Impact of COVID-19 infection during the postoperative period in patients who underwent gastrointestinal surgery: a retrospective study.

Purpose: The coronavirus disease 2019 (COVID-19) pandemic has led to significant global casualties. This study examines the postoperative impact of COVID-19 on patients who underwent gastrointestinal surgery, considering their heightened vulnerability to infections and increased morbidity and mortality risk. Methods: This retrospective observational study was conducted at a tertiary center and patients who underwent gastrointestinal surgery between January 2022 and February 2023 were included. Postoperative COVID-19 infection was defined as the detection of severe acute respiratory syndrome coronavirus 2 RNA by RT-PCR within 14 days after surgery. Propensity score matching was performed including age, sex, American Society of Anesthesiology physical status classification, and emergency operation between the COVID-19-negative (-) and -positive (+) groups. Results: Following 1:2 propensity score matching, 21 COVID-19(+) and 42 COVID-19(-) patients were included in the study. In the COVID-19(+) group, the postoperative complication rate was significantly higher (52.4% vs. 23.8%, P = 0.023). Mechanical ventilator requirement, intensive care unit (ICU) admission, and readmission rate did not significantly differ between the 2 groups. The median length of ICU (19 days vs. 4 days, P < 0.001) and hospital stay (18 vs. 8 days, P = 0.015) were significantly longer in the COVID-19(+) group. Patients with COVID-19 had a 2.4 times higher relative risk (RR) of major complications than patients without COVID-19 (RR, 2.37; 95% confidence interval, 1.254-4.467; P = 0.015). Conclusion: COVID-19 infection during the postoperative period in gastrointestinal surgery may have adverse outcomes which may increase the risk of major complications. Preoperative COVID-19 screening and protocols for COVID-19 prevention in surgical patients should be maintained.

Wearable and Wavelength-Tunable Near-Infrared Organic Light-Emitting Diodes for Biomedical Applications.

Near-infrared organic light-emitting diodes (NIR OLEDs) have significant potential for wearable phototherapeutic applications because of the unique properties of the OLEDs, including their free-form electronics and the excellent biomedical effects of NIR emission. In spite of their tremendous promise, given that the majority of NIR OLEDs in previous research have relied on the utilization of an intrinsically brittle indium tin oxide (ITO) electrode, their practicality in the field of wearable electronics is inherently constrained. Here, we report wearable and wavelength-tunable NIR OLEDs that employ a high-performance NIR emitter and an innovative architecture by replacing the ITO with a silver (Ag) electrode. The NIR OLEDs permit wavelength tuning of emissions from 700 to 800 nm and afford stable operation even under repeated bending conditions. The NIR OLEDs provide a lowered device temperature of 37.5 °C even during continuous operation under several emission intensities. In vitro experiments were performed with freshly fabricated NIR OLEDs. The outcomes were evaluated against experimental results performed using the same procedure utilizing blue, green, and red OLEDs. When exposed to NIR light irradiation, the promoting effect of cell proliferation surpassed the proliferative responses observed under the influence of visible light irradiation. The proliferation effect of human hair follicle dermal papilla cells is clearly related to the irradiation wavelength and time, thus underscoring the potential of wavelength-tunable NIR OLEDs for efficacious phototherapy. This work will open novel avenues for wearable NIR OLEDs in the field of biomedical application.

Recurrence Patterns and Risk Factors after Curative Resection for Colorectal Cancer: Insights for Postoperative Surveillance Strategies.

