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BACKGROUND: The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated. METHODS: Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses. RESULTS: All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools. CONCLUSION: While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:41 issue:7 pages:971-981 ispartof: location:United States status: published

BackgroundRisk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk.MethodsWe analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan–Meier analyses, log-rank testing and Cox proportional hazards models.ResultsData from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk.ConclusionsModified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

BACKGROUND: A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities. METHODS: We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities. RESULTS: The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities. CONCLUSIONS: Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:42 issue:1 pages:102-114 ispartof: location:United States status: published

BackgroundSince 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival.MethodsWe analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010–2014 and 2015–2019.ResultsA total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010–2014 and 2015–2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2–90.9%) and 90.8% (95% CI 89.3–92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0–70.8%) and 70.5% (95% CI 67.8–73.4%), respectively).ConclusionsThe use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed.

BACKGROUND: Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients. METHODS: We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension). FINDINGS: The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p

The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO

Background— For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). Methods and Results— We analyzed data from Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year survival ( P =0.006) in patients on anticoagulation compared with patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant ( P =0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio, 0.79; 95% confidence interval, 0.66–0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. Conclusions— The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01347216.

Increased dyspnea and reduced exercise capacity in pulmonary arterial hypertension (PAH) can be partly attributed to impaired respiratory muscle function. This prospective study was designed to assess the impact of exercise and respiratory training on respiratory muscle strength and 6-min walking distance (6MWD) in PAH patients. Patients with invasively confirmed PAH underwent 3 weeks of in-hospital exercise and respiratory training, which was continued at home for another 12 weeks. Medication remained constant during the study period. Blinded observers assessed efficacy parameters at baseline (I) and after 3 (II) and 15 weeks (III). Respiratory muscle function was assessed by twitch mouth pressure (TwPmo) during nonvolitional supramaximal magnetic phrenic nerve stimulation. Seven PAH patients (4 women; mean pulmonary artery pressure 45 ± 11 mmHg, median WHO functional class 3.1 ± 0.4, idiopathic/associated PAH n = 5/2) were included. The training program was feasible and well tolerated by all patients with excellent compliance. TwPmo was I: 0.86 ± 0.37 kPa, II: 1.04 ± 0.29 kPa, and III: 1.27 ± 0.44 kPa, respectively. 6MWD was I: 417 ± 51 m, II: 509 ± 39 m, and III: 498 ± 39 m, respectively. Both TwPmo (+0.41 ± 0.34 kPa, +56 ± 39 %) and 6MWD (+81 ± 30 m, +20 ± 9 %) increased significantly in the period between baseline and the final assessment (pairwise comparison: p = 0.012/

The objective of this prospective study was to assess safety and efficacy of exercise training in a large cohort of patients with different forms and World Health Organization (WHO) functional classes of chronic pulmonary hypertension (PH). 183 patients with PH (pulmonary arterial hypertension (PAH), chronic thromboembolic PH and PH due to respiratory or left heart diseases received exercise training in hospital for 3 weeks and continued at home. Adverse events have been monitored during the in-hospital training programme. Efficacy parameters were evaluated at baseline, and after 3 and 15 weeks. After 3 and 15 weeks, patients significantly improved the distance walked in 6 min (6MWD) compared to baseline, scores of quality of life, WHO functional class, peak oxygen consumption, oxygen pulse, heart rate and systolic pulmonary artery pressure at rest and maximal workload. The improvement in 6MWD was similar in patients with different PH forms and functional classes. Even in severely affected patients (WHO functional class IV), exercise training was highly effective. Adverse events, such as respiratory infections, syncope or presyncope, occurred in 13% of patients. Exercise training in PH is an effective but not a completely harmless add-on therapy, even in severely diseased patients, and should be closely monitored.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. These guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the use of these drugs in patients with chronic lung disease and PH is not recommended. This recommendation, however, is not always in agreement with medical needs as physicians feel sometimes inclined to also treat other forms of pulmonary hypertension which may affect the quality of life and survival of these patients in a similar manner as in PAH. In June 2010, a consensus conference was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology (DGK, DGP and DGPK). To this end, a number of working groups were initiated, one of which was specifically dedicated to the diagnosis and treatment of PH due to chronic lung disease. This manuscript describes in detail the results and recommendations of this working group which were last updated in October 2011.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

