Postchemoradiation laparoscopic resection and intraoperative electron-beam radiation boost in locally advanced rectal cancer: long-term outcomes

Background

In selected patients with rectal cancer, laparoscopic surgery is as safe as open surgery, with similar resection margins and completeness of resection. In addition, recovery is faster after laparoscopic surgery. We analyzed long-term outcomes in a group of patients with locally advanced rectal cancer (LARC) treated with preoperative therapy followed by laparoscopic surgery and intraoperative electron-beam radiotherapy (IOERT).

Methods and materials

From June 2005 to December 2010, 125 LARC patients were treated with 2 induction courses of FOLFOX-4 (oxaliplatin 85 mg/m²/d1, intravenous leucovorin at 200 mg/m²/d1–2, and an intravenous bolus of 5-fluorouracil 400 mg/m²/d1–2) and preoperative chemoradiation (4,500–5,040 cGy) followed by total mesorectal excision (laparoscopic, 35 %; open surgery, 65 %) and a presacral boost with IOERT.

Results

Patients in the laparoscopic surgery group lost less blood (median 200 vs 350 mL, p < 0.01) and had a shorter hospital stay (7 vs 11 days; p = 0.02) than those in the open surgery group. Laparoscopic procedures were shorter than open surgery procedures (270 vs 302 min; p = 0.67). Postoperative morbidity (32 vs 44 %; p = 0.65), RTOG grade ≥3 acute toxicity (25 vs 25 %; p = 0.97), and RTOG grade ≥3 chronic toxicity (7 vs 9 %; p = 0.48) were similar in the laparoscopy and open surgery groups. The median follow-up time for the entire cohort of patients was 59.5 months (range 7.8–90); no significant differences were observed between the groups in locoregional control (HR 0.91, p = 0.89), disease-free survival (HR 0.80, p = 0.65), and overall survival (HR 0.67, p = 0.52).

Conclusions

Postchemoradiation laparoscopically assisted IOERT is feasible, with an acceptable risk of postoperative complications, shorter hospital stay, and similar long-term outcomes when compared to the open surgery approach.     

Intraventricular dyssynchrony predicts mortality and morbidity after cardiac resynchronization therapy: a study using cardiovascular magnetic resonance tissue synchronization imaging.

OBJECTIVES: We aimed to assess a novel measure of left ventricular (LV) dyssynchrony, a cardiovascular magnetic resonance-tissue synchronization index (CMR-TSI), in patients with heart failure (HF). A further aim was to determine whether CMR-TSI predicts mortality and major cardiovascular events (MCE) after cardiac resynchronization therapy (CRT). BACKGROUND: Cardiac dyssynchrony is a predictor of mortality in patients with HF. The unparalleled spatial resolution of CMR may render CMR-TSI a predictor of clinical benefit after CRT. METHODS: In substudy A, CMR-TSI was assessed in 66 patients with HF (age 60.8 +/- 10.8 years, LV ejection fraction 23.9 +/- 12.1% [mean +/- SD]) and 20 age-matched control subjects. In substudy B, CMR-TSI was assessed in relation to clinical events in 77 patients with HF and with a QRS > or =120 ms undergoing CRT. RESULTS: In analysis A, CMR-TSI was higher in patients with HF and a QRS <120 ms (79.5 +/- 31.2 ms, p = 0.0003) and in those with a QRS > or =120 ms (105.9 +/- 55.8 ms, p < 0.0001) than in control subjects (21.2 +/- 8.1 ms). In analysis B, a CMR-TSI > or =110 ms emerged as an independent predictor of the composite end points of death or unplanned hospitalization for MCE (hazard ratio [HR] 2.45; 95% confidence interval [CI] 1.51 to 4.34, p = 0.0002) or death from any cause or unplanned hospitalization for HF (HR 2.15; 95% CI 1.23 to 4.14, p = 0.0060) as well as death from any cause (HR: 2.6; 95% CI 1.29 to 6.73, p = 0.0061) and cardiovascular death (HR 3.82; 95% CI 1.63 to 16.5, p = 0.0007) over a mean follow-up of 764 days. CONCLUSIONS: Myocardial dyssynchrony assessed by CMR-TSI is a powerful independent predictor of mortality and morbidity after CRT.     

