D. von Mallek

Unteres, kloakogenes Rektumviertel

ZusammenfassungDas distale Rektumviertel ist ein Kloakenanteil. Nur die proximalen drei Viertel gehören zum Darm. Nur sie haben ein Mesorektum. Zehn Besonderheiten kennzeichnen das kloakogene Rektumviertel: 1. die Blut- und Lymphgefäßversorgung, 2. die embryologischen und vergleichend anatomischen Befunde, 3. das zentrale Haltesystem der Denonvilliers-Faszie, 4. die besondere Innervation, 5. die Missbildung des Kontinenzorgans, 6. die MR-Bilder und die histologischen Großschnitte, 7. die PET-CT-Befunde, 8. die Muskelwandarchitektur, 9. die Kontinenzregulation, 10. der Sitz der meisten postoperativen Lokalrezidive des Rektumkarzinoms trotz automatischer Entfernung des Mesorektums, seit 100 Jahren.AbstractThe distal quarter of the rectum is derived from the cloaca and can be viewed as a specialized “sensory organ”. Only the proximal three quarters of the rectum stem phylogenetically from intestinal tissues. Therefore, only this upper portion has an associated mesorectum. A significant amount of data support the notion that profound differences exist between the enterogenic, upper segments and the cloacogenic, lower segment of the rectum: 1. differing supply with blood and Iymph vessels, 2. embryologic and comparative anatomic findings, 3. the central support system provided by Denonvilliers’ fascia, 4. specialized innervation, 5. malformations of the continence organ, 6. findings on magnetic resonance images and histologic macro sections, 7. findings on PET-CT images, 8. the muscular wall architecture of different portions of the rectum, 9. differences in basic function (storage vs continence), 10. location of most postoperative local recurrences of rectal carcinomas, even when complete mesorectal resection was performed, since hundred jears.

PET-CT-Untersuchungen der Halterung und Kontinenz der Beckenorgane

ZusammenfassungAn allen Beckenorganen sind, wie an allen Organen in den Körperhöhlen, keine Haltebänder nachweisbar, wie wir sie am Skelett erkennen. Die Beckenorgane werden trotzdem, sogar wenn sie ihren Inhalt entleeren, festgehalten. Die schon lange bekannte, unauffällige glatte Muskulatur, verstreut im Fettfüllgewebe des Beckens und an den Beckenfaszien, ganz besonders an der Denonvilliers-Faszie, ist ihr Haltesystem. Mit dem PET-CT kann das statistisch signifikant als natürliche Spontanaktivität nachgewiesen werden. Sie ist am stärksten an der Denonvilliers-Faszie. Auch die Kontinenz, Anfüllung und Entleerung hängen mit dieser Spontanaktivität und der damit verbundenen Aufsteifung in den Beckenhohlorganen zusammen. Bei der chirurgischen Therapie aller Störungen, die fließend zu Normalbefunden übergehen und oft falsch gedeutet werden, muss ihr Versagen berücksichtigt werden.AbstractLike all other organs in the chest or abdominal cavities, pelvic organs are not suspended by specialized ligaments such as those in the skeletomuscular system. In spite of this, the organs of the pelvis remain well suspended within their cavity even during evacuation. This support system for these organs consists of inconspicuous smooth muscle elements scattered throughout pelvic structural fat tissue and fascial structures, in particular Denonvilliers’ fascia. We used PET-CT studies to identify spontaneous muscle activity in the pelvis, which is strongest at Denonvilliers’ fascia. We were able to correlate continence function, filling, and evacuation of pelvic organs with this spontaneous muscle activity that leads to stiffening and relaxation of the muscular walls of these organs. During the course of different disease processes such as visceral prolapse, these pelvic support structures are prone to fail gradually. Surgical interventions should take the pelvic support system into account to avoid therapeutic errors.

