NF-кB promotes aggresome formation via upregulating HDAC6 and in turn maintaining Vimentin cage.

Proteasome inhibitors have been applied to anticancer therapy by accumulating toxic misfolded proteins. However, chemical inactivation of proteasome generates aggresome, a Vimentin cage-enclosed subcellular structure quarantining HDAC6-Dynein-transported misfolded proteins before the protein toxicants are degraded by autophagy. Hence, aggresome may attenuate proteasome inhibitor drug-induced cytotoxicity. To solve the problem, it is imperative to characterize how cells assemble aggresome. By examining aggresomes in six cell lines, A549 cells were selectively studied for their bigger cell size and moderate aggresome-forming activity. Aggresome grew in size upon continuous exposure of A549 cells to proteasome inhibitor MG132 and reached a mature size around the 16th to 24th hour of treatment. Mechanistic studies revealed that NF-кB translocated to the nucleus in MG132-treated cells, and chemical activation or knockdown of NF-кB enhanced or prohibited aggresome assembly. Further analyses showed that NF-кB upregulated HDAC6, and HDAC6 maintained the Vimentin cage by interacting with Vimentin p72, a key modification of the intermediate filament contributing to aggresome formation. Remarkably, chemical inactivation of NF-кB synergized MG132-induced cell mortality. All the findings suggest that NF-кB dictates aggresome assembly via upregulating HDAC6, and NF-кB inhibitor may serve as a potential drug potentiating proteasome inhibitor medicine-induced cytotoxicity during the treatment of cancer cells.NEW & NOTEWORTHY The study reveals a new mechanism guiding MG132-triggered aggresome formation. NF-кB is quickly activated upon exposure to MG132, and NF-кB upregulates the misfolded protein recognizing factor HDCA6. In addition to collecting misfolded proteins, HDAC6 also binds Vimentin and maintains the Vimentin cage, which quarantines toxic misfolded proteins and protects cells from being toxified by those protein toxicants. Therapeutically, chemical inactivation of NF-кB synergizes MG132-induced cytotoxicity, providing a new strategy to defeat cancers.

Improving lung function capacity in patients with chronotropic incompetence using closed loop stimulation: A randomized crossover study.

BACKGROUND: Chronotropic incompetence (CI) severely limits exercise tolerance due to impaired heart rate responses. This study investigated whether pacemaker with closed-loop stimulation (DDD-CLS) pacing, which provides rate acceleration in response to exertion, could enhance lung function and cardiopulmonary capacity compared pacemaker without CLS pacing in patients with CI. METHODS: This randomized crossover trial included 32 patients with CI who were compared to each CLS and DDD pacing over 2 months. Spirometry was used to assess the forced vital capacity (FVC). Cycling-based cardiopulmonary exercise testing (CPET) measured peak oxygen uptake (peak VO2). RESULTS: DDD-CLS pacing yielded significantly higher FVC (2.2 ± 0.8 L) versus DDD pacing (2.0 ± 0.7 L), p = 0.036, a 3.2% improvement. Moreover, those in the DDD-CLS mode showed a significantly higher FEV1 of 1.8 ± 0.6 L compared to the DDD mode of 1.7 ± 0.5 L (p = 0.03). Compared with DDD pacing, DDD-CLS pacing also achieved superior peak VO2 (14.9 ± 4.0 vs 12.2 ± 3.7 mlO2/kg/min, p < 0.001) and peak heart rate (106.9 ± 9.7 vs 98.3 ± 19.8 bpm, p = 0.013). DDD-CLS and DDD pacing modes showed significant correlations between FVC and peak VO2 and between peak VO2 and peak heart rate during CPET. CONCLUSIONS: Compared with DDD mode, DDD-CLS pacing provided physiological chronotropic support to improve cardiopulmonary function during exertion, which enhanced lung capacity in patients with CI.

Enhancement of bicycle exercise capacity in patients with chronotropic incompetence through closed-loop stimulation: a randomized crossover trial.

