M. Schenck

Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide

Wilson disease is caused by accumulation of Cu2+ in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu2+ triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu2+-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu2+ induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.

Ceramide-induced cell death in malignant cells

Ceramide has been shown to be capable to trigger apoptosis in almost any cell, including tumor cells. Ceramide is generated by a de novo pathway or by sphingomyelinases. Sphingomyelinases hydrolyze sphingomyelin in biological membranes to release ceramide and they are named acid, neutral and alkaline sphingomyelinase depending on their maximum activity at acid, neutral and alkaline pH values, respectively. Stimuli that trigger a release of ceramide to mediate apoptosis include CD95, TNF-receptor, DR5, gamma-irradiation, cytotoxic drugs, UV-light, bacteria, viruses, some forms of developmental death, anti-CD20 and disruption of the cells contact with its matrix, to name a few. Here, we will focus on the role of acid sphingomyelinase in malignant tumors, which function in apoptosis is best characterized and documented by genetic models. We will discuss concepts that unify the biological actions of ceramide and describe the role of ceramide in important anti-tumor treatment modalities, such as gamma-irradiation and chemotherapy.

Rolle der Lymphadenektomie bei Patienten mit invasivem Urothelkarzinom der Harnblase

High-grade urothelial carcinomas of the bladder represent high-risk tumors and despite radical surgery and pelvic lymph node dissection patients have a lifelong risk for tumor progression and metastases. Since extended lymph node dissection detected metastases outside the fields of normal pelvic lymphadenectomy, it was concluded that all patients undergoing radical cystectomy should receive extended lymph node dissection. The article reviews published data discussing the question of whether lymph node dissection has prognostic or therapeutic relevance.ZusammenfassungDas High-grade-Urothelkarzinom der Harnblase stellt für den Patienten ein Hochrisikotumor dar. Selbst durch die radikale Zystektomie und pelvine Lymphadenektomie weisen Patienten mit invasiven Harnblasenkarzinomen ein hohes Risiko für eine lymphogene und hämatogene Metastasierung auf. Die Tatsache, dass bei extendierter Lymphadenektomie lymphogene Metastasen außerhalb der Grenzen der normalen pelvinen Lymphadenektomie gefunden wurden, legt nahe, allen Patienten eine extendierte Lymphknotendissektion zukommen zu lassen. In der vorliegenden Arbeit werden publizierte Daten zu dieser Thematik zusammengefasst, die die Frage nach der prognostischen und der therapeutischen Bedeutung der Lymphkontendissektion im Rahmen der radikalen Zystektomie bearbeiten.AbstractHigh-grade urothelial carcinomas of the bladder represent high-risk tumors and despite radical surgery and pelvic lymph node dissection patients have a lifelong risk for tumor progression and metastases. Since extended lymph node dissection detected metastases outside the fields of normal pelvic lymphadenectomy, it was concluded that all patients undergoing radical cystectomy should receive extended lymph node dissection. The article reviews published data discussing the question of whether lymph node dissection has prognostic or therapeutic relevance.

[The revival of "uroscopy": an easy way to evaluate the anastomotic region after radical retropubic prostatectomy].

OBJECTIVE The cystogram after retropubic radical prostatovesiculectomy (RRP) examines the condition of the anastomosis region. There is no clear temporal recommendation for the determination of urine extravasation in cases of early removal of the catheter. This study investigates the macroscopic and microscopic examination of the bladder catheter urine after RRP. PATIENTS AND METHODS The catheter urine of 110 patients after RRP was macroscopically and microscopically examined and compared with the results of transrectal ultrasound and cystogram with regard to urine extravasation. RESULTS The examination of cloudy or bloody catheter urine indicated an extravasation in 32 of 33 cases (positive predictive value 97%; sensitivity 74%), for clear urine, there was sufficient anastomosis in 66 of 77 cases without any extravasation (negative predictive value 86%; specificity 99%). By performing a microscopic urine analysis unremarkable anastomosis was predicted only in 23 of 67 cases, which leads to a specificity of 34%. This shows that microscopic urine sediment is an inappropriate instrument to evaluate the anastomotic region. CONCLUSION In cases of macroscopic pathological urine findings, further diagnostics are not recommended; in 97% of the cases, extravasation is expected. The macroscopic urine examination sets a trend for other examinations like cystogram or dynamic transrectal ultrasound (dTRUS).

