Bei fortgeschrittenen rektosigmoidalen Karzinomen sollte grundsätzlich die chirurgische Resektion angestrebt werden. Es gibt allerdings zahlreiche der zumeist alten Patienten, die einer solchen Therapieform nicht zugeführt werden können (Inoperabilität, Ablehnung der Operation). Für diese Patienten stellt die palliative, endoskopische Lasertherapie nach wie vor eine effiziente Alternative dar. Im Rahmen einer prospektiven Untersuchung von 61 Patienten wurde über einen 3jährigen Beobachtungszeitraum der Einfluß der palliativen Therapie mit dem Neodym:YAG-Laser auf die Symptomatologie fortgeschrittener rektosigmoidaler Tumore analysiert. Die Ergebnisse bestätigten den auch in anderen Studiengruppen beschriebenen Kurzzeiteffekt (Behandlungsdauer bis zu 3 Monaten), wonach die tumorbedingte Darmokklusion durch den Laser beherrscht werden kann und damit die Anlage eines Anus praeter vermieden wird. Besonderes Augenmerk wurde auf 32 Patienten gelegt, die längerfristig behandelt wurden, da bezüglich eines Langzeiteffekts in der Literatur kaum Angaben zu finden sind. Behandlungs-dauer: min. 3,5, max. 16,8 Monate. Tumorlokalisation: Rektum und rektosigmoidaler Übergang. Die Ergebnisse der ersten 3 Behandlungsmonate (statistisch signifikanter Rückgang für abdominale Beschwerden und peranale Blutungen) lassen sich nicht fortsetzen, aber es wird eine Art "steady state" erreicht. Die wichtigste Zielgröße der Therapie, die Sicherung der Darmpassage, konnte bei dieser Patientengruppe in 87,5 % erreicht werden. Die methodenbedingte Komplikationsrate liegt bei 6,3 %; die therapiebedingte Letalität beträgt 0 %. Problematisch ist der Anteil von Patienten mit Stuhlinkontinenz, der im Verlauf der Therapie von 6,2 % auf 40,6 % drastisch anstieg. Dennoch sahen nahezu 90 % der Patienten ihre Lebensqualität erhalten, da es sich meist um Inkontinenz I. oder II. Grades handelt, was von der Mehrzahl der Patienten angesichts ihrer Lebenssituation toleriert wird. Somit stellt die endoskopische Lasertherapie auch unter dem Aspekt der Langzeitpalliation die Behandlung der Wahl dar. Im Vergleich mit der palliativen Anlage eines Anus praeter besitzt der Laser trotz Wieder-holungsbehandlungen deutliche Vorteile: die Therapie ist ambulant durchführbar, kostengünstiger, komplikationsärmer und führt zur besseren Symptombeeinflussung. / The symptomatology of advanced rectosigmoid carcinomas by palliative therapy with the Neodymium:YAG-laser. In principle surgical resection should be aspired to in advanced rectosigmoid carcinomas. Nevertheless, there are numerous, mostly older patients, who cannot receive such a therapy (inoperability, refusal of operation). For those patients palliative, endoscopical lasertherapy is still an efficient alternative. The influence of the palliative therapy with the Nd:YAG-laser on the symptomatology of advanced rectosigmoid tumours was investigated in a prospective study of 61 patients over a 3-year period. The results also confirm the short-term effect reported by other study groups (duration of treatment up to 3 months) that occlusion of the colon can be controlled by laser-therapy and thereby the application of a colostomy may be avoided. Special attention was given to 32 patients treated for a longer duration, since reference in the medical literature relating to long-term effects of lasertherapy are rarely to be found. Duration of treatment: 3,5 to 16,8 months. Tumour location: rectum and rectosigmoid. The results of lasertherapy during the first 3 months (statistically significant reduction of abdominal symptoms and bleeding) cannot continue but it can be achieve a steady state. The maintenance of luminal patency as the most important aim of therapy in these group of patients was achieved in 87,5 %. The rate of method-related complication was 6,3 %; the treatment-related mortality was 0 %. Problematic is the increase in fecal incontinence from 6,2 % to 40,6 % seen in the patient group during the therapy. However nearly 90 % of the patients did not report significant reduction in life quality, since most fecal incontinence can be classified as first or second degree, which is tolerated by the patients in their current life situation. Consequently, the endoscopical laser-therapy is the treatment of choice also under the aspect of long-term palliation. The laser has clear advantages in comparison with the palliative colostomy in spite of the need for repeated applications: possibility of outpatient treatment, cost-effectiveness, low complication rate and better influence on symptomatology.

