Role of new molecular approaches for the early diagnosis of bladder cancer in clinical practice

There is an urgent need to improve the performance of urine cytology for the diagnosis of bladder cancer. In preliminary studies, telomerase activity evaluated by telomeric repeat amplification protocol (TRAP) assay and chromosomal aneuploidy detected by fluorescence in situ hybridization (FISH) in the diagnosis of bladder cancer have produced important results. Urine cell-free (UCF) DNA has also been proposed as a potential marker for early bladder cancer diagnosis. In the first study the diagnostic performance of TRAP assay and FISH analysis was assessed, while the second study evaluated the potential role of UCF DNA integrity in early bladder cancer diagnosis. In the first cross-sectional study, 289 consecutive patients who presented with urinary symptoms underwent cystoscopy and cytology evaluation. In the second study, UCF DNA was isolated from 51 bladder cancer patients, 46 symptomatic patients, and 32 healthy volunteers. c-Myc, BCAS1 and HER2 gene sequences longer than 250 bp were quantified by real time PCR to verify UCF DNA integrity. In the first study, sensitivity and specificity were 0.39 and 0.83, respectively, for cytology; 0.66 and 0.72 for TRAP; 0.78 and 0.60 for the cytology and TRAP combination; 0.78 and 0.78 for the cytology, TRAP and FISH combination; and 0.65 and 0.93 for the TRAP and FISH combination. In the second study, at the best cutoff of 0.1 ng/µl, UCF DNA integrity analysis showed a sensitivity of 0.73 and a specificity of 0.84 in healthy individuals and 0.83 in symptomatic patients. The preliminary results suggest that these biomarkers could potentially be used for the early diagnosis of bladder cancer, especially in high-risk populations (e.g, symptomatic individuals exposed to occupational risk) who may benefit from the use of noninvasive diagnostic tests in terms of cost-benefit.

Influence of polyvascular disease on cardiovascular event rates. Insights from the REACH Registry

Cardiovascular event rates have been shown to increase substantially with the number of symptomatic disease locations. We sought to assess the risk profile, management and subsequent event rates of polyvascular disease patients. Consecutive outpatients were assessed for atherosclerotic risk factors and medications in the REACH Registry. A total of 19,117 symptomatic patients in Europe completed a 2-year follow-up: 77.2% with single arterial bed disease (coronary artery or cerebrovascular or peripheral arterial disease) and 22.8% with polyvascular disease (>/= 1 disease location). Polyvascular disease patients were older (68.5 +/- 9.4 vs 66.3 +/- 9.9 years, p < 0.0001), more often current or former smokers (64.9% vs 58.7%, p < 0.0001), and more often suffered from hypertension (59.5% vs 46.6%, p < 0.0001) and diabetes (34.5% vs 25.9%, p < 0.0001) than single arterial bed disease patients. Despite more intense medical therapy, risk factors (smoking, hypertension, low fasting glucose, and low fasting total cholesterol) were less often controlled in polyvascular disease patients. This was associated with substantially more events over 2 years compared with single arterial bed disease patients (cMACCE [cardiovascular death/non-fatal stroke/non-fatal MI] odds ratio, 1.63 [95% CI, 1.45-1.83], p < 0.0001). In conclusion, polyvascular disease patients have more cardiovascular risk factors, and the prognosis for these patients is significantly worse than for patients with single arterial bed disease. This suggests a need to improve detection and consequent medical treatment of polyvascular disease.

Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists

Despite the fact that consensus guidelines recommend long-term dopamine agonist (DA) therapy as a first-line approach to the treatment of small prolactinoma, some patients continue to prefer a primary surgical approach. Concerns over potential adverse effects of long-term medical therapy and/or the desire to become pregnant and avoid long-term medication are often mentioned as reasons to pursue surgical removal. In this retrospective study, 34 consecutive patients (30 female, 4 male) preferably underwent primary pituitary surgery without prior DA treatment for small prolactinomas (microprolactinoma 1-10 mm, macroprolactinoma 11-20 mm) at the Department of Neurosurgery, University of Bern, Switzerland. At the time of diagnosis, 31 of 34 patients (91%) presented with symptoms. Patients with microprolactinomas had significantly lower preoperative prolactin (PRL) levels compared to patients with macroprolactinomas (median 143 μg/l vs. 340 μg/l). Ninety percent of symptomatic patients experienced significant improvement of their signs and symptoms upon surgery. The postoperative PRL levels (median 3.45 μg/l) returned to normal in 94% of patients with small prolactinomas. There was no mortality and no major morbidities. One patient suffered from hypogonadotropic hypogonadism after surgery despite postoperative normal PRL levels. Long-term remission was achieved in 22 of 24 patients (91%) with microprolactinomas, and in 8 of 10 patients (80%) with macroprolactinomas after a median follow-up period of 33.5 months. Patients with small prolactinomas can safely consider pituitary surgery in a specialized centre with good chance of long-term remission as an alternative to long-term DA therapy.

Recent developments for surgical aortic valve replacement: the concept of sutureless valve technology

Aortic stenosis has become the most frequent type of valvular heart disease in Europe and North America and presents in the large majority of patients as calcified aortic stenosis in adults of advanced age. Surgical aortic valve replacement has been recognized to be the definitive therapy which improves considerably survival for severe aortic stenosis since more than 40 years. In the most recent period, operative mortality of isolated aortic valve replacement for aortic stenosis varies between 1–3% in low-risk patients younger than 70 years and between 4 and 8% in selected older adults. Long-term survival following aortic valve replacement is close to that observed in a control population of similar age. Numerous observational studies have consistently demonstrated that corrective surgery in symptomatic patients is invariably followed by a subjective improvement in quality of life and a substantial increase in survival rates. More recently, transcatheter aortic valve implantation (TAVI) has been demonstrated to be feasible in patients with high surgical risk using either a retrograde transfemoral or transsubclavian approach or an antegrade, transapical access. Reported 30-day mortality ranges between 5 and 15%) and is acceptable when compared to the risk predicted by the logistic EuroSCORE (varying between 20 and 35%) and the STS Score, although the EuroScore has been shown to markedly overestimate the effective operative risk. One major concern remains the high rate of paravalvular regurgitation which is observed in up to 85% of the patients and which requires further follow-up and critical evaluation. In addition, long-term durability of these valves with a focus on the effects of crimping remains to be addressed, although 3-5 year results are promising. Sutureless biological valves were designed to simplify and significantly accelerate the surgical replacement of a diseased valve and allow complete excision of the calcified native valve. Until now, there are 3 different sutureless prostheses that have been approved. The 3f Enable valve from ATS-Medtronic received CE market approval in 2010, the Perceval S from Sorin during Q1 of 2011 and the intuity sutureless prosthesis from Edwards in 2012. All these devices aim to facilitate valve surgery and therefore have the potential to decrease the invasivness and to shorten the conventional procedure without compromise in term of excision of the diseased valve. This review summarizes the history and the current knowledge of sutureless valve technology.

Secondary stroke prevention: patent foramen ovale, aortic plaque, and carotid stenosis

Stroke is the most debilitating cardiovascular event. It has a variety of causes that may be present simultaneously. In young or otherwise healthy people, the search for a patent foramen ovale (PFO) has become standard. In stroke of the elderly, atherosclerosis and atrial fibrillation are in the foreground but the PFO should not be ignored. The risk of a PFO-related stroke over time is controversial and so is its prevention by device closure. The association of proximal aortic plaques in arteries subtending the brain and stroke is considered strong, ignoring that it is as putative as that of the PFO. Statins can prevent progression of such plaques. Antiplatelet agents in asymptomatic and surgical endarterectomy in symptomatic patients or highly ulcerated lesions are the treatment of choice. Stenting with protection devices was shown competitive in selected patients.

