[Real-life experiences with Brolucizumab in recalcitrant neovascular age-related macular degeneration]. / Erste Erfahrungen mit Brolucizumab bei neovaskulärer altersabhängiger Makuladegeneration und Therapierefraktärität unter der bisherigen Anti-VEGF-Therapie.

BACKGROUND: Pivotal clinical trials have proven brolucizumab to be a potent intravitreal anti-vascular endothelial growth factor (VEGF) drug in patients with neovascular age-related macular degeneration (nAMD). Therefore, it seems to be a promising drug also in patients with recalcitrant nAMD. This article presents the results of patients who were switched to brolucizumab due to persistent fluid under previous anti-VEGF treatment. METHODS: In this study 21 eyes were retrospectively analyzed in which treatment was switched to brolucizumab due to persistent intraretinal (IRF), subretinal (SRF) and/or sub-retinal pigment epithelium (sub-RPE fluid) fluid despite long-term anti-VEGF treatment. Functional and spectral domain optical coherence tomography (SD-OCT) data were investigated at diagnosis of nAMD (I), at switch to brolucizumab (II), 4 weeks after upload of brolucizumab (III) and at first reactivation of macular neovascularization (MNV, IV). RESULTS: There were no significant changes in fluid distribution between (I) and (II). After upload of brolucizumab (III) a significant reduction of central subfield retinal thickness (CSRT, p = 0.0001), SRF (p = 0.004) and sub-RPE fluid (p = 0.04), but no visual acuity improvement (p = 0.56) were observed. CONCLUSION: Intravitreal brolucizumab treatment can achieve significant reductions particularly of SRF and sub-RPE in patients refractory to previous anti-VEGF treatment. Future studies should further investigate the effects of brolucizumab in patients with recalcitrant nAMD.

[Treatment adherence and effectiveness of anti-Vascular Endothelial Growth Faktor(VEGF) treatment of diabetic macular edema in the clinical routine : Comparison between cooperative and unicentric organization of treatment]. / Therapieadhärenz und Effektivität bei der Anti-Vascular Endothelial Growth Faktor(VEGF)-Therapie des diabetischen Makulaödems im klinischen Alltag : Vergleich zwischen einer kooperativen und einer unizentrischen Organisation der Behandlung.

BACKGROUND: Intravitreal injection of anti-vascular endothelial growth factor (VEGF) is an established method for treatment of diabetic macular edema (DME); however, to ensure the best possible functional results continuous treatment of patients over a long period with regular control visits are necessary. The adherence of patients to the treatment is of great importance for success. METHODS: In order to make implementation of treatment easier for patients, an internet-based referral platform was established to enable the follow-up examination to be performed by an ophthalmologist using spectal domain optical coherence tomography (SD-OCT) close to the patients place of residence. Based on 50 patients the effectiveness of this cooperative treatment (IT-Cooperation) was compared to 50 patients who were controlled in the treatment center for DME patients over a period of 2 years. RESULTS: Patients in the IT-Cooperation group received an average of 6.3 injections in the first year of follow-up compared to the lower number of 5.2 injections for patients attending the treatment center. During the second year the average number of injections decreased to 2.7 (IT-Cooperation) and 2.4 (treatment center). Patients of the IT-Cooperation showed an average of 12.0 control visits in contrast to the average number of 9.6 visits (p < 0.01) for patients attending the treatment center in the first year of observation. This difference between the two groups was significant and was confirmed in the second year of follow-up with 8.3 visits in the IT-Cooperation group compared to 4.4 visits in the treatment center group (p < 0.01). CONCLUSION: The greater number of follow-up examinations close to the patient's place of residence for the IT-Cooperation group significantly improved the quality of treatment adherence in DME patients; however, intensive exchange of information between the ophthalmologist performing the control examinations and the treatment center where the injections were carried out is mandatory.

[The heart catheter table is not the operating table : Intraindividual comparison of pulmonary artery pressures]. / Der Herzkathetertisch ist nicht der OP-Tisch : Intraindividueller Vergleich der pulmonalarteriellen Druckwerte.

