Purpose Molecular testing of colorectal cancers (CRCs) to improve patient care and outcomes of targeted and conventional therapies has been the center of many recent studies, including clinical ...trials. Evidence-based recommendations for the molecular testing of CRC tissues to guide epidermal growth factor receptor (EGFR) -targeted therapies and conventional chemotherapy regimens are warranted in clinical practice. The purpose of this guideline is to develop evidence-based recommendations to help establish standard molecular biomarker testing for CRC through a systematic review of the literature. Methods The American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to develop an evidence-based guideline to help establish standard molecular biomarker testing, guide targeted therapies, and advance personalized care for patients with CRC. A comprehensive literature search that included over 4,000 articles was conducted to gather data to inform this guideline. Results Twenty-one guideline statements (eight recommendations, 10 expert consensus opinions and three no recommendations) were established. Recommendations Evidence supports mutational testing for genes in the EGFR signaling pathway, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize molecular testing for predictive and prognostic molecular biomarkers involve selection of assays, type of specimens to be tested, timing of ordering of tests and turnaround time for testing results. Additional information is available at: www.asco.org/CRC-markers-guideline and www.asco.org/guidelineswiki.
Aim: To determine if the mode of presentation of venous thromboembolism (VTE), as deep vein thrombosis (DVT) or pulmonary embolism (PE), predicts the likelihood and type of recurrence. Methods: We ...carried out a patient‐level meta‐analysis of seven prospective studies in patients with a first VTE who were followed after anticoagulation was stopped. We used Kaplan‐Meier analysis to determine the cumulative incidence of recurrent VTE according to mode of presentation, and multivariable Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mode of and extent of DVT as potential risk factors for recurrence. Results: The 5‐year cumulative rate of recurrent VTE in 2554 patients was 22.6%. In 869 (36.1%) patients with PE, the 5‐year rate of any recurrence (DVT or PE) was 22.0%, and recurrence as PE was 10.6%. In 1365 patients with proximal DVT, the 5‐year recurrence rate was 26.4%, and recurrence with PE was 3.6%. The risk of recurrence as PE was 3.1‐fold greater in patients presenting with symptomatic PE than in patients with proximal DVT (HR, 3.1; 95% CI, 1.9–5.1). Patients with proximal DVT had a 4.8‐fold higher cumulative recurrence rate than those with distal DVT (HR, 4.8; 95% CI, 2.1–11.0). Conclusion: Whilst DVT and PE are manifestations of the same disease, the phenotypic expression is predetermined. Patients presenting with PE are three times more likely to suffer recurrence as PE than patients presenting with DVT. Patients presenting with calf DVT are at low risk of recurrence and at low risk of recurrence as PE.
Background and Objectives
Outcomes for gastrointestinal peritoneal metastases (GI‐PM) are worse compared to systemic metastases, with a paucity of data exploring extended mutation profiling. An ...exploratory mutation analysis in GI‐PMs was performed as a “proof of concept” of potential predictive values of profiling in GI‐PM and rates of actionable mutations.
Methods
The study included 40 GI‐PM patients: 14 low‐grade mucinous carcinoma peritonei and 26 HG‐PM (12 colons, 10 appendix, 4 small bowels). Demographics, histologies, peritoneal cancer indexes, cytoreduction scores, and survival data were collected. NGS 50‐gene mutation profiling was performed on 38 specimens. The association of mutations with survival was evaluated in high‐grade PM.
Results
KRAS, TP53, and SMAD4 mutations were observed in 61%, 29%, and 8% of cases across all tumor histologies. In 66% cases >1 mutations occurred, associated with decreased survival in HG‐PM: 32 vs 73 months, P = .03. TP53 or SMAD4 mutations were associated with decreased survival in HG‐PM: 22 vs 48 months, P = .02. Actionable mutations were detected in 70%.
Conclusion
Actionable mutations were detected at high rates. GI‐PMs have similar mutational profiles and TP53, SMAD4, and/or >1 mutation were associate with decreased survival in HG‐PM. This data supports the concept of the extended mutation profiling utility in GI‐PM warranting further investigation.
Background: In patients with unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is anchored on estimating the risk of disease recurrence.
Objectives: We aimed to ...develop a score that could predict the recurrence risk following a first episode of unprovoked VTE, pooling individual patient data from seven prospective studies.
Methods: One thousand eight hundred and eighteen cases with unprovoked VTE treated for at least 3 months with a vitamin K antagonist were available for analysis. Optimism‐corrected Cox regression coefficients were used to develop a recurrence score that was subsequently internally validated by bootstrap analysis.
Results: Abnormal D‐dimer after stopping anticoagulation, age < 50 years, male sex and VTE not associated with hormonal therapy (in women) were the main predictors of recurrence and were used to derive a prognostic recurrence score (DASH, D‐dimer, Age, Sex, Hormonal therapy) showing a satisfactory predictive capability (ROC area = 0.71). The annualized recurrence risk was 3.1% (95% confidence interval CI, 2.3–3.9) for a score ≤ 1, 6.4% (95% CI, 4.8–7.9) for a score = 2 and 12.3% (95% CI, 9.9–14.7) for a score ≥ 3. By considering at low recurrence risk those patients with a score ≤ 1, life‐long anticoagulation might be avoided in about half of patients with unprovoked VTE.