PET-CT-Untersuchungen zur Stammzellkarzinogenese im Kolorektalbereich

Formation of cancer stem cells which are both rare and variably therapy-resistant marks the beginning of a new disease without precursors. Based on molecular changes, these cells are derived from normal cells and exhibit pre-programmed malignant behaviour. In vitro studies have shown that hybrid cancers which behave in a similar way to Dukes A, B or C cancers in vivo can be produce by horizontal gene transfer. The level of aggressiveness follows a Galton curve in the probability distribution. In the current paper we analyzed colorectal cancers by PET-CT in follow-up studies which extended over several years. We conclude that the primary tumors behave differently from distant metastases. Radical exstirpation of the primary tumor is able to cure the malignant process if the homing area is resected. The primary tumor acts as the supplier of cancer stem cells for metastases which appear in different organs. When chemotherapy is administered the distribution of metastases in different organs appears dependent of the response or non-response of cancer stem cells to this therapy. Large numbers of colorectal carcinomas existed for the same time duration before death (15 years) independent of the malignancy grade. The tumor metastasizes immediately after formation. The primary tumor and the metastases appear variably quickly depending on the malignancy grade and are autonomic processes.

Voraussage der Prognose des Pankreaskarzinoms in seinem Homing-Areal

ZusammenfassungDas Homing-Areal ist ein genetisch geprägter Ort, an dem ein Primärmalignom und sein Lokalrezidiv entstehen. Eine erfolgreiche radikale Operation muss das Homing-Areal gründlich entfernen. Im Kolonbereich ist das oft möglich. Die Homing-Grenzen sind weit vom Tumor entfernt und die wenigen, sehr langen Metastasenstraßen ebenso. Beim Pankreas ist, wie bei allen Drüsen, das Homing-Areal auf die Drüse selbst beschränkt. Seinen Homing-Charakter beweist ein Pankreaskarzinom dadurch, dass die in der Drüse verteilten Inselzellgebiete gemieden werden. Bei ihrer Entwicklung im Duodenum-descendens-Drüsenareal hat das Pankreas dessen embryologisch angelegtes ventrales und dorsales Mesenterium bis auf Reste verbraucht. Seine kurzen Lymphstraßen, zahlreich zentrifugal die Drüse verlassend, münden in Lymphknoten, die das Pankreas zu allermeist mit den Nachbarorganen gemeinsam hat. Die Lymphknoten sind in Stockwerken und nicht in flachen Mesenterien angelegt. Der Plan einer Radikaloperation ist sehr schwer durchführbar.AbstractThe homing area is a genetically defined location where primary malignancy originates and local recurrences occur. In order to be completely successful, curative resections of malignant tumors have to eradicate the homing area. This is possible in colon resection where the borders of the homing area are distant from the tumor and the lymph nodes can easily be resected to remove possible node metastases. In contrast, the homing area of the pancreas comprises only the gland itself, similar to all other glandular organs. The high specificity of the homing area is demonstrated by the finding that even pancreatic islets are spared by the malignant disease. During fetal development the pancreas loses most of the original dorsal and ventral mesentery. Via short lymphatic pathways, metastatic cells leave the gland in a centrifugal manner and find their way to regional lymph nodes that often share drainage with other neighboring organs. The lymph nodes are arranged in multiple layers and not in flat mesentery-like structures. Radical resections are therefore difficult to achieve.The homing area is a genetically defined location where primary malignancy originates and local recurrences occur. In order to be completely successful, curative resections of malignant tumors have to eradicate the homing area. This is possible in colon resection where the borders of the homing area are distant from the tumor and the lymph nodes can easily be resected to remove possible node metastases. In contrast, the homing area of the pancreas comprises only the gland itself, similar to all other glandular organs. The high specificity of the homing area is demonstrated by the finding that even pancreatic islets are spared by the malignant disease. During fetal development the pancreas loses most of the original dorsal and ventral mesentery. Via short lymphatic pathways, metastatic cells leave the gland in a centrifugal manner and find their way to regional lymph nodes that often share drainage with other neighboring organs. The lymph nodes are arranged in multiple layers and not in flat mesentery-like structures. Radical resections are therefore difficult to achieve.