BACKGROUND: Patients undergoing cardiac surgery need extensive and invasive monitoring, which needs to be individually adapted for each patient and requires a diligent risk-benefit analysis. The use of a pulmonary artery catheter (PAC) seems to be justifiable in certain cases; therefore, the preoperative diagnosis of pulmonary hypertension represents an indication for perioperative monitoring with PAC in the S3 guidelines of the German Society for Anesthesiology and Intensive Care Medicine (DGAI). In many cases, however, this preoperative diagnosis cannot be confirmed intraoperatively. OBJECTIVE: We wanted to find out whether this is just an impression or whether there actually are significant differences between preoperative, intraoperative and postoperative pulmonary artery pressures. MATERIAL AND METHODS: After obtaining ethical approval, we retrospectively compared the pulmonary pressures of cardiac surgery patients with an elevated pulmonary pressure during preoperative right heart catheterization with those obtained intraoperatively and postoperatively by means of a PAC. All patients with a preoperatively documented pulmonary artery pressure of 40 mmHg or above and an intraoperative use of a PAC during a 4-year period were included. Exclusion criteria were intracardiac shunts, cardiogenic shock, emergency procedures, pulmonary hypertension of non-cardiac origin and a time span of more than 1 year between right heart catheterization and surgery. We included 90 patients. RESULTS: In the whole group and in the subgroups (according to diagnosis, time elapsed between heart catheterization and operation and pulmonary pressure), there were significant differences between preoperative and intraoperative pulmonary and systemic pressures. Systemic and pulmonary artery pressures were significantly higher during preoperative catheterization than intraoperatively. The systemic systolic pressure/systolic pulmonary pressure ratio, however, remained constant. The intraoperative and postoperative systemic and pulmonary artery pressures showed no significant differences. As a normal ejection fraction does not exclude heart failure with preserved ejection fraction and as we did not have any information on this condition, we did not group the patients according to the ejection fraction. CONCLUSION: An elevated pulmonary pressure obtained preoperatively during right heart catheterization is not indicative of an elevated pulmonary pressure either intraoperatively or postoperatively. There are various explanations for the differences (e.g., different physiological and pathophysiological settings, such as sedation with potential hypercapnia versus anesthesia with vasodilation when measured; newly prescribed medication coming into effect between the right heart catheterization and surgery; intraoperative positioning). Even though the inherent risks of a PAC seem to be low, we recommend refraining from using a PAC in patients with a once documented elevated pulmonary pressure by default. As an alternative we suggest estimating the pulmonary pressure by transesophageal echocardiography (TEE) as an aid to decide whether the patient will benefit from the use of a PAC. Especially if it is not possible to identify tricuspid valve regurgitation for determining the peak gradient, it is helpful to check for additional signs of pulmonary hypertension. But we also have to bear in mind that in the postoperative period only a PAC can provide continuous measurement of pulmonary pressure.

Dose calculation and verification of the Vero gimbal tracking treatment delivery.

The Vero linear accelerator delivers dynamic tumor tracking (DTT) treatment using a gimbal motion. However, the availability of treatment planning systems (TPS) to simulate DTT is limited. This study aims to implement and verify the gimbal tracking beam geometry in the dose calculation. Gimbal tracking was implemented by rotating the reference CT outside the TPS according to the ring, gantry, and gimbal tracking position obtained from the tracking log file. The dose was calculated using these rotated CTs. The geometric accuracy was verified by comparing calculated and measured film response using a ball bearing phantom. The dose was verified by comparing calculated 2D dose distributions and film measurements in a ball bearing and a homogeneous phantom using a gamma criterion of 2%/2 mm. The effect of implementing the gimbal tracking beam geometry in a 3D patient data dose calculation was evaluated using dose volume histograms (DVH). Geometrically, the gimbal tracking implementation accuracy was <0.94 mm. The isodose lines agreed with the film measurement. The largest dose difference of 9.4% was observed at maximum tilt positions with an isocenter and target separation of 17.51 mm. Dosimetrically, gamma passing rates were >98.4%. The introduction of the gimbal tracking beam geometry in the dose calculation shifted the DVH curves by 0.05%-1.26% for the phantom geometry and by 5.59% for the patient CT dataset. This study successfully demonstrates a method to incorporate the gimbal tracking beam geometry into dose calculations. By combining CT rotation and MU distribution according to the log file, the TPS was able to simulate the Vero tracking treatment dose delivery. The DVH analysis from the gimbal tracking dose calculation revealed changes in the dose distribution during gimbal DTT that are not visible with static dose calculations.

