Monitoring radiotherapy induced tissue changes in localized prostate cancer by multi-parametric magnetic resonance imaging (MP-MRI).

PURPOSE: To evaluate the utility of multi-parametric magnetic resonance imaging (MP-MRI), including dynamic contrast-enhanced MRI and diffusion-weighted MRI, for monitoring tumor tissue changes after volumetric-modulated arc radiotherapy in localized prostate cancer (PCa), and to compare the radiotherapy induced tumor tissue changes between conventional, moderate and extreme hypofractionated groups. Furthermore, we aimed to evaluate if follow-up by MRI has an incremental value compared to the standard care by prostate-specific antigen (PSA) serum level measurement. MATERIALS AND METHODS: Fifty-five men (mean age: 70±5 [SD] years; range: 60-79 years) with biopsy-proven PCa underwent MRI examination before radiotherapy, and at 3 and 12 months after radiotherapy. Pharmacokinetic analysis post-processing platform with dedicated software (Tissue 4D) was used to generate colorized parametric maps of enhancing tumors. The volume transfer constant (Ktrans), reflux constant (Kep), and initial area under curve (iAUC) were calculated from the tumors. Tumor apparent diffusion coefficient (ADC) value was measured on the ADC map. The patients were allocated into three radiotherapy groups: 17 conventional (39×2Gy), 16 moderate (20×3Gy) and 22 extreme hypofractionated (5×7.25Gy) regimen. RESULTS: Sixty lesions were detected in the prostates of the 55 patients. Follow-up MRI showed decreases in tumor size and degree of enhancement. Ktrans, Kep, and iAUC all decreased at 3 months (P<0.001, respectively) and decreased further at 12 months (P<0.001, respectively). ADC increased at 3 months (P<0.001) and increased further at 12 months (P<0.001). There were no significant differences in the percentage changes of the measured MP-MRI parameters of the tumors from baseline to 12 months between the conventional, moderate and extreme hypofractionated regimen groups. CONCLUSION: MP-MRI is a reliable tool for lesion detection and follow-up, providing both qualitative and quantitative data.

Correlation between apparent diffusion coefficient value on diffusion-weighted MR imaging and Gleason score in prostate cancer.

OBJECTIVES: To investigate whether diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) correlates with prostate cancer aggressiveness and further to compare the diagnostic performance of ADC and normalized ADC (nADC: normalized to non-tumor tissue). PATIENTS AND METHODS: Thirty pre-treatment patients (mean age, 69years; range: 59-78years) with prostate cancer underwent magnetic resonance imaging (MRI) examination, including DWI with three b values: 50, 400, and 800s/mm2. Both ADC and nADC were correlated with the Gleason score obtained through transrectal ultrasound-guided biopsy. RESULTS: The tumor minimum ADC (ADCmin: the lowest ADC value within tumor) had an inverse correlation with the Gleason score (r=-0.43, P<0.05), and it was lower in patients with Gleason score 3+4 than in those with Gleason score 3+3 (0.54±0.11×103mm2/s vs. 0.64±0.12×10-3mm2/s, P<0.05). Both the nADCmin and nADCmean correlated with the Gleason score (r=-0.52 and r=-0.55, P<0.01; respectively), and they were lower in patients with Gleason score 3+4 than those with Gleason score 3+3 (P<0.01; respectively). Receiver operating characteristic (ROC) analysis showed that the area under the ROC curve was 0.765, 0.818, or 0.833 for the ADCmin, nADCmin, or nADCmean; respectively, in differentiating between Gleason score 3+4 and 3+3 tumors. CONCLUSION: Tumor ADCmin, nADCmin, and nADCmean are useful markers to predict the aggressiveness of prostate cancer.

Altered complexity and correlation properties of R-R interval dynamics before the spontaneous onset of paroxysmal atrial fibrillation.