Abbreviated versions of the risk stratification strategy of the European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines have been recently validated in patients with pulmonary arterial hypertension. We aimed to investigate their prognostic value in medically treated chronic thromboembolic pulmonary hypertension (CTEPH) patients from the COMPERA registry, which collects six variables of interest (World Health Organization Functional Class, 6-min walk distance, brain natriuretic peptide, right atrial pressure, cardiac index and mixed venous oxygen saturation).We included patients with at least one follow-up visit, no pulmonary endarterectomy and at least three of the six variables available, and classified the patients into low-, intermediate- and high-risk groups. As a secondary analysis, the number of noninvasive low-risk criteria was counted. The association between risk assessment and survival was evaluated.Data from inclusion and follow-up (median 7 months) visits were available for 561 and 231 patients, respectively. Baseline 1- and 5-year survival estimates were significantly different (p

We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III. In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0-2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Riociguat was generally well tolerated. Asymptomatic hypotension (SBP

Abnormalities in alveolar coagulation occur in idiopathic pulmonary fibrosis (IPF). Anticoagulants attenuate bleomycin-induced lung fibrosis in animals. In this study, we first examined the pharmacokinetics of inhaled heparin in healthy subjects. Second, we investigated the safety and tolerability of heparin inhalation in IPF patients.Coagulation assays were performed in blood and bronchoalveolar lavage fluid samples from 19 healthy volunteers after inhalation of increasing amounts of unfractionated heparin. The acute effects of heparin inhalation on lung function and exercise capacity and the safety and tolerability of chronic heparin inhalation for 28 days were assessed in 20 IPF patients in an open-label exploratory pilot study.In healthy subjects, inhalation of 150,000 IU heparin ("filled dose") significantly increased the partial thromboplastin time and anti-factor Xa activity in blood samples indicating the threshold dose. The local alveolar anticoagulant effect was detectable up to 72 h, and the alveolar half-life was estimated at 28 h. In IPF-patients, no acute deleterious effects on pulmonary function, gas exchange, or exercise capacity were noted after inhalation of the threshold dose. During chronic treatment, where one-fourth of the threshold dose was inhaled every 12 h for 28 days to obtain a steady-state anticoagulant activity in the alveolar space approximating the anticoagulant activity observed after threshold dose inhalation, no heparin-related side effects, such as hemoptysis or heparin-induced antibodies and thrombocytopenia, were detected in any patient, and median lung function values, exercise capacity, and quality of life scores appeared largely unaltered. Three adverse and one serious adverse events were noted; however, the relation of these events to the heparin inhalation was assessed as "unlikely" or "no relation" in each case.Inhaled heparin appears to be safe and well tolerated in IPF patients. Future clinical trials are required to demonstrate the long-term safety and efficacy of inhaled heparin in IPF.

