Prognostic Surrogate Research Articles

Disease severity prognostication in primary sclerosing cholangitis: a validation of the Anali scores and comparison with the potential functional stricture.

Our aim was twofold. First, to validate Anali scores with and without gadolinium (ANALIGd and ANALINoGd) in primary sclerosing cholangitis (PSC) patients. Second, to compare the ANALIs prognostic ability with the recently-proposed potential functional stricture (PFS). This retrospective study included 123 patients with a mean age of 41.5 years, who underwent gadoxetic acid-enahnced MRI (GA-MRI). Five readers independently evaluated all images for calculation of ANALIGd and ANALINoGd scores based upon following criteria: intrahepatic bile duct change severity, hepatic dysmorphia, liver parenchymal heterogeneity, and portal hypertension. In addition, hepatobiliary contrast excretion into first-order bile ducts was evaluated on 20-minute hepatobiliary-phase (HBP) images to assess PFS. Inter- and intrareader agreement were calculated (Fleiss´and Cohen kappas). Kaplan-Meier curves were generated for survival analysis. ANALINoGd, ANALIGd, and PFS were correlated with clinical scores, labs and outcomes (Cox regression analysis). Inter-reader agreement was almost perfect(ϰ = 0.81) for PFS, but only moderate-(ϰ = 0.55) for binary ANALINoGd. For binary ANALIGd, the agreement was slightly better on HBP (ϰ = 0.64) than on arterial-phase (AP) (ϰ = 0.53). Univariate Cox regression showed that outcomes for decompensated cirrhosis, orthotopic liver transplantation or death significantly correlated with PFS (HR (hazard ratio) = 3.15, p < 0.001), ANALINoGd (HR = 6.42, p < 0.001), ANALIGdHBP (HR = 3.66, p < 0.001) and ANALIGdAP (HR = 3.79, p < 0.001). Multivariate analysis identified the PFS, all three ANALI scores, and Revised Mayo Risk Score as independent risk factors for outcomes (HR 3.12, p < 0.001; 6.12, p < 0.001; 3.56, p < 0.001;3.59, p < 0.001; and 4.13, p < 0.001, respectively). ANALINoGd and GA-MRI-derived ANALI scores and PFS could noninvasively predict outcomes in PSC patients. The combined use of Anali scores and the potential functional stricture (PFS), both derived from unenhanced-, and gadoxetic acid enhanced-MRI, could be applied as a diagnostic and prognostic imaging surrogate for counselling and monitoring primary sclerosing cholangitis patients. Primary sclerosing cholangitis patients require radiological monitoring to assess disease stability and for the presence and type of complications. A contrast-enhanced MRI algorithm based on potential functional stricture and ANALI scores risk-stratified these patients. Unenhanced ANALI score had a high negative predictive value, indicating some primary sclerosing cholangitis patients can undergo non-contrast MRI surveillance.

Performance status as a prognostic surrogate in hepatocellular carcinoma: Role of albumin-bilirubin and easy-albumin-bilirubin grade.

Performance status (PS) is associated with the severity of liver cirrhosis and is also an important survival determinant in hepatocellular carcinoma (HCC). Albumin-bilirubin (ALBI) grade and easy (EZ)-ALBI grade have been proposed to evaluate liver dysfunction in HCC, but their role in patients with different PS is unclear. We aimed to investigate the prognostic role of ALBI and EZ-ALBI grade in a large HCC cohort with variable PS. A total of 3355 newly diagnosed HCC patients between 2002 and 2018 were identified and retrospectively analyzed. Independent prognostic predictors associated with survival were investigated using the Cox proportional hazards model. Patients with poor PS had decreased survival compared with those with good PS. In the Cox model, creatinine ≥1.2 mg/dL, α-fetoprotein (AFP) ≥20 ng/mL, vascular invasion, distant metastasis, total tumor volume >100 cm 3 , presence of ascites, ALBI grades 2 and 3, EZ-ALBI grade 2 and grade 3, PS 1-4, and noncurative treatment were independently associated with higher mortality in the entire cohort (all p < 0.001). ALBI grade and EZ-ALBI grade can well stratify overall survival in subgroup patients with PS 0, PS 1-2, and PS 3-4 (all p < 0.001). Patients with good PS have better long-term survival compared with those with poor PS. ALBI and EZ-ALBI grade can discriminate long-term outcome in the entire cohort as well as in patients with different PS. ALBI and EZ-ALBI are objective and feasible prognostic models to evaluate liver dysfunction in HCC patients independent of PS.