BACKGROUND: Trigger mechanisms for the onset of paroxysmal atrial fibrillation (AF) in patients without structural heart disease are not well established. New analysis methods of heart rate (HR) variability based on nonlinear system theory may reveal features and abnormalities in R-R interval behavior that are not detectable by traditional analysis methods. The purpose of this study was to reveal possible alterations in the dynamics of R-R intervals before the spontaneous onset of paroxysmal AF. METHODS AND RESULTS: Traditional time and frequency domain HR variability indices, along with the short-term scaling exponent alpha(1) and approximate entropy (ApEn), were analyzed in 20-minute intervals before 92 episodes of spontaneous, paroxysmal AF in 22 patients without structural heart disease. Traditional HR variability measures showed no significant changes before the onset of AF. A progressive decrease occurred both in ApEn (1.09+/-0.26 120 to 100 minutes before AF; 0.88+/-0.24 20 to 0 minutes before AF; P<0.001) and in alpha(1) (1.01+/-0.28 120 to 100 minutes before AF, 0.89+/-0.28 20 to 0 minutes before AF; P<0.05) before the AF episodes. Both ApEn (0. 89+/-0.27 versus 1.02+/-0.30; P<0.05) and alpha(1) (0.91+/-0.28 versus 1.27+/-0.21; P<0.001) were also lower before the onset of AF compared with values obtained from matched healthy control subjects. CONCLUSIONS: A decrease in the complexity of R-R intervals and altered fractal properties in short-term R-R interval dynamics precede the spontaneous onset of AF in patients with no structural heart disease. Further studies are needed to determine the physiological correlates of these new, nonlinear HR variability measures.

Induction characteristics of thiopentone/suxamethonium, propofol/alfentanil or halothane alone in children aged 1-3 years.

The aim of this study was to compare the effect of three different induction techniques, with or without neuromuscular block, on tracheal intubation, haemodynamic responses and cardiac rhythm. Ninety children, aged 1-3 years, undergoing day-case adenoidectomy were randomly allocated to three groups: group TS received thiopentone 5 mg kg-1 and suxamethonium 1.5 mg kg-1, group H 5 Vol.% halothane and group PA alfentanil 10 micrograms kg-1 and propofol 3 mg kg-1 for induction of anaesthesia. No anti-cholinergics were used. Holter-monitoring of the heart rate and rhythm was started at least 15 min before induction of anaesthesia and continued until 3 min after intubation. Tracheal intubation was performed by an anaesthetist blinded to the induction method and judged as excellent, moderate or poor according to ease of laryngoscopy, position of vocal cords and incidence of coughing after intubation. Tracheal intubation was successful at the first attempt in all children in groups TS and H and but only in 80% in group PA (P = 0.001). Intubating conditions were excellent in 22 (73%), 22 (73%) and one (3%) of the patients in groups TS, H and PA, respectively (P = 0.001). Cardiac dysrhythmias (supraventricular extrasystole or junctional rhythm) occurred in two (7%) patients in groups PA and H each (NS). Bradycardia occurred in 0 (0%), four (14%) and six (21%) children in groups TS, H and PA, respectively (P = 0.007 PA vs. TS, P = 0.03 H vs. TS). In conclusion, induction of anaesthesia with propofol 3 mg kg-1 and alfentanil 10 micrograms kg-1 without neuromuscular block did not provide acceptable intubating conditions in children 1-3 years, although it preserved arterial pressure better than thiopentone/suxamethonium or halothane. Cardiac dysrhythmias were few regardless of the induction method.

Urinary albumin excretion rate is independently related to autonomic neuropathy in type 2 diabetes mellitus.