Detection of exon deletions within an entire gene (CFTR) by relative quantification on the LightCycler

BACKGROUND: Cystic fibrosis (CF) is associated with at least 1 pathogen point sequence variant on each CFTR allele. Some symptomatic patients, however, have only 1 detectable pathogen sequence variant and carry, on the other allele, a large deletion that is not detected by conventional screening methods. METHODS: For relative quantitative real-time PCR detection of large deletions in the CFTR gene, we designed DNA-specific primers for each exon of the gene and primers for a reference gene (beta2-microglobulin). For PCR we used a LightCycler system (Roche) and calculated the gene-dosage ratio of CFTR to beta2-microglobulin. We tested the method by screening all 27 exons in 3 healthy individuals and 2 patients with only 1 pathogen sequence variant. We then performed specific deletion screenings in 10 CF patients with known large deletions and a blinded analysis in which we screened 24 individuals for large deletions by testing 8 of 27 exons. RESULTS: None of the ratios for control samples were false positive (for deletions or duplications); moreover, for all samples from patients with known large deletions, the calculated ratios for deleted exons were close to 0.5. In addition, the results from the blinded analysis demonstrated that our method can also be used for the screening of single individuals. CONCLUSIONS: The LightCycler assay allows reliable and rapid screening for large deletions in the CFTR gene and detects the copy number of all 27 exons.

[Pneumatosis cystoides intestinalis: a rare illness in adults]

Pneumatosis cystoides intestinalis (PCI) is a rare illness in adults with gas filled blebs found in the submucosa or subserosa of the bowel wall. The main localization is the terminal ileum although all parts of the intestine can be affected. Clinical symptoms can vary from aqueous-slimy, bloody diarrhea to constipation and/or vague abdominal pain. Patients can also be completely asymptomatic. In symptomatic patients the therapy of PI is based on the assumed pathogenesis, so that a combined treatment of metronidazole 1500 mg daily during a period of 6-8 weeks additionally and oxygen application (PaO2 of 200-350 mmHg) for 7 days is suggested. In addition, elemental diets are recommended. Complications are indicated in the literature with 3%. In particular mechanical ileus, invagination and perforation as well as substantial intestinal bleeding up to the volvolus lead to further diagnostic and therapeutic steps. A surgical intervention is reserved for rare cases.

[HIV-associated thrombocytopenia]

Thrombocytopenia is a relatively frequent hematological complication of HIV (human immunodeficiency virus) infection. The incidence of thrombocytopenia in a cohort of 359 homo- or bisexual men with HIV infection was 3%, while it was 9% in a cohort of 321 HIV positive persons with a history of intravenous drug abuse. We followed 42 thrombocytopenic patients prospectively to study the clinical significance of thrombocytopenia in these patients. Thrombocytopenia was significantly more severe in intravenous drug abusers than in homo- or bisexual men: 52% of the drug abusers had thrombocyte counts below 10,000/mm3, compared with only 9% of the homo- or bisexual men. Symptoms of bleeding, almost always harmless skin or mucosal bleeding, were found in 45% of patients with a history of intravenous drug abuse and in 18% of the homo- or bisexual men. Life-threatening bleeding episodes did not occur during a median observation period of approximately one year. Prednisone was the most commonly used drug in symptomatic thrombocytopenia and had demonstrable effect only while being administered. After medication was stopped the thrombocyte counts usually fell to pretreatment values. Our findings suggest that therapy of HIV-associated thrombocytopenia should be reserved for severely symptomatic patients, particularly since this symptom of HIV infection rarely causes serious complications and we do not know the influence of drugs such as corticosteroids on the progression rate of HIV-infection.

Evaluation of magnetic resonance colonography at 3.0 Tesla regarding diagnostic accuracy and image quality

OBJECTIVES: To assess magnetic resonance (MR)-colonography (MRC) for detection of colorectal lesions using two different T1w three-dimensional (3D)-gradient-recalled echo (GRE)-sequences and integrated parallel data acquisition (iPAT) at a 3.0 Tesla MR-unit. MATERIALS AND METHODS: In this prospective study, 34 symptomatic patients underwent dark lumen MRC at a 3.0 Tesla unit before conventional colonoscopy (CC). After colon distension with tap water, 2 high-resolution T1w 3D-GRE [3-dimensional fast low angle shot (3D-FLASH), iPAT factor 2 and 3D-volumetric interpolated breathhold examination (VIBE), iPAT 3] sequences were acquired without and after bolus injection of gadolinium. Prospective evaluation of MRC was performed. Image quality of the different sequences was assessed qualitatively and quantitatively. The findings of the same day CC served as standard of reference. RESULTS: MRC identified all polyps >5 mm (16 of 16) in size and all carcinomas (4 of 4) correctly. Fifty percent of the small polyps 0.6). CONCLUSIONS: MRC using 3D-GRE-sequences and iPAT is feasible at 3.0 T-systems. The high-resolution 3D-FLASH was slightly preferred over the 3D-VIBE because of better image quality, although both used sequences showed no statistical significant difference.

