Accurate staging of non-metastatic colon cancer with CT: the importance of training and practice for experienced radiologists and analysis of incorrectly staged cases.

PURPOSE: To investigate whether locoregional staging of colon cancer by experienced radiologists can be improved by training and feedback to minimize the risk of over-staging into the context of patient selection for neoadjuvant therapy and to identify potential pitfalls of CT staging by characterizing pathologic traits of tumors that remain challenging for radiologists. METHODS: Forty-five cases of stage I-III colon cancer were included in this retrospective study. Five experienced radiologists evaluated the CTs; 5 baseline scans followed by 4 sequential batches of 10 scans. All radiologists were trained after baseline scoring and 2 radiologists received feedback. The learning curve, diagnostic performance, reader confidence, and reading time were evaluated with pathologic staging as reference. Pathology reports and H&E slides of challenging cases were reviewed to identify potential pitfalls. RESULTS: Diagnostic performance in distinguishing T1-2 vs. T3-4 improved significantly after training and with increasing number of reviewed cases. Inaccurate staging was more frequently related to under-staging rather than over-staging. Risk of over-staging was minimized to 7% in batch 3-4. N-staging remained unreliable with an overall accuracy of 61%. Pathologic review identified two tumor characteristics causing under-staging for T-stage in 5/7 cases: (1) very limited invasive part beyond the muscularis propria and (2) mucinous composition of the invading part. CONCLUSION: The high accuracy and specificity of T-staging reached in our study indicate that sufficient training and practice of experienced radiologists can ensure high validity for CT staging in colon cancer to safely use neoadjuvant therapy without significant risk of over-treatment, while N-staging remained unreliable.

Interrater agreement of contouring of the neurovascular bundles and internal pudendal arteries in neurovascular-sparing magnetic resonance-guided radiotherapy for localized prostate cancer.

BACKGROUND AND PURPOSE: Radiation damage to neural and vascular tissue, such as the neurovascular bundles (NVBs) and internal pudendal arteries (IPAs), during radiotherapy for prostate cancer (PCa) may cause erectile dysfunction. Neurovascular-sparing magnetic resonance-guided adaptive radiotherapy (MRgRT) aims to preserve erectile function after treatment. However, the NVBs and IPAs are not routinely contoured in current radiotherapy practice. Before neurovascular-sparing MRgRT for PCa can be implemented, the interrater agreement of the contouring of the NVBs and IPAs on pre-treatment MRI needs to be assessed. MATERIALS AND METHODS: Four radiation oncologists independently contoured the prostate, NVB, and IPA in an unselected consecutive series of 15 PCa patients, on pre-treatment MRI. Dice similarity coefficients (DSCs) for pairwise interrater agreement of contours were calculated. Additionally, the DCS of a subset of the inferior half of the NVB contours (i.e. approximately prostate midgland to apex level) was calculated. RESULTS: Median overall interrater DSC for the left and right NVB was 0.60 (IQR: 0.54 - 0.68) and 0.61 (IQR: 0.53 - 0.69) respectively and for the left and right IPA 0.59 (IQR: 0.53 - 0.64) and 0.59 (IQR: 0.52 - 0.64) respectively. Median overall interrater DSC for the inferior half of the left NVB was 0.67 (IQR: 0.58 - 0.74) and 0.67 (IQR: 0.61 - 0.71) for the right NVB. CONCLUSION: We found that the interrater agreement for the contouring of the NVB and IPA improved with enhancement of the MRI sequence as well as further training of the raters. The agreement was best in the subset of the inferior half of the NVB, where a good agreement is clinically most relevant for neurovascular-sparing MRgRT for PCa.

Impact of perioperative blood transfusions on oncologic outcomes after radical cystectomy: A systematic review and meta-analysis of comparative studies.