[Visual acuity in anti-VEGF therapy for AMD : Can specific characteristics in the SD-OCT help?] / Visusprognose bei der Anti-VEGF-Therapie der AMD : Können spezifische Charakteristika im SD-OCT weiterhelfen?

BACKGROUND: The efficacy of anti-VEGF therapy in exudative AMD has been established in several large clinical trials using a fixed injection regimen as well as a SD-OCT-based PRN regimen. In these studies, after the first three injections, an increase of the mean visual acuity was observed, which could be stabilized with constant treatment for up to 24 months. However, the specific course of the visual acuity is very different between individuals. The aim of the present study was to correlate specific initial SD-OCT parameters with the course of visual acuity in order to characterize factors that may be important for the individual visual prognosis. PATIENTS AND METHODS: In a prospective case study, the visual course and SD-OCT changes of 156 patients with minimum follow-up of 12 months (mean 80.1 months) were analysed. Visual acuity (LogMar) was investigated at regular intervals and correlated with specific SD-OCT parameters (foveal thickness, height of sub-retinal fluid or presence of associated PED, presence of intra-retinal cysts, length of IS/OS break, choroidal thickness). RESULTS: The initial increase in visual acuity could be stabilized over time. This effect was associated with a decrease in foveal retinal thickness, which also persisted over time. While sub-retinal fluid, presence of PED, and choroidal thickness showed no prognostic relevance for the change in visual acuity, the presence of more advanced central retinal thickness, of intra-retinal cysts or a longer break in the IS/OS junction were associated with a less favourable development of visual acuity. CONCLUSION: In the present study, the presence of more advanced central retinal thickness, of intra-retinal cysts or a larger IS/OS break correlated significantly with a worse visual prognosis. These might be clinical signs for more extensive pre-existing intra-retinal changes. Further analysis and new diagnostic tools may prove this and may result in specific additive neuroprotective or regenerative therapeutic approaches in exudative AMD.

[Compliance of age related macular degeneration patients undergoing anti-VEGF therapy : Analysis and suggestions for improvement]. / Compliance von Patienten mit altersabhängiger Makuladegeneration unter Anti-VEGF-Therapie : Analyse und Verbesserungsvorschläge.

BACKGROUND: Activity-based treatment regimens with anti-vascular endothelial growth factor (anti-VEGF) are currently the gold standard for treatment of exudative age-related macular degeneration (nAMD). Whereas injection frequencies of approximately seven injections in the first year and six in the second year are expected with a pro re nata (PRN) regimen, retrospective real life observations have recorded significantly reduced numbers of injections. This study was carried out to investigate the reasons for the reduction in follow-up control appointments and to find out whether a telemedicine network could influence the motivation and compliance for regular control examinations and treatment. MATERIAL AND METHODS: The patient collective included 210 eyes from 191 patients with nAMD treated by anti-VEGF therapy in 2010 and 2011. The activity-based anti-VEGF treatment, control examinations and treatment intervals were performed according to the guidelines over a mean follow-up of 2 years. In another collective of 100 eyes from 100 patients with treatment of nAMD 2 groups were observed: 1 group with patients for whom control examinations were carried out close to home including an online transmission of the results to the treating retinal center and another group in which the patients had to be examined in the treatment center. RESULTS: After 140 weeks 50 % of the patients in the first collective regularly attended control examinations and after 1 year the number was 79 %. After 2 years the probability of continuous supervision is given for only 62 % of the patients, whereas in 38 % the treatment was terminated. Of these patients treatment was terminated in 8 % due to valid criteria, whereas in 30 % of the patients the termination was unintentional. The main reason (38 %) for an unintentional termination of examination and treatment was the frequent and long journey. Patients in the second collective had a significantly higher compliance with respect to the control examinations (p < 0.001) and number of injections (p = 0.02) over the period of nearly 2 years due to the introduction of electronic transmission of images. CONCLUSION: A long-term therapy of nAMD in the clinical routine can be achieved by a close relationship with the ophthalmologist, continuous follow-up controls and therapy cycles. A close telemedical networking between the ophthalmologist and the treatment center can lead to better patient compliance. Furthermore, the construction of such platforms represents a challenge not only for the treatment of nAMD but also for other diseases.