AIMS: This study aimed to investigate the effectiveness of closed-loop stimulation (CLS) pacing compared with the traditional DDD mode in patients with chronotropic incompetence (CI) using bicycle-based cardiopulmonary exercise testing (CPET). METHODS AND RESULTS: This single-centre, randomized crossover trial involved 40 patients with CI. Patients were randomized to receive either DDD-CLS or DDD mode pacing for 2 months, followed by a crossover to the alternative mode for an additional 2 months. Bicycling-based CPET was conducted at the 3- and 5-month follow-up visits to assess exercise capacity. Other cardiopulmonary exercise outcome measures and health-related quality of life (QoL) were also assessed. DDD-CLS mode pacing significantly improved exercise capacity, resulting in a peak oxygen uptake (14.8 ± 4.0 vs. 12.0 ± 3.6 mL/kg/min, P < 0.001) and oxygen uptake at the ventilatory threshold (10.0 ± 2.2 vs. 8.7 ± 1.8 mL/kg/min, P < 0.001) higher than those of the DDD mode. However, there were no significant differences in other cardiopulmonary exercise outcome measures such as ventilatory efficiency of carbon dioxide production slope, oxygen uptake efficiency slope, and end-tidal carbon dioxide between the two modes. Patients in the DDD-CLS group reported a better QoL, and 97.5% expressed a preference for the DDD-CLS mode. CONCLUSION: DDD-CLS mode pacing demonstrated improved exercise capacity and QoL in patients with CI, highlighting its potential as an effective pacing strategy for this patient population.

Experiences in reverse sequence esophagectomy: a promising alternative for esophageal cancer surgery.

OBJECTIVES: McKeown esophagectomy is a standard and significant component of multimodality therapy in esophageal cancer, however, experience in switching the resection and reconstruction sequence in esophageal cancer surgery is not available. Here, we have retrospectively reviewed the experience of reverse sequencing procedure at our institute. METHODS: We retrospectively reviewed 192 patients who had undergone minimally invasive esophagectomy (MIE) with McKeown esophagectomy between August 2008 and Dec 2015. The patient's demographics and relevant variables were evaluated. The overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS: Among the 192 patients, 119 (61.98%) received the reverse sequence MIE (the reverse group) and 73 patients (38.02%) received the standard operation (the standard group). Both patient groups had similar demographics. There were no inter-group differences existed in blood loss, hospital stay, conversion rate, resection margin status, operative complication, and mortality. The reverse group had shorter total operation time (469.83 ± 75.03 vs 523.63 ± 71.93, p < 0.001) and thoracic operation time (181.22 ± 42.79 vs 230.41 ± 51.93, p < 0.001). The 5-year OS and DFS for both groups were similar (44.77% and 40.53% in the reverse group vs 32.66% and 29.42% in the standard group, p = 0.252 and 0.261, respectively). Similar results were observed even after propensity matching. CONCLUSIONS: The reverse sequence procedure had shorter operation times, especially in the thoracic phase. The reverse sequence MIE is a safe and useful procedure when postoperative morbidity, mortality, and oncological outcomes are considered.

Impact of tumor disappearance ratio on the prognosis of lung adenocarcinoma ≤2 cm in size: A retrospective cohort study.

BACKGROUND/PURPOSE: Lung cancer patients can have advanced-stages at diagnosis, even the tumor size is ≤2 cm. We aimed to study the relationship between image characteristics, clinical, and patholoigcal results. METHODS: We retrospectively enrolled patients with lung adenocarcinoma at Taichung Veterans General Hospital and Chang Gung Memorial Hospital from 2007 to 2015, who were diagnosed with treatment naïve primary tumor lesions at sizes less than 2 cm, as measured by computed tomography (CT) scans. The patient was analyzed for lymph node (LN) and distant metastasis evaluation, with clinicopathological characteristics, including tumor-disappearance ratio (TDR) (tumor diameter at the mediastinal/lung window) over chest CT scans, pathological diagnosis, disease-free survival (DFS), and overall survival (OS). RESULTS: Totally 280 patients were surveyed initially and showed significantly increase of clinical LN involvement and distant metastasis when TDR ≤75% compared with >75% (21.6% vs 0% for LN involvement; 27.1% vs 0% for distant metastasis; both p < 0.001). We included 199 patients having surgical treatment and follow-up for the survival analysis. With a TDR ≤75%, significantly worse DFS (HR, 19.23; 95% CI, 2.60-142.01; p = 0.004) and a trend of worse OS (HR, 4.97; 95% CI, 0.61-40.61; p = 0.134) were noted by Kaplan-Meier method. TDR ≤75% revealed more advanced pathological stage, and more tumors containing micropapillary or solid subtypes when diagnosed adenocarcinoma. CONCLUSION: For lung cancer patients with primary tumor ≤2 cm, TDR ≤75% was related to more advanced stages, the presence of micropapillary or solid components of adenocarcinoma subtypes, worse DFS, and a trend of worse OS.