This study aimed at systematically analyzing and evaluating the impact of perioperative blood transfusions (PBT) on oncologic outcomes of patients undergoing radical cystectomy for bladder cancer. This systematic review follows the recommendations of the Cochrane Handbook for Systematic Reviews and Interventions and was conducted in line with the PRISMA statement and the AMSTAR II criteria. A comprehensive database search was performed based on the PICO criteria. Two independent reviewers performed all screening steps and quality assessment. Risk of bias and certainty in evidence were assessed with the Newcastle Ottawa Scale for non-randomized trials and the GRADE approach. Of 1123 identified studies 20 were eligible for qualitative analysis and 15 for quantitative analysis reporting on 21,915 patients. Receiving a PBT was associated with an increased risk of all-cause mortality (hazard ratio (HR) [95% confidence interval (CI)]: 1.29 [1.18, 1.40]; p < 0.001), cancer-specific mortality (HR [CI]: 1.27 [1.15; 1.41]; p < 0.001) and disease recurrence (HR [CI]: 1.22 [1.12; 1.34]; p < 0.001). Subgroup analysis of transfusion timing revealed a significantly increased risk of mortality with intraoperative or combined intra- and postoperative transfusions compared to postoperative transfusion only for all three outcomes (p < 0.001). Leukocyte-depletion was associated with increased all-cause mortality, but not cancer-specific mortality. The administration of PBT negatively impacts oncological outcomes after radical cystectomy. Therefore, careful treatment indication and strict adherence to transfusion guidelines is encouraged in order to avoid adverse effects during the perioperative course.

Radiofrequency ablation and chemotherapy versus chemotherapy alone for locally advanced pancreatic cancer (PELICAN): study protocol for a randomized controlled trial.

BACKGROUND: Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26-34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking. METHODS: The "Pancreatic Locally Advanced Unresectable Cancer Ablation" (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA. DISCUSSION: The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment. TRIAL REGISTRATION: Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018.

Peritoneal flap for lymphocele prophylaxis following robotic-assisted laparoscopic radical prostatectomy with pelvic lymph node dissection: study protocol and trial update for the randomized controlled PELYCAN study.

BACKGROUND: Data from interventional studies suggest that a peritoneal flap after pelvic lymph node dissection (LND) during laparoscopic, robotic-assisted radical prostatectomy (RARP) may reduce the rate of symptomatic lymphoceles in transperitoneal approach. However, most of these studies are not conducted in a randomized controlled fashion, thus limiting their scientific value. A recent prospective, randomized, controlled trial (RCT) did not show superiority of a peritoneal flap while further trials are lacking. Therefore, the aim of the presented RCT will be to show that creating a peritoneal flap decreases the rate of symptomatic lymphoceles compared to the current standard procedure without creation of a flap. METHODS/DESIGN: PELYCAN is a parallel-group, patient- and assessor-blinded, phase III, adaptive randomized controlled superiority trial. Men with histologically confirmed prostate cancer who undergo transperitoneal RARP with pelvic LND will be randomly assigned in a 1:1 ratio to two groups-either with creating a peritoneal flap (PELYCAN) or without creating a peritoneal flap (control). Sample size calculation yielded a sample size of 300 with a planned interim analysis after 120 patients, which will be performed by an independent statistician. This provides a possibility for early stopping or sample size recalculation. Patients will be stratified for contributing factors for the development of postoperative lymphoceles. The primary outcome measure will be the rate of symptomatic lymphoceles in both groups within 6 months postoperatively. Patients and assessors will be blinded for the intervention until the end of the follow-up period of 6 months. The surgeon will be informed about the randomization result after performance of vesicourethral anastomosis. Secondary outcome measures include asymptomatic lymphoceles at the time of discharge and within 6 months of follow-up, postoperative complications, mortality, re-admission rate, and quality of life assessed by the EORTC QLQ-C30 questionnaire. DISCUSSION: The PELYCAN study is designed to assess whether the application of a peritoneal flap during RARP reduces the rate of symptomatic lymphoceles, as compared with the standard operation technique. In case of superiority of the intervention, this peritoneal flap may be suggested as a new standard of care. TRIAL REGISTRATION: German Clinical Trials Register DRKS00016794 . Registered on 14 May 2019.