An exploratory study investigating the metabolic activity and local cytokine profile in patients with melanoma treated with pazopanib and paclitaxel.

BACKGROUND: There is a medical need for new drugs in patients with BRAF wild-type metastatic melanoma. Pazopanib is a multitarget tyrosine kinase inhibitor with antitumour and antiangiogenic activity. OBJECTIVES: The primary aim was to investigate the metabolic response to pazopanib monotherapy and pazopanib plus paclitaxel in patients with BRAF wild-type melanoma. Secondary end points were the early cytokine and chemokine profiles and histological findings. METHODS: Pazopanib (400 mg twice daily) was administered orally from days 1 to 10 and from days 14 to 70. An intravenous infusion with paclitaxel (150 mg m-2 body surface) was administered on days 14, 35 and 56. Metabolic response evaluation was performed before treatment, after treatment with pazopanib (day 10) and after treatment with pazopanib and paclitaxel (day 70). Skin biopsy of metastatic tissue for chemokine and cytokine expression analysis and histology and immunohistochemistry (CD68, CD163) evaluation, and blood samples were taken at the same time points. RESULTS: Two patients failed screening and 17 were dosed. Of 67 adverse events, nine (13%) were grade 3 or 4. Five of 14 evaluable patients had a partial metabolic response at day 10 under pazopanib monotherapy. The response rate at day 70 under combined pazopanib-paclitaxel treatment was 0%. Immunohistochemistry revealed an increase of M2-like macrophages in nonresponders compared with responders. We observed a significant upregulation of five cytokines (CXCL1, CXCL2, CXCL13, CCL22 and SPP1) in responding vs. nonresponding lesions. Overall, the median progression-free survival was 70 days (range 5-331), which did not differ significantly between responders (148 days) and nonresponders (70 days, P = 0·17). CONCLUSIONS: In this patient population pazopanib efficacy was limited. Response is associated with low M2-like macrophage density and increased expression of several chemokines.

[Change of therapy from ranibizumab to aflibercept for recurrent or persistent exudative age-related macular degeneration]. / Therapiewechsel von Ranibizumab zu Aflibercept bei rezidivierender oder persistierender exsudativer altersbedingter Makuladegeneration.

BACKGROUND: Even during consistent anti-vascular endothelial growth factor (VEGF) therapy a reactivation of exudative age-related macular degeneration (AMD) lesions can be observed in many patients. The present case series examined whether a switch from ranibizumab to aflibercept is safe and whether differences in potency can be observed. PATIENTS AND METHODS: In 56 consecutive patients with recurrent activity of AMD according to the morphological criteria of the spectral domain optical coherence tomography (SD-OCT) examination, a change to aflibercept was made after 6-41 (mean 18.9, SD 6.3) injections with ranibizumab. In all controls and before each injection logMAR visual acuity was measured and a SD-OCT (volume scan) was performed in addition to the clinical examination. RESULTS: The mean visual acuity was stable under both therapies. The analysis of the morphological parameters showed a greater reduction of the retinal thickness after the change in therapy (mean retinal thickness within 1000 µm and central foveal thickness) compared to the initial treatment. The changes in the subretinal fluid as well as the height of an associated pigment epithelial detachment (PED) did not show any significant differences. The analysis of the morphological parameters at the level of the photoreceptors showed a decrease in discontinuity in the ellipsoid layer and also in the external limiting membrane (ELM). CONCLUSION: In patients with recurrent or high SD-OCT-based activity of exudative AMD lesions, a switch of the treatment strategy from ranibizumab to aflibercept can achieve a new functional stability in spite of multiple pretreatment. We found morphological indications of a regression of intraretinal edema and improvement in the photoreceptor area. In the context of a well-defined treatment strategy, a switch from anti-VEGF therapy to a similar active substance is safe. Before a definitive evaluation can be made, prospective controlled conditions are required to verify the clinical benefits of the switch.

