[Personalized drug therapy based on genetics. Possibilities and examples from clinical practice]. / Personalisierte Arzneitherapie auf genetischer Grundlage. Möglichkeiten und Beispiele aus der Praxis.

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.

[Pathways of regional lymph node metastases originating from soft tissue sarcomas]. / Der Weg regionärer Lymphbahnmetastasen bei Weichgewebssarkomen.

Lymph node metastases originating from soft tissue sarcomas are very rare and the reason for this is unclear. While this observation was less important in former times when ultraradical excision and amputation were the norm, modern reconstructive surgical treatment options have to take the possibility of lymphatic metastases into account.We attempted to identify parameters that may be predictive of lymphatic metastases in a cohort of 1,597 patients with soft tissue sarcomas of whom 26 patients (1.6  %) had regional lymph node (RLN) metastases. We studied these RLN metastases with recently described techniques that enabled us to histologically visualize lymphatic vessels.We conclude that sarcomas should not be evaluated from a histogenetic perspective but more on the basis of regional topography of the lymphatic vasculature. As we described previously, two different lymphatic systems should be differentiated: lymphatic vessel system I (LGS I) contains RLN and lymph vessels are mostly superficial; however, there are also vessels near large blood vessels of the extremities. System LGS II is more delicate and its vessels run into the musculature, a metastatic homing area of many sarcomas. Lymph vessels of system LGS II drain directly into veins without intervening lymph nodes. Sarcomas with LGS I drainage will form RLN metastases. In contrast, sarcomas with LGS II drainage will do so only after surgical resection if system LGS I has been opened.

[Prediction of prognosis of pancreatic cancer based on the homing area]. / Voraussage der Prognose des Pankreaskarzinoms in seinem Homing-Areal.

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.

[The crural diaphragm belongs to the pharyngeo-cardial continence organ (PET-CT and impedance measurements on the stretch sphincter and its fixation in the hiatus oesophageus of the diaphragm)]. / Das krurale Zwerchfell gehört zum ösophagokardialen Kontinenzorgan (PET-CT und Impedanzmessung am Dehnverschluss und seine Verankerung im Hiatus oesophageus des Zwerchfells).

This paper provides evidence that pharyngeo-cardial propulsion in the oesophagus follows similar principles as translocation of luminal contents in other locations in the body. In brief, the following statements are discussed in the paper: 1. Only animals with a lung-based respiratory system have an oesophagus. 2. Its bulky muscular wall is made up of the elastic fibres which ensure that the oesophagus stays elastic during an entire lifetime. 3. While short-segment ring sphincter systems exist in several locations in the body, the lower oesophageal sphincter is maximally elongated. This configuration helps with the propulsion of luminal contents in addition to this sphincter's opening and occlusive functions. 4. The musculature of the diaphragm is genetically related to the cervical muscles. The crural portion of the diaphragm works in coordination with the lower oesophageal stretch sphincter. 5. Gastro-oesophageal reflux disease is fairly common. In patients with this disorder, the oesophagus is too short and the stretch sphincter remains patent for abnormal periods of time. 6. When the stretch sphincter is surgically retightened by transposition of the oesophageal cardia into the abdomen, a proper function of the regulatory lower oesophageal stretch sphincter can be restored. 7.-9. All fundoplication procedures place the lower oesophageal sphincter under stretch, squeeze and create an oesophageal wrap out of gastric fundus tissue. X-ray images confirm in many patients undergoing fundoplication that the anatomic stretch sphincter already starts above and proximally to the plicated cuff.

[Medical technology and medical education]. / Medizintechnik in der ärztlichen Aus-, Weiter- und Fortbildung.

The education of medical professionals is divided into medical studies, postgraduate training leading to the qualification as a specialist, and continuing professional development. During education, all scientific knowledge and practical skills are to be acquired, which enable the physician to practice responsibly in a specialized medical area. In the present article, relevant curricula are analyzed regarding the consideration of medical device-related topics, as the clinical application of medical technology has reached a central position in modern patient care. Due to the enormous scientific and technical progress, this area has become as important as pharmacotherapy. Our evaluation shows that medical device-related topics are currently underrepresented in the course of medical education and training and should be given greater consideration in all areas of medical education. Possible solutions are presented.

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

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.

[Medical devices and patient safety from the clinicians' view]. / Medizinprodukte und Patientensicherheit aus der Perspektive des Klinikers.