The comprehensive complication index (CCI): proposal of a new reporting standard for complications in major urological surgery.

PURPOSE: The comprehensive complication index (CCI) is a new tool for reporting the cumulative burden of postoperative complications on a continuous scale. This study validates the CCI for urological surgery and its benefits over the Clavien-Dindo-Classification (Clavien). MATERIAL AND METHODS: Data from a prospectively maintained data base of all consecutive patients at a university care-center was analyzed. Complications after radical cystectomy (RC), radical prostatectomy (RP), and partial nephrectomy (PN) were classified using the CCI and Clavien system. Differences in complications between the CCI and the Clavien were assessed and correlation analyses performed. Sample size calculations for hypothetical clinical trials were compared between CCI and Clavien to evaluate whether the CCI would reduce the number of required patients in a clinical trial. RESULTS: 682 patients (172 RC, 297 RP, 213 PN) were analyzed. Overall, 9.4-46.6% of patients had > 1 complication cumulatively assessed with the CCI resulting in an upgrading in the Clavien classification for 2.4-32.4% of patients. Therefore, scores between the systems differed for RC: CCI (mean ± standard deviation) 26.3 ± 20.8 vs. Clavien 20.4 ± 16.7, p < 0.001; PN: CCI 8.4 ± 14.7 vs. Clavien 7.0 ± 11.8, p < 0.001 and RP: CCI 5.8 ± 11.7 vs. Clavien 5.3 ± 10.6, p = 0.102. The CCI was more accurate in predicting LOS after RC than Clavien (p < 0.001). Sample size calculations based in the CCI (for future hypothetical trials) resulted in a reduction of required patients for all procedures (- 25% RC, - 74% PN, - 80% RP). CONCLUSION: The CCI is more accurate to assess surgical complications and reduces required sample sizes that will facilitate the conduction of clinical trials.

The additive value of restaging-CT during neoadjuvant chemotherapy for gastric cancer.

INTRODUCTION: Computed tomography (CT) is used for restaging of gastric cancer patients during neoadjuvant chemotherapy (NAC). The treatment strategy could be altered after detection of distant interval metastases, possibly leading to a reduction in unnecessary chemotherapy cycles, its related toxicity, and surgical procedures. The aim of this study was to evaluate the additive value of restaging-CT during NAC in guiding clinical decision making in gastric cancer. MATERIALS AND METHODS: This retrospective, multicenter cohort study identified all patients with surgically resectable gastric adenocarcinoma (cT1-4a-x, N0-3-x, M0-x), who started NAC with curative intent. Restaging-CT was performed after 2 out of 3 cycles of NAC. The primary outcome was treatment alterations made based on restaging-CT by a multidisciplinary tumor board. Confirmation of metastases was obtained by surgery or biopsy. RESULTS: Between 2007 and 2015, CT-restaging was performed in 122 out of 152 included patients and timed after 2 cycles (n = 76) or after 3 cycles (n = 46) of NAC. Restaging-CT revealed a metastasis in 1 out of 122 restaged patients (1%) after which surgical resection was omitted, whereas 4 patients (3%) with distant interval metastases were not identified by restaging-CT and underwent a futile laparotomy. In 5 out of 76 patients (7%) disease progression was detected while undergoing NAC, leading to omission of the 3rd cycle of chemotherapy. CONCLUSION: The additive value of restaging-CT during NAC in gastric cancer is limited in guiding clinical decision making and therefore not recommended. Further studies may identify subgroups that may benefit of alternative diagnostic modalities.

Early recovery after surgery for radical cystectomy: comprehensive assessment and meta-analysis of existing protocols.