Predicting Survival of Patients with Nonmetastatic Breast Cancer Based on Fibrinogen-to-Albumin Ratio and Lymphocyte-to-Monocyte Ratio: A Nomogram-Based Assessment

Background: Parameters of systemic inflammation have received attention as prognostic surrogates in various malignant tumors. Fibrinogen-to-albumin ratio (FAR) and lymphocyte-to-monocyte ratio (LMR) correlate with tumor growth and dissemination. We aimed to bring the combination of FAR and LMR (FAR-LMR) together to establish novel nomograms for survival and recurrence in nonmetastatic breast cancer patients. Methods: We retrospectively recruited 461 female patients with nonmetastatic breast cancer from January 2011 to December 2013 in our hospital and randomly assigned them into the training cohort (N = 318) and the validation cohort (N = 143). The potential predictive factors for overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Cox proportional hazards models and log-rank test. Results: Elevated FAR was associated with poor OS (p < 0.001) and DMFS (p = 0.02), whereas increased LMR was associated with satisfactory OS (p = 0.01) and LRFS (p = 0.01). High FAR combined with low LMR was associated with less favorable OS (p = 0.001), LRFS (p = 0.005), and DMFS (p = 0.003) Based on multivariate analysis, FAR-LMR, tumor size, lymph node metastasis, age, and pathologic status contributed to prognostic nomograms of OS, DMFS, and LRFS. Nomograms presented exceptional performance for 3-, 5-, and 8-year OS, DMFS, and LRFS prediction compared with clinical TNM stage. The C-index was significantly higher than that of TNM stage, either of FAR or LMR (3-year: 0.709 vs. 0.621 vs. 0.544 vs. 0.641, 5-year: 0.761 vs. 0.597 vs. 0.605 vs. 0.677, 8-year: 0.84 vs. 0.62 vs. 0.539 vs. 0.623). Conclusions: We developed and validated a convenient predictive model for the survival outcomes of patients with nonmetastatic breast cancer. The nomograms can be utilized as auxiliary tools to provide prognostic information.

Evaluating clinical efficacy of hospital-based surveillance with mammography and ultrasonography for breast cancer

Periodic mammography and/or sonography examinations are conducted across numerous hospitals nationalwidely, especially for antedees with a positive mammography screening. Despite the regular practice, clinical efficacy of hospital-based breast cancer surveillance remains unclear. Specifically, the impact of surveillance interval upon survival and prognostic surrogates stratified by menopausal status, as well as malignant transition rate should be deciphered. We retrieved cancer registry to ascertain 841 breast cancers with surveillance history through administration data. Healthy controls underwent breast surveillance and were concurrently free of cancer. More benign diseases rather than cancers were identified from premenopausal women (age ≤50 years) with sonography alone within one year, as well as older women (age >50) with both mammography and sonography one to two years before a cancer or benign diagnosis. Among breast cancers, mammography alone during the antecedent one to two years had a protective effect for diagnosing carcinoma in situ rather than invasive cancer (age-adjusted odds ratio: 0.048, P=0.016). Three-state time homogeneous Markov model showed that hospital-based breast surveillance within 2 years of disease onset reduced the malignant transition rate by 65.16% (59.79-76.74%). The clinical efficacy of breast cancer surveillance was evidenced.

CO90 A Systematic Literature Review of Prognostic Factors and Surrogate Endpoint Analyses in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

CO90 A Systematic Literature Review of Prognostic Factors and Surrogate Endpoint Analyses in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Current Challenges and Perspectives on Developing a Clinical Trial Design for ADPKD.

Current Challenges and Perspectives on Developing a Clinical Trial Design for ADPKD.