Objective Aim of study was to evaluate the urodynamic findings in patients with infantile cerebral palsy. Material and methods In 29 patients (aged 3-53), a videourodynamic investigation was performed after evaluation of urological anamnesis, clinical assessment and sonographic determination of residual urine. The patients were divided into group 1 (23 symptomatic patients aged 5 years and older with recurrent urinary tract infection, pollakiuria or urinary incontinence) and group 2 (6 asymptomatic patients). Results In group 1, 21/23 patients (91%) had reduced compliance (0.6 - 16.4 ml/cmH(2)O) and 16/23 patients (70%) increased leak point pressure (> 40 cmH(2)O). In all 23 patients, detrusor instability and detrusor sphincter dyssynergia (during voiding) was found. Fluoroscopy showed bladder trabeculation or diverticula in 14 patients (61%) and 2nd-3rd degree vesicoureterorenal reflux in 2 patients (9%). In group 2, 2/6 patients (33%) had reduced compliance (0.7 and 5.8 ml/cmH(2)O) and 4/6 (67%) increased leak point pressure (> 40 cmH(2)O). In 5/6 patients (83%), detrusor instability and detrusor sphincter dyssynergia was seen. Fluoroscopy showed bladder trabeculation in 3 patients (50%), whereas no reflux was observed. Only one of the 29 patients (3 %) showed no pathological videourodynamic or anamnestic findings. Conclusions We conclude that videourodynamic assessment should be performed in all patients with infantile cerebral palsy. The decision should not be based on clinical symptoms such as pollakiuria, recurrent urinary tract infection or urinary incontinence.

Riociguat is the first oral soluble guanylate cyclase stimulator shown to improve pulmonary hemodynamics in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (PH). This pilot study assessed the impact of a single dose of riociguat on hemodynamics, gas exchange, and lung function in patients with PH associated with chronic obstructive pulmonary disease (COPD). Adults with COPD-associated borderline or manifest PH (pulmonary vascular resistance > 270 dyn·s·cm−5, mean pulmonary artery pressure ≥ 23 mmHg, ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity < 70%, and partial pressure of oxygen and carbon dioxide in arterial blood > 50 and ≤ 55 mmHg, respectively) received riociguat 1 or 2.5 mg during right heart catheterization. Twenty-two patients completed the study (11 men, 11 women, aged 56–82 years; 1-mg group: n = 10 [mean FEV1: 43.1%]; 2.5-mg group: n = 12 [mean FEV1: 41.2%]). Riociguat caused significant improvements (P < 0.01) from baseline in mean pulmonary artery pressure (1 mg: −3.60 mmHg [−11.44%]; 2.5 mg: −4.83 mmHg [−14.76%]) and pulmonary vascular resistance (1 mg: −58.32 dyn·s·cm−5 [−15.35%]; 2.5 mg: −123.8 dyn·s·cm−5 [−32.96%]). No relevant changes in lung function or gas exchange were observed. Single doses of riociguat were well tolerated and showed promising hemodynamic effects without untoward effects on gas exchange or lung function in patients with COPD-associated PH. Placebo-controlled studies of chronic treatment with riociguat are warranted.

Ziel der Untersuchung: Erfassung der Langzeitergebnisse der endoskopischen subureteralen Kollageninjektion bei vesikoureteralem Reflux (VUR). Material und Methode: Untersucht wurden prospektiv 86 Patienten (Durchschnittsalter 8 Jahre) mit 128 refluxiven ureterorenalen Einheiten (URU). Alle Patienten wurden mit subureteraler Kollageninjektion behandelt und mittels Miktionszysturethrographien oder videourodynamischen Untersuchungen nachbeobachtet. Ergebnisse: Bei 128 URU wurden 157 subureterale Kollageninjektionen durchgefuhrt. Dies beinhaltet 27 Zweitinjektionen und 2 Drittinjektionen. Bei 65 behandelten URU lag ein primarer, bei 19 URU ein sekundarer Reflux vor. Bei 28 URU lag ein sekundarer Reflux infolge einer neurogenen Blasenfunktionsstorung vor, 7 URU wurden nach erfolgloser offen-chirurgischer Antirefluxplastik mit Kollageninjektionen behandelt, 9 URU bei Ureter duplex. Nach einer Nachbeobachtungszeit von 24 Monaten fand sich ein Refluxrezidiv bei 83% der URU nach primarem Reflux, bei 56% der URU nach sekundarem Reflux, bei 85% der URU nach Reflux bei neurogener Blasenfunktionsstorung, bei 67% der URU nach Reflux im Rahmen eines Ureter duplex und bei 34% nach zuvor fehlgeschlagener offen-chirurgischer Antirefluxplastik. Nach Zweitinjektion waren nach einer Nachbeobachtungszeit von 24 Monaten noch 35% der Patienten refluxfrei. Beurteilung: Aufgrund dieser Daten halten wir die subureterale Kollageninjektion im Langzeitverlauf fur nicht geeignet, vesikoureterale Refluxe dauerhaft zu beseitigen.