PURPOSE: Different enhanced recovery after surgery (ERAS) protocols (EP) for radical cystectomy (RC) have been published. Protocols highly differ in number of included items and specific measures. MATERIALS AND METHODS: A systematic review and meta-analysis on EPs in RC were performed using the databases MedLine, Cochrane Library, Web of science, and Google Scholar. The specific ERAS measures of the protocols were extracted, analyzed, and compared. Pooling of available outcome data was performed for length of stay, complications, readmission rate, and time to defecation. RESULTS: The search yielded a total of 860 studies of which 25 studies were included in qualitative and 22 in quantitative analysis. Oral bowel preparation (BP) was omitted in 24/25 (96%) EPs, optimized fluid management was administered in 22/25 (88%) EPs and early mobilization (postoperative day 1) in 21/25 (84%). Gum chewing (n = 12, 46%), metoclopramide (n = 11, 44%), and alvimopan (n = 6, 24%) were the most common measures to prevent postoperative ileus. Our meta-analysis revealed a significant benefit in favor of EPs for the outcome parameters length of stay [mean difference (MD) - 3.46 d, 95% confidence interval (CI) - 4.94 to - 1.98, p < 0.01], complications [Odds ratio (OR) = 0.76, 95% CI 0.61-0.94, p = 0.01] and time to defecation (MD - 1.37 d, 95% CI - 2.06 to - 0.69, p < 0.01). Readmission rate did not show a significant difference (OR = 0.73, 95% CI 0.52-1.03, p = 0.07). CONCLUSION: Current EPs focus on omitting oral BP, early mobilization, and optimized fluid management while they differ in methods preventing postoperative ileus. Our meta-analysis revealed a benefit in introducing these protocols into clinical practice.

Radical cystectomy under continuous antiplatelet therapy with acetylsalicylic acid.

INTRODUCTION: Aim of this study was to analyse the perioperative outcome of patients undergoing radical cystectomy under continuous antiplatelet therapy with acetylsalicylic acid. MATERIALS AND METHODS: Using prospectively maintained databases of two departments of urology, we identified 461 consecutive patients who underwent radical cystectomy for bladder cancer (2011-2017). Patients were divided into three groups: 1) on-going antiplatelet therapy with acetylsalicylic acid (n = 50), 2) discontinuing antiplatelet therapy (n = 65) and 3) no antiplatelet therapy (n = 346). Perioperative outcome was compared between the three groups using ANOVA, likelihood ratio or Kruskal Wallis test with post-hoc testing. Uni- and multivariate analyses were performed to identify predictor for perioperative complications and transfusion. RESULTS: Group 1 showed an average estimated blood loss of 732 ±â€¯424, group 2 752 ±â€¯488 and group 3 810 ±â€¯544 ml (p = 0.51). There was no significant difference in transfusion rate (44% in group 1, 45% and 39% in groups 2 and 3, p = 0.63). Severe complications occurred in 26%, 15% and 15% in groups 1-3 (p = 0.19). Ischemic complications were more often observed in group 1 (n = 4, 8%) and 2 (n = 5, 8%) than group 3 (n = 7, 2%), p = 0.02. 90-day readmission (n = 99, 22%) and mortality rate (n = 10, 2.2%) were low and did not show any significant differences between the groups. In uni- and multivariate analysis ongoing therapy with acetylsalicylic acid was no independent risk factor for transfusion or severe complications. CONCLUSION: Perioperative continuation of therapy with acetylsalicylic acid in radical cystectomy is safe with no difference in intraoperative blood loss, transfusion rate, complications or mortality.

Evaluation of PET and laparoscopy in STagIng advanced gastric cancer: a multicenter prospective study (PLASTIC-study).