This study aimed to assess recurrence patterns and related risk factors following curative resection of colorectal cancer (CRC). This retrospective observational study was conducted at a tertiary care center, including 2622 patients with stage I-III CRC who underwent curative resection between 2008 and 2018. Hazard rates of recurrence were calculated using a hazard function. The primary outcome was the peak recurrence time after curative resection and secondary outcomes were prognostic factors associated with recurrence. Over a median follow-up period of 53 months, the overall, locoregional and systemic recurrence rates were 8.9%, 0.7%, and 8.5%, respectively. Recurrence rates were significantly higher for rectal cancer (14.9% overall, 4.4% locoregionally, and 12.3% systemically) than for colon cancer (all p < 0.001). The peak recurrence time was 11 months, with variations in hazard rates and curves depending on the tumor location, stage, and risk factors. Patients with AL or CRM involvement exhibited a distinct pattern, with a high hazard rate in the early postoperative period. Understanding these recurrence patterns and risk factors is crucial for establishing effective postoperative surveillance strategies. Our findings suggested that short-interval surveillance should be considered during the first 2 years post-surgery, particularly for high-risk patients who should receive early attention.

Plasma Circulating Cell-free DNA in Advanced Hepatocellular Carcinoma Patients Treated With Radiation Therapy.

BACKGROUND/AIM: Although radiation therapy (RT) is an effective and safe treatment when administered locally for various stages of hepatocellular carcinoma (HCC), adequate biomarkers that are predictive of therapeutic efficacy have not been identified. We evaluated the clinical utility of circulating cell-free DNA (cfDNA) to predict treatment response of patients with HCC treated with RT. PATIENTS AND METHODS: We prospectively recruited 37 patients diagnosed with HCC between March 2019 and May 2020. All patients were treated with RT as salvage therapy. Whole peripheral blood was collected twice, one before RT (baseline; V1) and another aliquot one week after the end of RT (V2). We determined whether cfDNA genomic copy number variations (CNVs) could predict treatment outcome. An I-score was calculated from the plasma cfDNA that reflected CNVs of cfDNA, which is evidence of genomic instability. RESULTS: The I-score at V1 exhibited a strong correlation with the planning target volume (PTV) (coefficient=0.65) and was a predictive marker for progression-free survival (PFS). In particular, a mean I-score value at V1 of ≥6.3 had a significant positive correlation with PFS (p=0.017). Compared with patients who had a complete response (CR) following RT, non-CR patients had a higher mean I-score value at V2 ≥6.2 (p=0.034). Furthermore, I-score values at V1 and V2 and the delta I-score ratio were significantly associated with a pre-RT alpha-fetoprotein level ≥200 among non-CR patients. CONCLUSION: I-score values calculated from plasma cfDNA represent a potential biomarker for predicting treatment outcomes in patients with advanced HCC receiving RT.

Copy number aberrations in circulating tumor DNA enables prognosis prediction and molecular characterization of breast cancer.

BACKGROUND: Low-pass whole-genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis is a versatile tool for somatic copy number aberration (CNA) detection, and this study aims to explore its clinical implication in breast cancer. METHODS: We analyzed LP-WGS ctDNA data from 207 metastatic breast cancer (MBC) patients to explore prognostic value of ctDNA CNA burden and validated it in 465 stage II-III triple-negative breast cancer (TNBC) patients who received neoadjuvant chemotherapy in phase III PEARLY trial (NCT02441933). The clinical implication of locus level LP-WGS ctDNA profiling was further evaluated. RESULTS: We found that a high baseline ctDNA CNA burden predicts poor overall survival and progression-free survival of MBC patients. The post hoc analysis of the PEARLY trial showed that a high baseline ctDNA CNA burden predicted poor disease-free survival independent from pathologic complete response (pCR), validating its robust prognostic significance. The 24-month disease-free survival rate was 96.9% and 55.9% in [pCR(+) and low I-score] and [non-pCR and high I-score] patients, respectively. The locus-level ctDNA CNA profile classified MBC patients into 5 molecular clusters and revealed targetable oncogenic CNAs. LP-WGS ctDNA and in vitro analysis identified the BCL6 amplification as a resistance factor for CDK4/6 inhibitors. We estimated ctDNA-based homologous recombination deficiency status of patients by shallowHRD algorithm, which was highest in the TNBC and correlated with platinum-based chemotherapy response. CONCLUSIONS: These results demonstrate LP-WGS ctDNA CNA analysis as an essential tool for prognosis prediction and molecular profiling. Particularly, ctDNA CNA burden can serve as a useful determinant for escalating or de-escalating (neo)adjuvant strategy in TNBC patients.