Objective: We prospectively analyzed the dose dependent outcome and side effects of neurogenic bladder patients with intravesical application of oxybutynin at our centre. Materials and methods: We examined the data of 32 patients with neurogenic bladders and detrusor hyperreflexia. We registered clinical outcome, continence situation, side effects and urodynamic data of patients with (A) standard dosages of intravesical oxybutynin (0.3 mg/kg bodyweight per day) and (B) with increasing dosages in steps of 0.2 mg/kg bodyweight per day up to 0.9 mg/kg bodyweight per day. Results: We examined 32 patients aged 1 to 34 years, mean age 12 years. 21/32 patients became totally continent with the dosage (A). They showed a significant (P

Ziel dieser Untersuchung war die Evaluation der optimalen und effektiven Diagnostik beim praoperativen Staging von Nierenzellkarzinomen mit Kavazapfen. Ist der Einsatz der MRT gerechtfertigt? Es wurden 7 Nierenzellkarzinome der Tumorstadien T3b und T3c praoperativ in der CT und MRT untersucht und das Staging mit dem histopathologischen Ergebnis korreliert. In der MRT wurden 4 von 7 Kavazapfen in ihrer Ausdehnung korrekt und sicher beurteilt, in der CT keiner korrekt und sicher. Die MRT mit Gadolinium ist der CT im Staging von Nierenzellkarzinomen der hohen Tumorstadien uberlegen und kann hier die Kavographie ersetzen. Die MRT ist in den Fallen, in denen sonographisch ein hohes Tumorstadium mit Kavazapfen vermutet wird, als praoperative Diagnostik gerechtfertigt.

Purpose: We evaluated the long-term efficacy of subureteral glutaraldehyde cross-linked collagen injection (GAX 35 * *Collagen Corp., Palo Alto, California.) for endoscopic treatment of vesicoureteral reflux in patients with neurogenic bladder dysfunction due to meningomyelocele. Materials and Methods: We prospectively studied 12 women and 8 men (26 ureteral renal units) with a median age of 8 years (range 1 to 51) who had neurogenic bladder due to meningomyelocele. Reflux into single collecting systems was treated with subureteral collagen injection (GAX 35). Followup with video urodynamics included voiding cystography. Results: All patients performed intermittent catheterization to control the bladder. During the study all bladders were areflexic with normal compliance. Preoperative reflux according to the International Reflux Study Classification was grade I in 1, II in 9, III in 10, IV in 4 and V in 2 ureteral renal units. All patients were treated with subureteral collagen injection (mean volume 1.9 ml., range 0.7 to 3.5). Reflux resolved initially in all but 2 cases. Mean followup was 16 months (range 1 to 71). Reflux was still absent in only 15% of treated units after 24 months. Conclusions: Our data suggest that endoscopic subureteral collagen injection in neurogenic bladder cases is not effective with long-term followup. New biocompatible and biodegradable materials should be tested to control vesicoureteral reflux.

Der Fall einer Spontanruptur der Niere aufgrund eines Urothelkarzinoms eine Woche post partum wird vorgestellt. Die Diagnose wurde erst intraoperativ gestellt. Die Prognose ist im Vergleich zum rechtzeitig erkannten und therapierten Karzinom infaust. Die Patientin war in regelmasiger gynakologischer Betreuung und wies uber 6 Monate die typischen Symptome eines Urothelkarzinoms auf. Der Tumor wurde trotz regelmasiger sonographischer Kontrollen in der Schwangerschaft nicht diagnostiziert. Die Diagnostik und Behandlung von Nierenzellkarzinomen in der Schwangerschaft wird diskutiert.