Tumor burden score as a new prognostic surrogate in patients with hepatocellular carcinoma undergoing radiofrequency ablation: role of albumin-bilirubin (ALBI) grade vs easy ALBI grade

ABSTRACT Introduction Tumor burden score (TBS) was proposed to represent tumor burden in solid tumors, including hepatocellular carcinoma (HCC). The prognostic role of TBS in HCC patients in relation to recently introduced liver reserve markers, albumin-bilirubin (ALBI) grade, and easy (EZ)-ALBI grade, is unclear. We aimed to investigate the feasibility of TBS in HCC patients undergoing radiofrequency ablation (RFA). Research design and methods A total of 576 treatment-naïve patients with HCC undergoing RFA were analyzed. The multivariate Cox analysis was used to identify independent predictors associated with tumor recurrence and long-term survival. Results Patients with high TBS had increased risk of tumor recurrence and mortality compared with those with low TBS. The Cox analysis showed that serum ɑ-fetoprotein (AFP) level >20 ng/mL, medium and high TBS, ALBI grade 2 and grade 3, EZ-ALBI grade 2 and grade 3 were associated with tumor recurrence and decreased patient survival (all p <0.05). In addition, TBS can reliably stratify tumor recurrence and overall survival in different ALBI and EZ-ALBI grade groups. Conclusions TBS is a simple and feasible prognostic surrogate to predict tumor recurrence and survival in HCC patients undergoing RFA. Its prognostic ability remains stable in patients with variable liver functional reserve.

Serum Chloride and Admission Status Are Potential Prognostic Markers of High-Risk Polyps: A Prospective Characterization of Colorectal Polyps in a Tertiary Hospital in Saudi Arabia.

Background: Colorectal cancer (CRC) is the most common cancer in men in Saudi Arabia. Other than age and family history, clinical and laboratory prognostic surrogates that may aid in streamlining and prioritization of screening colonoscopies are scarce. Through the examination of the local prevalence of advanced and malignant colorectal polyps, we hypothesized that the presence of certain clinical or laboratory parameters may signify an association with having high-risk polyps.Methods: A prospective study over a period of one year starting on January 21, 2018 and involving all adult patients undergoing colonoscopy at King Saud Medical City, Riyadh. Of the total 1,104 recruited patients, 717 were included. The patients were sub-grouped based on the presence or absence of polyps. Patients with polyps were further sub-grouped into high-risk or low-risk polyps. Comparisons between groups were performed using univariate, relative risks (RRs), and multivariate analyses.Results: Our polyp detection rate was 34.7% and our adenoma detection rate was 21.3%. The prevalence of advanced adenoma was 15.2% and the prevalence of malignant polyps was 6.7%. Several prognostic markers were associated with high-risk polyps such as advanced age (RR = 1.35, 95% confidence interval [CI]: 1.03 to 1.78), male gender (RR = 1.18, 95% CI: 1.06 to 1.31), inpatient status (RR = 1.46, 95% CI: 1.04 to 2.21), and low serum chloride (RR = 1.89, 95% CI: 1.05 to 2.37). With multivariate analysis, the hazard ratios for inpatient status and hypochloremia were 1.67 (95% CI: 1.034 to 2.612) and 1.12 (95% CI: 1.011 to 1.265), respectively.Conclusion: We report the prevalence of malignant colorectal polyps in Saudi Arabia which was not reported before. Two unique prognostic markers for high-risk polyps were identified, namely, inpatient status and hypochloremia.

The prognostic value of high-density lipoprotein cholesterol in patients with decompensated cirrhosis: a propensity score matching analysis