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.

Liquid biopsy using cfDNA to predict radiation therapy response in solid tumors.

PURPOSE: This study explored the potential feasibility of cell-free DNA (cfDNA) in monitoring treatment response through the measurement of chromosomal instabilities using I-scores in the context of radiation therapy (RT) for other solid tumors. MATERIALS AND METHODS: This study enrolled 23 patients treated with RT for lung, esophageal, and head and neck cancer. Serial cfDNA monitoring was performed before RT, 1 week after RT, and 1 month after RT. Low-depth whole-genome sequencing was done using Nano kit and NextSeq 500 (Illumina Inc.). To measure the extent of genome-wide copy number instability, I-score was calculated. RESULTS: Pretreatment I-score was elevated to more than 5.09 in 17 patients (73.9%). There was a significant positive correlation between the gross tumor volume and the baseline I-score (Spearman rho = 0.419, p = 0.047). The median I-scores at baseline, post-RT 1 week (P1W), and post-RT 1 month (P1M) were 5.27, 5.13, and 4.79, respectively. The I-score at P1M was significantly lower than that at baseline (p = 0.002), while the difference between baseline and P1W was not significant (p = 0.244). CONCLUSION: We have shown the feasibility of cfDNA I-score to detect minimal residual disease after RT in patients with lung cancer, esophageal cancer, and head and neck cancer. Additional studies are ongoing to optimize the measurement and analysis of I-scores to predict the radiation response in cancer patients.

Highly Air-Stable, Flexible, and Water-Resistive 2D Titanium Carbide MXene-Based RGB Organic Light-Emitting Diode Displays for Transparent Free-Form Electronics.

Flexible see-through displays are considered to be the next generation smart display, providing improved information flow, safety, situational awareness, and overall user experience in smart windows, automotive displays, glass-form biomedical displays, and augmented reality systems. 2D titanium carbides (MXenes) are promising material as electrodes of the transparent and flexible displays due to their high transparency, metallic conductivity, and flexibility. However, current MXene-based devices have insufficient air stability and lack engineering schemes to develop matrix-addressable display forms with sufficient pixels to display information. Here, we develop an ultraflexible and environmentally stable MXene-based organic light-emitting diode (OLED) display by combining high performance MXene electrodes, flexible OLEDs, and ultrathin and functional encapsulation systems. The MXene material was synthesized and used to fabricate a highly reliable MXene-based OLED that can stably operate in air condition for over 2000 h, endure repetitive bending deformation of 1.5 mm radius, and maintain environmental stability for 6 h when exposed to wet surroundings. The RGB MXene-based OLEDs were fabricated, (1691 cd m-2 at 40.4 mA cm-2 for red, 1377 cd m-2 at 4.26 mA cm-2 for green, and 1475 cd m-2 at 18.6 mA cm-2 for blue) and a matrix-addressable transparent OLED display was demonstrated that could display letters and shapes.

Shallow Whole-Genome Sequencing of Cell-Free DNA (cfDNA) Detects Epithelial Ovarian Cancer and Predicts Patient Prognosis.