Comparison of Arrhythmia Detection by 24-Hour Holter and 14-Day Continuous Electrocardiography Patch Monitoring.

BACKGROUND: Although 24-hour Holter monitoring is routinely used for patients with suspected paroxysmal arrhythmia, its sensitivity in detecting such arrhythmias is insufficient. METHODS: We compared a 14-day electrocardiography (ECG) monitor patch - a single-use, noninvasive, waterproof, continuous monitoring patch - with a 24-hour Holter monitor in 32 consecutive patients with suspected arrhythmia. RESULTS: The 14-day ECG patch was well tolerated, and its rates of detection of relevant arrhythmias on days 1, 3, 7, and 14 were 13%, 28%, 47%, and 66%, respectively. The detection rate of paroxysmal arrhythmias was significantly higher for the 14-day ECG patch than for the 24-hour Holter monitor (66% vs. 9%, p < 0.001). Among the 32 patients, 202 atrial fibrillation or atrial flutter episodes were detected in 6 patients (22%) with the 14-day ECG patch; however, only 1 atrial fibrillation episode was detected in a patient (3%, p < 0.05) with the 24-hour Holter monitor. Other clinically relevant arrhythmias recorded on the 14-day ECG patch included 21 (65.5%) episodes of supraventricular tachycardia, 2 (6.3%) long pause, and 2 (6.3%) ventricular arrhythmias. The mean dermal response score immediately after removal of the 14-day ECG patch from the patients was 0.64, which indicated minimal erythema. CONCLUSIONS: The 14-day ECG patch was well tolerated and allowed for longer continuous monitoring than the 24-hour Holter monitor, thus resulting in improved clinical accuracy in the detection of paroxysmal arrhythmias. Future studies should examine the long-term effectiveness of 14-day ECG patches for managing selected patients.

Overexpression of Aurora-A bypasses cytokinesis through phosphorylation of suppressed in lung cancer.

Mitosis is a complicated process by which eukaryotic cells segregate duplicated genomes into two daughter cells. To achieve the goal, numerous regulators have been revealed to control mitosis. The oncogenic Aurora-A is a versatile kinase responsible for the regulation of mitosis including chromosome condensation, spindle assembly, and centrosome maturation through phosphorylating a range of substrates. However, overexpression of Aurora-A bypasses cytokinesis, thereby generating multiple nuclei by unknown the mechanisms. To explore the underlying mechanisms, we found that SLAN, a potential tumor suppressor, served as a substrate of Aurora-A and knockdown of SLAN induced immature cytokinesis. Aurora-A phosphorylates SLAN at T573 under the help of the scaffold protein 14-3-3η. The SLAN phosphorylation-mimicking mutants T573D or T573E, in contrast to the phosphorylation-deficiency mutant T573A, induced higher level of multinucleated cells, and the endogenous SLAN p573 resided at spindle midzone and midbody with the help of the microtubule motor MKLP1. The Aurora-A- or SLAN-induced multiple nuclei was prevented by the knockdown of 14-3-3η or Aurora-A respectively, thereby revealing a 14-3-3η/Aurora-A/SLAN cascade negatively controlling cytokinesis. Intriguingly, SLAN T573D or T573E inactivated and T573A activated the key cytokinesis regulator RhoA. RhoA interacted with SLAN np573, i.e., the nonphosphorylated form of SLAN at T573, which localized to the spindle midzone dictated by RhoA and ECT2. Therefore, we report here that SLAN mediates the Aurora-A-triggered cytokinesis bypass and SLAN plays dual roles in that process depending on its phosphorylation status.

Therapeutic plasma exchange in the treatment of complicated Plasmodium falciparum malaria: A case report.