In a prospective study of 80 patients, we investigated the association of kidney graft rejection with pretransplant CD4 helper/suppressor function, B cell responses, and in vitro cytokine secretion. A pokeweed mitogen-driven allogeneic coculture system was used to assess CD4 helper/suppressor function and T cell-dependent B cell responses. SAC I was used for T cell- and monocyte-independent stimulation of B cell cultures. B cell differentiation was assessed in a reverse hemolytic plaque assay. ELISAs were used to determine in vitro cytokine secretion. None of the 12 patients with pretransplant CD4 helper defects (< 10 % helper activity) had acute rejection episodes in contrast to 32 of 68 (47 %) patients with normal pretransplant CD4 helper function (P = 0.001). Patients with pretransplant CD4 helper defects exhibited better 3-year graft function than patients without CD4 helper defects (serum creatinine of functioning grafts: 1.2 ± 0.1 mg/dl compared to 1.7 ± 0.1 mg/dl, P < 0.05). Low pretransplant IL-10 responses (< 100 pg/ml; 14/80 patients) were significantly associated with a low incidence of acute rejection episodes (P < 0.01) and good 3-year graft function (P < 0.05). These data show that impaired pretransplant Th2 responses–CD4 help and IL-10 responses–predict a low risk of kidney graft rejection and good 3-year graft function, whereas Th1 (IL-2, IFN-γ ) and B cell/monocyte responses are not of predictive value.

1493 patients were enrolled in 55 centers in Europe, Canada, Australia and the USA comparing the efficacy of mycophenolate mofetil (MMF) in daily doses of 2 and 3 g with placebo/azathioprine (PLA/AZA) for the prevention of acute rejection in renal transplant patients. Acute rejections and graft loss and death at 1 year were measured per trial and these data were combined and analyzed in a pooled fashion. The three pooled treatment groups were well balanced regarding demographic characteristics and cause of renal failure leading to transplantation. At one year the graft survival rate was 90.4 % and 89.2 % in the MMF 2 g and 3 g groups compared with 87.6 % in the PLA/AZA-group. MMF 2 and 3 g were significantly better than PLA/AZA in reducing biopsy proven rejection at one year: 40.8 % placebo/aza vs. 19.8 % in the MMF 2 g group and 16.5 % in the MMF 3 g group.

Improving organ preservation techniques for transplantation is one of the most important goals of transplantation research. We have established a new, nonfreezing cryopreservation method to optimize the viability of rat kidneys for transplantation with up to 4 M dimethylsulphoxide (DMSO) in EuroCollins solution (EC) at -5 degrees C to -15 degrees C. We have confirmed the occurrence of a tubular and glomerular defect pattern that mediates acute tubular necrosis (ATN) and that may be a cause of major histocompatibility complex (MHC) independent immunological components of chronic transplant rejection. The extent of this defect [transplant survival and function, 31P-NMR spectroscopy, histological defect index] in the nonfreezing cryopreserved groups (n = 22) is significantly (P = 0.017) lower than in the simple cold storage group (n = 12). Quality and localization of the lesions in kidney transplants can elucidate the context of organ preservation, progressive hyperfiltration defects, and the occurrence of graft failure without elevated frequency of acute rejection episodes. These results indicate that further efforts to provide higher pretransplant organ viability without using it to prolong cold storage intervals may provide better insight into MHC-independent factors of chronic transplant failure and may result in improved long-term transplant outcome.