Despite the progress in diagnostics and therapeutics, epithelial ovarian cancer (EOC) remains a fatal disease. Using shallow whole-genome sequencing of plasma cell-free DNA (cfDNA), we investigated biomarkers that could detect EOC and predict survival. Plasma cfDNA from 40 EOC patients and 20 healthy subjects were analyzed by shallow whole-genome sequencing (WGS) to identify copy number variations (CNVs) and determine the Z-scores of genes. In addition, we also calculated the genome-wide scores (Gi scores) to quantify chromosomal instability. We found that the Gi scores could distinguish EOC patients from healthy subjects and identify various EOC histological subtypes (e.g., high-grade serous carcinoma). In addition, we characterized EOC CNVs and demonstrated a relationship between RAB25 amplification (alone or with CA125), and disease-free survival and overall survival. This study identified RAB25 amplification as a predictor of EOC patient survival. Moreover, we showed that Gi scores could detect EOC. These data demonstrated that cfDNA, detected by shallow WGS, represented a potential tool for diagnosing EOC and predicting its prognosis.

Development and performance evaluation of an artificial intelligence algorithm using cell-free DNA fragment distance for non-invasive prenatal testing (aiD-NIPT).

With advances in next-generation sequencing technology, non-invasive prenatal testing (NIPT) has been widely implemented to detect fetal aneuploidies, including trisomy 21, 18, and 13 (T21, T18, and T13). Most NIPT methods use cell-free DNA (cfDNA) fragment count (FC) in maternal blood. In this study, we developed a novel NIPT method using cfDNA fragment distance (FD) and convolutional neural network-based artificial intelligence algorithm (aiD-NIPT). Four types of aiD-NIPT algorithm (mean, median, interquartile range, and its ensemble) were developed using 2,215 samples. In an analysis of 17,678 clinical samples, all algorithms showed >99.40% accuracy for T21/T18/T13, and the ensemble algorithm showed the best performance (sensitivity: 99.07%, positive predictive value (PPV): 88.43%); the FC-based conventional Z-score and normalized chromosomal value showed 98.15% sensitivity, with 40.77% and 36.81% PPV, respectively. In conclusion, FD-based aiD-NIPT was successfully developed, and it showed better performance than FC-based NIPT methods.

Pharmacokinetics and Genetic Factors of Atorvastatin in Healthy Korean Subjects.

Background: Statins are the most popular agents for the primary and secondary prevention of cardiovascular disease; however, the pharmacokinetic parameters and associated genetic factors in the Korean population have not been fully elucidated. This study explored the pharmacokinetic properties of atorvastatin and the association between genetic variations and atorvastatin pharmacokinetics in healthy Korean subjects. Methods: Atorvastatin (80 mg) was administered to 35 healthy Korean volunteers. Plasma levels of atorvastatin and its metabolites were measured sequentially using liquid chromatography-tandem mass spectrometry from 0 to 24 h after atorvastatin administration. Customized next-generation sequencing analysis was performed covering all coding exons of 15 genes, as well as 46 single-nucleotide variants in 29 genes related to statin pharmacokinetics. Results: The mean area under the concentration-time (AUC) and Cmax (maximum peak concentration) were 269.0 ng/ml∙h and 84.3 ng/ml, respectively, which were approximately two times higher than those reported in Caucasians. Genetic analysis revealed that eight genetic variants in ABCB1, ABCG2, APOA5, CETP, and CYP7A1 contributed to the AUC of atorvastatin. The atorvastatin AUC0-24 h prediction model was developed based on age and eight genetic variants using multivariate linear regression (adjusted R 2 = 0.878, p < 0.0001). Conclusion: This study shows that the pharmacokinetic properties of atorvastatin in Koreans are different from those in Caucasians and that atorvastatin AUC0-24 h could be predicted based on age and eight genetic variants of ABCB1, ABCG2, APOA5, CETP, and CYP7A1.

Targeted next generation sequencing of circulating tumor DNA provides prognostic information for management in breast cancer patients.

