The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

Background and AimsDiabetes Mellitus (DM) is chronic conditions with devastating multi-systemic complication and may be associated with severe form of Coronavirus Disease 2019 . We conducted a systematic review and meta-analysis in order to investigate the association between DM and poor outcome in patients with COVID-19 pneumonia. MethodsSystematic literature search was performed from several electronic databases on subjects that assess DM and outcome in COVID-19 pneumonia. The outcome of interest was composite poor outcome, including mortality, severe COVID-19, acute respiratory distress syndrome (ARDS), need for intensive care unit (ICU) care, and disease progression. ResultsThere were a total of 6452 patients from 30 studies. Meta-analysis showed that DM was associated with composite poor outcome (RR 2.38 [1.88,3.03], p<0.001; I 2 : 62%) and its subgroup which comprised of mortality (RR 2.12 [1.44, 3.11], p<0.001; I 2 : 72%), severe COVID-19 (RR 2.45 [1.79, 3.35], p<0.001; I 2 : 45%), ARDS (RR 4.64 [1.86,11.58], p=0.001; I 2 : 9%), and disease progression (RR 3.31 [1.08, 10.14], p=0.04; I 2 : 0%). Meta-regression showed that the association with composite poor outcome was influenced by age (p=0.003) and hypertension (p<0.001). Subgroup analysis showed that the association was weaker in studies with median age ≥55 years-old (RR 1.92) compared to <55 years-old (RR 3.48), and in prevalence of hypertension ≥25% (RR 1.93) compared to <25% (RR 3.06). Subgroup analysis on median age <55 years-old and prevalence of hypertension <25% showed strong association (RR 3.33) ConclusionDM was associated with mortality, severe COVID-19, ARDS, and disease progression in patients with COVID-19.

Background: Patients critically ill with coronavirus disease-2019 (COVID-19) feature hyperinflammation, and the associated biomarkers may be beneficial for risk stratification. We aimed to investigate the association between several biomarkers, including serum C-reactive protein (CRP), procalcitonin (PCT), D-dimer, and serum ferritin, and COVID-19 severity. Methods: We performed a comprehensive systematic literature search through electronic databases. The outcome of interest for this study was the composite poor outcome, which comprises mortality, acute respiratory distress syndrome, need for care in an intensive care unit, and severe COVID-19. Results: A total of 5350 patients were pooled from 25 studies. Elevated CRP was associated with an increased composite poor outcome [risk ratio (RR) 1.84 (1.45, 2.33), p < 0.001; I2: 96%] and its severe COVID-19 (RR 1.41; I2: 93%) subgroup. A CRP ⩾10 mg/L has a 51% sensitivity, 88% specificity, likelihood ratio (LR) + of 4.1, LR- of 0.5, and an area under curve (AUC) of 0.84. An elevated PCT was associated with an increased composite poor outcome [RR 3.92 (2.42, 6.35), p < 0.001; I2: 85%] and its mortality (RR 6.26; I2: 96%) and severe COVID-19 (RR 3.93; I2: 63%) subgroups. A PCT ⩾0.5 ng/ml has an 88% sensitivity, 68% specificity, LR+ of 2.7, LR- of 0.2, and an AUC of 0.88. An elevated D-dimer was associated with an increased composite poor outcome [RR 2.93 (2.14, 4.01), p < 0.001; I2: 77%], including its mortality (RR 4.15; I2: 83%) and severe COVID-19 (RR 2.42; I2: 58%) subgroups. A D-dimer >0.5 mg/L has a 58% sensitivity, 69% specificity, LR+ of 1.8, LR- of 0.6, and an AUC of 0.69. Patients with a composite poor outcome had a higher serum ferritin with a standardized mean difference of 0.90 (0.64, 1.15), p < 0.0001; I2: 76%. Conclusion: This meta-analysis showed that an elevated serum CRP, PCT, D-dimer, and ferritin were associated with a poor outcome in COVID-19. The reviews of this paper are available via the supplemental material section.

Background: We conducted a systematic review and meta-analysis to evaluate the latest evidence on the association between cerebrovascular, and cardiovascular diseases and poor outcome in patients with Coronavirus Disease 2019 (COVID-19) pneumonia. Methods: A comprehensive systematic literature search was performed using PubMed, SCOPUS, EuropePMC, and Cochrane Central Database. The outcome of interest was composite poor outcome that comprised of mortality and severe COVID-19. Results: A total of 4448 patients were obtained from 16 studies. Cerebrovascular disease was associated with an increased composite poor outcome (RR 2.04 [1.43,2.91], p<0.001; I 2 : 77%). Subgroup analysis revealed that cerebrovascular disease was associated with mortality (RR 2.38 [1.92,2.96], p<0.001; I 2 : 0%) and showed borderline significance for severe COVID-19 (RR 1.88 [1.00,3.51], p = 0.05; I 2 : 87%). Cardiovascular disease was associated with increased composite poor outcome (RR 2.23 [1.71,2.91], p<0.001; I 2 : 60%), mortality (RR 2.25 [1.53,3.29], p<0.001; I 2 : 33%) and severe COVID-19 (RR 2.25 [1.51,3.36], p<0.001; I 2 : 76%). Meta-regression demonstrate that the association was not influenced by gender, age, hypertension, diabetes, and respiratory comorbidities. Furthermore, the association between cerebrovascular disease and poor outcome was not affected by cardiovascular diseases and vice versa. Conclusion: Cerebrovascular and cardiovascular diseases were associated with an increased risk for poor outcome in patients with

Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57-88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88-100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher's exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.CSF-tDNA | CNS tumors | biomarker