Severe falciparum malaria is associated with multiple organ dysfunction and a high rate of fatal outcome. Malaria is a world-wide disease in tropical areas through the bites of vector mosquitoes. Parasitic protozoans introduced by the mosquito's saliva to the blood travel to the liver then mature and reproduce. In humans, malaria is caused by Plasmodium falciparum, P. malariae, P. ovale, P. vivax, and P. knowlesi, and P. falciparum causes most deaths. Typical malaria symptoms include fever, chills, fatigue, headache, nausea, and vomiting. In severe cases, it can cause jaundice, seizures, coma, or death. Jaundice, caused by intravascular hemolysis is a usual complication of malaria, especially in patients with P. falciparum infection. The use of exchange transfusion in malaria is not currently advocated by the Centers of Disease Control and Prevention (CDC) of the United States of America. The role of therapeutic plasma exchange as an adjunctive therapy in malaria has not been widely discussed in the literature. Here, we present a 23-year-old patient with jaundice, acute renal failure, and cerebral involvement who was successfully treated with plasma exchange and hemodialysis.

EGFR mutation and lobar location of lung adenocarcinoma.

The objective of this study was to investigate the associations among lung cancer location, and epidermal growth factor receptor (EGFR) mutation status. Treatment-naive, pathologically confirmed lung adenocarcinomas with tumor specimens available for genetic analysis were included from 2011 through 2014. Overall, 1771 patients with lung adenocarcinoma were included for analysis, after excluding those with carcinoma not otherwise specified, or synchronous multiple primary lung cancers. The median age was 64 years, and the female:male and never smoker:ever smoker ratios were 930:855 (52:48%) and 1167:604 (65:35%), respectively. The EGFR mutation rate was 56%. Among patients, 1093 (62%) had primary tumors in the upper lobes. Compared with the characteristics of the EGFR wild-type, tumors with EGFR activating mutations were more common in women (P < 0.001), never smokers (P < 0.001), and in the upper lobes (P = 0.004). Among EGFR activating mutations, compared with the EGFR exon 19 deletion, L858R mutation were more common in women (P = 0.002), never smokers (P = 0.038), and the upper lobes P < 0.0005). The present study is the first to address that different pulmonary lobar locations might harbor different EGFR mutation subtypes. We demonstrated that adenocarcinomas with L858R mutation, rather than exon 19 deletion or wild-type EGFR gene, prefer to locate over the upper lungs. This phenomenon was more significant in females and never-smokers, implying the result of complex interactions between genetic susceptibility and environmental factors. Therefore, EGFR L858R mutation and exon 19 deletion may not be identical disease entity from the point of carcinogenesis.

Congenital Anomaly of Single Dominant Right Coronary Artery with Hypoplastic Left Coronary Artery.

UNLABELLED: With the popularization of new imaging technology, more people are deciding to undergo non-invasive studies such as multidetector computerized tomography (MDCT) before receiving coronary angiography. For this reason, coronary anomalies of coronary artery are being encountered more frequently. We here report a 68-year-old male presenting with typical angina. The MDCT images suggested chronic total occlusion of the left anterior descending (LAD) artery with collateral circulation from the right coronary artery (RCA). The patient's coronary angiography showed a congenital coronary anomaly with a single dominant RCA supplying the entire coronary circulation of the heart with both LAD and left circumflex artery hypoplasia. KEY WORDS: Angiography; Anomaly; Computerized tomography; Coronary artery.

Left Ventricular Perforation Following Transcutaneous Pigtail Catheter Placement Mimicking Anterior Wall Myocardial Infarction: An Unusual Complication.

In modern medical practice, procedures that involve the use of catheters are common. These procedures can range from percutaneous coronary and peripheral vascular interventions to using catheters to drain fluid. However, complications associated with catheter usage can arise, and the most severe one is the puncture of a vital organ due to catheter misplacement. In this case, we present a rare complication related to the use of a pigtail catheter, which caused perforation of the left ventricular free wall. The patient presented with an electrocardiogram showing ST segment elevation in the anterior wall, indicative of a heart attack. The patient underwent coronary angiography, which showed that the coronary arteries were unblocked. However, during the procedure, the medical team suspected that the pigtail catheter was stuck in the left ventricle chamber, based on the use of fluoroscopy. This suspicion was later confirmed using computer tomography. To address the issue, the patient underwent an emergent cardiorrhaphy, which was performed immediately. Fortunately, the patient survived the complication.

2024 multidisciplinary consensus on image-guided lung tumor ablation from the Taiwan Academy of Tumor Ablation.

