Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA.

Multi-cancer early detection remains a key challenge in cell-free DNA (cfDNA)-based liquid biopsy. Here, we perform cfDNA whole-genome sequencing to generate two test datasets covering 2125 patient samples of 9 cancer types and 1241 normal control samples, and also a reference dataset for background variant filtering based on 20,529 low-depth healthy samples. An external cfDNA dataset consisting of 208 cancer and 214 normal control samples is used for additional evaluation. Accuracy for cancer detection and tissue-of-origin localization is achieved using our algorithm, which incorporates cancer type-specific profiles of mutation distribution and chromatin organization in tumor tissues as model references. Our integrative model detects early-stage cancers, including those of pancreatic origin, with high sensitivity that is comparable to that of late-stage detection. Model interpretation reveals the contribution of cancer type-specific genomic and epigenomic features. Our methodologies may lay the groundwork for accurate cfDNA-based cancer diagnosis, especially at early stages.

Genomic Instability of Circulating Tumor DNA as a Prognostic Marker for Pancreatic Cancer Survival: A Prospective Cohort Study.

Genomic instability of circulating tumor DNA (ctDNA) as a prognostic biomarker has not been evaluated in pancreatic cancer. We investigated the role of the genomic instability index of ctDNA in pancreatic ductal adenocarcinoma (PDAC). We prospectively enrolled 315 patients newly diagnosed with resectable (n = 110), locally advanced (n = 78), and metastatic (n = 127) PDAC from March 2015 through January 2020. Low-depth whole-genome cell-free DNA sequencing identified genome-wide copy number alterations using instability score (I-score) to reflect genome-wide instability. Plasma cell-free and matched tumor tissue DNA from 15 patients with resectable pancreatic cancer was sequenced to assess the concordance of chromosomal copy number alteration profiles. Associations of I-score with clinical factors or survival were assessed. Seventy-six patients had high genomic instability with I-score > 7.3 in pre-treatment ctDNA; proportions of high I-score were 5.5%, 5.1%, and 52% in resectable, locally advanced, and metastatic stages, respectively. Correlation coefficients between Z-scores of plasma and tissue DNA at segment resolution were high (r2 = 0.82). Univariable analysis showed the association of I-score with progression-free survival in each stage. Multivariable analyses demonstrated that clinical stage-adjusted I-scores were significant factors for progression-free and overall survival. In these patients, ctDNA genomic I-scores provided prognostic information relevant to progression-free survival in each clinical stage.

Usefulness of C-MAC video laryngoscope in direct laryngoscopy training in the emergency department: A propensity score matching analysis.

OBJECTIVES: We determined the usefulness of C-MAC video laryngoscope (C-MAC) as a safe training tool for the direct laryngoscopy technique in the emergency department. METHODS: We retrospectively analyzed an institutional airway registry of adult (≥18 years old) patients from April 2014 through October 2016. In this study, the operator used C-MAC as a direct laryngoscope (DL) with limited access to the screen, and the supervisor instructed the operator via verbal feedback while watching the screen. Patients were categorized into the DL group if a conventional DL was used and the C-DL group if a C-MAC used as a DL. RESULTS: Of 744 endotracheal intubations, 163 propensity score-matched pairs were generated (1-to-n matching: C-DL group, 163 vs. DL group, 428). For the propensity-matched groups, the overall first pass success rate was 69%, while those in the C-DL and DL groups were 79% and 65%, respectively. Overall, multiple attempts were required in 8% of patients, with 4% in the C-DL group and 9% in the DL group. The overall complication rate was 11%, with 4% in the C-DL group and 14% in the DL group. In multivariable analysis, the adjusted odds ratios of C-DL use for first pass success, multiple attempts, and complications were 2.05 (95% confidence interval [CI] 1.18-2.87, p < 0.01), 0.38 (95% CI 0.15-0.94; p < 0.01), and 0.28 (95% CI 0.12-0.63; p < 0.01), respectively. CONCLUSIONS: Our study suggests that the C-MAC could be useful for training residents in the direct laryngoscopy while ensuring patient safety in the emergency department.

Upper airway obstruction resulting from acute mucosal injury induced by direct ingestion of sodium picosulfate/magnesium citrate powder.

A 59-year-old man presented to the emergency department with a chief complaint of sore throat after swallowing sodium picosulfate/magnesium citrate powder for bowel preparation, without first dissolving it in water. The initial evaluation showed significant mucosal injury involving the oral cavity, pharynx, and epiglottis. Endotracheal intubation was performed for airway protection in the emergency department, because the mucosal swelling resulted in upper airway compromise. After conservative treatment in the intensive care unit, he underwent tracheostomy because stenosis of the supraglottic and subglottic areas was not relieved. The tracheostomy tube was successfully removed after confirming recovery, and he was discharged 3 weeks after admission.