Drs Suissa and Galie postulate that the 21% reduction in mortality observed in patients with idiopathic (IPAH) pulmonary arterial hypertension (PAH) who received anticoagulants was mainly the result of immortal time bias rather than a true drug effect. We can assure them that this was not the case. Anticoagulation was started within 3 months after diagnosis in 92.4% of all patients (94.8% after 6 months and 97.4% after 12 months).1 In addition, we included only incident cases. Hence, it is highly unlikely that immortal time bias had a major impact on our findings. In fact, it is possible that the lack of sustained exposure to anticoagulants in the group of ever-users resulted in an underestimation of the therapeutic potential of anticoagulants. Finally, if immortal time bias were truly a driver of our results, it would have shifted the survival of patients with other forms of PAH in the same direction as in patients with IPAH. The opposite was the case, which leaves us confident that our results and their interpretation are robust. Dr Bertoletti and colleagues raise the issue that comorbidities may have affected our results. This point has been addressed already in our Discussion, where we stated as 1 of the limitations of our study that comorbidities were not systematically assessed in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and that the presence of comorbidities might have affected the decision to use or not to use anticoagulants, as well as survival. The COMPERA population with its relatively advanced average age reflects the changing PAH phenotype in the Western world. Our findings suggest that anticoagulation may be useful in patients with a contemporary phenotype of IPAH but probably not in patients with other forms of PAH. The decision to start or to withhold anticoagulants …

Die Indikationen fur eine organerhaltende Nierentumorchirurgie haben sich in den letzten 10 Jahren erweitert. Anerkannte Indikationen sind bilaterale Nierentumoren, Nierentumoren bei Patienten mit funktionellen und anatomischen Einzelnieren sowie bei Patienten mit eingeschrankter Nierenfunktion, denen nach Tumornephrektomie eine dialysepflichtige Niereninsuffizienz droht (imperative Indikationen). Durch operationsstrategische Verbesserungen – wie Perfusion in Hypothermie und Work-bench-Chirurgie konnen auch Patienten mit multiplen und fortgeschrittenen Nierentumoren zu uber 95 % vor einer Nephrektomie mit anschliesender Dialyse bewahrt werden. Beeinflust durch die exzellenten Funfjahresuberlebensraten von uber 80 % nach organerhaltender Nierentumorchirurgie in imperativen Indikationen empfehlen zunehmend mehr Zentren die Ausweitung der parenchymsparenden Nierentumorchirurgie auf ein selektioniertes Patientengut mit kontralateral gesunder Niere (elektive Indikationen). Hier zeigen sich bei Nachbeobachtungszeiten von durchschnittlich 40 Monaten ahnliche Uberlebensraten wie nach Tumornephrektomie. Bei einer Inzidenz bilateraler Nierenkarzinome von lediglich 2 % erscheint jedoch der Benefit der elektiven Resektion gering. Die lokale Rezidivrate nach elektiver organerhaltender Nierentumorchirurgie ist zwar bisher gering (durchschnittlich unter 5 %), allerdings kann die tatsachliche Haufigkeit der sich meist nach 4 Jahren manifestierenden Spatrezidive wegen noch kurzer Nachbeobachtungszeiten noch nicht abgeschatzt werden. Die Prognose nach Manifestation lokaler Rezidive ist in den meisten Fallen infaust.

In dieser retroperspektiven Studie untersuchten wir die klinische Wertigkeit des De-novo-Nierenzellkarzinoms bei chronisch dialysepflichtigen Patienten im Vergleich zu Empfangern einer Transplantatniere. Im Zeitraum der letzten 15 Jahre beobachteten wir den klinischen Verlauf dieser Patienten. Von 788 durchgefuhrten Nephrektomien konnten 21 Patienten identifiziert werden, die zum Zeitpunkt der Diagnose des Nierenzellkarzinoms terminal niereninsuffizient waren. Ausgewertet wurden Daten zur klinischen Symptomatik, Tumorhistologie und zum klinischen Verlauf. 14 Patienten waren in chronischer Hamodialysebehandlung, 7 Patienten verfugten uber ein stabiles Nierentransplantat. 92 % der Dialysengruppe hatte zum Zeitpunkt der Operation keine Fernmetastasen, keiner dieser Patienten ist bisher an dem RCC verstorben. 71 % der transplantierten Patienten hatte hingegen zum Zeitpunkt der Operation ein bereits organuberschreitendes Tumorwachstum oder Fernmetastasen. 3 Patienten sind zwischenzeitlich an ihrer Erkrankung verstorben. Das aggressive Tumorwachstum des Nierenzellkarzinoms in dieser Patientenpopulation macht somit eine engmaschige Kontrolle der Eigenniere vor und nach Nierentransplantation erforderlich.