In this article, the multidisciplinary team of the Taiwan Academy of Tumor Ablation, who have expertise in treating lung cancer, present their perspectives on percutaneous image-guided thermal ablation (IGTA) of lung tumors. The modified Delphi technique was applied to reach a consensus on clinical practice guidelines concerning ablation procedures, including a comprehensive literature review, selection of panelists, creation of a rating form and survey, and arrangement of an in-person meeting where panelists agreed or disagreed on various points. The conclusion was a final rating and written summary of the agreement. The multidisciplinary expert team agreed on 10 recommendations for the use of IGTA in the lungs. These recommendations include terms and definitions, line of treatment planning, modality, facility rooms, patient anesthesia settings, indications, margin determination, post-ablation image surveillance, qualified centers, and complication ranges. In summary, IGTA is a safe and feasible approach for treating primary and metastatic lung tumors, with a relatively low complication rate. However, decisions regarding the ablation technique should consider each patient's specific tumor characteristics.

EGFR exon 19 in-frame deletion and polymorphisms of DNA repair genes in never-smoking female lung adenocarcinoma patients.

We explored potential associations between genetic polymorphisms in genes related to DNA repair and detoxification metabolism and epidermal growth factor receptor (EGFR) mutations in a cohort of 410 never-smoking patients with lung adenocarcinoma. Multivariate-adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CI) of EGFR mutation status in association with the genotypes of DNA repair and detoxification metabolism genes were evaluated using logistic regression analysis. We found an association between in-frame deletion in EGFR exon 19 and a single nucleotide polymorphism (SNP) rs1800566C/T located in NQO1 (aOR, 2.2 with 95% CI, 1.0-4.8) in female never-smokers. The SNP rs744154C/G in ERCC4 was also associated with the EGFR exon 19 in-frame deletion both in never-smokers (aOR, 1.7 with 95% CI, 1.0-3.0) and female never-smokers (aOR, 1.9 with 95% CI, 1.0-3.6). Although the association was marginally significant in multivariate logistic regression analysis, the A/A genotype of rs1047840 in EXO1 was associated with a 7.6-fold increase in the occurrence of the EGFR exon 19 in-frame deletion in female never-smokers. Moreover, risk alleles in NQO1, ERCC4 and EXO1 were associated with an increasing aOR of the EGFR exon 19 in-frame deletion both in never-smokers (p = 0.007 for trend) and female never-smokers (p = 0.002 for trend). Our findings suggest that the in-frame deletion in EGFR exon 19 is associated with polymorphisms in DNA repair and detoxification metabolism genes in never-smoking lung adenocarcinoma patients, especially in females.

Identification of Coronary Culprit Lesion in ST Elevation Myocardial Infarction by Using Deep Learning.

OBJECTIVE: Early revascularization of the occluded coronary artery in patients with ST elevation myocardial infarction (STEMI) has been demonstrated to decrease mortality and morbidity. Currently, physicians rely on features of electrocardiograms (ECGs) to identify the most likely location of coronary arteries related to an infarct. We sought to predict these culprit arteries more accurately by using deep learning. METHODS: A deep learning model with a convolutional neural network (CNN) that incorporated ECG signals was trained on 384 patients with STEMI who underwent primary percutaneous coronary intervention (PCI) at a medical center. The performances of various signal preprocessing methods (short-time Fourier transform [STFT] and continuous wavelet transform [CWT]) with different lengths of input ECG signals were compared. The sensitivity and specificity for predicting each infarct-related artery and the overall accuracy were evaluated. RESULTS: ECG signal preprocessing with STFT achieved fair overall prediction accuracy (79.3%). The sensitivity and specificity for predicting the left anterior descending artery (LAD) as the culprit vessel were 85.7% and 88.4%, respectively. The sensitivity and specificity for predicting the left circumflex artery (LCX) were 37% and 99%, respectively, and the sensitivity and specificity for predicting the right coronary artery (RCA) were 88.4% and 82.4%, respectively. Using CWT (Morlet wavelet) for signal preprocessing resulted in better overall accuracy (83.7%) compared with STFT preprocessing. The sensitivity and specificity were 93.46% and 80.39% for LAD, 56% and 99.7% for LCX, and 85.9% and 92.9% for RCA, respectively. CONCLUSION: Our study demonstrated that deep learning with a CNN could facilitate the identification of the culprit coronary artery in patients with STEMI. Preprocessing ECG signals with CWT was demonstrated to be superior to doing so with STFT.