Successful fibrinolytic and therapeutic hypothermic management of cardiac arrest following massive pulmonary embolism.

Massive pulmonary embolism (MPE) with hemodynamic instability is a clinical condition with a poor prognosis and high mortality rates. There are no definitive treatment options for cardiac arrest due to MPE. A 52-year-old female presented at our emergency department with cardiac arrest, and a 62-year-old female presented after achieving return of spontaneous circulation of cardiac arrest from a local hospital, respectively. In each case, computed tomographic pulmonary angiography after return of spontaneous circulation demonstrated heavy burdens of pulmonary embolism in the pulmonary arteries. We immediately started therapeutic hypothermia and fibrinolytic therapy. They were transferred to the thoracic surgery and cardiology departments respectively, and then discharged with a cerebral performance categories scale score of 1. In summary, we report two cases of out-of-hospital cardiac arrest due to MPE in which fibrinolytic therapy was successfully combined with therapeutic hypothermia.

Independent prognostic factors of 861 cases of oral squamous cell carcinoma in Korean adults.

Oral squamous cell carcinoma (OSCC) accounts for 4.5% of all malignant tumors in Korean males and 3.5% in Korean females. The high recurrence rate, and in particular the high local recurrence rate, constitutes a major therapeutic problem for the Korean population, yet there is a paucity of reports addressing the independent predictors of response and survival rate of OSCC in Korea. The present study was designed to investigate the prognostic value of clinical and demographic data within a set of 861 cases of OSCC in Korea. The medical records of 861 OSCC patients who received treatment between 1984 and 1996 at 22 Korean hospitals were reviewed retrospectively with respect to several patient characteristics, including age at diagnosis, gender, location, TNM stage, and treatment. Independent patient-related and treatment-related factors that significantly influenced disease outcome after treatment were analyzed. To assess the independent factors affecting survival rate, univariate and multivariate regression analyses of the survival data were performed using the Cox proportional hazards model. A tree-structured survival model was also derived using survival tree with unbiased detection of interaction (STUDI). The multivariate Cox regression analysis showed that age, gender, composite stage, and treatment method were significant independent prognostic factors. Radiation dose, stage, size of tumor mass, and age of patient also strongly impacted survival time. OSCC is an extremely malignant carcinoma whose prognostic factors are multiple and complex. Based on the findings of this study, we believe that the prognosis of OSCC might depend directly on cancer stage as determined by the TNM system. Furthermore, the survival rate is positively affected by treatment of the neck upon presentation of the cancer, as this can prevent late neck disease due to persistent growth of occult metastases.

Therapeutic efficacy of transcatheter arterial chemoembolization as compared with hepatic resection in hepatocellular carcinoma patients with compensated liver function in a hepatitis B virus-endemic area: a prospective cohort study.

PURPOSE: Identifying a special subgroup of hepatocellular carcinoma (HCC) patients who may benefit from transcatheter arterial chemoembolization (TACE) when compared with the standard treatment of hepatic resection (HR) warrants research in Asian countries. PATIENTS AND METHODS: From January 1993 to December 1994, 182 patients with operable HCC (Child-Pugh class A and International Union Against Cancer [UICC] stage T1-3N0M0) were enrolled. After initial TACE and lipiodol computed tomography, 91 received HR and 91, who refused the operation, received repeated sessions of TACE. After stratification according to the tumor stage (UICC and Cancer of the Liver Italian Program [CLIP]) and lipiodol retention pattern, the survival rates of the two treatment groups were compared. The median follow-up period was 83 months. RESULTS: As of December 31, 2000, 48 patients who underwent HR and 68 patients who underwent TACE had died. In a subgroup analysis according to tumor stage, the HR group survival rate was significantly higher than the TACE group in both UICC T1-2N0M0 (P =.0058) and CLIP 0 (P =.0027) subgroups. However, there was no significant difference in either UICC T3N0M0 (P =.7512) or CLIP 1-2 (P =.5366) subgroups. Even in patients with UICC T1-2N0M0 HCC, when lipiodol was compactly retained, the survival rate of the HR group was comparable to that of the TACE group (P =.0596). CONCLUSION: TACE proved to be as effective as HR in the subpopulations with UICC T3N0M0 or CLIP 1-2 HCC and adequate liver function, and even with UICC T1-2N0M0 HCC when lipiodol was compactly retained in the tumor. In such cases, the choice of treatment modality between TACE and HR may be left to the patient's preference.