OBJECTIVE: To evaluate if urinary albumin excretion rate (UAER) is independently related to subclinical autonomic neuropathy in type 2 diabetes. DESIGN: A controlled cross-sectional study. SETTING: Primary health care centre. SUBJECTS: Consecutive recently diagnosed (< 1 year) type 2 diabetic patients (group A, n = 150) and patients with long-standing (median 11 years) type 2 diabetes (group B, n = 146) chosen at random. A nondiabetic control group (group C, n = 150) matched for age and gender to group A. MAIN OUTCOME MEASURES: Neuropathy by cardiovascular reflex tests and UAER by nephelometry. METHODS: Univariate statistics in group A + B (t-test chi 2- or McNemars test) with Valsalva and breathing ratios as categorical grouping variables and the independent variables gender, smoking, systolic and diastolic blood pressure, fasting serum cholesterol, HDL cholesterol, triglycerides, haemoglobin A1c, glucagon stimulated C-peptide, fasting and postload 1 and 2 h blood glucose and serum insulin, UAER, coronary heart disease and congestive heart failure. Logistic regression analyses in group A + B with Valsalva and breathing ratios as dependent categorical variables and age, systolic blood pressure, congestive heart failure, coronary heart disease, fasting blood glucose, serum triglycerides and UAER as independent variables. RESULTS: Compared to nondiabetic subjects the diabetic patients of both groups were at increased risk of neuropathy as judged by the Valsalva ratio (P < 0.01). In known diabetic patients with a UAER > or = 30 mg 24-1 h neuropathy was more common than amongst their normoalbuminuric counterparts (Valsalva test P = 0.007, breathing test P = 0.02). In logistic regression analysis UAER independently explained abnormal Valsalva (P = 0.015) and breathing tests (P = 0.04) in the group A + B. CONCLUSIONS: UAER is independently related to subclinical autonomic neuropathy in type 2 diabetes.

Effect of pre-treatment with intravenous atropine or glycopyrrolate on cardiac arrhythmias during halothane anaesthesia for adenoidectomy in children.

We studied the effect of anticholinergics on the incidence of cardiac arrhythmias during paediatric anaesthesia. ASA I-II children (n = 77) undergoing adenoidectomy were randomly allocated to three groups. Intravenous atropine 0.02 mg kg-1 was given in group A (n = 25), glycopyrrolate 0.004 mg kg-1 in group G (n = 27) and physiological saline in group P (n = 25) 3 min before the induction of anaesthesia. The children breathed spontaneously under halothane anaesthesia with 66% nitrous oxide in oxygen after induction with thiopentone and succinylcholine. Perioperative monitoring of the ECG (Holter recordings) and oxygen saturation was carried out. Ventricular tachycardia occurred in 16.0%, 18.5% and 12.0% of the children in groups A, G and P respectively (ns). The incidence of ventricular arrhythmias (ventricular tachycardia, ventricular bigeminy, ventricular premature beats > 10) was 20.0% in group A, 44.4% in group G and 36.0% in group P (ns). Bradycardia (< 70 beats min-1) was observed in 0.0%, 14.8% and 24.0% of patients in groups A, G and P respectively (A vs P, P < 0.05). The use of anticholinergics did not influence the incidence of ventricular arrhythmias during halothane anaesthesia in children. Bradycardia was more common in the placebo group than in the atropine group.

Late results of paraoesophageal hiatus hernia repair with fundoplication.

BACKGROUND: Most published reports on results of surgical treatment for paraoesophageal hiatus hernia have been based on patient questionnaires, and seldom included endoscopy or barium meal examinations. METHODS: Eight pure and 14 mixed-type paraoesophageal hernias were evaluated a median of 37 (range 2-241) months after surgical repair. An antireflux procedure was done in 19 cases. Before operation all had endoscopy or barium meal (20 and 19 patients respectively); after operation 19 had endoscopy and 12 also had barium meal examination. Oesophageal 24 h pH monitoring was done in five cases before surgery, and in 11 afterwards. RESULTS: Preoperative symptoms of reflux were reported by 18, and were often accompanied by dysphagia, postprandial vomiting or epigastric pain. Symptoms improved after operation, and 21 of the 22 patients were satisfied with the result. At follow-up examination, a recurrent hernia was found in eight of the 19 patients examined. Four of these hernias were sliding, two were mixed type and two purely paraoesophageal. DISCUSSION: Recurrence of symptoms was associated with persistence of reflux rather than hernia recurrence. Concomitant antireflux procedure is recommended in all operations for mixed-type hiatus hernia, but it should also be considered for purely paraoesophageal hernia if reflux cannot be excluded before operation, or if retro-oesophageal dissection is needed.

Kinetics of chlorambucil in vitro: effects of fluid matrix, human gastric juice, plasma proteins and red cells.