Mean 20-year followup of Bernese periacetabular osteotomy

The goal of the Bernese periacetabular osteotomy is to correct the deficient acetabular coverage in hips with developmental dysplasia to prevent secondary osteoarthrosis. We determined the 20-year survivorship of symptomatic patients treated with this procedure, determined the clinical and radiographic outcomes of the surviving hips, and identified factors predicting poor outcome. We retrospectively evaluated the first 63 patients (75 hips) who underwent periacetabular osteotomy at the institution where this technique was developed. The mean age of the patients at surgery was 29 years (range, 13-56 years), and preoperatively 24% presented with advanced grades of osteoarthritis. Four patients (five hips) were lost to followup and one patient (two hips) died. The remaining 58 patients (68 hips) were followed for a minimum of 19 years (mean, 20.4 years; range, 19-23 years) and 41 hips (60%) were preserved at last followup. The overall mean Merle d'Aubigné and Postel score decreased in comparison to the 10-year value and was similar to the preoperative score. We observed no major changes in any of the radiographic parameters during the 20-year postoperative period except the osteoarthritis score. We identified six factors predicting poor outcome: age at surgery, preoperative Merle d'Aubigné and Postel score, positive anterior impingement test, limp, osteoarthrosis grade, and the postoperative extrusion index. Periacetabular osteotomy is an effective technique for treating symptomatic developmental dysplasia of the hip and can maintain the natural hip at least 19 years in selected patients. LEVEL OF EVIDENCE: Level III, prognostic study.

Patent foramen ovale and ventricular septal defect closure

Despite the growing recognition of the patent foramen ovale (PFO), particularly when associated with an atrial septal aneurysm, as risk factor for several disease manifestations (above all paradoxical embolism), the optimal treatment strategy for symptomatic patients remains controversial. Percutaneous PFO closure is a minimally invasive procedure which can be performed with high success and low morbidity. For secondary prevention of recurrent embolic events, it appears to be clinically at least as effective as oral anticoagulation. Ventricular septal defects (VSDs) are the most common congenital heart defects. Percutaneous VSD closure is more intricate than PFO closure. It is associated with a significant risk of both peri-interventional and mid-term complications. In suitable patients with congenital VSD, device closure may well be the preferred treatment both for muscular or perimembranous VSDs and for residual defects after surgical VSD closure. The risk of complete atrioventricular conduction block remains a concern in the perimembranous group. The history, technique and clinical role of percutaneous PFO and VSD closure are discussed, with emphasis on current problems and future developments.

Real-time quantitative PCR to determine chlamydial load in men and women in a community setting

We used a PCR method to quantify the loads of Chlamydia trachomatis organisms in self-collected urine and vulvovaginal swab (VVS) samples from 93 women and 30 men participating in the Chlamydia Screening Studies Project, a community-based study of individuals not seeking health care. For women, self-collected VVS had a higher mean chlamydial load (10,405 organisms/ml; 95% confidence interval [95% CI], 5,167 to 21,163 organisms/ml) than did first-void urines (FVU) (503 organisms/ml; 95% CI, 250 to 1,022 organisms/ml; P < 0.001). Chlamydial loads in female and male self-collected FVU specimens were similar (P = 0.634). The mean chlamydial load in FVU specimens decreased with increasing age in females and males. There was no strong statistical evidence of differences in chlamydial load in repeat male and female FVU specimens taken when patients attended for treatment a median of 23.5 (range, 14 to 62) and 28 (range, 13 to 132) days later, respectively, or in VVS taken a median of 35 (range, 14 to 217) days later. In this study, chlamydial load values for infected persons in the community who were not seeking treatment were lower than those published in other studies involving symptomatic patients attending clinical settings. This might have implications for estimates of the infectiousness of chlamydia. The results of this study provide a scientific rationale for preferring VVS to FVU specimens from women.