Emerging evidence has implicated that high-density lipoprotein cholesterol (HDL-C) as a prognostic surrogate in the context of cirrhosis. However, an exact cutoff has not been fully elucidated. We aimed to clarify optimal cutoff of HDL-C for short-term mortality based on time-to-event analysis and validated this association by performing propensity score matching (PSM) analysis. A total of 238 patients with decompensated cirrhosis were enrolled. The optimal cutoff of HDL-C was initially determined by X-tile program. Independent risk factors for 180-day mortality were identified by multiple Cox regression. The Kaplan-Meier method was implemented to generate survival curves. A 1:2 ratio PSM was performed to diminish selection bias and potential confounders. The X-tile implied that the difference in survival was most significant for HDL <0.4mmol/L (<16mg/dL). Circulating HDL <0.4mmol/L exhibited an independent risk factor both in the entire cohort and PSM subset (HR 2.696, 95% CI 1.082-6.791, P = 0.033; HR 2.735, 95% CI 1.027-7.734, P = 0.048). Furthermore, HDL-C combined with conventional scoring systems had higher AUCs associated with poor prognosis than Child-Pugh classification or model for end-stage liver disease (MELD) in isolation (0.78 vs 0.66; 0.74 vs 0.54, P < 0.05 for both). HDL-C <0.4 mmol/L may serve as a readily available and robust cutoff for stratifying cirrhotic patients at high 180-day mortality risk. The incorporation of HDL-C to Child-Pugh classification or MELD has the potentials to provide substantially clinical relevance without extra economic cost.

Left atrial reservoir strain as a predictor of cardiac outcome in patients with heart failure: the HaFaC cohort study

BackgroundThe left atrium (LA) is a key player in the pathophysiology of systolic and diastolic heart failure (HF). Speckle tracking derived LA reservoir strain (LASr) can be used as a prognostic surrogate for elevated left ventricular filling pressure similar to NT-proBNP. The aim of the study is to investigate the correlation between LASr and NT-proBNP and its prognostic value with regards to the composite endpoint of HF hospitalization and all-cause mortality within 1 year.MethodsOutpatients, sent to the echocardiography core lab because of HF, were enrolled into this study. Patients underwent a transthoracic echocardiographic examination, commercially available software was used to measure LASr. Blood samples were collected directly after the echocardiographic examination to determine NT-proBNP.ResultsWe included 174 HF patients, 43% with reduced, 36% with mildly reduced, and 21% with preserved ejection fraction. The study population showed a strong inverse correlation between LASr and log-transformed NT-proBNP (r = − 0.75, p < 0.01). Compared to NT-proBNP, LASr predicts the endpoint with a comparable specificity (83% vs. 84%), however with a lower sensitivity (70% vs. 61%).ConclusionLASr is inversely correlated with NT-proBNP and a good echocardiographic predictor for the composite endpoint of hospitalization and all-cause mortality in patients with HF.Trial registration:https://www.trialregister.nl/trial/7268

A Feasibility Study Evaluating the Use of Cell-free DNA Analysis in Laboratory Brain Cancer Investigations