The mechanisms involved in the bioavailability of chlorambucil or 4-[p-(bis[2-hydroxyethyl]amino)phenyl]-butyric acid are poorly understood. The effects of different matrices on the disintegration of chlorambucil were investigated by HPLC, 1H NMR, 31P NMR, and mass spectrometry. Cellular incorporation and protein binding of the drug in vitro was assessed with [3H]-chlorambucil. Decomposition of chlorambucil and its major metabolite, phenylacetic acid mustard, to mono- and dihydroxy derivatives, was significantly faster in water than in PBS, (phosphate-buffered saline, pH 7.4). The hydrolysis of chlorambucil was as fast in plasma ultrafiltrate as in PBS; plasma proteins, preferentially albumin, prevented this disintegration. In phosphate-buffered media, two additional stabile hydrolysis products were found which were characterised as the mono- and bis-phosphates of 4-[p-(bis[2-hydroxyethyl]amino)phenyl]butyric acid, results of the reaction of nucleophilic buffer species with the aziridinium ion intermediates. Chlorambucil bound covalently to plasma proteins and was incorporated into red cells. These interactions are likely to have a significant role in vivo, reducing the bioavailability of the drug. High H+ concentration associated with high chloride concentration in human gastric juice had a stabilizing effect on chlorambucil. Incorporation of [3H]-chlorambucil into red cells was inhibited in a concentration-dependent fashion by whole human plasma as well as by albumin. We conclude that the chemico-biological interactions demonstrated in the present investigation provide explanations for the remarkable pharmacokinetic differences observed intra- and inter-individually in the clinical use of chlorambucil. The present information is important, when clinical or in vitro evaluation of efficacy and bioavailability of chlorambucil is considered.

Natural course of gastroesophageal reflux disease: 17-22 year follow-up of 60 patients.

OBJECTIVE: To elucidate the long-term course of conservatively managed gastroesophageal reflux disease without H2-antagonists or omeprazole. DESIGN: Clinical trial, uncontrolled. SETTING: Gastroenterological outpatient department of a teaching hospital. PATIENTS: Sixty of 87 patients consecutively referred for severe gastroesophageal reflux symptoms and with objectively proven pathological reflux. MEASUREMENTS: Esophagoscopy, esophagography, cinecardiography of cardiac region, standard reflux test, and confirmatory Bernstein-Baker test. Follow-up included a standardized interview, esophagoscopy with biopsy, and 24-h pH monitoring. RESULTS: At follow-up 17-22 yr after referral, symptoms were less than at the time of referral in 36 of the 50 nonoperated patients (six now symptom-free), were unchanged in five, and were worse in nine patients. Medication for reflux symptoms was no longer used by 34 of the nonoperated patients. The prevalence of erosive esophagitis fell from 40% at referral to 27% at follow-up endoscopy; 42% of the studied patients had pathological 24-h pH, and the endoscopies revealed six new cases of Barrett's metaplasia. Of the 41 nonoperated patients examined with both endoscopy and 24-h pH, 27 (66%) had erosive esophagitis and/or pathological pH values. Of the 10 operated patients, all had fewer symptoms at follow-up than they had at referral (nine were symptom-free). The prevalence of erosive esophagitis fell from 60% at referral to 10% at follow-up. One of the 10 patients had pathological 24-h pH at follow-up. Neither the presence of esophagitis or hiatal hernia nor the severity of symptoms at the time of referral predicted the course of the disease of the conservatively treated patients. CONCLUSIONS: The severity of the symptoms declines in the long term, but pathological reflux persists in most of the conservatively treated patients. Thus, the reflux itself is not self-limiting, and therapy should be designed with this in mind.

Effects of mitogens on androgen receptor-mediated transactivation.