BACKGROUND: Initial staging of gastric cancer consists of computed tomography (CT) and gastroscopy. In locally advanced (cT3-4) gastric cancer, fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT or PET) and staging laparoscopy (SL) may have a role in staging, but evidence is scarce. The aim of this study is to evaluate the impact and cost-effectiveness of PET and SL in addition to initial staging in patients with locally advanced gastric cancer. METHODS: This prospective observational cohort study will include all patients with a surgically resectable, advanced gastric adenocarcinoma (cT3-4b, N0-3, M0), that are scheduled for treatment with curative intent after initial staging with gastroscopy and CT. The modalities to be investigated in this study is the addition of PET and SL. The primary outcome of this study is the proportion of patients in whom the PET or SL lead to a change in treatment strategy. Secondary outcome parameters are: diagnostic performance, morbidity and mortality, quality of life, and cost-effectiveness of these additional diagnostic modalities. The study recently started in August 2017 with a duration of 36 months. At least 239 patients need to be included in this study to demonstrate that the diagnostic modalities are break-even. Based on the annual number of gastrectomies in the participating centers, it is estimated that approximately 543 patients are included in this study. DISCUSSION: In this study, it is hypothesized that performing PET and SL for locally advanced gastric adenocarcinomas results in a change of treatment strategy in 27% of patients and an annual cost-reduction in the Netherlands of €916.438 in this patient group by reducing futile treatment. The results of this study may be applicable to all countries with comparable treatment algorithms and health care systems. TRIAL REGISTRATION: NCT03208621 . This trial was registered prospectively on June 30, 2017.

Evaluation of motion correction for clinical dynamic contrast enhanced MRI of the liver.

Motion correction of 4D dynamic contrast enhanced MRI (DCE-MRI) series is required for diagnostic evaluation of liver lesions. The registration, however, is a challenging task, owing to rapid changes in image appearance. In this study, two different registration approaches are compared; a conventional pairwise method applying mutual information as metric and a groupwise method applying a principal component analysis based metric, introduced by Huizinga et al (2016). The pairwise method transforms the individual 3D images one by one to a reference image, whereas the groupwise registration method computes the metric on all the images simultaneously, exploiting the temporal information, and transforms all 3D images to a common space. The performance of the two registration methods was evaluated using 70 clinical 4D DCE-MRI series with the focus on the liver. The evaluation was based on the smoothness of the time intensity curves in lesions, lesion volume change after deformation and the smoothness of spatial deformation. Furthermore, the visual quality of subtraction images (pre-contrast image subtracted from the post contrast images) before and after registration was rated by two observers. Both registration methods improved the alignment of the DCE-MRI images in comparison to the non-corrected series. Furthermore, the groupwise method achieved better temporal alignment with smoother spatial deformations than the pairwise method. The quality of the subtraction images was graded satisfactory in 32% of the cases without registration and in 77% and 80% of the cases after pairwise and groupwise registration, respectively. In conclusion, the groupwise registration method outperforms the pairwise registration method and achieves clinically satisfying results. Registration leads to improved subtraction images.

Improving early diagnosis of pulmonary infections in patients with febrile neutropenia using low-dose chest computed tomography.

We performed a prospective study in patients with chemotherapy induced febrile neutropenia to investigate the diagnostic value of low-dose computed tomography compared to standard chest radiography. The aim was to compare both modalities for detection of pulmonary infections and to explore performance of low-dose computed tomography for early detection of invasive fungal disease. The low-dose computed tomography remained blinded during the study. A consensus diagnosis of the fever episode made by an expert panel was used as reference standard. We included 67 consecutive patients on the first day of febrile neutropenia. According to the consensus diagnosis 11 patients (16.4%) had pulmonary infections. Sensitivity, specificity, positive predictive value and negative predictive value were 36%, 93%, 50% and 88% for radiography, and 73%, 91%, 62% and 94% for low-dose computed tomography, respectively. An uncorrected McNemar showed no statistical difference (p = 0.197). Mean radiation dose for low-dose computed tomography was 0.24 mSv. Four out of 5 included patients diagnosed with invasive fungal disease had radiographic abnormalities suspect for invasive fungal disease on the low-dose computed tomography scan made on day 1 of fever, compared to none of the chest radiographs. We conclude that chest radiography has little value in the initial assessment of febrile neutropenia on day 1 for detection of pulmonary abnormalities. Low-dose computed tomography improves detection of pulmonary infiltrates and seems capable of detecting invasive fungal disease at a very early stage with a low radiation dose.