Die Wiedergeburt der „Harnschau“

OBJECTIVE The cystogram after retropubic radical prostatovesiculectomy (RRP) examines the condition of the anastomosis region. There is no clear temporal recommendation for the determination of urine extravasation in cases of early removal of the catheter. This study investigates the macroscopic and microscopic examination of the bladder catheter urine after RRP. PATIENTS AND METHODS The catheter urine of 110 patients after RRP was macroscopically and microscopically examined and compared with the results of transrectal ultrasound and cystogram with regard to urine extravasation. RESULTS The examination of cloudy or bloody catheter urine indicated an extravasation in 32 of 33 cases (positive predictive value 97%; sensitivity 74%), for clear urine, there was sufficient anastomosis in 66 of 77 cases without any extravasation (negative predictive value 86%; specificity 99%). By performing a microscopic urine analysis unremarkable anastomosis was predicted only in 23 of 67 cases, which leads to a specificity of 34%. This shows that microscopic urine sediment is an inappropriate instrument to evaluate the anastomotic region. CONCLUSION In cases of macroscopic pathological urine findings, further diagnostics are not recommended; in 97% of the cases, extravasation is expected. The macroscopic urine examination sets a trend for other examinations like cystogram or dynamic transrectal ultrasound (dTRUS).

Prinzipielle Probleme der Lymphknotenchirurgie

M. Schenck1, 3 · G. Lüm men1, 3 · M. Stusch ke2, 3 · K. W. Schmid4 · H. Rüb ben1, 3 1 Kli nik für Uro lo gie, Kin der u ro lo gie und Uroon ko lo gie, Uni ver si täts kli ni kum, Es sen 2 Kli nik für Strah len the ra pie, Uni ver si täts kli ni kum, Es sen 3 In ter dis zi pli näre Ra dio-Uro-On ko lo gie, Uni ver si täts kli ni kum, Es sen 4 In sti tut für Pa tho lo gie, Uni ver si täts kli ni kum, Es sen

Die Patientenaufklärung zur Prostatakarzinomfrüherkennung ist unzureichend

Men that undergo an early detection investigation should be informed of the advantages and disadvantages as well as of the therapeutic consequences. In this study the quality of information was checked using the state of scientific knowledge of the patients.An informative consultation was carried out before the early detection investigation using a clarification brochure and an examination by a urologist. A questionnaire was also filled out after the investigation. A total of 1,536 men were questioned. Although 47% of the men had previously undertaken a PSA at least once, only 55% knew their own test result. Subjectively 82% of men felt well informed. In contrast one-third did not know the significance of an increased PSA level. In the field of patient clarification for the early detection for prostate cancer there are considerable deficits but the information received was considered adequate by the participants. However, more than one-third did not understand the significance of the PSA level.

Operative Geschlechtsangleichung im Alter

ZusammenfassungHintergrundDie geschlechtsangleichende Operation (GAO) von Mann zu Frau wird zunehmend auch von den älteren Patientinnen nachgefragt.ErgebnisseNach unserem Kenntnisstand wird hier das erste Mal der Zusammenhang von Alter der Patientinnen und peri- und postoperativem Auftreten von Komplikationen untersucht. Anhand der präsentierten Daten kann gezeigt werden, dass eine altersbezogene Beschränkung für diesen Eingriff aufgrund von peri- und postoperativen Komplikationen nicht gerechtfertigt ist.SchlussfolgerungIndividuell sind Gesundheitsstatus und Selbstversorgungsfähigkeit, sowie körperliche bzw. psychologische Einschränkungen zu berücksichtigen werden, um einen erfolgreichen postoperativen Verlauf und subjektive Zufriedenheit der Patientinnen zu erreichen.AbstractBackgroundGender reassignment surgery (GRS) from male to female is increasingly being requested by older female patients.ResultsTo the best of our knowledge this study has for the first time investigated the correlation between the age of patients and perioperative and postoperative complications. The presented data show that an age-related limitation for this intervention due to perioperative and postoperative complications is not justified.ConclusionHealth status and capability for self-sufficiency as well as physical and psychological limitations must be individually considered in order to achieve a successful postoperative course and a subjective satisfaction of patients.BACKGROUND Gender reassignment surgery (GRS) from male to female is increasingly being requested by older female patients. RESULTS To the best of our knowledge this study has for the first time investigated the correlation between the age of patients and perioperative and postoperative complications. The presented data show that an age-related limitation for this intervention due to perioperative and postoperative complications is not justified. CONCLUSION Health status and capability for self-sufficiency as well as physical and psychological limitations must be individually considered in order to achieve a successful postoperative course and a subjective satisfaction of patients.