The effects of mitogens and agents affecting tyrosine phosphorylation signaling on androgen-regulated transcription were investigated. CV-1 and HeLa cells were cotransfected with an androgen receptor (AR) expression vector and an androgen-responsive chloramphenicol acetyltransferase (CAT) reporter gene driven by the mouse mammary tumor virus promoter. Growth factors [epidermal growth factor (EGF) and insulin-like growth factor I] that activate receptor tyrosine kinases, an inhibitor of phosphotyrosine phosphatases (vanadate), or an inhibitor of tyrosine kinases (genistein) did not influence basal promoter activity or that of unliganded AR. However, EGF, insulin-like growth factor I, and vanadate enhanced AR-dependent transactivation by 1.5- to 2.5-fold, and genistein diminished it by two thirds in the presence of androgen. None of the treatments affected pRSV-CAT or pSV-beta-galactosidase expression, suggesting that gross activation of the transcription machinery was not involved. A reporter with two androgen response elements (AREs) in front of the thymidine kinase promoter (p delta ARE2tk-CAT) was used to examine promoter specificity. EGF activated this reporter even in the absence of androgen. However, when EGF was used concomitantly with testosterone, it augmented the action of androgen. Vanadate enhanced androgen-induced transactivation 2-fold without altering basal promoter activity. Neither EGF nor vanadate altered immunoreactive AR content or elicited changes in the receptor's DNA-binding properties. The intracellular content of hormone-binding AR was not influenced by EGF, but was decreased by vanadate and increased by genistein, as judged by [3H]mibolerone binding assays. An AR form lacking the hormone-binding domain (delta 641-902 mutant) transactivated p delta ARE2tk-CAT reporter similar to or better than the wild-type receptor in the presence of androgen. The transactivation by the delta 641-902 mutant was augmented by EGF and vanadate, but was attenuated by genistein, implying that the steroid-binding region is not critical for regulatory events initiated by tyrosine phosphorylation. Collectively, these data indicate that there is cross-talk between androgen-mediated signaling systems and growth factor/receptor tyrosine kinase pathways.

Mutual transcriptional interference between RelA and androgen receptor.

Cross-modulation between androgen receptor (AR) and NF-kappaB/Rel proteins was studied using various androgen- and NF-kappaB-regulated reporter genes under transient transfection conditions. In COS-1 cells, elevated expression of RelA (p65) repressed AR-mediated transactivation in a dose-dependent manner, whereas NFkappaB1 (p50), another major member of the NF-kappaB family, did not influence transactivation. The repression of AR appeared to involve the N-terminal region of the protein between residue 297 and the DNA-binding domain. RelA-mediated transrepression could not be overcome by increasing the amount of AR. Transcriptional interference between RelA and AR was mutual in that cotransfected AR was able to attenuate transactivation by RelA in a dose- and steroid-dependent fashion. An excess of RelA was able to rescue the repression to some extent. Immunological analyses of RelA and AR protein levels indicated that transrepression was not due to reciprocal decrease in their amounts. Neither did AR increase the concentration of IkappaBalpha, which can sequester and inactivate RelA. Electrophoretic mobility shift assays using extracts from cotransfected cells and purified recombinant proteins showed that AR and RelA did not significantly influence each other's DNA binding activity. Nevertheless, protein-protein interaction experiments demonstrated a weak association between AR and RelA. Collectively, these data suggest that the mutual repression in intact cells is due to formation of AR-RelA complexes that are held together by another partner or to competition for a coactivator required for transcription.

Two antireflux operations: floppy versus standard Nissen fundoplication.

The effects of fundic mobilization in Nissen fundoplication on belching ability, abdominal gas volume, bloating and flatus were assessed in a prospective, randomized study of 25 patients with refractory gastro-oesophageal reflux disease. Reflux was cured regardless of fundic mobilization. Subjective ability to belch was restored to preoperative in 73% of the patients with fundic mobilization, compared to 50% without. About 10% in both groups totally lost their ability to belch. Disturbance from flatus increased postoperatively slightly in both groups, but from bloating it remained the same or even diminished. The residual intra-abdominal radioactivity (median (interquartile range)) after provoked belching was preoperatively 8.9% (4.4-12.0) with and 13.2% (6.8-15.2) without fundic mobilization, compared to 36.7% (31.1-40.9) of the controls (P < 0.05). After fundoplication this residual activity was normalized in both study groups. Disturbance from postoperative bloating or flatus were not related to the ability of belching. Preoperatively symptomatic patients tended to have more complaints postoperatively. In conclusion, fundic mobilization restored belching ability slightly more effectively without compromising antireflux efficacy, but there did not seem to be any advantage regarding flatus or bloating.

Rhythm disturbances after blood and crystalloid cardioplegia in coronary artery bypass grafting.