Background: Lithium augmentation is a first-line strategy for depressed patients resistant to antidepressive therapy, but little is known about patients’ subsequent long-term course or outcome predictors. We investigated long-term outcomes of unipolar depressed patients who had participated in a study on the effects of lithium augmentation on the hypothalamic-pituitary-adrenocortical system using the combined dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test. Methods: Twelve to 28 months (mean 18.6 ± 4.6 months) after lithium augmentation, 23 patients were assessed with a standardized interview, of which 18 patients had complete DEX/CRH test results. Relapse was diagnosed by DSM-IV criteria (Structured Clinical Interview for DSM-IV; SCID I). Results: Only 11 patients (48%) had a favorable follow-up, defined as absence of major depressive episodes during the observation period. Patients with a favorable and an unfavorable course did not differ in clinical or sociodemographic parameters, endocrinological results or continuation of lithium. However, fewer previous depressive episodes tended to correlate (p = 0.09) with a favorable course. Conclusion: Results from studies using the DEX/CRH test to predict relapse in depressed patients treated with antidepressants were not replicated for lithium augmentation. Our finding could reflect the elevation of DEX/CRH results by lithium, independent of clinical course. Limitations of the study are its small sample size, the heterogeneous clinical baseline conditions and the lack of lithium serum levels. The fact that lithium continuation did not predict the course might be related to the difference between the efficacy of lithium in controlled studies and its effectiveness in naturalistic settings. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: Prophylactic mastectomies in carriers of mutations in BRCA1 or BRCA2 are becoming increasingly more accepted. We investigated the outcome after prophylactic mastectomy, especially regarding satisfaction with the procedure, in a monocenter study. Methods: BRCA1/2 mutation carriers and non-carriers with elevated pedigree-based cancer risk were followed prospectively in a structured surveillance program between 2000 and 2017. A retrospective telephone survey was conducted among all patients with documented prophylactic mastectomy. Complications and satisfaction with the decision for prophylactic mastectomy were recorded. Results: 39 patients who opted for a prophylactic mastectomy (38 BRCA1/2 mutation carriers and 1 noncarrier) were interviewed. Mostly nipple-sparing mastectomy with reconstruction was performed (87%). Half of the patients (22/39; 56.4%) had a history of unilateral breast cancer. The median time since prophylactic mastectomy was 5.6 years. While 61.5% did not report any complications, flap loss was seen in 15% (3/20) and moderate limitations in everyday life were present in 20% (7/35). An improvement in quality of life was noticed by 82% after prophylactic mastectomy and no patient expressed regret with regard to the decision. Conclusions: Prophylactic mastectomy is a procedure with risk for long-term complications in some cases. Our results confirm high satisfaction with the decision and improved quality of life.

Background: Lithium augmentation is a first-line strategy for depressed patients resistant to antidepressive therapy, but little is known about patients’ subsequent long-term course or outcome predictors. We investigated long-term outcomes of unipolar depressed patients who had participated in a study on the effects of lithium augmentation on the hypothalamic-pituitary-adrenocortical system using the combined dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test. Methods: Twelve to 28 months (mean 18.6 ± 4.6 months) after lithium augmentation, 23 patients were assessed with a standardized interview, of which 18 patients had complete DEX/CRH test results. Relapse was diagnosed by DSM-IV criteria (Structured Clinical Interview for DSM-IV; SCID I). Results: Only 11 patients (48%) had a favorable follow-up, defined as absence of major depressive episodes during the observation period. Patients with a favorable and an unfavorable course did not differ in clinical or sociodemographic parameters, endocrinological results or continuation of lithium. However, fewer previous depressive episodes tended to correlate (p = 0.09) with a favorable course. Conclusion: Results from studies using the DEX/CRH test to predict relapse in depressed patients treated with antidepressants were not replicated for lithium augmentation. Our finding could reflect the elevation of DEX/CRH results by lithium, independent of clinical course. Limitations of the study are its small sample size, the heterogeneous clinical baseline conditions and the lack of lithium serum levels. The fact that lithium continuation did not predict the course might be related to the difference between the efficacy of lithium in controlled studies and its effectiveness in naturalistic settings. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Alveolar macrophages (AMs) are lung tissue-resident macrophages that can be expanded in culture, but it is unknown to what extent culture affects their in vivo identity. Here we show that mouse long-term ex vivo expanded AMs (exAMs) maintained a core AM gene expression program, but showed culture adaptations related to adhesion, metabolism and proliferation. Upon transplantation into the lung, exAMs reacquired full transcriptional and epigenetic AM identity, even after several months in culture and could self-maintain long-term in the alveolar niche. Changes in open chromatin regions observed in culture were fully reversible in transplanted exAMs and resulted in a gene expression profile indistinguishable from resident AMs. Our results indicate that long-term proliferation of AMs in culture did not compromise cellular identity in vivo. The robustness of exAM identity provides new opportunities for mechanistic analysis and highlights the therapeutic potential of exAMs.