The recombinant bifunctional protein αCD133-GPVI promotes repair of the infarcted myocardium in mice.

BACKGROUND: Bone-marrow-derived progenitor cells are important in myocardial repair mechanisms following prolonged ischemia. Cell-based therapy of diseased myocardium is limited by a low level of tissue engraftment. OBJECTIVES: The aim of this study was the development of the bifunctional protein αCD133-glycoprotein (GP)VI as an effective treatment for supporting vascular and myocardial repair mechanisms. RESULTS: We have generated and characterized a bifunctional molecule (αCD133-GPVI) that binds both to the subendothelium of the injured microvasculature and to CD133(+) progenitor cells with high affinity. αCD133-GPVI enhances progenitor cell adhesion to extracellular matrix proteins and differentiation into mature endothelial cells. In vivo studies showed that αCD133-GPVI favors adhesion of circulating progenitor cells to the injured vessel wall (intravital microscopy). Also, treatment of mice undergoing experimental myocardial infarction with αCD133-GPVI-labeled progenitor cells reduces infarction size and preserves myocardial function. CONCLUSIONS: The bifunctional trapping protein αCD133-GPVI represents a novel and promising therapeutic option for limiting heart failure of the ischemic myocardium.

Alignment of training curriculum and surgical practice: implications for competency, manpower, and practice modeling.

OBJECTIVE: The attractiveness of pediatric surgery (PS) as a specialty includes its primary role in the care of multisystemic disease. We were interested in identifying changes in operative case quality and quantity when comparing PS residents to PS practitioners. METHODS: The 2006 Accreditation Council for Graduate Medical Education PS resident current procedural terminology (CPT) code database (26,077 resident cases) was merged with the 2006 Kids' Inpatient Database of International Classification of Diseases (ICD)-9 procedure codes (230,504 practitioner cases) and categorized by case type and volumes according to a resident CPT reference file. Cases were categorized into 84 procedure types. A recent estimate of 691 practicing pediatric surgeons was used as denominator to calculate case volume per surgeon. Our analysis focused on the PS index cases and we compared PS residents to subspecialty board certified general pediatric surgeons in practice. We excluded cases that may be performed by general surgeons without PS training. RESULTS: Our data indicate that, on average, 501 cases are performed annually by each PS resident. We identified significant differences in case volume per surgeon between training and practice for most PS index cases.CONCLUSIONS The PS index case quantity declined significantly from training to practice. If a volume to outcome relationship applies to these complex and infrequent PS cases, then to sustain and improve clinical quality post-training will require a new paradigm of continued learning. Additionally, a relook at the optimal manpower and more focused regionalization is warranted.

[How physicians inform about colorectal cancer and screening]. / Arztliche Aufklärung über Darmkrebs und Darmkrebsvorsorge.

Screening colonoscopy is an efficient and safe instrument for the early detection of colonic neoplasia. The cumulative participation rate in Germany remains low with 15.5% of eligible men and 17.2% of eligible women. Reasons for this are not well understood. Especially physicians have an important role. The aim of this study was to analyse information and recommendations of primary care physicians, urologists and gynaecologists on colorectal cancer screening. A survey of 239 primary care physicians, urologists and gynaecologists by a structured questionnaire on information concerning colorectal cancer and colorectal cancer prevention was carried out. Statistical analysis was performed by pair-wise comparison of the three groups. There were only small differences between primary care physicians, urologists and gynaecologists. Primary care physicians offer patients more consulting time for this information than the other two groups. In the majority of cases colonoscopy is recommended. Gynaecologists less often recommend the classical guaiac-based faecal occult blood test, but more frequently immunochemical tests. The complication rate of colonoscopy is overestimated at 1.25% (0 - 40%). The majority of physicians have previously participated in colorectal cancer screening. Information about the risk of colorectal cancer and screening has a high priority. The level of knowledge of physicians may be improved.