The peri-esophageal connective tissue layers and related compartments: visualization by histology and magnetic resonance imaging.

An organized layer of connective tissue coursing from aorta to esophagus was recently discovered in the mediastinum. The relations with other peri-esophageal fascias have not been described and it is unclear whether this layer can be visualized by non-invasive imaging. This study aimed to provide a comprehensive description of the peri-esophageal fascias and determine whether the connective tissue layer between aorta and esophagus can be visualized by magnetic resonance imaging (MRI). First, T2-weighted MRI scanning of the thoracic region of a human cadaver was performed, followed by histological examination of transverse sections of the peri-esophageal tissue between the thyroid gland and the diaphragm. Secondly, pretreatment motion-triggered MRI scans were prospectively obtained from 34 patients with esophageal cancer and independently assessed by two radiologists for the presence and location of the connective tissue layer coursing from aorta to esophagus. A layer of connective tissue coursing from the anterior aspect of the descending aorta to the left lateral aspect of the esophagus, with a thin extension coursing to the right pleural reflection, was visualized ex vivo in the cadaver on MR images, macroscopic tissue sections, and after histologic staining, as well as on in vivo MR images. The layer connecting esophagus and aorta was named 'aorto-esophageal ligament' and the layer connecting aorta to the right pleural reflection 'aorto-pleural ligament'. These connective tissue layers divides the posterior mediastinum in an anterior compartment containing the esophagus, (carinal) lymph nodes and vagus nerve, and a posterior compartment, containing the azygos vein, thoracic duct and occasionally lymph nodes. The anterior compartment was named 'peri-esophageal compartment' and the posterior compartment 'para-aortic compartment'. The connective tissue layers superior to the aortic arch and at the diaphragm corresponded with the currently available anatomic descriptions. This study confirms the existence of the previously described connective tissue layer coursing from aorta to esophagus, challenging the long-standing paradigm that no such structure exists. A comprehensive, detailed description of the peri-esophageal fascias is provided and, furthermore, it is shown that the connective tissue layer coursing from aorta to esophagus can be visualized in vivo by MRI.

Costs of admission for paediatric pneumonia in a setting of human immunodeficiency virus infection.

BACKGROUND: Pneumonia in South African children remains a major public health concern. The costs of hospital admission for pneumonia should be determined, especially where human immunodeficiency virus (HIV) infection is common. OBJECTIVE: To determine the hospital costs of children (HIV-infected vs. non-HIV-infected) admitted for the management of pneumonia and compare them in the public and fee-for-service sectors. METHODS: A retrospective review of paediatric admissions in 2007 was performed. Costs were determined for the public and fee-for-service sectors. Outcome measures included hospital mortality and comparative costs of admission. RESULTS: There were 132 admissions in a public sector facility (67% HIV-infected), and 7882 in the fee-for-service sector (1.2% HIV-infected). Total mortality was respectively 25% in the public and 0.04% in the fee-for-service sectors. The mean cost for HIV-infected patients was respectively US$639.06 and US$10 540.04 in the public and fee-for-service sectors. For non-HIV-infected patients, the cost was respectively US$399.45 and US$3936.87. Length of stay for HIV-infected patients was longer by respectively 1.8 days and 5.7 days in the public sector among admissions to the ward and to the paediatric intensive care unit. CONCLUSION: Admission for HIV-infected children with pneumonia costs significantly more in both sectors. Preventive strategies are needed.

Vasodilatory capacity of the cerebral vasculature in patients with carotid artery stenosis.