Wie sollen Urologen venöse subkutane Portsysteme implantieren

BACKGROUND Since 1999 urologists at the University of Essen in Germany have performed subcutaneous implantation of venous port systems, controlled by intravasal ECG. METHODS Between December 1999 and June 2011 implantation of venous port systems was performed in 241 male (69.5%) and 106 (30.5%) female patients. The port systems were implanted subcutaneously above the pectoralis major muscle under local anesthesia. If it was not possible to isolate the cephalic vein or safe catheter implantation was not feasible, puncture of the subclavian vein was performed. RESULTS The median follow-up was 491.6 days (2-2568), and 163.254 catheter days (mean 239 days, range 2-2604) were documented. During the follow-up period 191 (55.1%) patients died. The mean surgical implantation and explantation time was 36.5 min (14-85 min) and 25.4 min (10-46 min), respectively; 79.7% were implanted and controlled by ECG. Altogether, 390 devices were used in 379 surgical procedures, 355 implantations (91.1%) and 35 explantations (8.9%). Implanted vessels were the cephalic vein in 303 patients (85.6%) and the subclavian vein in 51 (14.4%) patients. Of 35 explanted devices, the explantation was necessary due to complications in 28 (8.0%) cases: infection n=6 (1.7%, 0.036 per 1,000 catheter days), occlusion n=8 (2.3%, 0.049 per 1,000 catheter days), dislocation n=7 (2.0%, 0.042 per 1,000 catheter days), deep vein thrombosis of the upper extremity n=6 (1.7%, 0.037 per 1,000 catheter days), and clotting n=1(0.3%, 0.006 per 1,000 catheter days). Premature catheter removal (<30 days post-op) was required in six cases (1.9%, 0.036 per 1,000 catheter days) due to complications: three catheter dislocations/malfunctions (0.9%, 0.019 per 1,000 catheter days), one port-related infection, one pocket port infection, and one deep vein thrombosis of the upper extremity (0.3%, 0.006 per 1,000 catheter days). Other problems described in the literature like pneumothorax, vein perforation, or pinch-off syndrome did not occur. CONCLUSIONS Implantation of port systems with ECG control of the catheter tip position is related to a few cases of adverse events and good surgical outcomes. Furthermore, it has also shown great advantages in offering immediate support and early therapy initiation with a fast learning curve for the training urologists. The results of the presented analysis are comparable to those of surgical or radiological departments reported in the literature and provide good evidence that this procedure should be extended to urological centers with a high volume of chemotherapy patients.

Molecular aspects of lymph node metastasis

ZusammenfassungBekannt ist, dass mit zunehmender Tumorausdehnung die Wahrscheinlichkeit des Befalls der drainierenden, regionären Lymphknoten zunimmt. Man geht davon aus, dass der Lymphabfluss anatomisch definierten Wegen folgt. Die genauen molekularbiologischen Mechanismen der Bildung neuer Lymphgefäße während der Tumorgenese scheinen komplex zu sein, sodass zzt. noch keine genauen Erkenntnisse über diesen Prozess vorliegen. Bisher gesichert ist, dass die Molekülgruppe der vaskulären endothelialen Wachstumsfaktoren (VEGF) und Podoplanin als Schlüssel für die Proliferation von Lymphgefäßen des Tumors identifiziert wurden. Daneben scheinen Chemokinrezeptoren samt Tumorzellen wesentliche Schritte der lymphogenen Metastasierung wie Migration, Invasion und Proliferation zu steuern. Molekulare Mechanismen der Tumorentstehung, der hämatogenen und lymphatischen Metastasierung können durch den Einsatz neuer diagnostischer und therapeutischer Ansätze in der Therapie von Tumorpatienten zunehmend besser verstanden werden. Gleichzeitig erhöhen sich dadurch die Chancen, mit Arzneimitteln die Prozesse wie Zellwachstum, Apoptose, Angiogenese oder Metastasierung, die bei Krebserkrankungen außer Kontrolle geraten sind, therapeutisch zu beeinflussen.AbstractThe risk of local and systemic lymphatic metastasis of a tumor increases with the size of the malignant neoplasia. Lymph vessels are generated in the tumor and seem to follow anatomically defined pathways. However, the precise molecular and biological mechanisms seem to be complex and require definition. At present, molecules belonging to the vascular endothelial growth factors family and podoplanin have been identified as key for the proliferation of the tumor’s lacteals. Molecular mechanisms of the tumor origin and the hematogenic and lymphatic dissemination are increasingly better defined by the use of new diagnostic and therapeutic approaches for tumor patients. Simultaneously, we might be able to influence processes such as cell growth, apoptosis, angiogenesis, and lymphogenic dissemination by novel drugs and thereby develop novel approaches for tumor treatment. Chemokine receptors seem to control essential steps of lymphogenic dissemination such as migration, invasion, and proliferation of tumor cells.The risk of local and systemic lymphatic metastasis of a tumor increases with the size of the malignant neoplasia. Lymph vessels are generated in the tumor and seem to follow anatomically defined pathways. However, the precise molecular and biological mechanisms seem to be complex and require definition. At present, molecules belonging to the vascular endothelial growth factors family and podoplanin have been identified as key for the proliferation of the tumors lacteals. Molecular mechanisms of the tumor origin and the hematogenic and lymphatic dissemination are increasingly better defined by the use of new diagnostic and therapeutic approaches for tumor patients. Simultaneously, we might be able to influence processes such as cell growth, apoptosis, angiogenesis, and lymphogenic dissemination by novel drugs and thereby develop novel approaches for tumor treatment. Chemokine receptors seem to control essential steps of lymphogenic dissemination such as migration, invasion, and proliferation of tumor cells.