Acceleration of chronic myeloproliferation by enforced expression of Meis1 or Meis3 in Icsbp-deficient bone marrow cells.

Identifying genetic pathways that cooperate in leukemogenesis facilitates our understanding of the molecular mechanisms at play. Interferon consensus sequence-binding protein (ICSBP) is a tumor suppressor, whose downregulation cooperates with BCR-ABL and NUP98-TOP1 gene products to accelerate leukemia induction in mouse models. Similarly, Meis1 synergizes with HoxA9 or NUP98-HOX (but not NUP98-TOP1) fusion genes to promote the early onset of leukemia. To investigate whether Icsbp deficiency interacts with Meis1 or its family member Meis3, we transplanted Icsbp(-/-) bone marrow (BM) cells after transduction with Meis1 or Meis3 retroviral vectors. Here, we show that enforced expression of Meis1 or Meis3 in Icsbp(-/-) BM cells induces a fatal, invasive myeloproliferative disease. Secondary mutations, such as activation of Mn1, led to the progression to acute myeloid leukemia in a few mice. Interestingly, expression of endogenous Meis1 and Meis3 mRNAs was repressed in the granulocytic progenitor population of Icsbp(-/-) mice. These results reveal a novel collaboration between Icsbp deficiency and Meis1/Meis3 in the acceleration of chronic myeloid leukemia-like disease.

Elective nephron sparing surgery should become standard treatment for small unilateral renal cell carcinoma: Long-term survival data of 216 patients.

OBJECTIVES: Our experiences with elective nephron-sparing surgery (NSS) for renal cell carcinoma (RCC) in a consecutive series of 216 patients are presented. Clinicopathological features and long-term oncological outcome is compared to patients treated with radical nephrectomy (RN). METHODS: Between 1975 and 2002, NSS was performed in 488 patients; 311 of these patients had elective indications. Renal cell carcinoma was found in 241/311 patients (77.5%). Long-term follow up data could be obtained in 216/311 patients. Cancer-specific survival was estimated using the Kaplan-Meier method. Cox's regression analysis and log-rank tests were used to evaluate independent predictive values of different clinicopathological features. Survival data of the 216 patients after NSS surgery were compared to 369 patients with small RCC treated with RN. RESULTS: After a mean follow up of 66 months (median 64 months) 29 (13.4%) of 216 patients treated with NSS had died, 4 of them (1.8%) tumour-related. Tumour recurrence was detected in 12 patients (5.6%). 204 patients (94.4%) were free of tumour at last follow-up. Cancer specific survival rates at 5 and 10 years for patients treated with NSS (RN) were 97.8% (95.5%) and 95.8% (84.4%). CONCLUSIONS: Elective NSS surgery provides optimal long-term outcome in patients with small localized RCC. Compared to RN, renal parenchyma is preserved without any disadvantage in survival rates. Consequently elective NSS should be accepted as gold standard for small renal tumours.

Contributions of the sympathetic nervous system, glutathione, body mass and gender to blood pressure increase with normal aging: influence of heredity.

Body mass and sympathetic activity increase with aging and might underlie blood pressure (BP) elevation. Increased body mass index (BMI) may elevate BP by increasing sympathetic activity. Glutathione (GSH) can decrease BP, and declines with aging. We measured systolic (SBP) and diastolic BP, BMI, plasma (NE(pl)) and urine norepinephrine (NEu), and plasma GSH in n=204 twins across the age spectrum. BP correlated directly with BMI, NEpl, and NEu, but inversely with GSH. Age correlated with BP, BMI, NEpl, and NEu. BP, BMI, NEpl, and NEu were higher in older subjects than younger subjects, whereas GSH was lower with aging. In older subjects with high (above median) NEpl, SBP was 8 mmHg higher than in those of comparable age with low NE. In younger subjects with high GSH, BP was significantly lower than in younger subjects having low GSH. NEu was significantly reduced in young high-BMI subjects vs young low-BMI subjects. The heritability (h2) of NEpl, NEu, and GSH ranged from approximately 50 to approximately 70%, and these biochemical quantities were considerably more heritable than BP. We conclude that increases in sympathetic activity contribute to aging-induced SBP elevations, especially in older females. GSH reductions apparently participate in aging-induced BP elevations, most strongly in males. BMI increases contribute to BP elevations, particularly in younger subjects. BMI elevations apparently raise BP mainly by peripheral mechanisms, with generally little sympathetic activation. Substantial h(2) for plasma GSH, NE, and urine NE suggests that such traits may be useful 'intermediate phenotypes' in the search for genetic determinants of BP.

