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.

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.

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.

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.

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.

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.

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.

The Influence of Socioeconomic Status on Esophageal Cancer in Taiwan: A Population-Based Study.

BACKGROUND: Esophageal cancer has extreme worldwide demographic and histologic variations in occurrence; thus, understanding the pathogenesis of esophageal cancer must be region- or country-based. We examined the incidence and tumor stage at diagnosis of esophageal cancer in relation to patients' socioeconomic status (SES) in Taiwan. METHOD: This retrospective cohort study used data from Taiwan's National Health Insurance Research Database and Taiwan Cancer Registry collected between January 2008 and December 2014. The records of 40- to 79-year-old patients diagnosed with esophageal cancer were retrieved. The distribution of the crude incidence rates of esophageal cancer by occupation and income variables was studied retrospectively. Cox proportional hazard model was used to adjust for potential confounders and compare the esophageal cancer incidence among four independent variables: age, gender, occupation, and income. Logistic regression analysis was applied to find the power of the independent variables on the odds ratio of late-stage presentation. RESULTS: The analysis included 7763 subjects. Esophageal squamous cell carcinoma (ESCC) was the predominant histological type (96.6%) and 94.4% of patients were male. The peak affected age for ESCC was 50 to 59 years, whereas the risk of esophageal adenocarcinoma increased progressively with age. The risk of ESCC was significantly unfavorable for the most disadvantaged group, either in occupation or income, while in EAC, risk was unrelated to either factor. The stage of cancer at diagnosis was lower in the highest income groups than in the other two groups. CONCLUSION: Significant SES disparities in esophageal cancer incidence, based on occupation and income, are present in Taiwan. Low SES populations have a higher percentage of late-stage diagnosis. Resolution of the increasing socioeconomic disparities and narrowing the gaps in health inequities in Taiwan are needed.

Good prediction of treatment responses to neoadjuvant chemoradiotherapy for esophageal cancer based on preoperative inflammatory status and tumor glucose metabolism.

To develop a tool for predicting pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (neoCRT) in patients with esophageal cancer by combining inflammatory status and tumor glucose metabolic activity. This study included 127 patients with locally advanced esophageal cancer who had received neoCRT followed by esophagectomy from 2007 to 2016. We collected their neutrophil-lymphocyte ratio (NLR) and standardized uptake value (SUV) obtained from fluorodeoxyglucose positron emission tomography (PET/CT) before and after neoCRT. Univariate and multivariate logistic regression analyses were performed to identify potential predictive factors for pCR. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of predictors were calculated. Between pCR and non-pCR groups, there were no statistically significant differences in patient characteristics, such as sex, age, site, and clinical T/N stage. Multivariate analyses identified four independent predictors for pCR, including pre-OP NLR < 5.4 [OR 11.179; 95% CI 8.385-13.495; p = 0.003], NLR change (ΔNLR) < 3 [OR 4.891; 95% CI 2.274-9.180; p = 0.005], changes in SUV (ΔSUV) > 7.2 [OR 3.033; 95% CI 1.354-6.791; p = 0.007], and SUV changes ratio (ΔSUV ratio) > 58% [OR 3.585; 95% CI 1.576-8.152; p = 0.002]. ΔNLR had the highest accuracy and NPV (84.3% and 90.3%, respectively). Combined factors of ΔNLR < 3 and ΔSUV ratio > 58% had the best PPV for pCR (84.8%). Inflammatory status (ΔNLR) and tumor glucose metabolic activity (ΔSUV ratio), when considered together, constitute a promising low-invasive tool with high efficacy for prediction of treatment response before surgery.

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.

Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma.

Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93-28.32, p < 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine.

Lymphovascular Invasion as the Major Prognostic Factor in Node-Negative Esophageal Cancer After Primary Esophagectomy.

BACKGROUND: Studies addressing both lymphovascular invasion (LVI) and perineural invasion (PNI) in patients with esophageal squamous cell carcinoma (ESCC) treated with or without neoadjuvant therapy are limited. We aimed to analyze the incidence and prognostic significance of LVI and PNI in patients with thoracic ESCC. METHODS: This retrospective study included 520 patients with ESCC: 174 patients after neoadjuvant treatment followed by surgery and 346 after primary esophagectomy, from two medical centers. The relationships between LVI, PNI, and other histological factors were evaluated. The Cox regression model was used for survival analysis. RESULTS: Positive LVI and PNI were noted in 35.6% and 22.4% of patients with residual primary tumor after neoadjuvant treatment and in 39.6% and 24.0% of patients who underwent primary esophagectomy, respectively. In patients with neoadjuvant treatments, the 5-year overall survival rates were 12.7% and 28.3% in patients with positive LVI and negative LVI, respectively (p = 0.001). The 5-year overall survival rates were 6.4% and 29.9% in patients with positive PNI and negative PNI, respectively (p < 0.001). In patients who did not receive neoadjuvant treatment, the 5-year overall survival rates were 28.2% and 61.1% in patients with positive LVI and negative LVI, respectively (p < 0.001). The 5-year overall survival rates were 30.2% and 52.5% in patients with positive PNI and negative PNI (p < 0.001). In subgroup analysis, the presence of PNI was an independent prognostic factor in patients with neoadjuvant treatments, whereas the presence of LVI had more significant prognostic impact in patients with node-negative ESCC after primary esophagectomy. CONCLUSIONS: Both LVI and PNI statuses are significant prognostic factors for patients with ESCC. However, the prognostic impact of LVI was majorly in the subgroup of node-negative patients who received primary esophagectomy.

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.

Lung Tumorigenesis Alters the Expression of Slit2-exon15 Splicing Variants in Tumor Microenvironment.