Background: Circulating tumor DNA (ctDNA) is a non-invasive biomarker for evaluating cancer prognosis. The aim of this study was to analyze the genomic profile of circulating tumor DNA (ctDNA) in breast cancer patients, and evaluate its clinical implications. Methods: Targeted sequencing of ctDNA was performed in 38 patients using commercially available Oncomine Breast cfDNA panel. Whole exome sequencing was performed on matched tumor DNA (n=20). Survival analysis and response to chemotherapy in the study population were evaluated. The detected genomic variants were validated and serially monitored with droplet digital polymerase chain reaction (ddPCR) in 5 patients. Results: At least one variant or copy number alteration was detected in the ctDNA of 31 of 38 (82%) breast cancer patients, with the most common variants being in TP53 (50%), PIK3CA (15%) and ESR1 (14%). When comparing genomic profiles of ctDNA and those of matched tumor DNA in 20 patients, the concordance rate was 9.7% among positives. The patients with variants in TP53 showed significantly poorer overall survival than those without [hazard ratio (HR) =3.90, 95% confidence interval (CI): 1.10-13.84, P=0.035] and its impact was also statistically significant in multivariate analysis with breast cancer subtype included. In serially monitored results, changes in the allele frequency of somatic variants (PI3KCA, TP53) of ctDNA were found to be reflective of response to chemotherapy. Conclusions: The genomic profile of ctDNA reflects and provides additional information to the tumor DNA genome profile. Follow-up monitoring of mutations detected in ctDNA is useful in the clinical management of breast cancer patients.

Aberrant Transcript Usage Is Associated with Homologous Recombination Deficiency and Predicts Therapeutic Response.

BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors that cause low precision in predicting samples that will respond to PARP inhibitors and DNA damaging agents. Here we present molecular and clinical evidence of transcriptional HRD (tHRD) that is based on aberrant transcript usage (aTU) of minor isoforms. Specifically, increased TU of nonfunctional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Functional assays validated the association of aTU with impaired HR activity. Machine learning-based tHRD detection by the transcript usage (TU) pattern of key genes was superior to directly screening for gHRD or BRCA1/2 mutations in accurately predicting responses of cell lines and patients with cancer to PARP inhibitors and genotoxic drugs. This approach demonstrated the capability of tHRD status to reflect functional HR status, including in a cohort of olaparib-treated ovarian cancer with acquired platinum resistance. Diagnostic tests based on tHRD are expected to broaden the clinical utility of PARP inhibitors. SIGNIFICANCE: A novel but widespread transcriptional mechanism by which homologous recombination deficiency arises independently of BRCA1/2 mutations can be utilized as a companion diagnostic for PARP inhibitors.

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.

Prenatal diagnosis of combined methylmalonic acidemia and homocystinuria cobalamin C type using clinical exome sequencing and targeted gene analysis.

BACKGROUND: Combined methylmalonic acidemia and homocystinuria is a rare inherited disorder of intracellular cobalamin metabolism caused by biallelic variants in one of the following genes: MMACHC (cblC), MMADHC (cblD), LMBRD1 (cblF), ABCD4 (cblJ), THAP11 (cblX-like), and ZNF143 (cblX-like), or a hemizygous variant in HCFC1 (cblX). Prenatal diagnosis of combined methylmalonic acidemia with homocystinuria is crucial for high-risk couples since the disorder can be life-threatening for offspring. We would like to describe two infant deaths both of which are likely attributable to cblC despite not having a genetic confirmation, and subsequent pregnancy and prenatal genetic testing. METHODS: Parental clinical exome sequencing and targeted Sanger sequencing of MMACHC gene in amniotic fluid was performed to check the carrier status of the fetus. RESULTS: Parental clinical exome sequencing revealed a heterozygous pathogenic variant [NM_015506.2:c.217C>T (p.Arg73*)] in the MMACHC gene of the mother and [NM_015506.2:c.609G>A (p.Trp203*)] in the MMACHC gene of the father. Targeted Sanger sequencing of MMACHC gene in amniotic fluid revealed that the fetus carried only one nonsense variant [NM_015506.2:c.609G>A (p.Trp203*)], which was inherited from the father. The mother delivered a healthy baby and the neonate did not show any symptoms or signs of combined methylmalonic acidemia and homocystinuria after birth. CONCLUSION: We present a case of prenatal diagnosis with parental exome sequencing, which successfully diagnosed the carrier status of the fetus and parents in a combined methylmalonic acidemia and homocystinuria family.