In daily routine, clinically orientated physicians are confronted with various, often highly sophisticated medical devices. To ensure safe handling and usage, licensees and operators of those devices have to follow regulations and laws given by the German medical device legislation. For the clinician as an active user of the technology, basic knowledge of these regulations is essential. Quality-based health care focuses on the important issue of patient safety. Medical devices have made their way into virtually every sector of patient care. However, despite usage of these devices bearing substantial risk of adverse events, the problem of safe handling of sophisticated technology plays only a minor part in medical academic studies, medical specialist training, and manda nottory continuing education of physicians. The option of further education is needed to ensure patient safety and protect operators of medical devices.

[Incidents of malfunction of mechanical heart valves as reported to the German Medical Devices Vigilance System]. / Vorkommnismeldungen bei mechanischen Herzklappenprothesen. Auswertung des deutschen Medizinprodukte-Beobachtungs- und Meldesystems im Bundesinstitut für Arzneimittel und Medizinprodukte.

BACKGROUND: The purpose of this study was to collect the experience gained from risk assessment of incidents associated with mechanical heart valves as reported to the German Medical Devices Vigilance System. METHODS: All events in connection with the use of prosthetic heart valves which had been reported to the Federal Institute for Drugs and Medical Products were identified in the Institute's anonymized database. Subsequently all information that had been obtained and the reports of investigations by the various responsible manufacturer of medical products were retrospectively analysed. RESULTS: Of 53 incident reports the aortic valve position was involved 32 times, the mitral valve position 21 times. 17 cases of leaflet breakage, 12 of leaflet dysfunction, 6 of valve thrombosis, 4 of paravalvular leakage, 4 of damage to the suture ring, 3 of endocarditis and 7 of various other singular defects were reported. The outcome was mostly very serious (re-surgery, prolongation of surgery, death). Corrective actions taken by the manufacturers consisted of recalls, advisory notices and stoppage of production. CONCLUSIONS: The Medical Devices Vigilance System is able to detect product failures of mechanical heart valves and to initiate corrective action. As the reporting rate over more than 10 years is relatively low, it can be assumed that in general mechanical heart valves are safe medical devices. The quality of incident reporting by manufactures and users of medical devices should be improved to reduce the number of undetected and unsolved incidents.

[Survey of incidents associated with injectable dermal fillers reported to the German Medical Devices Vigilance System]. / Vorkommnismeldungen zu injizierbaren Füllmaterialien : Auswertung des Medizinprodukte-Beobachtungs- und Meldesystems in Deutschland.

The purpose of this study was to address the experience gained from the risk assessment of incident reports associated with the use of dermal filler materials. In total, 136 incident reports were registered between January 1, 2000, and September 30, 2005. A retrospective survey of all reports was conducted. 143 patients were concerned; the symptom most frequently reported was the formation of nodules (n = 89). The majority of cases resulted in either conservative or surgical treatment (n = 93). In 4 cases the implementation of corrective action with respect to the medical device became necessary. As a result of the severity or the incidence of undesired effects of wrinkle correction deficiencies of the products involved may become obvious. Thus, following German medical device legislation, the criteria for an incident to be reported may be met.

[Technical limits of PET/CT with 18FDG in prostate cancer]. / Technische Grenzen des PET/CT mit 18FDG beim Adenokarzinom der Prostata.

There is increasing evidence that (18)FDG-PET is not useful for the imaging of primary prostate cancer. The aim of this examination was to prove whether or not these poor results are due to technical deficiencies of the examination method like older image reconstruction techniques, extensive (18)FDG-tracer activity in the bladder or improper contrast staining of the rectum. We examined three patients with primary prostate cancer using a modern combined PET/CT system, continuous irrigation of the bladder and an air-inflated rectal balloon catheter. PET/CT images show an exact depiction of both the prostate and all surrounding anatomic structures but no enhanced uptake of radiotracer in the tumour. Therefore, the mentioned poor results of (18)FDG-PET seem not to be due to technical deficiencies.

[Imaging, anatomic, and surgical considerations for rectal organs and function following radical resection of a rectal carcinoma]. / Unteres, kloakogenes Rektumviertel. Anatomie und chirurgische Bedeutung für Mastdarmvorfall, Inkontinenz, Rektozele und Radikaloperation beim Rektumkarzinom.

The 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 lymph 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 years.

[PET-CT studies of the support system and continence function of pelvic organs. The pivotal importance of Denonvilliers' fascia for surgical procedures]. / PET-CT-Untersuchungen der Halterung und Kontinenz der Beckenorgane. Die Zentralstellung der Denonvilliers-Faszie -- Bedeutung für die chirurgische Therapie.

