Noninvasive Imaging in Cardiac Resynchronization Therapy—Part 2: Follow‐up and Optimization of Settings

Cardiac resynchronization therapy (CRT) has become a therapeutic option for drug‐refractory heart failure. Several noninvasive imaging techniques play an increasingly important role before and after device implantation. This review highlights the acute and long‐term CRT benefits after implantation as assessed with echocardiography and nuclear imaging. Furthermore, optimization of CRT settings, in particular atrioventricular and interventricular delay, will be discussed using echocardiography and other (device‐based) techniques.     

External Vibration Interference of Activity Based Rate Responsive Pacemakers

The change of the pacing rate in response to external vibration interference was assessed in four rate responsive pacemakers with a piezoelectric crystal (Medtronic Activitrax 8403, Siemens Sensolog 3, Biotronik Ergos 01, and Medtronic Legend 8417) and one with an accelerometer (CPI Excel VR 1119). They were tested in the laboratory. External vibration was simulated in vitro by exposing the different pacemakers to a controlled sinusoidal vibration force generated by a Millar pressure vibration amplifier type MGM-30 (Millar Instruments, Inc., Houston, TX, USA). All pacemakers were programmed at standard settings. Two types of vibration forces were applied: (1) one with varying amplitude but with constant vibration frequency; and (2) one with varying frequency but with constant vibration amplitude. In this manner curves of pacing rate versus vibration forces versus vibration frequency were obtained. High vibration forces and low vibration frequencies were associated with the highest pacing rate response. In this experimental setting, the pacemaker based on the accelerometer principle apparently was the least sensitive to high frequency vibrations, which are known to be related to environmental interference. It also seemed more appropriately responsive in the lower frequency range, which is more appropriate for the detection of true physiological activity.     

IN SITU HYBRIDIZATION AND FLOW CYTOMETRIC ANALYSIS OF COLORECTAL TUMOURS SUGGESTS TWO ROUTES OF TUMOURIGENESIS CHARACTERIZED BY GAIN OF CHROMOSOME 7 OR LOSS OF CHROMOSOMES 17 AND 18

Chromosomal aberrations in colonic tumourigenesis were investigated by fluorescence in situ hybridization (FISH) with centromere-specific DNA probes and correlated to flow cytometry (FCM) results in a series of tissues including normal colonic epithelium, adenomas, and carcinomas, as well as adenomas adjacent to carcinomas. No numerical chromosome aberrations were detected in normal colonic epithelium, except for an extra chromosome X in one case. In the adenomas, the most frequently occurring chromosome aberration was a trisomy for chromosome 7, occurring in 37 per cent of the cases. In the carcinomas, two distinct routes of genetic aberration could be established on the basis of correlation with FCM: one with and one without endoreduplication. In the carcinomas without endoreduplication, trisomy or tetrasomy for chromosome 7 was detected in 12 out of 15 cases (80 per cent). In three of these cases, trisomy 7 was found in combination with loss of chromosome 17 and/or chromosome 18. In 87 per cent of the carcinomas with endoreduplication, loss of chromosome 17 and/or 18 was found, while in only one case was gain of chromosome 7 detected. In the adenomas adjacent to carcinomas, trisomy 7 was found in 36 per cent of the cases. In these cases, the concomitant adenocarcinomas showed the same numerical chromosome 7 aberration, plus extra aberrations for other chromosomes. In only two cases the carcinoma demonstrated trisomy 7 with a normal adjacent adenoma. These results suggest that gain of chromosome 7 is a significant aberration in the tumourigenesis of colonic carcinomas in which no endoreduplication has occurred. No marked clinico-pathological differences were observed between tumours of either route of tumourigenesis in this series.     

A Th2-score in the tumor microenvironment as a predictive biomarker of response to Bacillus Calmette Guérin in patients with non-muscle invasive bladder carcinoma: A retrospective study

Intravesical Bacillus Calmette Guerin (BCG) is the gold standard therapy for intermediate/high-risk nonmuscle invasive bladder cancer (NMIBC). However, the response rate is ~60%, and 50% of non-responders will progress to muscle-invasive disease. BCG induces massive local infiltration of inflammatory cells (Th1) and ultimately cytotoxic tumor elimination. We searched for predictive biomarker of BCG response by analyzing tumor-infiltrating lymphocyte (TIL) polarization in the tumor microenvironment (TME) in pre-treatment biopsies. Pre-treatment biopsies from patients with NMIBC who received adequate intravesical instillation of BCG (n = 32) were evaluated retrospectively by immunohistochemistry. TME polarization was assessed by quantifying the T-Bet+ (Th1) and GATA-3+ (Th2) lymphocyte ratio (G/T), and the density and degranulation of EPX+ eosinophils. In addition, PD-1/ PD-L1 staining was quantified. The results correlated with BCG response. In most non-responders, Th1/Th2 markers were compared in pre-and post-BCG biopsies. ORR was 65.6% in the study population. BCG responders had a higher G/T ratio and a greater number of degranulated EPX+ cells. Variables combined into a Th2-score showed a significant association with higher scores in responders (p = 0.027). A Th2-score cut-off value >48.1 allowed discrimination of responders with 91% sensitivity but lower specificity. Relapse-free survival was significantly associated with the Th2-score (p = 0.007). In post-BCG biopsies from recurring patients, TILs increased Th2-polarization, probably reflecting BCG failure to induce a pro-inflammatory status and, thus, a lack of response. PD-L1/PD-1 expression was not associated with the response to BCG. Our results support the hypothesis that a preexisting Th2-polarized TME predicts a better response to BCG, assuming a reversion to Th1 polarization and antitumor activity.