Is carotid endarterectomy a trainee operation?

BACKGROUND: Recent dramatic changes in surgical training resulting from working-hour regulations may lead to lack of competence. Traditionally, carotid surgery has been the domain of specialists. This study was designed to compare the outcome of carotid endarterectomy performed by vascular surgical trainees versus vascular surgeon (VS). METHODS: A retrospective study of 1,379 consecutive patients who underwent carotid endarterectomy as the sole procedure under local or general anesthesia (from 1995-2004) was performed. All patients were admitted to the intensive care unit for 24 hours. Trainees performed 475 (34.5%) and vascular specialists performed 904 (65.5%) operations. RESULTS: Patient characteristics with regard to preoperative neurological status were similar. Trainees operated on 61.4% symptomatic patients and VS on 56.8% (P = 0.09). Shunt use did not differ (16% trainee vs. 17.8% VS). Clamping time and total operating time were longer among trainees (41.9 vs. 33.5 min, P < 0.001; and 121.2 vs. 101.8 min, P < 0.001, respectively). Postoperative stroke and death rates (3.2% vs. 3.1% and 0.4% vs. 0.9%, respectively) did not differ. Peripheral nerve complications were more common among trainees (12.2% vs. 6.5%; P < 0.0001); 99.6% of these nerve injuries had resolved at 3 months' follow-up. CONCLUSIONS: Carotid endarterectomy can be performed safely by a trainee vascular surgeon when assisted and supervised by a specialist vascular surgeon.

Overview of Treatment Options, Clinical Results, and Controversies in the Management of Femoroacetabular Impingement

The surgical management of symptomatic femoroacetabular impingement (FAI) generally is indicated after the failure of a trial of nonsurgical treatment. Surgical planning includes an assessment of the labrochondral pathology as well as of the acetabular and proximal femoral bony deformity. Advanced articular cartilage disease generally is associated with poorer outcomes. Surgical hip dislocation and hip arthroscopy have been used, with favorable early outcomes and low complication rates. Careful patient selection is important in predicting the success of the surgical management of symptomatic FAI. A trial of nonsurgical management generally is recommended, but limited information exists regarding its success. The early outcomes of both open and arthroscopic surgical techniques demonstrate significant improvement in most patients, with relatively low rates of complications. Because poorer clinical outcomes are associated with more advanced articular cartilage degeneration, improved strategies for the earlier identification and disease staging of symptomatic patients may enhance the long-term outcomes of both nonsurgical and surgical management.

Congenital portosystemic shunt: characterization of a multisystem disease

OBJECTIVES Congenital portosystemic shunts (CPSSs) are rare but increasingly recognized as a cause of important multisystem morbidity. We present new cases and a systematic literature review and propose an algorithm for the identification and care of affected patients. METHODS We reviewed the charts of consecutive patients seen in our pediatric liver clinic between 2003 and 2010 and systematically reviewed the literature of cases with CPSS. RESULTS We identified 316 published cases and 12 patients in our own clinic. Of the published cases (177 male), 185 had an extrahepatic and 131 an intrahepatic portosystemic shunt. Diagnosis was made at any age, from prenatal to late adulthood. Cardiac anomalies were found in 22% of patients. The main complications were hyperammonemia/neurological abnormalities (35%), liver tumors (26%), and pulmonary hypertension or hepatopulmonary syndrome (18%). The spectrum of neurological involvement ranged from changes in brain imaging, subtle abnormalities on neuropsychological testing, through learning disabilities to overt encephalopathy. Spontaneous shunt closure occurred mainly in infants with intrahepatic shunts. Therapeutic interventions included shunt closure by surgery or interventional radiology techniques (35%) and liver transplantation (10%) leading to an improvement of symptoms in the majority. These findings mirror the observations in our own patients. CONCLUSIONS In this largest review of the reported clinical experience, we identify that children with CPSS may present with otherwise unexplained developmental delay, encephalopathy, pulmonary hypertension, hypoxemia, or liver tumors. When CPSS is diagnosed, children should be screened for all of these complications. Spontaneous closure of intrahepatic shunts may occur in infancy. Closure of the shunt is indicated in symptomatic patients and is associated with a favorable outcome.