Transition from initiation to promoter proximal pausing requires the CTD of RNA polymerase II.

The C-terminal domain (CTD) of mammalian RNA polymerase II consists of 52 repeats of the consensus hepta-peptide YSPTSPS, and links transcription to the processing of pre-mRNA. Although Pol II with a CTD shortened to five repeats (Pol II Delta5) is transcriptionally inactive on chromatin templates, it is not clear whether CTD is required for promoter recognition in vivo. Here, we demonstrate that in the context of chromatin, Pol II Delta5 can bind to the c-myc promoter with the same efficiency as wild type Pol II. However, Pol II Delta5 does not form a stable initiation complex, and does not transcribe promoter proximal sequences. Fluorescence recovery after photobleaching (FRAP) experiments with cells expressing enhanced green fluorescent protein (EGFP)-tagged Delta5 or wildtype Pol II revealed a single, highly mobile Pol II Delta5 fraction whereas wildtype Pol II yielded less mobile fractions. These data suggest that CTD is not required for promoter recognition, but rather for subsequent formation of a stable initiation complex and isomerization to an elongation competent complex.

[Exercise therapy as a therapeutic concept]. / Bewegungstherapie als therapeutisches Prinzip.

Lack of exercise is a primary cause for today's level of morbidity and mortality in the Western world. Thus, exercise as a therapeutic modality has an important role. Beneficial effects of exercise have been extensively documented, specifically in primary and secondary prevention of coronary heart disease (CHD), diabetes mellitus, hypertension, disorders of fat metabolism, heart insufficiency, cancer, etc. A regular (at least 3 x per week) endurance training program of 30-40 min duration at an intensity of 65-70% of VO(2)max involving large muscle groups is recommended. The specific exercise activity can also positively affect individuals with orthopedic disease patterns, i.e., osteoporosis, back pain, postoperative rehabilitation, etc. Endurance strength training in the form of sequential training involving approx. 8-10 different exercises for the most important muscle groups 2 x per week is a suitable exercise therapy. One to three sets with 8-12 repetitions per exercise should be performed until volitional exhaustion of the trained muscle groups among healthy adults and 15-20 repetitions among older and cardiac patients. Apart from a positive effect on the locomotor system, this type of strength training has positive effects on CHD, diabetes mellitus, and cancer.

Current TNM classification of renal cell carcinoma evaluated: revising stage T3a.