Abstract Aims Circulating tumour DNA (ctDNA), shed from solid cancers in to the plasma, represents an exciting analyte for diagnosis and monitoring of disease in cancer patients. However, its use in glioma brain cancer patients represents a challenge, due to reduced permeability of the blood brain barrier. This pilot study sought to investigate the practical aspects and clinical utility of using cell-free DNA (cfDNA) in glioma tests in a NHS diagnostic laboratory. Firstly, we investigated the potential of ctDNA as a proxy for the brain cancer biopsy; where cfDNA analysis was compared to the paired FFPE brain specimen for relevant glioma genetic biomarkers. Secondly, ctDNA constitutes a portion of the overall cfDNA and there is evidence cfDNA metrics per se may also be of value as prognostic tools and surrogates of tumour burden. Additionally, we investigated a potential role for cfDNA metrics in prognostic impact; linking cfDNA concentrations to clinical outcome measures. Method 10ml peripheral blood was collected in specialist preservative tubes and cfDNA isolated using an extraction kit (Qiagen MinElute ccfDNA kit). cfDNA concentration and purity was assessed using chip-based automated electrophoresis. Where relevant (12/39 cases), cfDNA samples were run though laboratory tests of IDH variant detection, 1p19q co-deletion assessment and MGMT promoter methylation analysis. Results were compared with ‘standard of care’ brain biopsy tests. A potential correlate of cfDNA concentration and clinical outcomes data were assessed in a sub-cohort of glioblastoma patients (n=32). The cohort was divided in to 2 groups – high cfDNA vs. low cfDNA - based on whether a subject’s extracted sample cfDNA concentration fell above or below the mean. Comparison of overall survival in months between subjects was checked for normal distribution using the Shapiro-Wilk t-test. The test of equity of survival distributions for the high cfDNA vs. low cfDNA was then analysed as a Kaplan-Meier curve. Results The protocol delivered cfDNA of high purity, averaging 91%, within the plasma nucleic acid fraction, however the cfDNA concentrations (mean ≈1ng µl-1) fell below the conventional limit of detection of the laboratory tests. In spite of the low concentration, cfDNA samples did generate test PCR amplicon; however results reflected the germline DNA profile rather than the new somatic changes of the tumour. The cfDNA analysis did not pick up the tumour biomarkers seen in the paired tumour biopsy sample. In a second part of the study, cfDNA concentrations for the glioblastoma cohort were assessed in the context of their clinical outcomes data. The data showed a correlate where high cfDNA concentration in the extracted sample was independently associated with inferior outcome in terms of overall survival, with Log Rank significance p=0.014 (Figure 1). Conclusion The cfDNA yields from a 10ml blood sample were consistently too low to meet the limit of detection requirements of the standard laboratory neuropathology genetic tests and glioma tumour profile could not be picked up against the germline background. Thus, in spite of the considerable advantages to glioma plasma molecular testing, using cfDNA as a proxy for a brain biopsy would currently not be possible in our routine diagnostic environment. However, within the limitations of the pilot project testing strategy, the data showed an interesting correlate where high cfDNA concentration was independently associated with inferior outcome in terms of overall survival for glioblastoma patients. Given the simplicity of obtaining this quantifiable metric, there are grounds for further investigations as to its utility; not only with survival outcomes, but also potential correlation with the clinical assessment of tumour burden, blood brain barrier integrity and disease pseudoprogression.

The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99-not applicable], compared with 117 days (95% CI, 106-143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. SIGNIFICANCE: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659.

Genome-wide association study to reveal novel germline markers of melanoma survival.

9581 Background: Cutaneous melanoma (CM) is the most invasive form of skin cancer accounting for ̃80% of all skin cancer related deaths. While tumor staging (based on recent AJCC classification) is routinely used in prognostic assessment, a large fraction of the outcomes is not explained by AJCC staging system. This urges for the discovery of a more personalized prognostic surrogates. Growing evidence highlights the role of germline genetics in CM progression; yet, to date no systematic prognostic germline study has been conducted in melanoma. We performed the first genome-wide association analysis (GWAS) to identify germline variants associated with melanoma survival. Methods: A cases/case GWAS was performed using the Infinium global screening array (GSA v3.0) to genotype 1,117 stage 0-III melanoma patients with no history of immunotherapy treatments ascertained at New York University Langone Health (NYULH). We randomly divided the study cohort into a discovery (N=630) and a validation (N=487) sets and tested the association of &gt; 5 million imputed germline variants with melanoma overall survival (OS) by fitting Cox-proportional hazard ratio (HR) regression in an additive genetic model adjusting for sex, age at diagnosis, AJCC 8th staging, tumor anatomic sites, and top 3 principal components. Results: We found 151 independent variants associated with melanoma OS (p&lt; 5×10−5) in the discovery cohort. Two of these associations validated in the independent replication set ( Bonferroni threshold for 151 tests: p &lt; 0.003) with enhanced clinical and statistical significance in the pooled meta-analysis: rs4128212 [HR =2.47(1.75-3.48); p=2.2× 10−7], and rs13212644 [HR =2.59 (1.72-3.88); p=4.2× 10−6]. We further tested the combined effect of these two variants and found the presence of at least one risk allele of the variants associated with a substantially increased risk of death, surpassing GWAS level of significance (HR=3.74 (2.43-5.74); p=1.5×10−9). Conclusions: We present the results of first GWAS testing an association of germline variation with melanoma OS. Stemming from a unique patient population with extensive clinical follow-up data, we identified two prognostic germline loci with large HR effect size &gt;2.5 that were independently validated. The observed association is independent of established histopathologic markers. While rs4128212 was mapped to a putative cancer prognostic gene locus (PLPP4: phospholipid phosphatase 4), rs13212644 was an eQTL (expression quantitative trait loci) for GCLC (Glutamate-Cysteine Ligase Catalytic Subunit), a key regulator in glutathione synthesis previously linked with favorable melanoma survival. The significantly enhanced combined effect of these two loci (HR &gt;3.5; p&lt;5×10−9) indicates a great promise for their clinical utility as independent personalized predictive markers of melanoma progression.