Conclusions: The DASH prediction rule appears to predict recurrence risk in patients with a first unprovoked VTE and may be useful to decide whether anticoagulant therapy should be continued indefinitely or stopped after an initial treatment period of at least 3 months.
Summary
Background
ABO blood type is an inherited trait associated with coagulation factor levels and vascular outcomes.
Objectives
To assess the association of blood type with stroke and whether ...blood type contributes to racial disparities in stroke in the United States.
Patients and Methods
The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study recruited 30 239 participants between 2003 and 2007. Using a case‐cohort design, blood type was genotyped in 646 participants with stroke and a 1104‐participant cohort random sample. Cox models that adjusted for Framingham stroke risk factors were used to assess the association of blood type with stroke.
Results
During 5.8 years of follow‐up, blood types A or B vs. type O were not associated with stroke. Blood type AB vs. O was associated with an increased risk of stroke (adjusted hazard ratio HR 1.83, 95% confidence interval CI 1.01–3.30). The association of blood type AB vs. O was greater in those without diabetes (adjusted HR 3.33, 95% CI 1.61–6.88) than those with diabetes (adjusted HR 0.49, 95% CI 0.17–1.44) (P interaction = 0.02). Factor VIII levels accounted for 60% (95% CI 11%–98%) of the association of AB blood type and stroke risk.
Conclusion
Blood type AB is associated with an increased risk of stroke that is not attenuated by conventional stroke risk factors, and factor VIII levels were associated with 60% of the association. While blood type AB is rare in the US population, it is a significant stroke risk factor and may play an important role in stroke risk in these individuals.
•BioFire Respiratory Panel 2.1 SARS-CoV-2 assay high sensitivity and specificity.•Comparable performance to gold standard tests for low level viral RNA detection.•Rapid, sample-to-answer, syndromic ...testing for respiratory pathogens with SARS-CoV-2.
We evaluated the performance of the BioFire® Respiratory Panel 2.1 (RP2.1) in the detection of SARS CoV-2 in comparison against three other SARS CoV-2 EUA assays. In these studies, the RP2.1 panel had 98 % positive percent agreement (48/49) and 100 % negative percent agreement (49/49). Since 30 % of nasopharyngeal swab specimens have a SARS CoV-2 Ct >30 and thus detection of virus in low titers is clinically relevant, a sample with a high titer was diluted and each 10 fold dilution was tested in triplicate and compared against 6 other EUA approved SARS CoV-2 assays. These data suggested that the BioFire® RP2.1 panel, along with four other SARS CoV-2 assays (Roche cobas, Cepheid Xpert Xpress, BioFire® Defense COVID19, and NECoV19), consistently detected viral RNA at the 10−7 dilution. Overall, these studies suggest that the BioFire® RP2.1 assay can be used to detect acute cases of SARS CoV2 in addition to patients with low viral titer later in disease presentation.
CONTEXT Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the ...potential to improve prediction. OBJECTIVE To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480 325 person-years of follow-up of 24 955 men and 23 339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (≤0.90) was 18.7% (95% confidence interval CI, 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio HR, 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 95% CI, 2.3-3.7 for men vs 3.0 95% CI, 2.0-4.4 for women). A low ABI (≤0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.
Summary
Background
Venous thrombosis is common in the older population. Assessment of risk factors is necessary to implement preventive measures.
Objectives
We studied the associations between ...immobility‐related risk factors and thrombosis, specifically, hospitalization, surgery, fractures, plaster cast use, minor injuries, and transient immobility at home, in an older population.
Patients and Methods
Analyses were performed in the Age and Thrombosis, Acquired and Genetic risk factors in the Elderly (AT‐AGE) study, a two‐center population‐based case‐control study. Consecutive cases aged > 70 years with a first‐time thrombosis (n = 401) and control subjects > 70 years old without a history of thrombosis (n = 431) were included. Exclusion criteria were active malignancy and severe cognitive disorders. We calculated odds ratios (OR) with 95% confidence intervals (95% CI) after adjustment for age, sex, body mass index, study center, and population‐attributable risks.
Results
There was a 15‐fold (OR 14.8, 95% CI 4.4–50.4) increased risk of thrombosis within 2 weeks after hospital discharge. Surgery (OR 6.6, 95% CI 3.7–11.6), fractures (OR 12.7, 95% CI 3.7–43.7), plaster cast (OR 6.2, 95% CI 2.0–18.9), minor leg injuries (OR 1.9, 95% CI 1.1–3.3), and transient immobility at home (OR 5.0, 95% CI 2.3–11.2) were all associated with thrombosis risk over 3 months. The population‐attributable risks for in‐hospital immobility was 27%, and for out‐of‐hospital immobility, 15%.
Conclusions
In those > 70 years of age, in‐hospital and out‐of hospital immobility are strong risk factors for thrombosis. Additional studies on preventive measures during immobilization in this age group should not focus solely on hospital settings.
Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis-related genes to identify prognostic or predictive biomarkers for cetuximab treatment.
...Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy ± cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models.
High tumor mRNA levels of HER2 hazard ratio (HR), 0.64; P = 0.002 and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025).
Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity.
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