Case report of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome: first report in Korea with a novel mutation in the SMAD4 gene.

Juvenile polyposis/hereditary hemorrhagic telangiectasia (JPS/HHT) syndrome is a rare, autosomal dominant disorder caused by mutations in the SMAD4 gene, presenting with features of both juvenile polyposis syndrome (JPS) and HHT. Reports and studies of JPS/HHT syndrome are mostly from Western countries, while there are scarce reports from East Asian countries. We report a case of a Korean boy who had been previously diagnosed with JPS at 7 years and had first visited to our center at 15 years of age. Genetic studies of the patient and parents revealed a novel variant in the SMAD4 gene, SMAD4 c.1146_1163del; p.His382_Val387del (NM_005359.5), which had developed de novo. Numerous pedunculated and sessile polyps were observed throughout the gastrointestinal (GI) tract. Mucocutaneous telangiectases were observed on the lips, tongue, and jejunum, and arteriovenous malformations (AVMs) were observed in both lungs. This is the first case report of JPS/HHT syndrome in Korea, with a novel deletion variant in the SMAD4 gene. Patients with JPS should undergo genetic evaluation of associated genes including SMAD4, and those with genetically confirmed SMAD4 variants should undergo further evaluation for coexisting asymptomatic AVMs in order to prevent life-threatening complications of thrombotic emboli and pulmonary hemorrhage.

A Population-Based Analysis of BRCA1/2 Genes and Associated Breast and Ovarian Cancer Risk in Korean Patients: A Multicenter Cohort Study.

In this study, we performed a comprehensive analysis of BRCA1/2 variants and associated cancer risk in Korean patients considering two aspects: variants of uncertain significance (VUS) and pathogenic or likely pathogenic variants (PLPVs) in BRCA1 and BRCA2. This study included 5433 Korean participants who were tested for BRCA1/2 genes. The BRCA1/2 variants were classified following the standards/guidelines for interpretation of genetic variants and using a multifactorial probability-based approach. In Korea, 15.8% of participants had BRCA1 or BRCA2 PLPVs. To estimate the additional sample numbers needed to resolve unclassified status, we applied a simulation analysis. The simulation study for VUS showed that the smaller the number of samples, the more the posterior probability was affected by the prior probability; in addition, more samples for BRCA2 VUS than those of BRCA1 VUS were required to resolve the unclassified status, and the presence of clinical information associated with their VUS was an important factor. The cumulative lifetime breast cancer risk was 59.1% (95% CI: 44.1-73.6%) for BRCA1 and 58.3% (95% CI: 43.2-73.0%) for BRCA2 carriers. The cumulative lifetime ovarian cancer risk was estimated to be 36.9% (95% CI: 23.4-53.9%) for BRCA1 and 14.9% (95% CI: 7.4-28.5%) for BRCA2 carriers.

Genome-wide and size-based cell-free DNA indices as predictive biomarkers for locally advanced esophageal squamous cell carcinoma treated with preoperative or definitive chemoradiotherapy.