One hundred consecutive patients scheduled for coronary artery bypass grafting were randomized to receive either blood or crystalloid cardioplegia. Successful Holter monitoring for rhythm disturbances was done before and immediately after the operation in 83 cases. With both modes of cardioplegia there were increases in the occurrence of rhythm disturbances postoperatively. The increases were mostly statistically significant. There was no intergroup differences in the occurrence of arrhythmias. The association between these disturbances and cross-clamp times, myocardial temperatures during cross-clamping, myocardial fibrillation times during and after cross-clamping, CK-MB values and perioperative infarction all indicated ischaemia or incomplete myocardial protection as a major cause of the immediate postoperative rhythm disturbances.

Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation.

The effect of modulators of protein phosphorylation on the transcriptional activity of the androgen receptor (AR) was studied under transient expression conditions. Activators of protein kinase-A [8-bromo-cAMP (8-Br-cAMP)] and protein kinase-C (phorbol 12-myristate 13-acetate) or an inhibitor of protein phosphatase-1 and -2A (okadaic acid) influenced minimally pMMTV-chloramphenicol acetyl-transferase (CAT) activity in CV-1 cells cotransfected with an AR expression plasmid in the absence of androgen. In the presence of testosterone, however, all compounds enhanced AR-mediated transactivation by 2- to 4-fold. A nonsteroidal antiandrogen, Casodex, behaved as a pure antagonist; it blunted the action of testosterone and was not rendered agonistic by activators of protein kinase-A. A reporter plasmid containing two androgen response elements (AREs) in front of the thymidine kinase promoter (pARE2tk-CAT) was also used to examine promoter specificity. It was activated by 8-Br-cAMP, forskolin, or okadaic acid even without AR or androgen. However, when forskolin or okadaic acid was used together with androgen and AR, the resulting AR-dependent transactivation of pARE2tk-CAT was more than additive. Intact DNA- and ligand-binding domains, but not the N-terminal amino acid residues 40-147, of the receptor were mandatory for the synergism between protein kinase-A activators and androgen. Immunoreactive AR content in transfected COS-1 cells was not influenced by exposure to 8-Br-cAMP. Similar results were obtained by ligand binding assays. Quantitative or qualitative differences were not observed in DNA-binding characteristics between receptors extracted from cells treated with testosterone with or without protein kinase-A activator. Collectively, the synergistic stimulation of AR-dependent transactivation by androgen and protein kinase activators is not due to changes in cellular AR content or affinity of the receptor for the cognate DNA element; rather, this phenomenon seems to result from altered interaction of ligand-activated AR with other proteins in the transcription machinery.

Barrett's esophagus after cardiomyotomy for esophageal achalasia.

Heller's myotomy for esophageal achalasia was performed on 64 patients in the 24 yr up to 1988. After follow-up averaging 13 yr, 46 patients were reexamined with endoscopy, biopsy, and manometry. Barrett's metaplasia of the distal esophagus was found in four patients 6, 13, 20, and 23 yr after the myotomy. These four also underwent ambulatory 24-h pH monitoring. They had the lowest distal esophageal sphincter pressures (1-5 mm Hg), and all four had symptoms of gastroesophageal reflux and pathologic pH values (< 4 in the distal esophagus for 32-62% of the total recording time). Because of heightened risk for the development of Barrett's metaplasia following cardiomyotomy for esophageal achalasia, with increased liability to carcinoma of the esophagus, regular endoscopic surveillance of these patients is advisable.

Acute effects of calcium carbonate and citrate on secondary hyperparathyroidism in chronic renal failure.

Two grams of elemental calcium as carbonate or citrate were given after an overnight fast to 14 patients with advanced renal failure (serum creatinine 759 +/- 365 mumol/l, mean +/- SD). The suppressibility of their hyperparathyroidism was confirmed with a calcium infusion test. Both calcium citrate and carbonate increased significantly plasma ionized calcium (6.8 and 4.5%, respectively) and total calcium (9.3 and 6.0%), p less than 0.001. In the majority of the patients, calcium citrate but not carbonate increased plasma calcium sufficiently to induce the suppression of hyperparathyroidism. The decrease of plasma intact parathyroid hormone was 35.9 +/- 24.8% (mean +/- SD); p less than 0.001) after calcium citrate and 9.2 +/- 18.9% (mean +/- SD; NS) after calcium carbonate.