BACKGROUND AND PURPOSE: Impairment of the cerebral autoregulation is an important predictor of TIA and stroke in patients with an ICA stenosis. The autoregulative status can be assessed directly by measuring the vasodilatory capacity of the cerebral arteries. The aim of our study was to investigate the vasodilatory capacity of the proximal and distal cerebral vasculature in patients with an ICA stenosis and healthy control subjects by combining MRA with an acetazolamide provocation challenge. MATERIALS AND METHODS: Fourteen functionally independent patients (mean age, 67.2 ± 8.7 years) with a symptomatic ICA stenosis and 19 healthy controls (mean age, 63.1 ± 7.2 years) were included. MRA was performed before and 20 minutes after intravenous administration of acetazolamide. The vasodilatory capacity of 11 proximal and distal cerebral vessels was assessed by measuring the increase in vessel diameter after acetazolamide. RESULTS: In the hemisphere ipsilateral to the ICA stenosis, there was no increase in diameter after acetazolamide, whereas a significant increase was measured in the contralateral hemisphere for the A1 and A2 segments of the ACA, the pericallosal artery, and the BA. A significant diameter increase was measured in all except 1 vessel of the controls. The vasodilatory capacity was significantly lower ipsilateral to the ICA stenosis compared with the A1 segment of the ACA and the P2 segment of the PCA in the controls. CONCLUSIONS: MRA combined with an acetazolamide provocation challenge can measure normal and impaired vasodilatory capacity of the cerebral vasculature.

Perindopril: do randomised, controlled trials support an ACE inhibitor class effect? A meta-analysis of clinical trials.

BACKGROUND: Due to the lack of face-to-face trials between ACE inhibitors, clinicians and third-party funders may assume they provide similar outcomes. As a result, ACE inhibitors may be prescribed interchangeably and deemed to provide the same outcomes for all patients when used chronically, that is for more than six months. OBJECTIVE: This meta-analysis aims to dispute the assumption of a class effect when prescribing ACE inhibitors (ACEIs), since the evidence from all the clinical trials is not uniform and therefore a direct comparison is impossible. METHODS: Published randomised, controlled trials were selected using an applicable literature search for all ACEIs, irrespective of drug combination, for any cardiovascular outcome (both composite and individual outcomes were included). The average length of ACEI exposure per trial had to be longer than six months). This meta-analysis was performed using odds ratios as the parameter of efficacy in a fixed-effects model. RESULTS/CONCLUSION: Perindopril resulted in significantly fewer patients reaching the primary endpoint versus all other ACEIs combined. The results were consistent for myocardial infarction, stroke and mortality (5 vs 11%, p = 0.0001). Perindopril alone or as part of combination therapy in clinical trials seemed to deliver clear and consistent outcome differences compared to other ACEI trials. In the presence of positive outcomes from robust randomised, controlled trials for perindopril, one cannot assume a class effect for all ACEIs.

Early onset of a decreased intracellular magnesium and phosphate concentration in smooth muscle cell of SHR.

A decrease in total magnesium content is not a direct proof of a decreased magnesium ion concentration. It could reflect a phosphate alteration or an ATP metabolism disorder. Plasma phosphate levels are lower in spontaneously hypertensive rats (SHRs) than in Wistar-Kyoto rats (WKYs), and defects in membrane regulation or mitochondrial ATP synthase occur. Only sparse data exist concerning cellular magnesium and phosphate concentrations in hypertensive cells. In aortic smooth muscle cells from 10 SHRs of the Münster strain and 10 age-matched normotensive WKY rats, the intracellular phosphate and magnesium content was measured by electron probe X-ray microanalysis (Camscan CS 24 apparatus, Cambridge, U.K.). The Mg++ content was 0.09 +/- 0.15 g/kg dry weight in SHRs versus 1.15 +/- 0.10 g/kg dry weight in WKY rats (p < 0.01). Vascular smooth muscle phosphate content was 23.6 +/- 0.79 g/kg dry weight in WKY rats versus 15.81 +/- 1.22 g/kg dry weight in SHRs (p < 0.01). In aortic smooth muscle cells of one month old SHRs intracellular magnesium was measured as 1.05 +/- 0.08 versus 1.09 +/- 0.09 g/kg dry weight in WKYs. Intracellular phosphate concentration in one month old SHRs was 18.71 +/- 2.41 versus 21.36 +/- 1.25 g/kg dry weight in WKYs (eight animals in each group). Aortic smooth muscle cells of SHRs are caracterized by markedly lowered intracellular phosphate and magnesium concentrations, resulting in an altered ATP-metabolism, as described earlier. Possibly a membrane defect or a magnesium deficiency or disturbed magnesium channels are responsible for the early onset in the pathogenesis of primary hypertension.