Like 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.

Tc-99m labelled anti CD 66 antigranulocyte antibody imaging for assessment of bone marrow reserve.

Patients with metastatic disease to the bone marrow are at risk of significant hematologic toxicity, if they undergo myelotoxic chemotherapy. Tc-99m labelled Anti CD 66 monoclonal antibody imaging is a useful, noninvasive approach to the assessment of bone marrow reserve under such circumstances.

[Lymph vascularity and lymph node metastases on PET and PET-CT: immunohistological and clinical observations]. / Das Lymphgefässsystem (LGS I und II) aus chirurgischer Sicht. Lymphgefässe und Lymphknotenabsiedlungen, nach PET, PET-CT, immunhistologischen und klinischen Beobachtungen.

Sarcomatous malignancies only rarely develop regional lymph node metastases: about 2.7% of our evaluated cases. In this paper we provide evidence supporting a new hypothesis that two entirely separate lymph vascular systems exist in humans. One system (LGS I) exists in close proximity to the epithelium and drains into regional lymph nodes. Only sarcomas that originate in the epithelium or its immediate proximity are able to form regional lymph node metastases. The vast majority of sarcomatous malignancies (97.4% of cases) do not give rise to lymph node metastases, since they originate in proximity to a second, more deeply localized lymph node system (LGS II) in the mesenchymally derived tissues of the body. This second system has no connection to regional lymph nodes. Supporting evidence is provided by experience in the operative treatment of extremity lymphedema, PET-CT examinations, radionuclear lymphography, and scientific investigations using antibodies specifically directed at the elements of the lymph vascular system.

[Survey of incidents associated with hip and knee replacement devices. Analysis of the surveillance and registration system for medical products for the years 2000-2002]. / Vorkommnisse bei Hüft- und Knieendoprothesen. Auswertung des Medizinprodukte-Beobachtungs- und -Meldesystems für die Jahre 2000 bis 2002.

BACKGROUND: The purpose of this study was to address the experience gained from the risk assessment of incidents associated with hip and knee joint replacement devices. METHODS: A total of 274 incidents were reported throughout the years 2000-2002. A retrospective survey of all reports was conducted. RESULTS: Of all cases, 85.0% were associated with reported patient injury (n=274). In 88.4% of these cases injury consisted in revision surgery (n=233). Focusing on the cases alone where implant lifetime was known, 42.6% of these incidents occurred within the 1st year and 87.9% within 5 years (n=148). Only 20.4% of all incidents were caused by a production error (n=274); 36.2% of all incidents directly led to corrective action (n=274). In 10.2% the incident occurred at a time when corrective action had already been taken (n=274); this corresponds to 23.0% of all patients involved in incidents (n=291). CONCLUSION: In general, improvements in implant design during the past decade have increased the level of protection of health and safety of hip and knee joint replacement devices. Nevertheless, our data suggest that there is still a certain amount of design problems contributing to implant failure. By increasing the number of reports, users could help to enhance the safety of these devices.

[Demonstration of increased natural spontaneous activity of cranioesophageal and laryngeal muscles by PET-CT]. / Nachweis der natürlichen Spontanaktivität der kranioösophagealen und der Kehlkopfmuskulatur durch das PET-CT.

The muscles of the cranioesophageal sphincter system feature continuous natural spontaneous resting activity. Thus, they resemble the anorectal sphincter system. We studied metabolic activity and morphology of the proximal sphincter system at rest in 23 individuals (14 females, nine males) using PET-CT scanning. We found that metabolic activity was significantly higher than in other muscle groups of the body at rest (P=0.001). In contrast to the horizontally oriented anal sphincters, the proximal sphincter system is developed as a vertical assembly of long, interlocking muscular tubes. These are innervated by five cranial nerves and three sensory organ nerves and form a functional unit that extends from the orbicularis oris muscle via the pharynx and larynx to the lower esophageal sphincter. The larynx shows only one active muscle, i.e., the posterior cricoarytaenoid muscle, that maintains airway patency. The lower esophageal sphincter can be visualized by PET-CT as a vertically oriented stretching sphincter. It features a spiral-shaped design made up of muscle maxima and minima which correlates well with its asymmetric muscle activity. This complex proximal sphincter system shows great developmental variability among different animal species. However, the general functional principle is similar in all.