We report our preliminary results using a new magnetic resonance imaging technique for visualization of the urinary tract. Using the paramagnetic contrast medium gadolinium diethylene triamine penta-acetic acid (DTPA), we were able to obtain images of the urinary tract comparable to those obtained by conventional excretory urography. The major advantage of our technique is that besides good morphologic visualization, the excretion of gadolinium-DTPA can be studied simultaneously. We demonstrate our preliminary results in selected cases.

Objectives This study was performed to establish oncological guidelines for the surgical treatment of invasive penile cancer. Materials and methods The medical records of 51 patients with invasive penile cancer seen between 1968 and 1994 were reviewed in respect to treatment and long-term outcome. Results For stage T1 tumors treated with organ-preserving procedures the local recurrence rats was 56%, whereas no patient experienced a local recurrence after partial amputation. For stage T2 tumors, local recurrence rate was 100% (organ preservation) versus 20% (amputative procedures). There was no significant difference related to regional recurrence between surveillance, inguinal radiation and lymphadenectomy for stage N0 tumors. For N+ stages, survival was related to the extent of inguinal metastasis after dissection (5-year survival rate for N1: 71 vs. 33% for N2/3). Conclusions Organ-preserving procedures include a high risk of local and regional recurrence. Adjuvant regional lymphadenectomy seems beneficial only in patients with solitary metastasis.

Exercise training as an add-on to medical therapy has been shown to improve exercise capacity, quality of life, and possibly prognosis in patients with pulmonary hypertension (PH). The purpose of this study was to analyze the impact of exercise training on healthcare costs in PH. Estimated healthcare costs have been compared between patients with severe PH under optimized medical therapy only (control group) versus patients who received exercise training as an add-on to medical therapy (training group). Cost-analysis included a cost-estimation model of costs for baseline and follow-up visits and all PH-related healthcare events that occurred within the follow-up period. Time to clinical worsening and survival were assessed by clinical records, phone, and/or control visits. At baseline, the training (n = 58) and control group (n = 48) did not differ in age, gender, WHO-functional class, 6-min walking distance, hemodynamic parameters, or PH-targeted medication. During a follow-up of 24 ± 12 months, the training group had significantly better survival rates at 1 and 3 years and less worsening events (death, lung transplantation, hospitalization due to PH, new PAH-targeted medication) than the control group (15 vs. 25 events, p