Diese kumulative Habilitation untersucht die Rolle des Renin-Angiotensin-Aldosteron-Systems (RAAS) bei chronischen und akuten Regelvorgänge im Salz-Wasser-Haushalt an wachen Hunden. Nach einer Einführung in die Methodik der Langzeitstudien werden zunächst die zirkardianen und ultradianen Veränderungen der Natriumausscheidung beschrieben, die wir bei den Hunden beobachten konnten. Es scheint, als sei das Natriumausscheidungsmuster bei Hunden das Resultat endogener Rhythmizität und exogen, reaktiver Prozesse. Beide Komponenten scheinen zur Aufrechterhaltung der Natriumhomöostase beizutragen. Bei der Infusion natriumretinierender Hormone wie Aldosteron und Angiotensin II verschob sich ein größerer Anteil der täglichen Natrium- und Wasserausscheidung in die Abend- und Nachtstunden. Wir haben dieses Phänomen als "Nachtverschiebung" bezeichnet. In Bilanzstudien über vier Tage wurde dann der Frage nachgegangen, ob das Ganz-Körper-(GK)-Natrium eine kontrollierte Variable ist. Wir konnten zeigen, dass zwei Faktoren bei der Kontrolle des GK-Natriums eine wesentliche Rolle spielen, die Aktivität des RAAS und der renale Perfusionsdruck. Ist nur eine dieser Komponenten gestört, kann sie durch die andere - was das Einstellen eines 24-Stunden Bilanzgleichgewichtes angeht - ausgeglichen werden, allerdings nur unter Inkaufnahme eines veränderten GK-Natriumbestands. Ebenfalls über vier Tage wurde die Bedeutung des NO (Stickoxid) für die langfristige Regelung des Natriumbestandes untersucht. Dabei wurde gefunden, dass die Plasma-Renin-Aktivität (PRA) während NO-Synthase-Inhibition durchweg niedriger als bei intaktem NO-System war. Der Aldosteron / PRA Quotient war unter NOS-Inhibition deutlich größer als in den jeweiligen Protokollen ohne NOS-Inhibition. In Kurzzeitstudien (3-4 Stunden) wurden wache Hunde während akuter Hypoxie, die akut mit einer Verminderung des Natrium- und Wasserbestandes einhergehen kann ("Höhendiurese"), sowie während kontrollierter maschineller Beatmung mit hohen positiv-end-exspiratorischen (PEEP) Drucken, die zur Natrium- und Wasserretention führen kann, untersucht. Unter Hypoxie zeigte sich, dass das in niedrigen Plasma-Konzentrationen als Adenosin-1-Rezeptorantagonist wirkende Theophyllin den Abfall der PRA und des Angiotensin II unter Hypoxie verhindern kann. Auf der anderen Seite fiel die Plasma-Aldosteron-Konzentration während Hypoxie unabhängig davon, ob Theophyllin infundiert wurde, wahrscheinlich wegen einer verminderten Aktivität der 18-Hydroxylase während Hypoxie. Die Untersuchungen unter PEEP-Beatmung ergaben u.a., dass bei bilateral denervierten, wachen Hunden, deren Natriumzufuhr normal ist, den Nierennerven keine wesentliche Rolle für die zu beobachtende Wasser- und Natriumretention während maschineller Beatmung zukommt. / This cumulative thesis investigates on conscious dogs the role of the renin-angiotensin-aldosterone system (RAAS) during chronic and acute challenges of salt and water homeostasis. After introducing the methods of long term studies in dogs, circadian and ultradian oscillations of sodium excretion are being described. We demonstrated, that the sodium excretion pattern in dogs is the result of endogenous rhythms and exogenous reactive processes. Both components seem to contribute to sodium homeostasis. When infusing sodium retaining hormones, such as aldosterone and angiotensin II, a greater share of the daily sodium and water excretion was shifted towards the evening and the night. This phenomenon was termed "night shift". In balance studies over four days it was investigated whether the total body sodium is a controlled variable. Two factors were identified to play a pivotal role in controlling total body sodium: the activity of the RAAS and renal perfusion pressure. If only one of these components is disturbed, the respective other component is able to equilibrate the 24 h sodium balance, but only on a different level of total body sodium. Also over a period of four days the significance of NO (nitric oxide) for the long-term regulation of sodium balance was investigated. Among others, it was found that compared to an intact NO system, the plasma-renin activity (PRA) was always lower during NO synthase (NOS) inhibition, and the aldosterone / PRA ratio was greater during NOS inhibition. In short-term studies (lasting 3-4 hours) awake dogs were studied during hypoxia - which is usually combined with a reduced total body sodium and water ("high altitude diuresis") - as well as during controlled mechanical ventilation with positive-end-expiratory pressure (PEEP) - which often leads to sodium and water retention. It was demonstrated that the decline in PRA and angiotensin II during hypoxia - which is a typical finding in conscious dogs - can be prevented by theophyllin, which acts as an adenosin-1-receptor antagonist in lower concentrations. On the other hand, plasma aldosterone concentration declined during hypoxia independent of whether theophyllin was infused or not, probably due to a reduced 18-hydroxylase activity during hypoxia. The PEEP studies demonstrated among others, that in bilaterally denervated conscious dogs - whose sodium intake was normal - the renal nerves play no substantial role for the water and sodium retention observed during PEEP ventilation.

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