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer.

The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined. This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model. The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate. AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC. The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.

Background Parenchymal Enhancement on Breast MRI as a Prognostic Surrogate: Correlation With Breast Cancer Oncotype Dx Score.

PurposeBreast MRI background parenchymal enhancement (BPE) can potentially serve as a prognostic marker, by possible correlation with molecular subtype. Oncotype Dx, a gene assay, is a prognostic and predictive surrogate for tumor aggressiveness and treatment response. The purpose of this study was to investigate the association between contralateral non-tumor breast magnetic resonance imaging (MRI) background parenchymal enhancement and tumor oncotype score.MethodsIn this retrospective study, patients with ER+ and HER2− early stage invasive ductal carcinoma who underwent preoperative breast MRI, oncotype risk scoring, and breast conservation surgery from 2008–2010 were identified. After registration, BPE from the pre and three post-contrast phases was automatically extracted using a k-means clustering algorithm. Four metrics were calculated: initial enhancement (IE) relative to the pre-contrast signal, late enhancement, overall enhancement (OE), and area under the enhancement curve (AUC). Histogram analysis was performed to determine first order metrics which were compared to oncotype risk score groups using Mann–Whitney tests and Spearman rank correlation analysis.ResultsThis study included 80 women (mean age = 51.1 ± 10.3 years); 46 women were categorized as low risk (≤17) and 34 women were categorized as intermediate/high risk (≥18) according to Oncotype Dx. For the mean of the top 10% pixels, significant differences were noted for IE (p = 0.032), OE (p = 0.049), and AUC (p = 0.044). Using the risk score as a continuous variable, correlation analysis revealed a weak but significant correlation with the mean of the top 10% pixels for IE (r = 0.26, p = 0.02), OE (r = 0.25, p = 0.02), and AUC (r = 0.27, p = 0.02).ConclusionBPE metrics of enhancement in the non-tumor breast are associated with tumor Oncotype Dx recurrence score, suggesting that the breast microenvironment may relate to likelihood of recurrence and magnitude of chemotherapy benefit.

High-Density Lipoprotein Cholesterol Efflux Capacity as a Novel Prognostic Surrogate for Coronary Artery Disease.

Aim: We examined the impact of baseline high-density lipoprotein cholesterol efflux capacity (CEC) on major cardiac adverse events (MACE) in patients with coronary artery disease (CAD) during a long-term secondary prevention. Method: CEC was measured using a cell-based efflux system in (3)[H]-cholesterol-labeled J774 macrophages in apolipoprotein B-depleted plasma between January 2011 and January 2013. Patients with CAD were divided into 2 groups as a boundary CEC value of 1: 0.19 ≤ CEC ＜1 (impaired CEC group, mean CEC of 0.76±0.16, n =136), and 1 ≤ CEC ≤ 2.08 (enhanced CEC group, 1.20±0.19, n =44). MACE, comprised the incidence of cardiac death, non-fatal myocardial infarction, and any revascularizations (RV) without restenosis approximately 1 year after vascularization, was retrospectively investigated at September 2019. Impact of enhanced CEC on MACE among 22 variables was examined by applying a Cox proportional hazard model. Result: The frequency of MACE in impaired CEC group (16.9%, mean observational interval of 2111±888 days) was significantly higher than that in enhanced CEC group (2.3%, 2,252±685, p =0.013), largely driven by the significantly higher RV incidence (14.0 % versus 2.3 %, p =0.032). Enhancement of CEC was the significant predictor of MACE (hazard ratio: 0.11; 95% CI: 0.013-0.879; p =0.038). Conclusion: A baseline CEC level of more than 1 in patients with CAD brought favorable long-term clinical outcomes, suggesting that CEC is a useful prognostic and therapeutic surrogate for secondary prevention of CAD.