In a prospective study of 80 patients, we investigated the association of acute kidney graft rejection with pretransplant T helper/suppressor activity, B-cell responses, and in vitro cytokine secretion. Patients' CD4+ or CD8+ T cells were cocultured with control B cells and pokeweed mitogen for 6 days. SAC I was used for T cell- and monocyte-independent B-cell stimulation and pokeweed mitogen was used for T cell-dependent B-cell stimulation. B-cell differentiation was assessed in a reverse hemolytic plaque assay. Cytokine responses of T cells (interleukin [IL]-2, IL-10, gamma-interferon) and B cells/monocytes (IL-6, IL-8, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor) were determined in culture supernatants using ELISA. Subsets of CD4+ T cells, CD8+ T cells, and B cells were assessed by flow cytometry. None of 12 patients with pretransplant CD4 helper defects (CD4 helper activity < 10%) had acute rejection episodes, in contrast to 32 of 68 (47%) patients with normal pretransplant CD4 helper function (P = 0.001). Patients with pretransplant CD4 helper defects also had better 1-year graft function than patients without CD4 helper defects (serum creatinine 1.2 +/- 0.1 mg/dl and 1.7 +/- 0.1 mg/dl, respectively, P < 0.05). Pretransplant IL-10 responses were significantly associated with the occurrence of acute rejection episodes (P = 0.001) and impaired 1-year graft function (P < 0.001). All 14 patients with low pretransplant IL-10 responses (< 100 pg/ml) had 1-year serum creatinine values of < 1.5 mg/dl. Pretransplant B-cell defects and B cell/monocyte-derived cytokine secretion were not related to the incidence of graft rejection or infectious complications. Pretransplant CD8 suppressor-effector (CD11b+), cell counts were significantly associated with the occurrence of infections (P < 0.05). These results show that pretransplant CD4 helper defects and low IL-10 responses predict a low risk of graft rejection, whereas Th1 (IL-2, gamma-interferon) and B-cell/monocyte responses are not of predictive value.

To define the possible role of the VHL gene in the development of sporadic renal cell carcinomas, 91 different parenchymal tumours of the kidney have been investigated for mutation of the VHL gene by single strand conformation polymorphism (SSCP) and/or heteroduplex (HD) techniques. Chromosome 3p deletion was detected in 98 per cent of non-papillary renal cell carcinomas and in 25 per cent of chromophobe renal cell carcinomas. In 22 of the 43 non-papillary renal cell carcinomas, abnormally migrating DNA bands were detected by SSCP and/or HD analysis. No mobility shift was seen in any of the 23 chromophobe renal cell carcinomas. In addition, 15 papillary renal cell tumours and ten renal oncocytomas, which are characterized by genetic changes other than loss of chromosome 3p sequences, were analysed for mutation of the VHL gene. None of these tumours showed abnormal migration patterns. The results indicate that mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinoma.

This study focuses on the diagnostic and therapeutic challenge posed by spontaneous perirenal haematomas (SPHs). The medical records of 18 patients with SPHs seen in the past 8 years were reviewed with respect to aetiology, diagnosis and therapeutic management. SPH was secondary to angiomyolipoma (n = 4), polycystic kidneys (n =4), panarteritis nodosa (n = 3), renal cell carcinomas (RCCs, n = 2), glomerulonephritis, pyelonephritis, Morbus Wegener and cortical adenoma (one each). One case remained unclear. With appropriate imaging techniques (computed tomography and angiography) the underlying disorder was detected in 72%; in 4 cases the diagnosis was revealed by exploration and biopsy. Surgery was necessary in 16 patients. The cause of bleeding can be revealed by appropriate imaging in most cases. When imaging procedures fail to reveal the cause of SPH, exploration and biopsy are mandatory to exclude RCC. If the cause of SPH remains unclear even after exploration, patient monitoring by CT is justified.

Urinary diversion through intestinal segments is a widely used method after radical cystectomy. During the last few years, new methods of bladder substitution, continent ileal neobladders, were developed. We used the method described by Hautmann et al. in 1986. 70 cm of ileum is used to form a reservoir. The ureters are implanted into the reservoir, which is then anastomosed to the urethral stump. A known problem when intestine is used for urinary diversion is the absorption of urinary solutes leading to metabolic disturbances. Therefore, the absorption of vitamin B12, instilled into the neobladders of 20 patients, was measured and related to the postoperative interval. The results show a high absorption rate 2 weeks postoperatively that is reduced quickly and significantly (p < 0.001) within the first 10 months (from more than 30 to below 5%). One year to 23 months after the operation, some neobladders absorbed no vitamin B12 at all, whereas others still absorbed significantly but only small quantities. These results may probably be attributed to the loss of villous structure as well as atrophy of the epithelial surface.