Early-onset increased calcium and decreased magnesium concentrations and an increased calcium/magnesium ratio in SHR versus WKY.

Alterations in the metabolism of calcium and magnesium have been implicated in the pathogenesis of primary hypertension. Calcium influx across the external cellular membrane in smooth muscle cells and cardiomyocytes plays a crucial role in the control of cellular excitation contraction and impulse propagation. Intracellular calcium and magnesium concentrations are controlled by reversible binding to specific calcium binding proteins. The calcium and magnesium flux across the external membrane is regulated by a calcium pump (calcium-magnesium-ATPase), calcium channels and binding to the membrane. In cell membranes and in lymphocytes of essential hypertensives, our group showed increased calcium and decreased magnesium and an increased calcium/magnesium ratio in hypertensive cells. In this context, in aortic smooth muscle cells from 13 spontaneously hypertensive rats (SHR) of the Münster strain (systolic blood pressure 188.4+/-9.8 mmHg) and 13 normotensive rats (NT, systolic blood pressure 118.5+/-7.2 mmHg) aged 9 months, the intracellular calcium and magnesium contents were measured under nearly in vivo conditions by electron-probe microanalysis. Measurements were performed in aortic cryosections 3 microm thick. The calcium content was 124.7+/-4.5* mmol/kg dry weight in SHR versus 110.3+/-4.1 mmol/kg dry weight in NT (Means+/-SD, p < 0.01), the magnesium content was 35.5+/-3.9* in SHR versus 50.1+/-4.9 mmol/kg dry weight in NT /p < 0.01). The calcium/magnesium ratio was significantly increased in SHR versus NT (3.56+/-0.39* versus 2.23+/-0.27, p < 0.01). In hypertensive one month old animals the increase in the calcium/magnesium ratio was not as pronounced as in 9 month old animals. The calcium/magnesium ratio was measured 3.3+/-0.42 in SHR (n = 8) as compared to 2.51+/-0.39 in normotensive animals (n = 8, p < 0.01). Aortic smooth muscle cells from SHR are characterized by markedly elevated intracellular calcium and decreased intracellular magnesium contents compared with normotensive cells. The increased calcium/magnesium ratio in hypertensive cells may be a pathogenetic factor for the development of arteriosclerosis and hypertension.

[Epidemic of methicillin-resistant Staphylococcus aureus due to the transfer of 2 Dutch burn patients from a hospital outside of the Netherlands; who suffers the consequences?]. / Epidemie van meticillineresistente Staphylococcus aureus door overname uit een buitenlands ziekenhuis van 2 Nederlandse brandwondpatiënten; wie draagt de gevolgen?

Two burns patients who were transferred to the Central Military Hospital Utrecht from a foreign hospital, were found to be colonised with MRSA. During their 5-week hospitalisation, 21 healthcare workers and one patient became colonised with the same MRSA strain, despite isolation precautions. The department was closed for 29 days; 96 admissions were cancelled and 1411 screening cultures for MRSA were performed. Colonised healthcare workers were temporarily unable to work and additional costs were incurred for disposables and cleaning procedures. The resultant bill for this outbreak was approximately [symbol: see text] 122,500. MRSA outbreaks occur in hospitals with some degree of regularity, but the strong dispersal during this epidemic was exceptional. The transfer of possible MRSA-colonised patients from hospitals outside of the Netherlands sometimes faces opposition due to the considerable demands it makes on a hospital's personnel, organisation and finances. If this were to be compensated, then the currently successful Dutch MRSA policy could be coupled with a willingness to accept patients from hospitals outside of the Netherlands.