Personalisierte Arzneitherapie auf genetischer Grundlage

BACKGROUND Pharmacogenetics are an important component in the individualization of treatment; however, pharmacogenetic diagnostics have so far not been used to any great extent in clinical practice. A consistent consideration of individual patient factors, such as pharmacogenetics may help to improve drug therapy and increase individual safety and efficacy aspects. OBJECTIVE A brief summary of structures and effects of genetic variations on drug efficacy is presented. Some frequently prescribed pharmaceuticals are specified. Furthermore, the feasibility of pharmacogenetic diagnostics and dose recommendations in the clinical practice are described. CURRENT DATA The European Medicines Agency (EMA) as the European approval authority has already extended the drug labels of more than 70 pharmaceuticals by information on pharmacogenetic biomarkers and the U.S. Food and Drug Administration (FDA) more than 150. This is a crucial step towards targeted medicine. Guidelines on dose and therapy adjustments are provided by the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. CONCLUSION It is fundamental to consider individual patient factors for successful drug therapy. Dose and therapy recommendations based on pharmacogenetic diagnostics are highly important for individualization as well as improvement of safety and efficiency of drug therapy.

Personalisierte Arzneitherapie auf genetischer Grundlage@@@Personalized drug therapy based on genetics: Möglichkeiten und Beispiele aus der Praxis@@@Possibilities and examples from clinical practice

BACKGROUND Pharmacogenetics are an important component in the individualization of treatment; however, pharmacogenetic diagnostics have so far not been used to any great extent in clinical practice. A consistent consideration of individual patient factors, such as pharmacogenetics may help to improve drug therapy and increase individual safety and efficacy aspects. OBJECTIVE A brief summary of structures and effects of genetic variations on drug efficacy is presented. Some frequently prescribed pharmaceuticals are specified. Furthermore, the feasibility of pharmacogenetic diagnostics and dose recommendations in the clinical practice are described. CURRENT DATA The European Medicines Agency (EMA) as the European approval authority has already extended the drug labels of more than 70 pharmaceuticals by information on pharmacogenetic biomarkers and the U.S. Food and Drug Administration (FDA) more than 150. This is a crucial step towards targeted medicine. Guidelines on dose and therapy adjustments are provided by the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. CONCLUSION It is fundamental to consider individual patient factors for successful drug therapy. Dose and therapy recommendations based on pharmacogenetic diagnostics are highly important for individualization as well as improvement of safety and efficiency of drug therapy.

PET-CT-Untersuchungen zur Stammzellkarzinogenese im Kolorektalbereich@@@PET-CT studies of metastasizing cancer of the colon and rectum: Malignitätsvariabilität als mikroevolutionärer Prozess mit festgelegter Prognose@@@Variability of tumor aggressiveness as a micro-evolutionary process of cancer stem cells with predetermined prognosis

Formation of cancer stem cells which are both rare and variably therapy-resistant marks the beginning of a new disease without precursors. Based on molecular changes, these cells are derived from normal cells and exhibit pre-programmed malignant behaviour. In vitro studies have shown that hybrid cancers which behave in a similar way to Dukes A, B or C cancers in vivo can be produce by horizontal gene transfer. The level of aggressiveness follows a Galton curve in the probability distribution. In the current paper we analyzed colorectal cancers by PET-CT in follow-up studies which extended over several years. We conclude that the primary tumors behave differently from distant metastases. Radical exstirpation of the primary tumor is able to cure the malignant process if the homing area is resected. The primary tumor acts as the supplier of cancer stem cells for metastases which appear in different organs. When chemotherapy is administered the distribution of metastases in different organs appears dependent of the response or non-response of cancer stem cells to this therapy. Large numbers of colorectal carcinomas existed for the same time duration before death (15 years) independent of the malignancy grade. The tumor metastasizes immediately after formation. The primary tumor and the metastases appear variably quickly depending on the malignancy grade and are autonomic processes.