Clinical significance of Zinc finger E-box Binding homeobox 1 (ZEB1) in human gastric cancer.

BACKGROUND AND OBJECTIVES: Zinc finger E-box Binding homeobox 1 (ZEB1) encodes a transcription factor and is one of the epithelial-mesenchymal transition (EMT)-inducible genes that play a key role in tumor progression in various cancers. The aim of this study is to clarify the clinical significance of ZEB1 expression in gastric cancer patients. METHODS: One hundred thirty-four patients who underwent surgery for gastric cancer were evaluated. We analyzed ZEB1 mRNA levels by real-time reverse transcription PCR in gastric cancer tissue and adjacent normal mucosa. ZEB1 protein expression in primary cancer and in peritoneal dissemination samples was measured using immunohistochemical analysis. RESULTS: Expression of the ZEB1 gene was significantly higher in cancerous tissue than in adjacent normal mucosa. Increased ZEB1 expression was significantly associated with peritoneal dissemination, and was an independent prognostic factor. Logistic regression analysis revealed that increased ZEB1 expression was an independent risk factor for peritoneal dissemination. Immunohistochemical analysis indicated that ZEB1 was intensely expressed in both primary cancer and peritoneal dissemination samples. CONCLUSIONS: ZEB1 is an independent factor for peritoneal dissemination in patients with gastric cancer, and may therefore play a key role in the progression to peritoneal dissemination in gastric cancer patients.

Cancer-associated fibroblasts correlate with poor prognosis in rectal cancer after chemoradiotherapy.

Cancer-associated fibroblasts (CAFs) in the stroma play an important role in influencing the proliferation, invasion and metastasis of cancer cells. Fibroblast activation protein-α (FAP-α) is known as a marker of CAFs, while stromal cell-derived factor-1 (SDF-1) is primarily expressed by CAFs. Herein, we investigated whether the expression levels of these genes are associated with clinical outcome after pre-operative chemoradiotherapy (CRT) in rectal cancer patients. We obtained total RNA from residual cancer stroma using microdissection from a total of 52 rectal cancer specimens from patients who underwent pre-operative CRT, we performed transcriptional analyses, and the serum protein concentrations in 40 matched microdissected specimens were measured by enzyme-linked immunosorbent assay. Additionally, we sought to clarify the location of FAP-α and SDF-1 expression using immunohistochemical staining. Of the 52 patients, 15.6 and 36.8% showed detectable FAP-α and SDF-1 mRNA expression, respectively. A significant correlation was observed between stromal FAP-α and SDF-1 mRNA levels. Moreover, there was a significant correlation between stromal SDF-1 gene expression levels and serum protein levels. Patients who developed distant recurrences after CRT had positive expression of both genes (P<0.05). The positive expression of both genes was also associated with poor probability of recurrence-free and overall survival (P<0.05). Patients with elevated serum SDF-1 levels had equally poor overall survival as those with positive stromal SDF-1 gene expression (P<0.05). In immunohistochemistry, both FAP-α and SDF-1 expression was observed in certain activated fibroblasts. In conclusion, FAP-α and SDF-1 expression was shown to be involved in tumor re-growth and recurrence in rectal cancer patients treated with pre-operative CRT.

Double-counting of intracardiac electrogram during biatrial pacing.

BACKGROUND: Biatrial pacing has a significant problem with memory function that misinterprets normal sinus rhythm as atrial tachyarrhythmias and in addition estimation of the atrial pacing thresholds (biatrial and uniatrial pacing thresholds) is sometimes difficult because of small P waves. METHODS AND RESULTS: The intracardiac electrograms recorded by a pacemaker in 10 patients (age, 66.7+/-10.7 (SD) years) with implanted biatrial pacemakers were analyzed. Atrial sensing within the atrial refractory period after atrial pacing was counted in 6 of the 10 patients (timing of the double counting was 143+/-64 ms) when pacing failed in the left or right atrium. Atrial sensing within the atrial refractory period after atrial pacing disappeared when biatrial pacing was successfully performed. Atrial double-counts depend on interatrial conduction delay. The memory function of implanted pacemaker devices misinterpreted normal sinus rhythm as atrial tachyarrhythmias because of atrial double-counts. On the other hand, the biatrial pacing threshold was easily recognized using this phenomenon. CONCLUSIONS: The memory function of pacemaker devices is unreliable because of atrial double-counting during sinus rhythm in patients with biatrial pacing. However, the biatrial pacing threshold is easily checked using this phenomenon.