Slit2 expression is downregulated in various cancers, including lung cancer. We identified two Slit2 splicing variants at exon15-Slit2-WT and Slit2-ΔE15. In the RT-PCR analyses, the Slit2-WT isoform was predominantly expressed in all the lung cancer specimens and in their normal lung counterparts, whereas Slit2-ΔE15 was equivalently or predominantly expressed in 41% of the pneumothorax specimens. A kRasG12D transgenic mice system was used to study the effects of tumorigenesis on the expressions of the Slit2-exon15 isoforms. The results revealed that a kRasG12D-induced lung tumor increased the Slit2-WT/Slit2-ΔE15 ratio and total Slit2 expression level. However, the lung tumors generated via a tail vein injection of lung cancer cells decreased the Slit2-WT/Slit2-ΔE15 ratio and total Slit2 expression level. Interestingly, the lipopolysaccharide (LPS)-induced lung inflammation also decreased the Slit2-WT/Slit2-ΔE15 ratio. Since Slit2 functions as an anti-inflammatory factor, the expression of Slit2 increases in kRasG12D lungs, which indicates that Slit2 suppresses immunity during tumorigenesis. However, an injection of lung cancer cells via the tail vein and the LPS-induced lung inflammation both decreased the Slit2 expression. The increased Slit2 in the tumor microenvironment was mostly Slit2-WT, which lacks growth inhibitory activity. Thus, the results of our study suggested that the upregulation of Slit2-WT, but not Slit2-ΔE15, in a cancer microenvironment is an important factor in suppressing immunity while not interfering with cancer growth.

Impact of perineural invasion as a histopathological prognostic factor in ypStage II/III oesophageal squamous cell carcinoma†.

OBJECTIVES: The 8th edition American Joint Committee on Cancer Tumour-Nodes-Metastasis (TNM) staging system distinguishes between the clinical (c), pathological (p) and post-neoadjuvant pathological (yp) stage groups. However, the ability to discriminate between ypStage II and ypStage III is poor. We aim to identify prognostic factors in patients with ypStage II/III oesophageal squamous cell carcinoma. METHODS: The data of 150 patients with ypStage II/III oesophageal squamous cell carcinoma from 2 medical centres were retrospectively reviewed. The neoadjuvant treatments included chemotherapy with cisplatin and 5-fluorouracil, administered concurrently with external beam radiation. The determination of perineural invasion (PNI) was based on pathological reports. Survival curves were compared using the log-rank test, and multivariable survival analysis was performed with a Cox regression model. RESULTS: The 3-year/5-year overall survival rate/median survival in ypStages II, IIIa and IIIb were 35.3%/26.9%/21.9 [95% confidence interval (CI) 14.9-28.8] months, 33.8%/22.5%/22.4 (95% CI 20.1-24.7) months and 21.7%/14.0%/14.4 (95% CI 11.1-17.7) months, respectively (P = 0.07). The 3-year/5-year overall survival rate/median survival was 36.7%/26.4%/22.8 (95% CI 19.2-26.5) months in the absence of PNI and 6.9%/3.4%/9.1 (95% CI 8.9-9.4) months in the presence of PNI (P < 0.001). In the multivariable survival analysis, tumour location in the upper third of the thoracic oesophagus [hazard ratio (HR) 1.692, 95% CI 1.087-2.635; P = 0.020] and positive PNI (HR 3.316, 95% CI 2.005-4.905; P < 0.001) remained as independent prognostic factors. CONCLUSIONS: The existence of PNI after neoadjuvant treatment is closely associated with poor prognosis and could be incorporated into the TNM staging system for better discrimination between patients with ypStage II/III oesophageal squamous cell carcinoma.

Definite intensity-modulated radiotherapy with concurrent chemotherapy more than 4 cycles improved survival for patients with locally-advanced or inoperable esophageal squamous cell carcinoma.

We investigated which prognostic factor could improve survival for esophageal cancer patients who received definite concurrent chemoradiation (CCRT). Eighty patients with age ≥18, Karnofsky Performance Scale (KPS) ≥ 60, and clinical stage T1-4N0-3M0 esophageal squamous cell carcinoma were enrolled from July 2004 to December 2015. They underwent definite intensity-modulated radiotherapy (IMRT) with or without simultaneous integrated boost to the primary tumor, and reception of concurrent chemotherapy ≥ 1 cycle. The primary endpoints were overall survival (OS), locoregional progression-free survival (LRPFS) and distant metastasis-free survival (DMFS). The median follow-up duration for alive patients was 21.5 months. The rates of 2-, 3- and 5-year OS/LRPFS/DMFS were 23.8%/53.5%/49.3%, 19.1%/44.6%/49.3%, and 13.0%/44.6%/43.9%, respectively. Only the non-clinical complete response (non-cCR) after CCRT was an independent poor prognostic factor in OS (HR 3.101, 95% CI 1.535-6.265, p = 0.0016). Radiation dose >50.4 Gy and chemotherapy ≥4 cycles significantly predicted better LRPFS (p = 0.0361 and 0.0163, respectively). Poorly differentiated tumor and stage III disease have poor DMFS (p = 0.0336 and 0.0411, respectively), and chemotherapy ≥ 4 cycles was a better predictor (p = 0.0004). In subgroup analysis, patients who received radiation dose ≤50.4 Gy with concurrent chemotherapy ≥4 cycles had the best survival outcome with 1-, 2-, 3- and 5-year survival rates of 73.7%, 39.4%, 31.5% and 17.5%, respectively. In conclusion, definite radiotherapy with concurrent chemotherapy ≥4 cycles improved the survival for patients with inoperable or locally-advanced esophageal squamous cell carcinoma.

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.