum-based therapy for advanced squamous cell carcinomas of the anal canal (SCCA) implies a risk of substantial side effects, and data on second-line treatment options are limited. Paclitaxel and Capecitabine are a well-known regimen with a moderate toxicity profile, but its efficacy has not been evaluated. METHODS: We conducted a retrospective study using Danish Hospital Registers of patients treated with Paclitaxel and Capecitabine for inoperable, recurrent, or advanced metastatic SCCA in Denmark, between January 2000 and July 2018. RESULTS: A total of 52 patients met the eligibility criteria. Median age was 60.7 years (range 42-83). Efficacy was observed, with an overall response rate in patients receiving first-line (N = 28) and second-line (N = 23) Paclitaxel and Capecitabine of 39.3% (2 with complete responses) and 17.4%, respectively. Median progression-free survival (PFS) was 4.5 months (95% CI 3.3-5.9) and 3.8 months (95% CI 2.4-5.5) with OS of 6.7 months (95% CI 5.9-8.5) and 5.9 months (95% CI 3.9-14), respectively. Performance status ≥2 and neutrophil to lymphocyte ratio ≥4 were significantly associated with a short PFS. CONCLUSION: This study recognizes Paclitaxel and Capecitabine as a potential regimen for advanced SCCA, when recommended first-line therapy is not feasible or as a potential second-line treatment after failure of platinum-based chemotherapy.

Correlation between early dynamics in circulating tumour DNA and outcome from FOLFIRI treatment in metastatic colorectal cancer.

Chemotherapy resistance remains a challenge in the clinical management of metastatic colorectal cancer (mCRC). Here, early changes in cell-free circulating tumour DNA (ctDNA) levels were explored as a marker of therapeutic efficacy. Twenty-four mCRC patients were enrolled and treated with FOLFIRI based first-line therapy. Blood samples collected pre-treatment, at day 7, 14, 21, 60 and at progression were analysed for cell-free DNA (cfDNA) and ctDNA levels using digital droplet PCR. A subset of samples were additionally analysed by targeted sequencing. Patients with high pre-treatment ctDNA or cfDNA levels (≥75th centile) had significantly shorter progression free survival (PFS) than patients with lower levels. Despite an overall decline in ctDNA levels from pre-treatment to first CT-scan, serial analysis identified seven patients with temporary increases in ctDNA consistent with growth of resistant cells. These patients had shorter PFS and shorter overall survival. Targeted sequencing analyses of cfDNA revealed dramatic changes in the clonal composition in response to treatment. Our study suggests that increasing ctDNA levels during the first cycles of first-line FOLFIRI treatment is a predictor of incipient progressive disease and poorer survival. Thus, we demonstrate the importance of monitoring ctDNA levels as early as one week after treatment onset to enable early detection of treatment failure.

Early gestational age at preeclampsia onset is associated with subclinical atherosclerosis 12 years after delivery.

INTRODUCTION: Women with a history of preeclampsia have increased risk of cardiovascular disease later in life. However, it is unclear whether early gestational age at preeclampsia onset is associated with higher cardiovascular disease risk. This study aimed to test the association between gestational age at preeclampsia onset (including the early-onset/late-onset preeclampsia distinction) and subclinical atherosclerosis and arterial stiffness in age-matched women 12 years after index pregnancy. MATERIAL AND METHODS: Eligible participants were identified in two Danish registries. Main outcome measures were carotid plaque presence, carotid intima-media thickness, aortic pulse wave velocity, and augmentation index adjusted for heart rate. RESULTS: Twenty-four women with previous early-onset preeclampsia, 24 with previous late-onset preeclampsia and 24 with previous normotensive pregnancies were included after matching on age (±2 years) and time since delivery (±1 year). In all outcome measures, the early-onset group had the highest percentage or mean value. In the adjusted analysis, the early-onset group significantly differed from the late-onset group in all outcome measures except aortic pulse wave velocity. The early-onset group also had significantly higher carotid intima-media thickness (average and left) compared with the normotensive group. Gestational age at preeclampsia onset as a continuous variable was significantly associated to both carotid plaque presence and carotid intima-media thickness (average and right). CONCLUSIONS: Gestational age at preeclampsia onset is negatively associated with markers of subclinical atherosclerosis 12 years after delivery. Potentially, gestational age at preeclampsia onset might be helpful in directing cardiovascular disease prevention after preeclampsia.

Preeclampsia and cardiovascular disease risk assessment - Do arterial stiffness and atherosclerosis uncover increased risk ten years after delivery?

OBJECTIVES: Epidemiological studies associate preeclampsia with increased risk of premature cardiovascular disease (CVD) later in life. This study aims to make a comprehensive CVD risk assessment comparing women with previous preeclamptic pregnancies to women with previous normotensive pregnancies 10years after index pregnancy. STUDY DESIGN: A nested, matched, observational cohort study. MAIN OUTCOME MEASURES: Markers of arterial stiffness, aortic pulse wave velocity (aPWV) and augmentation index (AIx-75), and markers of atherosclerosis, carotid intima-media thickness (cIMT) and carotid plaque presence. Traditional CVD risk factors and 10-year and 30-year Framingham CVD risk scores were also assessed. RESULTS: Women were included from April 2014 to October 2014 at a tertiary referral hospital in Denmark. Twenty-one exposed women with a history of preeclampsia and 21 unexposed with a history of normotensive pregnancies were included. Ten years after delivery, significantly more exposed women suffered from hypertension and received antihypertensive treatment and significantly more fulfilled the hypertension-definition at screening. Previously preeclamptic women also tended to have more unfavorable CVD risk estimates. The Framingham risk scores seemed to extend the unfavorable CVD risk. The exposed women tended to have a higher aPWV compared to unexposed women, (P=0.057). No differences were shown in the other examined arteriosclerotic or atherosclerotic variables. CONCLUSIONS: Ten years after delivery, we found increased risk of hypertension and trend toward unfavorable CVD risk profile in 40-year-old previously preeclamptic women. However, arterial stiffness and atherosclerosis did not uncover any additional CVD risk information at this time point.