A new method for the determination of arylesterase activity in human serum using simulated body fluid

Arylesterase activity (EC 3.1.1.2), one of the three functions of the paraoxonase enzyme (PON1), is thought to protect low-density lipoproteins (LDL) and high-density lipoprotein (HDL) from oxidation and to facilitate reverse cholesterol transport. The Eckerson et al. method, which employs Tris/HCl buffer, has been extensively used and could be considered as the reference method, although it shows relatively low precision and reproducibility. Using simulated body fluid (SBF), which simulates blood electrolyte composition, a significant improvement in arylesterase activity determination was achieved. Modifications of SBF bicarbonate and chloride concentrations did not result in further improvements. To validate this method arylesterase activity was measured using SBF and Tris/HCl in 23 subjects with increased cardiovascular disease risk. Precision was significantly higher using SBF than with Tris/HCl. Data from both methods do not significantly differ in samples with arylesterase activity > or = 30.6 U/L using SBF, but do differ significantly when very low activity samples (< 30.6 U/L) were included. Differences suggest that the Tris/HCl buffer gives misleading activity results, especially in very low activity samples. For the first time, results suggest that SBF can successfully be used instead of Tris/HCl in arylesterase activity determination.     

Utility of NT-proBNP for diagnosing heart failure in a heterogeneous population of patients with dyspnea. Spanish multicenter study

INTRODUCTION AND OBJECTIVES: Recent studies have shown that brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are useful in the diagnosis of heart failure in patients presenting with dyspnea. However, the cutoff values used with these markers vary according to patient characteristics and dyspnea severity. The aim of this study was to investigate the diagnostic accuracy of using the plasma NT-proBNP level for identifying heart failure in a heterogeneous population of patients with dyspnea. METHODS: A multicentre study involving 247 consecutive patients with recent-onset dyspnea was carried out at 12 Spanish hospitals. Patients previously diagnosed with heart failure or any other condition known to cause dyspnea were excluded. RESULTS: Of the 247 patients, 161 (65%) had heart failure. The remaining 86 (35%) presented with dyspnea of non-cardiac origin. Plasma NT-proBNP levels were higher in patients with heart failure (5600 [7988] pg/mL vs 1182 [4406] pg/mL; P=.0001), and increased as functional status deteriorated (P=.036). The area under the receiver operating characteristic curve was 0.87 (0.02) (95% CI, 0.81-0.91) for the optimum cutoff value of 1335 pg/mL. The sensitivity of this cutoff value for diagnosing heart failure was 77% (95% CI, 70%-83%), the specificity was 92% (95% CI, 84%-97%), the positive predictive value was 94%, and the negative predictive value was 68%. CONCLUSIONS: The plasma NT-proBNP concentration provides an accurate means of diagnosing heart failure. However, the negative predictive value found in this study was somewhat lower than the values found in previous studies involving more homogeneous patient populations.     

Caspase-dependent and -independent DNA fragmentation in Sertoli and germ cells from men with primary testicular failure: relationship with histological diagnosis

BACKGROUND: Germ cell elimination and sperm DNA fragmentationin men with primary testiculopathies involve apoptosis-relatedprocesses whose mechanisms are poorly understood. This studyexamines the participation of typical (caspase-dependent) andatypical (caspase-independent) pathways in these processes.METHODS: Caspase activity and DNA fragmentation were evaluatedin Sertoli and germ cells from 63 men with non-obstructive azoospermiaand with different histological diagnoses who were undergoingtesticular biopsy for an assisted reproduction attempt. In eightof these men, phosphatidylserine externalization was also examined.RESULTS: The percentage of Sertoli cells showing caspase activityand DNA fragmentation was low and uniform in all diagnoses.In germ cells that remained tightly associated with Sertolicells despite vigorous mechanical treatment, the incidence ofboth caspase activity and DNA fragmentation was high, particularlyin men with maturation arrest. In Sertoli cell-free germ cells,high incidence of DNA fragmentation contrasted with low incidenceof caspase activity and phosphatidylserine externalization.CONCLUSIONS: In men with primary testicular failure, apoptosisof Sertoli cells is insignificant. Some germ cells undergo caspase-dependentapoptosis, show phosphatidylserine externalization and are tightlyassociated with Sertoli cells. Other germ cells show caspase-independentDNA fragmentation, do not externalize phosphatidylserine andlack a tight association with Sertoli cells.     

Identification of Intellectual Disability Genes in Female Patients with a Skewed X‐Inactivation Pattern

Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X‐linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X‐inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X‐inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole‐exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A. Interestingly, variants in genes escaping X‐inactivation presumably cause both XLID and skewing of X‐inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X‐linked variants in female patients.