PURPOSE: : Recent studies of rare cases of pT3a renal cell carcinoma extending directly into the adrenal gland showed worse survival than in other pT3a cases and recategorization as stage pT4 was suggested. We assessed the prognostic validity of a stage pT3a diagnosis based on perirenal fat infiltration. MATERIALS AND METHODS: : The records of 1,794 patients with renal cell carcinoma who underwent surgical resection between 1975 and 2000 at our institution were analyzed retrospectively. Focusing on pT3a tumors, as defined by perirenal fat infiltration, numerous clinical and histopathological parameters were investigated by univariate and multivariate statistical methods with cancer specific survival as the primary end point. RESULTS: : We identified 237 of 1,794 patients with perirenal fat infiltration, classified as having pT3a disease. In patients with pT3a tumors tumor size was a significant parameter predicting survival. The most significant cutoff value for tumor size in pT3a disease was 7 cm. Patients with distant metastasis had a worse prognosis independent of T classification. Therefore, to assess the prognostic value of the current T classification in regard to T3a tumors we excluded patients with tumor stage cM+ for further subgroup analysis. Survival comparison of pT1 pNall, cM0 (744 of 1,794 cases) and pT3a pNall, cM0 7 cm or less (100 of 237) as well as pT2 pNall, cM0 (265 of 1,794) and pT3a pNall, cM0 greater than 7 cm (93 of 237) yielded similar results. After splitting pT3a into a modified T1/T2 classification a significant difference in 5-year survival analysis for a modified T1/T2 stage was found (pT1 plus pT3a less than 7 cm 90% vs pT2 plus pT3a greater than 7 cm 73%, p <0.001). Subsequently multivariate analysis in all 1,794 patients showed that modified T stage was an independent significant predictor of cancer specific survival. CONCLUSIONS: : We suggest revising the current pT3a classification based on perirenal fat infiltration but rendering a modified pT1/pT2 classification, which resolves pT3a cases without the loss of prognostic validity. Perirenal fat infiltration should not be used to assign T category. Tumors directly infiltrating the adrenal gland should be reclassified as T4.

[Glossary on patient safety -- a contribution to on-target-definition and to appreciate the subjects of "patient safety"]. / Das Glossar Patientensicherheit -- Ein Beitrag zur Definitionsbestimmung und zum Verständnis der Thematik "Patientensicherheit" und "Fehler in der Medizin".

Since the release of the report "To Err is Human" by the American Institute of Medicine (IOM) the subject "Medical Risks, Errors and Patient Safety" has gained increasing interest in literature. In Germany, neither extensive statistics nor generally significant epidemiological studies regarding common errors associated with damages caused to patients' health exist. In recent years the subject has become increasingly interesting both in specialist discussion and it the lay press; it has become evident that the different use of terms, especially those originating from the Anglo-Saxon language, can lead to misunderstandings. Hence, as one of the first steps of its action programme, the expert panel "Patient Safety" of the German Agency for Quality in Medicine has compiled a glossary of technical terms to provide adequate support to the discussion this important subject of nomenclature.

Adrenal metastases in 1635 patients with renal cell carcinoma: outcome and indication for adrenalectomy.

PURPOSE: Routine removal of the ipsilateral adrenal gland in patients with renal cell carcinoma who undergo nephrectomy has been a matter of dispute. In a retrospective study we screened for subgroups of patients with renal cell carcinoma from a large single center patient population who may have benefited from ipsilateral adrenalectomy. MATERIALS AND METHODS: Radical nephrectomy was performed in 1635 patients at a single institution between 1980 and 2000. A total of 1010 patients underwent radical nephrectomy plus ipsilateral adrenalectomy, whereas in 625 no simultaneous adrenalectomy was performed. Numerous clinical and histopathological parameters were investigated by univariate and multivariate statistical methods for their predictive value in regard to cancer specific survival. RESULTS: Metastases in the adrenal gland were found in 5.5% of patients (56 of 1010) undergoing nephrectomy with adrenalectomy. Of 30 patients with adrenal metastasis and preoperative computerized tomography/magnetic resonance imaging 23 were found to have histological evidence of cancer, approaching a false-negative rate of 23.3%. All patients with false-negative computerized tomography/magnetic resonance imaging had a primary tumor of greater than 4 cm. Patients with adrenal metastases predominately had pT3 or greater tumor stage (82%). Cancer specific survival rates (75% vs 73% for adrenalectomy vs no adrenalectomy) and postoperative complications rates (7% vs 8%) did not differ significantly between the 2 groups. The prognosis in patients with a solitary adrenal metastasis (18 of 56) was more favorable than in patients with additional metastatic sites (38 of 56). CONCLUSIONS: Adrenal metastases from primary renal cell carcinoma were found significantly more often in patients with advanced tumor stages. Ipsilateral adrenalectomy should be recommended for all resectable renal cell carcinoma with a primary tumor of greater than 4 cm or with nonorgan confined tumor stages (T3 or greater) since a false-negative rate of about 20% can be expected with current imaging techniques.