Comparison of wide and narrow gastric conduit in esophageal cancer surgery.

BACKGROUND: Gastric conduit is most widely used method for esophageal reconstruction. Despite its popularity, certain complications, such as anastomotic leakage and strictures, remain to be resolved. In the present study, we reviewed the outcomes of narrow gastric conduit compared to wide gastric conduit reconstruction. METHODS: We retrospectively reviewed 493 patients with esophageal cancer who received esophagectomy with reconstruction in Taichung Veteran General Hospital, Taiwan between January 2010 and December 2019. We performed gastric conduit reconstruction with two different methods, narrow gastric conduit made of multistaples (more than four staples) and wide gastric conduit made of two or three staples. Among the 493 patients, 170 patients underwent wide gastric conduit formation and 323 patients underwent narrow gastric conduit. After propensity score matching, 140 patients from each group were matched by 1:1. RESULTS: The average anastomotic leakage rate is 80 of 493 (16.23%). The leakage rate, length of hospital stay, intensive care unit (ICU) admission, and ICU stay were significantly lower in the narrow gastric conduit group than in the wide gastric conduit group. The need for postoperation dilatation was significantly higher in wide gastric conduit group (19.41% vs 11.76%, p = 0.0217), and the time to first dilatation was similar in both groups ( p = 0.9808). Similar results were observed even after propensity score matching. In univariate analysis, the narrow gastric conduit, circular stapler, video-assisted thoracic surgery, and laparoscopic surgery were associated with a reduced risk of anastomotic leakage. However, these factors are not statistically significant in a multivariate logistic regression analysis. CONCLUSION: The narrow gastric conduit is not inferior to the wide gastric conduit and can be considered an alternative option for gastric conduit preparation.

Surgery or Surveillance for Esophageal Squamous Cell Carcinoma With Clinical Complete Response After Neoadjuvant Chemoradiotherapy.

We aimed to evaluate the role of esophagectomy in patients with esophageal squamous cell carcinoma with clinically complete response (cCR) after neoadjuvant chemoradiotherapy. Data of patients with locally advanced esophageal squamous cell carcinoma who achieved cCR after neoadjuvant chemoradiotherapy between October 2008 and September 2018 were retrospectively reviewed. The criteria for cCR include: (1) tumor resolution on computed tomography, (2) maximum standardized uptake value decrement >35% on positron-emission tomography-computed tomography scan, and (3) a negative endoscopic biopsy result. Overall survival (OS) and disease-free survival (DFS) were compared between patients who received surveillance only (surveillance) and those who underwent surgery. A total of 154 patients with cCR, including 54 in the surveillance group and 100 in the surgery group, were included. The 5-year OS rates in the surveillance and surgery groups were 47.9% and 36.9 %, respectively (P= 0.210). The 5-year DFS rates were 38.1% and 28.2%, respectively (P = 0.203). Surgery was not a prognostic factor in the multivariable analysis (OS: HR: 1.26, 95% CI: 0.69-2.33, P = 0.453; DFS: HR: 1.08, 95% CI: 0.60-1.96, P = 0.795). In the surgery group, ypT0N0, ypT+Nany, and ypT0N+ were noted in 54%, 37%, and 9% of patients, respectively. The 5-year OS rates were 55.8%, 22.2%, and 12.4%, respectively (P = 0.001). No survival differences were noted between the surveillance and surgery groups. However, 46% of cCR patients in the surgery group did not have pathological complete response, and their outcomes were poor. Esophagectomy may be the only way to identify patients with residual disease.

Whole exome sequencing and MicroRNA profiling of lung adenocarcinoma identified risk prediction features for tumors at stage I and its substages.