For locally advanced esophageal cancer, concurrent chemoradiotherapy (CRT) followed by surgery has been a standard treatment, while clinical studies showed comparable survival outcomes between definitive CRT and neoadjuvant CRT followed by surgery in patients responding to CRT. Thus, biomarkers are required to predict treatment outcomes and benefit of adding surgery after CRT. This prospective biomarker study examined the role of cell-free DNA (cfDNA) fragmentation profiles and genomic copy number variations (CNVs) in predicting treatment outcomes in esophageal squamous cell carcinoma patients treated with neoadjuvant or definitive CRT. The clinical response was evaluated after induction chemotherapy and after CRT. Fragment Ratio (FR)-score and I-score were calculated from plasma cfDNA reflecting fragment lengths and CNV of cfDNA, respectively. The association between indices of cfDNA (cfDNA concentration, FR-score, and I-score) and treatment outcomes (clinical response, time to progression [TTP], and overall survival [OS]) were evaluated. Sixty-one patients were included. Thirty patients received neoadjuvant CRT followed by surgery, whereas 31 received definitive CRT. Low baseline, post-induction chemotherapy, and post-CRT FR-scores and low post-induction I-score were significantly associated with improved treatment response (P < 0.05). Additionally, patients with surgery after CRT showed significantly longer survival than patients without surgery in the FR-score-high group (median TTP, 12.7 vs 3.4 months; P = 0.011; OS, not reached vs 12.9 months; P = 0.02), while there was no survival benefit with surgery in the FR-score-low group. FR-score may be a new biomarker to predict treatment response, residual tumor burden after CRT, and consequently, survival benefit of adding morbid surgery after CRT. FR-score has strength in a relatively simple and inexpensive methodology compared to deep sequencing, resulting in high availability and accessibility, despite limited sensitivity.

Parallel-Stacked Flexible Organic Light-Emitting Diodes for Wearable Photodynamic Therapeutics and Color-Tunable Optoelectronics.

Deformable organic light-emitting diode (OLED) based optoelectronic devices hold promise for various wearable applications including biomedical systems and displays, but current OLED technologies require high voltage and lack the power needed for wearable photodynamic therapy (PDT) applications and wearable displays. This paper presents a parallel-stacked OLED (PAOLED) with high power, more than 100 mW/cm2, at low voltage (<8 V). The current dispersion ratio can be tuned by optimizing the structure of the individual OLEDs stacked to create the PAOLED, allowing control of the PAOLED's wavelength shapes, current efficiency, and power. In this study, a fabricated PAOLED operated reliably for 100 h at a high power of 35 mW/cm2. Confirming its potential application to PDT, the measured singlet oxygen generation ratio of the PAOLED was found to be 3.8 times higher than the reference OLED. The high-power PAOLED achieved a 24% reduction in melanoma cancer cell viability after a short (0.5 h) irradiation. In addition, a white light PAOLED with color tuning was realized through OLED color combination, and a high brightness of over 30 000 cd/m2 was realized, below 8.5 V. In conclusion, the PAOLED was demonstrated to be suitable for a variety of low-voltage, high-power wearable optoelectronic applications.

Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer.

The use of multigene panel testing for patients with a predisposition to breast/ovarian cancer is increasing as the identification of variants is useful for diagnosis and disease management. We identified pathogenic and likely pathogenic (P/LP) variants of high-and moderate-risk genes using a 23-gene germline cancer panel in 518 patients with hereditary breast and ovarian cancers (HBOC). The frequency of P/LP variants was 12.4% (64/518) for high- and moderate-penetrant genes, namely, BRCA2 (5.6%), BRCA1 (3.3%), CHEK2 (1.2%), MUTYH (0.8%), PALB2 (0.8%), MLH1 (0.4%), ATM (0.4%), BRIP1 (0.4%), TP53 (0.2%), and PMS2 (0.2%). Five patients possessed two P/LP variants in BRCA1/2 and other genes. We also compared the results from in silico splicing predictive tools and exon splicing patterns from patient samples by analyzing RT-PCR product sequences in six P/LP intronic variants and two intronic variants of unknown significance (VUS). Altered transcriptional fragments were detected for P/LP intronic variants in BRCA1, BRIP1, CHEK2, PARB2, and PMS2. Notably, we identified an in-frame deletion of the BRCA1 C-terminal (BRCT) domain by exon skipping in BRCA1 c.5152+6T>C-as known VUS-indicating a risk for HBOC. Thus, exon splicing analysis can improve the identification of veiled intronic variants that would aid decision making and determination of hereditary cancer risk.