Changes in evoked QT intervals according to variations in atrioventricular delay and cardiac function in patients with implanted QT-driven DDDR pacemakers.

In patients with implanted DDD pacemaker, cardiac output is maximal when atrioventricular (AV) delay is set to give the maximum QT interval (QTI). QTI is used as a sensor of a rate-responsive pacemaker and the evoked QTI (eQTI) is measured as the time duration from the ventricular pace-pulse and the T sense point, which is the steepest point of the intracardiac T wave. The relationship between the changes in eQTI according to AV delay variations and cardiac function was studied in 13 patients (74.2+/-9.3 [SD] years old) with an implanted QT-driven DDDR-pacemaker. A special software module was downloaded into the pacemaker memory and a personal computer equipped with the special software was connected to the programmer for eQTI date-logging. AV delay was set at 100, 120, 150, 180 and 210 ms. Delta eQTI was defined as maximal eQTI - minimal eQTI. The ejection fraction (EF) was measured by echocardiography. When the AV delay was prolonged, eQTI gradually increased and reached a peak, and then decreased. Delta eQTI in patients with reduced cardiac function (EF <40%) was significantly greater than that in normal cardiac function (EF >55%, 7.6+/-4.9 vs 2.7+/-9.8 ms, p<0.05). There was significant negative correlation between EF and delta eQTI (r=-0.63, p<0.05). The peak of changes in eQTI according to AV delay variations was steeper in patients with reduced cardiac function than in those with normal cardiac function. In conclusion, changes in eQTI according to AV delay variation are greater in patients with reduced cardiac function than in those with normal cardiac function, and the AV delay that gives the maximal eQTI can be easily determined in patients with reduced cardiac function.

Optimal atrioventricular delay setting determined by QT sensor of implanted DDDR pacemaker.

QT interval (QTI) may change when cardiac function is improved by optimizing the AV delay. QTI is used as the sensor for rate responsive pacemakers. Evoked (e)QTI is measured as the time duration from the ventricular pace-pulse to the T sense point, which is the steepest point of the intracardiac T wave. The relationship between AV delay and eQTI and cardiac function was studied in 13 patients (74.2 +/- 9.3 [SD] years old) with an implanted QT-driven DDDR pacemaker. A special pacemaker software module was downloaded into the pacemaker memory for eQTI data logging. AV delay was set at 100, 120, 150, 180, 210, and 240 ms. Cardiac output (CO) was measured by continuous Doppler echocardiography. eQTI was 343.3 +/- 22.4, 345.1 +/- 22.5, and 343.4 +/- 23.2 ms (P < 0.01, repeated ANOVA) and CO was 4.2 +/- 0.8, 4.6 +/- 0.8, and 4.2 +/- 0.8 L/min (P < 0.0001, repeated ANOVA) when AV delay was set at the AV delay shortened by one step (AV[-]) and prolonged by one step (AV[+]) from the AV delay at which QT interval was maximum (AV[max]) in seven patients, in whom the peak AV delay at which the eQTI was maximal could be identified. eQTI decreased from 341.1 +/- 20.9 to 339.4 +/- 21.1 ms (P < 0.0001) and CO decreased from 4.4 +/- 1.4 to 4.1 +/- 1.3 L/min (P < 0.005) when AV delay was prolonged from AV(max) to AV(+) in all patients. eQTI decreased from 345.1 +/- 22.5 to 343.3 +/- 22.4 ms (P < 0.0005) and CO decreased from 4.6 +/- 0.8 to 4.2 +/- 0.8 L/min (P < 0.05) when AV delay was shortened from AV(max) to AV(-) in seven patients. Thus, CO was maximal when AV delay was set at the AV delay at which eQTI was maximal. In conclusion, the optimal AV delay can be predicted from the eQTI sensed by an implanted pacemaker, and automatic setting of the optimal AV delay can be achieved by the QT sensor of an implanted pacemaker.