OBJECTIVES: About 20% of stage I lung adenocarcinoma (LUAD) patients suffer a relapse after surgical resection. While finer substages have been defined and refined in the AJCC staging system, clinical investigations on the tumor molecular landscape are lacking. MATERIALS AND METHODS: We performed whole exome sequencing, DNA copy number and microRNA profiling on paired tumor-normal samples from a cohort of 113 treatment-naïve stage I Taiwanese LUAD patients. We searched for molecular features associated with relapse-free survival (RFS) of stage I or its substages and validated the findings with an independent Caucasian LUAD cohort. RESULTS: We found sixteen nonsynonymous mutations harbored at EGFR, KRAS, TP53, CTNNB1 and six other genes associated with poor RFS in a dose-dependent manner via variant allele fraction (VAF). An index, maxVAF, was constructed to quantify the overall mutation load from genes other than EGFR. High maxVAF scores discriminated a small group of high-risk LUAD at stage I (median RFS: 4.5 versus 69.5 months; HR = 10.5, 95% CI = 4.22-26.12, P < 0.001). At the substage level, higher risk was found for patients with high maxVAF or high miR-31; IA (median RFS: 32.1 versus 122.8 months, P = 0.005) and IB (median RFS: 7.1 versus 26.2, P = 0.049). MicroRNAs, miR-182, miR-183 and miR-196a were found correlated with EGFR mutation and poor RFS in stage IB patients. CONCLUSION: Distinctive features of somatic gene mutation and microRNA expression of stage I LUAD are characterized to complement the survival prognosis by substaging. The findings open up more options for precision management of stage I LUAD patients.

Low-Dose Computed Tomography Screening in Relatives With a Family History of Lung Cancer.

INTRODUCTION: The role of a family history of lung cancer (LCFH) in screening using low-dose computed tomography (LDCT) has not been prospectively investigated with long-term follow-up. METHODS: A multicenter prospective study with up to three rounds of annual LDCT screening was conducted to determine the detection rate of lung cancer (LC) in asymptomatic first- or second-degree relatives of LCFH. RESULTS: From 2007 to 2011, there were 1102 participants enrolled, including 805 and 297 from simplex and multiplex families (MFs), respectively (54.2% women and 70.0% never-smokers). The last follow-up date was May 5, 2021. The overall LC detection rate was 4.5% (50 of 1102). The detection rate in MF was 9.4% (19 of 202) and 4.4% (4 of 91) in never-smokers and in those who smoked, respectively. The corresponding rates for simplex families were 3.7% (21 of 569) and 2.7% (6 of 223), respectively. Of these, 68.0% and 22.0% of cases with stage I and IV diseases, respectively. LC diagnoses within a 3-year interval from the initial screening tend to be younger, have a higher detection rate, and have stage I disease; thereafter, more stage III-IV disease and 66.7% (16 of 24) with negative or semipositive nodules in initial computed tomography scans. Within the 6-year interval, only maternal (modified rate ratio = 4.46, 95% confidence interval: 2.32-8.56) or maternal relative history of LC (modified rate ratio = 5.41, 95% confidence interval: 2.84-10.30) increased the risk of LC. CONCLUSIONS: LCFH is a risk factor for LC and is increased with MF history, among never-smokers, younger adults, and those with maternal relatives with LC. Randomized controlled trials are needed to confirm the mortality benefit of LDCT screening in those with LCFH.

Adjuvant Chemotherapy for Pathological Node-Positive Disease in Squamous Cell Carcinoma of the Esophagus after Neoadjuvant Chemoradiotherapy Plus Surgery.

Purpose: The purpose of the present study is to determine the impact on survival using adjuvant chemotherapy on patients with locally advanced esophageal cancer. Materials and Methods: From 2007 to 2016, we enrolled 127 locally advanced esophageal squamous cell carcinoma patients treated with combined neoadjuvant chemoradiotherapy (nCRT) and surgery. For patients with the pathological residual primary disease (pT+) and/or residual node disease (pN+) after nCRT, adjuvant chemotherapy was also given after consideration of the toxicity of nCRT, patient performance, and/or comorbidity. The regimen of adjuvant chemotherapy was cisplatin 20 mg/m2/day and 5-fluorouracil 800 mg/m2/day on days 1 through 4 and 22 through 25. The primary endpoint was overall survival (OS). Results: From a total of 127 patients, 26 of them (20.5%) received adjuvant chemotherapy. In the multivariate analysis, pN+ diseases were independently associated with poor OS (hazard ratio (HR): 4.117, 95% confidence interval (CI): 1.366-12.404; p = 0.012). For those with pN+ diseases, their 5-year OS was 36.4% in the follow-up arm compared with 45.8% in the adjuvant chemotherapy arm (p = 0.094). Conclusions: Pathologic node-positive disease is associated with poor OS in locally advanced esophagus cancer patients after combined treatments with nCRT and surgery. Adjuvant chemotherapy appeared to have improved OS in pathologic node-positive diseases.