Clinical Utility of Plasma Cell-Free DNA in Adult Patients with Newly Diagnosed Glioblastoma: A Pilot Prospective Study.

The clinical utility of plasma cell-free DNA (cfDNA) has not been assessed prospectively in patients with glioblastoma (GBM). We aimed to determine the prognostic impact of plasma cfDNA in GBM, as well as its role as a surrogate of tumor burden and substrate for next-generation sequencing (NGS). We conducted a prospective cohort study of 42 patients with newly diagnosed GBM. Plasma cfDNA was quantified at baseline prior to initial tumor resection and longitudinally during chemoradiotherapy. Plasma cfDNA was assessed for its association with progression-free survival (PFS) and overall survival (OS), correlated with radiographic tumor burden, and subjected to a targeted NGS panel. Prior to initial surgery, GBM patients had higher plasma cfDNA concentration than age-matched healthy controls (mean 13.4 vs. 6.7 ng/mL, P < 0.001). Plasma cfDNA concentration was correlated with radiographic tumor burden on patients' first post-radiation magnetic resonance imaging scan (ρ = 0.77, P = 0.003) and tended to rise prior to or concurrently with radiographic tumor progression. Preoperative plasma cfDNA concentration above the mean (>13.4 ng/mL) was associated with inferior PFS (median 4.9 vs. 9.5 months, P = 0.038). Detection of ≥1 somatic mutation in plasma cfDNA occurred in 55% of patients and was associated with nonstatistically significant decreases in PFS (median 6.0 vs. 8.7 months, P = 0.093) and OS (median 5.5 vs. 9.2 months, P = 0.053). Plasma cfDNA may be an effective prognostic tool and surrogate of tumor burden in newly diagnosed GBM. Detection of somatic alterations in plasma is feasible when samples are obtained prior to initial surgical resection.

Prognostic Significance of Patient-Reported Outcomes in Cancer.

Performance status (PS), an established prognostic surrogate of cancer survival, is a physician-synthesized metric of patient symptoms and mobility that is prone to bias and subjectivity. The National Cancer Institute (NCI) Patient-Reported Outcomes Measurement Information System-Cancer (PROMIS-Ca) Bank, a patient-centric patient-reported outcome (PRO) evaluation of physical function (PF), fatigue, depression, anxiety, and pain, shares subject matter with PS and, therefore, may also be prognostic while eliminating physician interpretation. Patients at Huntsman Cancer Institute were assessed using the NCI PROMIS-Ca Bank. Using tablets at routine office visits, PF, fatigue, depression, anxiety, and pain scores were collected from patients with advanced melanoma, non-small-cell lung cancer, colorectal cancer, and breast cancer. A PRO score collected at a single time point within 6 months of metastatic diagnosis for each patient was merged with curated clinical outcome data. The association of PROs, overall survival (OS), and hospitalization-free survival (HFS) were assessed in multivariable analysis that included sex and cancer type. Two hundred eighty-two complete sets of patient data were available for analysis. All 5 PRO domains were strongly prognostic of OS and HFS. While the PRO domains were interrelated with moderate to strong correlations (0.40-0.79), multivariable regression suggested that PF was most strongly associated with the clinical outcomes of OS (P < .001) and HFS (P < .001). NCI PROMIS-Ca PROs may be prognostic of both cancer survival and likelihood of hospitalization. Future prospective studies are needed for all major prognostic factors to fully understand the independent prognostic value of PROs.

Characteristics of cancer susceptibility genes mutations in 282 patients with gastric adenocarcinoma.

ObjectiveTo reveal the distribution signature of cancer susceptibility genes in patients with gastric adenocarcinoma, offering a diagnostic and prognostic surrogate for disease risk management and therapeutic decisions.MethodsA total of 282 patients with gastric adenocarcinoma (182 males and 100 females) were enrolled in this study, with peripheral blood genomic DNA extracted. Mutations of 69 canonical cancer susceptibility genes or presumably tumor-related genes were analyzed by targeted capture-based high-throughput sequencing. Candidate mutations were particularly selected for discussion on tumor pathogenesis according to the American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsIn this study, 7.1% (20/282) of patients with gastric adenocarcinoma were found to harbor mutations of canonical or presumable cancer susceptibility genes. The detection rate in male patients (3.8%, 7/182) was significantly lower than that in female patients (13%, 13/100) (P=0.004). The most recurrent mutations were in A-T mutated (ATM) (1.1%, 3/282), followed by BRCA1, BRIP1 and RAD51D, all showed a detection rate of 0.7% (2/282). Mutations in three genes associated with hereditary gastric cancer syndromes were detected, namely, PMS2 and EPCAM associated with Lynch syndrome and CDH1 associated with hereditary diffuse gastric cancer. The detection frequencies were all 0.4% (1/282). Notwithstanding no significant difference observed, the age of patients with pathogenic mutations or likely pathogenic mutations is slightly younger than that of non-carriers (median age: 58.5 vs. 60.5 years old), while the age of patients with ATM mutations was the youngest overall (median age: 49.3 years old). ConclusionsOur study shed more light on the distribution signature and pathogenesis of mutations in gastric cancer susceptibility genes, and found the detection rate of pathogenic and likely pathogenic mutations in male patients was significantly lower than that in female patients. Some known and unidentified mutations were found in gastric cancer, which allowed us to gain more insight into the hereditary gastric cancer syndromes from the molecular perspective.

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome and Adjuvant Chemotherapy in Patients with Locally Advanced Rectal Cancer: Result from a Multicentre, Observational, Cohort Study

Background: NCCN's Rectal Cancer Guideline Panel recommends the American Joint Committee on Cancer and the College of American Pathologists tumor regression grading (AJCC/CAP TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC). Yet, the clinical significance of AJCC/CAP TRG system has not been fully defined. Methods: This was a retrospectively designed, multicentre and prospectively maintained cohort study. Of which, LARC cases from one institution formed discovery cohort to determine the relationship between AJCC/CAP TRG system and overall survival (OS), disease free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS), as well as the risk of disease progression (death, disease relapse, local recurrence, and distant metastasis). Moreover, patients from other institutions formed the validation cohort. Kaplan-Meier survival functions were computed and the hazard ratios calculated, with the Cox regression hazards model. Findings: The discovery cohort (940 cases) found and validation cohort (2156 cases) further confirmed that the inferior AJCC/CAP TRG categories were closely correlated with an unfavorable OS, DFS, LRFS and DMFS, as well as a higher risk of disease progression (all P < 0·05). Significantly, the pairwise comparison revealed that any 2 of the 4 TRG categories had a distinguished survival (OS, DFS, LRFS and DMFS) ratio and risk of disease progression. In contrast, the similar findings were not observed at the ypT and ypN stage categories patients, as some two consecutive ypT and ypN categories patients had the comparable survival (OS, DFS, LRFS and DMFS) ratio and risk of disease progression. Importantly, after the propensity score matching, Kaplan-Meier analysis showed that the AJCC/CAP TRG0 category patients treated with or without adjuvant chemotherapy had a similar OS, DFS, LRFS and DMFS. Conversely, for the AJCC/CAP TRG1-3 categories cases, adjuvant chemotherapy treatment significantly improved the 3-year OS (90·2% vs. 84·6%, P < 0·001). Receiver operating characteristic and multivariate analysis demonstrated AJCC/CAP TRG system was an independent prognostic surrogate in discovery cohort and validation cohort (all P < 0·05). Interpretation: Based on one of the largest dataset, AJCC/CAP TRG system, a useful prognostic surrogate, appears ideal for further strategizing therapy after nCRT for LARC. Funding: National Natural Science Foundation of China, International Center for Genetic Engineering and Biotechnology grant. Declaration of Interest: All authors declare no competing interests. Ethical Approval: The Clinical Ethics Review Committee at the Sixth Affiliated Hospital of Sun Yat-sen University approved this study.